Repeated Courses Of Treatment Research Articles

Long-term safety and frequency of repeat zuranolone treatment in patients with major depressive disorder rolling over from the randomised CORAL Study into the open-label SHORELINE Study

IntroductionZuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD.ObjectivesTo assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL.MethodsCORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course.ResultsAmong the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed.ConclusionsSafety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study.Disclosure of InterestG. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared

Сlinical and economic evaluation of various etiotropic chemotherapy regimens in patients with respiratory tuberculosis with multidrug and extensively drug resistance

Objective: analysis of clinical and economic efficiency of various etiotropic chemotherapy regimes in patients with respiratory tuberculosis with multidrug- and extensively drug-resistant (MDR and XDR) pathogen using the pharmacoeconomic modeling method (Markov model).Material and methods. A single-centre, observational, retrospective, cohort study was performed, which included patients who received treatment in clinics and affiliated organizations of the main Moscow tuberculosis institution during 2014–2019 regarding respiratory tuberculosis with the MDR/XDR pathogen. The data of 1387 patients were analysed, of which 1093 patients received “optimized basic regimen” (OBR) in accordance with the Federal Clinical Recommendations of 2015, 294 patients received etiotropic therapy in accordance with the recommendations of the World Health Organization of 2018–2019. To evaluate economic efficiency, the pharmacoeconomic costeffectiveness analysis and pharmacoeconomic modeling were used. When assessing the economic costs of treatment, the direct costs (medical and non-medical) were taken into account.Results. The study results showed that 68.4% of patients in the group with bedaquiline-containing chemotherapy regimens reached the outcome of “treatment successfully completed” (patient was cured or transfered into the III group of dispensary follow-up) compared to 51.8% in the OBR group. The use of “new” etiotropic therapy regimens is most economically justified in patients with ХDR-tuberculosis with repeated treatment courses: incremental cost-effectiveness ratios (ICER) were 24,530.20 and 21,526.50 rubles per 1 patient. Markov model was developed, transitions from one state to another were evaluated according to the results of clinical observations during the first 2 years of research.Conclusion. The use of the dynamic model of the patient state made it possible to refine the estimates of the effectiveness of the compared etiotropic chemotherapy regimens for tuberculosis with MDR/XDR pathogen. Based on the results of modeling the dynamics of patients in the interval of 2 to 10 years of treatment, the use of “new” regimens provides a significant increase in the proportion of treatment success (by 16.1–29.8% in different groups of patients and at different times), a decrease in mortality (by 6.1–11.0%), and in the proportion of those who interrupted treatment (by 8.0–21.8%) in comparison with OBR.

THE EFFECT OF PREVENTIVE MEASURES ON THE PROPERTIES OF ORAL FLUID IN CHILDREN AFTER RADICAL URANOPLASTY

Introduction. Among the causes of many functional disorders in cleft palate abnormalities there are imperfections of the anatomical structures of the upper jaw, formed at the stage of facial embryogenesis. Inadequate capacity of protective mechanisms in the oral cavity is manifested by a decrease in the proper functioning of the major and minor salivary glands and changes in the level of biologically active components in the oral fluid that are responsible for maintaining homeostasis, which requires a certain correction.
 Purpose of this study is to assess the effectiveness of the treatment and preventive measures after radical uranoplasty. Materials and Methods. 23 children aged 4 to 6 years with congenital cleft palate were involved in the study. Salivation rate, physicochemical and biochemical properties of the oral fluid were studied one month after surgery and after the completion of the monthly treatment course and receiving preventive measures.
 Results. The study has shown a decrease in salivation rate, pH level, and activity of α-amylase in oral fluid compared to the control group. Bilateral cleft defects showed more significant changes in the parameters. After one month of treatment and preventive measures, the salivation rate increased, and the physicochemical and biochemical properties of oral fluid improved. However, all values did not reach the control values, indicating the need for periodic repeated courses of treatment and prevention.
 Conclusion. Children with congenital cleft palate demonstrate decreased functioning of salivary glands that leads to a deterioration of the mechanical and chemical self-cleaning of the oral cavity. Changes in the physicochemical and biochemical properties of oral fluid disrupt its physiological balance thus, contributing to a deterioration of pH level and metabolic processes. Repeated treatment courses are necessary to maintain proper conditions for the mineralizing potential of oral fluid.

