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Aims: β3‐adrenoceptors (ARs) are an important drug target for the treatment of overactive bladder syndrome (OAB) and are under investigation for other indications. The human β3‐AR gene is polymorphic; an exchange of amino acid tryptophan (Trp) for arginine (Arg) in position 64 of the receptor protein is the most frequent and best‐studied polymorphism. A narrative review on the impact of β3‐AR polymorphisms on urological disease and its treatment is presented. Results: Two out of four studies have reported that the 64Arg allele was found more frequently in subjects with OAB than in healthy controls. A large study in a highly selective population (men undergoing prostatectomy for cancer treatment) did not confirm this. On the other hand, studies examining symptom severity typically found little difference between 64Arg and 64Trp carriers. In vitro studies with endogenously expressed β3‐AR reported a decreased lipolytic response in human adipose tissue. Studies with heterologously expressed receptors sometimes found a decreased responsiveness to agonists including β3‐AR agonists, but others did not confirm that. Conclusions: The overall evidence points to carriers of the 64Arg genotype expressing fewer and/or hypofunctional β3‐ARs and being associated with the presence of OAB but such findings were only detected inconsistently. If this hypofunctionality exists, the consequences may be of insufficient magnitude to allow a robust detection. Only adequately powered studies comparing responses with a β3‐AR agonist in 64Arg carriers versus wild‐type patients can address this. [ABSTRACT FROM AUTHOR]

Summary: Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. Objectives: To produce and evaluate the therapeutic performance of a new antibody–drug conjugate (Adcitmer®) targeting CD56 in preclinical models of MCC. Methods: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56‐targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56‐targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. Results: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56‐targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56‐mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. Conclusions: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors. What is already known about this topic? Merkel cell carcinoma (MCC) is an aggressive skin cancer.While immune checkpoint inhibitors constitute a major advance in treating patients with MCC with advanced disease, new therapeutic options are still urgently required.CD56, which is expressed by most MCC tumours, might constitute a therapeutic target for the development of antibody–drug conjugate therapies. What does this study add? We generated a CD56‐targeting monomethyl auristatin E (MMAE) bioconjugate antibody (Adcitmer®) and demonstrated its optimal biochemical properties, specific binding and cytotoxicity in vitro in MCC cell lines, and its capacity to reduce tumour growth in vivo in a MCC mouse model. What is the translational message? Adcitmer®, a new CD56‐targeting MMAE bioconjugate antibody, may represent a potential therapeutic option to be investigated as an alternative approach or in combination with immune checkpoint inhibitors in patients with inoperable MCC. Linked Comment: L. Leiendecker et al. Br J Dermatol 2022; 186:209–210. Plain language summary available online [ABSTRACT FROM AUTHOR]

Aims: Combination therapy of 5α‐reductase inhibitor and α‐blocker is a guideline‐endorsed therapeutic approach for patients with moderate‐to‐severe lower urinary tract symptoms or benign prostatic hyperplasia (LUTS/BPH) who are at risk of disease progression. We aimed to disentangle the contribution of clinical and demographic baseline characteristics affecting the risk of acute urinary retention or BPH‐related surgery (AUR/S) from the effect of treatment with drugs showing symptomatic and disease‐modifying properties. Methods: A time‐to‐event model was developed using pooled data from patients (n = 10 238) enrolled into six clinical studies receiving placebo, tamsulosin, dutasteride or tamsulosin‐dutasteride combination therapy. A parametric hazard function was used to describe the time to first AUR/S. Covariate model building included the assessment of relevant clinical and demographic factors on baseline hazard. Predictive performance was evaluated by graphical and statistical methods. Results: An exponential hazard model best described the time to first AUR/S in this group of patients. Baseline International Prostate Symptom Score, prostate‐specific antigen, prostate volume and maximum urine flow were identified as covariates with hazard ratio estimates of 1.04, 1.08, 1.01 and 0.91, respectively. Dutasteride monotherapy and tamsulosin‐dutasteride combination therapy resulted in a significant reduction in the baseline hazard (56.8% and 66.4%, respectively). By contrast, the effect of tamsulosin did not differ from placebo. Conclusions: Our analysis showed the implications of disease‐modifying properties of dutasteride and tamsulosin‐dutasteride combination therapy for the risk of AUR/S. It also elucidated the contribution of different baseline characteristics to the risk of these events. The use of tamsulosin monotherapy (symptomatic treatment) has no impact on individual long‐term risk. [ABSTRACT FROM AUTHOR]

This review article discusses the medical need for improved medical treatments of overactive bladder syndrome, and the hurdles and research required to address that need. Currently, few overactive bladder syndrome patients stay on long‐term treatment, largely because efficacy expectations are not met, and tolerability is considered insufficient for the chronic treatment of a non‐life‐threatening condition. Therefore, a medical need exists for improved tolerability and, even more importantly, improved efficacy. It is unlikely that major improvements of efficacy and tolerability can be achieved within the currently approved drug classes. Work in experimental animals suggests that many causes of overactive bladder syndrome exist – each with a distinct pathophysiology. This makes it unlikely that a single medication can address the pathophysiology and treatment needs of all overactive bladder syndrome patients; accordingly, any medication will appear to have only moderate efficacy in the overall group of overactive bladder syndrome patients, even if it fully eliminates symptoms within a subset of patients. It is proposed that only identification of subsets of patients with a defined pathophysiology (and biomarkers thereof) will allow the development and use of targeted treatment that can be highly effective in such subsets. [ABSTRACT FROM AUTHOR]

Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which can be administered intralesionally in patients with stage IIIB/C‐IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET‐CT and histological biopsies for response evaluation. Median follow‐up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1–2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza‐like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T‐VEC. Best ORR for T‐VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T‐VEC in early metastatic (stage IIIB/C‐IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma. What's new? Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which is