Abstract 547: Role of KDM4A in bladder cancer

Abstract Bladder cancer (BCa) is the most common malignancy of the urinary system in the United States. Most patients present with non-muscle invasive bladder cancer (NMIBC) that is treated with bladder preserving approaches. However, recurrence is high with a 50% chance to progression into muscle invasive bladder cancer (MIBC). Patients with MI disease are treated with aggressive surgery and/or systemic chemo-radiation, and more recently immune- and targeted therapies. Patients with BCa require life-long surveillance with expensive imaging, and repeated treatment courses, making BCa one of the most expensive malignancies throughout the patients’ lifespan. BCa therapies have been stagnant for almost four decades until 2016 when new immune and targeted therapies were approved for patients with locally advanced, recurrent, or metastatic disease, with an overall response of 15-29%. Thus, better understanding of the pathobiology of BCa is needed to identify actionable targets and develop novel therapeutics. In this respect, we have identified histone lysine demethylase 4A (KDM4A), also known as Jumanji D2A (JMJD2A) as a BCa onco-protein. We found that the expression of nuclear KDM4A significantly correlated with disease stage in patients’ tumors and in tobacco carcinogen-induced murine bladder tumors. KDM4A transcript expression significantly increased in bladder tumors compared to normal in TCGA data and three independent publicly available datasets. Knockdown of KDM4A in BCa cell lines significantly inhibited their proliferation and invasiveness. Interestingly, KDM4A transcripts exhibited significant inverse correlation with BCa tumor suppressor SPARC in five independent datasets. In addition, using phenotypic screening and computational modeling, we found that KDM4A is a direct target of verteporfin, a potent inducer of SPARC expression in BCa cell lines. Mechanistically, knockdown of KDM4A in BCa cell lines increased SPARC expression, whereas its overexpression inhibited basal and verteporfin-induced SPARC expression. Chromatin immune-precipitation (ChIP) assays indicated that verteporfin significantly inhibited the association of KDM4A with SPARC promoter. Together, our data underscore the oncogenic role of KDM4A in BCa and its potential as an actionable target. Citation Format: Bailey O. Warren, Ammar Y. Abdelfattah, Alia Ghoneum, Freddie Salsbury, Neveen A. Said. Role of KDM4A in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 547.

Predictability of response to rTMS in repeated treatment courses for patients with Major Depressive Disorder

Predictability of response to rTMS in repeated treatment courses for patients with Major Depressive Disorder

A case report a delayed diagnosis of tracheomalacia resulting in prolonged steroid therapy, repeated hospital admissions and CT scans

A 30-year-old patient was admitted with shortness of breath and cough. Previous electronic entries state a history of asthma and hay fever. Repeated clerking by junior doctor states admission for treatment of likely exacerbation of asthma. The patient failed to fully improve with repeated courses of oral corticosteroids, regular nebulisers and oral antibiotics. The patient failed to improve even after several repeated admissions for similar admissions. On each admission she was subjected to CT scan and steroid courses, and at one point even had the authenticity of her symptoms questioned. Eventually she was found to have a case of tracheomalacia. Unfortunately, despite the eventual diagnosis, the patient has suffered side effects due to the delayed diagnosis and repeated treatment courses.

MO599: Efficacy and Safety of Optimized Sodium Thiosulfate Therapy for Calciphylaxis in Chinese Patients

Abstract BACKGROUND AND AIMS Calciphylaxis is a rare life-threatening syndrome. Although sodium thiosulfate (STS) showed clinical improvement, some patients presented with serious adverse events and withdrew from treatment. The optimized STS approach included four features: repeated treatment courses, small initial dose, once daily, and escalating low-to-moderate dose. The optimized STS approach, named ‘Zhong Da STS Therapy’ (Zhong Da: the name of a hospital, affiliated with Southeast University, School of Medicine, Nanjing, Jiangsu, China), was generalized with four features: repeated treatment courses, small initial dose, daily medicine, and daily escalating low-to-moderate dose of STS. STS from the initial dose (5 g) was administered intravenously once daily escalating to the highest daily dose as a maintenance dose (no more than 10 g). This study retrospectively evaluated the efficacy and safety of optimized STS therapy for calciphylaxis in China. METHOD The medical records of maintenance hemodialysis or CKD patients who were first diagnosed with calciphylaxis and received STS treatment at Zhong Da Hospital affiliated to Southeast University between October 2017 and October 2019 were retrospectively evaluated. The exclusion criteria of this retrospective study were death at the time of diagnosis (retrospectively confirmed cases) and did not receive the optimized STS approach treatment. The data to evaluate the efficacy included the changes in skin lesions, pain relief, survival rate and laboratory data. Adverse events were summarized as safety parameters. RESULTS The mean age was 51.10 ± 14.85 years old and 71% of patients were male. By October 2019, 87.1% of patients survived, 74.2% markedly improved and 41.9% of patients were followed up for more than 1 year with 100% survival. About 27 (87.10%) patients had typical skin lesions with 66.70% ulceration and skin lesions showed a predominantly peripheral distribution. After the first course, skin lesions improved by 77.8%, and 38.1% of pain sufferers were free from analgesics. The reduction of the Numerical Pain Rating Scale (NPRS) (P < 0.001) is related significantly to the treatment course. Furthermore, during the entire treatment session, more than half of the patients (54.84%) never experienced adverse events, only one withdrew treatment and no one died from complications. And most adverse events appeared in the course of increasing the STS dose and would be relieved when we stopped adding it or decreased to the day-before dose. CONCLUSION Optimized STS therapy is a promising approach for calciphylaxis patients because it is relatively safe and associated with good outcomes.

Oral Vancomycin Prophylaxis for Clostridioides difficile

Oral Vancomycin Prophylaxis for <i>Clostridioides difficile</i>

Long-Term Outcomes of Single versus Multiple Courses of Viscosupplementation for Osteoarthritic Knee Pain: Real-World, Multi-Practice Experience Over a Six-Year Period.

IntroductionViscosupplementation (VS) is a safe and effective local treatment for osteoarthritis (OA) of the knee. While much research has been completed evaluating its efficacy, comparatively little research has been completed examining the effects of multiple, repeat courses of treatment versus a single course of treatment.MethodsWe retrospectively reviewed real-world data from a large cohort of patients receiving treatment for OA of the knee at 16 rehabilitation clinics. Patients were grouped based on whether they received a single course of treatment or multiple courses. Outcomes for this study included pain (measured via the visual analog scale, VAS) and functional ability (measured via the Western Ontario and McMaster Universities Arthritis Index (WOMAC)). Pain and function scores were collected at baseline (prior to treatment administration) and one week following each course of treatment.ResultsPatients receiving multiple courses of treatment saw greater improvements than those receiving a single course. For VAS, maximal improvement occurred after the fourth course (66% improvement: 1.7±1.2 vs 5.0±2.4 at baseline, p<0.0001). WOMAC scores saw maximal improvement up to the fourth course for all domains (pain: 74%: 2.5±3.3 vs 9.5±5.3, p<0.0001; stiffness: 61%: 1.3±1.0 vs 3.3±2.0, p<0.0001; function: 66%: 9.5±7.2 vs 28.3±14.1, p<0.0001). When scores from multiple courses were averaged, improvements were maintained through the fourth course for VAS (3.4±2.8) and all WOMAC domains (pain: 6.1±5.0; stiffness: 3.0±2.2; function: 23.4±17.3).DiscussionOur results indicate that multiple courses of treatment are associated with greater improvements than a single course of VS, and that these improvements continue through four courses of treatment.

Strongyloidiasis in clinical practice: challenges in diagnostics and treatment (brief review and clinical observations)

High priority of soil-transmitted helminths worldwide and in the Russian Federation is due to their vast distribution and the severe pathological features they induce in humans. Recently, it was observed that awareness of clinicians regarding this disease category was markedly decreased, although no significant decline of the disease occurrence has been recorded, whereas rate of imported cases of parasitic diseases including soil-transmitted helminths like strongyloidiasis mainly originating from subtropical or tropical countries rose in non-endemic regions. Lack of alertness on diseases like strongyloidiasis impedes timely diagnostics and treatment. Global prevalence of strongyloidiasis was estimated to range within 30—100 million people, however the World Health Organization (WHO) suggests that it was underestimated as precise data in endemic countries remain unknown. The occurrence of these helminths has been recorded in regions of temperate-continental climate: Western Ukraine, Belarus, Moldova, the Caucasus, Central Asia, as well as in Eastern Europe and the Mediterranean region. In the Russian Federation locally acquired infections are frequently recorded in the Krasnodar Territory and Rostov Region. Here, based on multi-year experience in management of patients with strongyloidiasis we present our data and brief review of publications and systematic literature related to the challenges of its clinical picture, diagnostics and treatment. Life cycle, basic biological parameters of free-living helminth in nature and distinctive features of autoinfection related to strongyloidiasis were reviewed. Special attention was paid to the risk of developing severe forms (hyperinfection and disseminated strongyloidiasis) especially in immunocompromised hosts: HIV infection, radiotherapy followed by chemotherapy, long-term corticosteroid use. Difficulties in diagnosing Strongy-loides stercoralis infection are due to its polymorphic and non-specific clinical manifestations, as well as the lack of clinical knowledge and awareness about the disease. Clinical importance of parasitological methods for larvae detection was underlined. It was noted that the drug of choice in therapy of strongyloidiasis is ivermectin unapproved yet in Russia, whereas albendazole as an alternative drug exerts poorer efficacy, justifying a need to repeat treatment courses to establish full recovery from the disease.

Peloidotherapy in Pediatric Practice in the Conditions of a Ballogray Resort

Introduction. Currently, sulfide silt mud of Lake Saka has been widely used in both adult and pediatric practice, which has a positive effect in the treatment of various diseases. The effectiveness of peloidotherapy in the rehabilitation treatment of children with a number of chronic and disabling diseases has been established. The purpose of the review is to summarize and analyze the accumulated experience of applying peloidotherapy in children with various diseases. In order to achieve a targeted effect, it is necessary to study previously carried out scientific studies on the in-depth study of the mechanism of therapeutic action of natural factors. Data on methodology of application of peloidotherapy based on highly mineralized silt sulphide mud of Black Sea resorts are presented. It is necessary to take into account the response of the child body to peloidotherapy, which depend on the individual capabilities of the body, in connection with which the parameters of mud treatment methods in pediatrics should be justified. Indications for peloidotherapy for diseases of the cardiovascular system have been developed. The purpose of application method of peloidotherapy in the complex of sanatorium treatment of children with chronic bronchitis, pneumonia and other bronchopulmonary diseases is recognized in order to provide reparative and regenerative, anti-inflammatory, trophostimulating, anti-inflammatory, resolving effect, to improve bronchial permeability, ventilation function.. The dynamics of endothelial dysfunction indices in children with rheumatoid arthritis under the influence of spa treatment using mud applications, the results of complex spa treatment of children with different forms of pyelonephritis in clinical-laboratory remission against the background of application of Saki silt mud were studied. In children with celiac disease the efficiency of therapeutic complex of physical factors influence on pathogenetic links of the disease is shown. Extensive experience has been gained in mud treatment of children with cerebral palsy. Conclusion. In peloidotherapy, individual approaches to comprehensive rehabilitation are applied depending on the clinical picture of the disease with repeated treatment courses.

Результати лікування хворих з поліпами ендометрія при застосуванні диференційованого підходу

The problem of treatment of endometrial polyps remains relevant, because it has high risks of malignancy and a steady tendency to increase the frequency of relapses and is inherent from 26 to 78% in women of different age categories. The objective: is to reduce the frequency of relapses of endometrial polyps by introducing a differentiated treatment strategy for patients with endometrial polyps based on the study of new pathogenesis links. Materials and methods. Clinical and laboratory examinations and treatment of 66 women diagnosed with endometrial polyp at the age of 24–43 years were carried out, which were further divided into two statistically equivalent groups: A (n=34) and B (n=32). All women received treatment according to the 4-stage algorithm of the current order of the Ministry of health of Ukraine No. 676 dated 31.12.2004. The difference in the management of group A patients was that their treatment was supplemented by immunomodulate therapy. At the first stage of the study, additional hysteroresectoscopy was performed, endometrial samples were obtained to determine its type of pathology, develop an immunohistochemical profile of the endometrium with the establishment of a receptor phenotype, identify the inflammatory process, and determine the state of the apoptosis system and the APUD system of the endometrium. Results. Active histological screening of the endometrial condition showed that signs of chronic endometritis (positive reaction of CD-138 and CD-68 markers) in women with endometrial polyp with physiological background endometrium were observed in 26.5% of group A patients after 3 months of treatment, which required a repeat course of treatment based on the results of viral and bacteriological examination. In group B, this rate was 46.9%. All the examined women, against the background of the use of gestagens, showed changes in the endometrial receptor phenotype, which were manifested by a decrease in the number of progesterone receptors in the glandular epithelium by an average of 1.4 times. However, the expression levels of Bcl-2 protein and EC cells had no statistical differences, since there were no signs of proliferation in the background endometrium, including local ones. Viral-bacterial screening of the study showed a sharp decrease in the number of pathogens in the endometrium, but in studies of patients of both groups, viral-bacterial associations were determined. Bacterial screening revealed the presence of anaerobic microflora. The study of the level of tumor necrosis factor in flushes from the uterine cavity indicated a unidirectional trend with the dynamics of the CD-138 index. The results of treatment of patients with endometrial polyp with physiological endometrium showed that the full effect of treatment in group A (antibacterial therapy with gestagens + immunomodulatory therapy) was determined after a year in 85.2% of patients, 14.8% of women had a relapse of endometrial polyp, in the group where patients received only antibacterial therapy with gestagens – a relapse was diagnosed in 37.5% of patients. Conclusion. Determining the tactics of differentiated treatment of endometrial polyps, it is necessary to take into account the results of immunohistochemical research and viral-bacterial control of the endometrial condition, which allows improving the results of treatment of endometrial polyps from 62.5% to 85.2 %, and is a prevention of relapse of endometrial polyp. Key words: endometrial polyps, hysteroscopy, endometrial immunohistochemical examination, apoptosis system, endometrial APUD system, viral-bacterial screening.

Rehabilitation program for patients with low anterior resection syndrome

To develop a rehabilitation program for patients with low anterior resection syndrome. The investigation was performed at 2 stages. During the first stage, 29 patients with LARS (17 (58.6%) men, mean age of the participants' 61.5±9.5 years), 12 (41.4%) women (mean age 61.2±7.8 years) were examined and received the course of conservative treatment with the use of biofeedback-therapy performed by the standard protocol. On the second stage, 17 patients (mean age 61.4±12.7 years) - 9 (52.9%) men, 8 (47.1%) women received biofeedback therapy in combination with tibial neuromodulation (TNM). Functional state of the rectum and the locking apparatus in all patients were evaluated by anorectal manometry: sphincterometry and studies of the reservoir function of the rectum before and after treatment. The developed complex of rehabilitation measures led to improved treatment results for patients with rectal cancer by improving the quality of life after low anterior resection, reducing the manifestations of LARS (by 47.8%). Stable positive results of treatment were maintained in 36.4% of patients, positive dynamics from the treatment according to the LARS scale decreased slightly in 54.5%, deterioration of indicators in 3-6 months after conservative rehabilitation was registered in 9.1% of cases. At the first stage maximal squeeze pressure improvement was reached in the whole cohort (p=0.047), at the second stage these trend was seen only for women for the pressure values at rest (p=0.01) and during squeeze (p=0.025). The data obtained allowed us to recommend a repeat course of treatment to 63.6% of patients. The authors modified and optimized a special complex of physical therapy for the rehabilitation of patients both in a medical institution and at home. These exercises are aimed at improving the functional state of the pelvic floor muscles and sphincter apparatus. Rehabilitation program for patients with low anterior resection syndrome should include: 1) biofeedback therapy to improve the holding function; 2) biofeedback therapy aimed at improving the reservoir function and sensitivity of the rectum to filling; 3) tibial neuromodulation. This program may help improving the contractility of the anal sphincter and reservoir function of the rectum, as well as the appearance of the urge to defecate.

1569 The Efficacy and Safety of Long-Term Management of Uterine Fibroids with Ulipristal Acetate

Study Objective To investigate the efficacy and safety of four repeated 12-week courses of 5 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. Design A retrospective, single-center observational study. Setting A university tertiary referral center. Patients or Participants One hundred seventy-one premenopausal women with symptomatic uterine fibroids. Interventions Four repeated 12-week treatment courses of daily 5 mg ulipristal acetate. Measurements and Main Results After four repeated 12-week courses, uterine bleeding was controlled in 93% of the women receiving 5 mg of ulipristal acetate. The rates of amenorrhea were 83% occurring within 9 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were –17%. Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently. Pain showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. Conclusion The results of this study demonstrate the efficacy and further support the safety profile of four repeated 12-week courses of 5 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids.

Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis.

BackgroundInfants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors.Methods and findingsTrials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach.Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference −0.12, 95%CI −0.18 to −0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2–5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes.ConclusionsIn this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

Primary Cutaneous T-Cell Lymphomas: Mycosis Fungoides and Sezary Syndrome.

Mycosis fungoides and Sézary syndrome are the most common subtypes of all primary cutaneous lymphomas and represent complex diseases that require a multidisciplinary assessment by dermatologists, oncologists, and pathologists. Staging and work-up are critical to guarantee an optimal treatment plan that includes skin-directed and/or systemic regimens depending on the clinical stage, tumor burden, drug-related side effect profile, and patient comorbidities. However, there is no cure and patients frequently relapse, requiring repeated treatment courses for disease control. The study of the tumor microenvironment and molecular mechanisms of these rare neoplasms may assist in the development of new immune therapies providing promising treatment approaches tailored for patients with relapse/refractory disease.

Effectiveness of Injectable Ibuprofen Salts and Indomethacin to Treat Patent Ductus Arteriosus in Preterm Infants: Observational Cohort Study

There is no injectable ibuprofen product marketed to treat patent ductus arteriosus (PDA) in newborns in Canada. The authors' institution has used ibuprofen arginine in the past. In the absence of published evidence supporting use of this salt form of ibuprofen for neonatal PDA, a retrospective analysis was undertaken. To compare the effectiveness and adverse effects of ibuprofen arginine, ibuprofen tromethamine, and indomethacin in the treatment of PDA. This retrospective observational cohort study, for patients admitted between 2009 and 2015, included preterm infants with symptomatic PDA who received at least one dose of injectable indomethacin, ibuprofen tromethamine, or ibuprofen arginine. Three effectiveness end points were analyzed: closure after one course of treatment, repeat medical treatment, and surgical ligation. The secondary end points included acute kidney injury, necrotizing enterocolitis, chronic lung disease, and time to full enteral feeding. A total of 179 infants were included. There were no differences among groups in terms of closure after one course of treatment (37/54 [69%] with indomethacin, 42/70 [60%] with ibuprofen tromethamine, and 28/55 [51%] with ibuprofen arginine; p = 0.21) or surgical ligation (10/54 [19%] with indomethacin, 13/70 [19%] with ibuprofen tromethamine, and 12/55 [22%] with ibuprofen arginine; p = 0.88). However, there was a difference regarding use of a repeat course of treatment, ibuprofen arginine having the highest rate (8/54 [15%] with indomethacin, 18/70 [26%] with ibuprofen tromethamine, and 20/55 [36%] with ibuprofen arginine; p = 0.04). After adjustment for gestational age, the association between ibuprofen arginine and increased use of a repeat course of treatment remained significant. The groups did not differ with respect to adverse effects. These results highlight the potential for differences in effectiveness among various salt forms of injectable ibuprofen and indomethacin. Because of the small sample size and retrospective methodology, confirmation of the present results through a larger prospective study is needed.

Safety of Repeated Injections of Sodium Hyaluronate (SUPARTZ) for Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

Though there is no consensus on its efficacy, knee osteoarthritis is symptomatically managed with intra-articular hyaluronic acid (IAHA). Recent reports suggest that IAHA may delay the need for total knee replacement, with the magnitude of delay proportional to the number of injection series. However, the safety of repeated injection series is reported to vary between commercial products. This report describes a systematic review of safety data on repeated treatment courses of SUPARTZ. We performed a systematic search of MEDLINE, Cochrane database, EMBASE, Web of Science, Google Scholar, and unpublished data. We included all human randomized controlled trials or observational studies with adverse event (AE) data for SUPARTZ in knee osteoarthritis. Two independent reviewers extracted data and evaluated study quality. Data were analyzed separately for the first and subsequent series of injections. The primary sources for repeated-injection data on SUPARTZ were a postmarket registry (N = 7404), 4 prospective studies (N = 127 total), and a retrospective study (N = 220). None of the sources reported increased frequency or severity of AEs with repeated injections. In the registry, 95% of multiple-injection-series patients who reported an AE did so during the first series. None of the AEs was serious, and most resolved spontaneously without medical intervention. The overall adverse event rate after repeat courses of SUPARTZ was 0.008 (95% confidence interval: 0.001-0.055). Multiple courses of SUPARTZ injections appear to be at least as safe, and probably safer, than the first course. This study supports the safety of repeat courses of SUPARTZ injections for knee osteoarthritis.

Impact of liposomal amphotericin B therapy on chronic pulmonary aspergillosis

To assess the clinical response and renal toxicity observed in chronic pulmonary aspergillosis (CPA) patients receiving ≥1 short-courses of liposomal amphotericin (LAmB) (AmBisome®) therapy. A retrospective audit of clinical response and renal function was undertaken in 71 CPA patients (41 male) treated with LAmB at the National Aspergillosis Centre, including 20 patients receiving repeated treatment courses or long-term therapy (n=5). Median age was 64 years (range 29-86 years). Treatment indications included respiratory symptoms (n=33; 46.5%), constitutional symptoms (n=2; 2.8%) or both (n=36; 50.7%). 48 patients (73.8%) responded to their first LAmB course. Quality of life (QOL) improvements occurred in 37 (92.5%) of 40 patients with sufficient data available. Response rates for repeated short-courses of LAmB were 76.6%; QOL improvements were observed in 91.7% of treatment courses. All patients on long-term therapy demonstrated a response. 34 (50%) and 17 (25%) patients respectively developed an increased risk of acute kidney injury (AKI) or actual AKI with their first treatment; a significant reduction in geometric mean eGFR was observed and a similar pattern occurred following their second treatment course. Whilst CPA is responsive to LAmB, caution should be exercised with repeated courses, if other treatments are available.

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACTIntroduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.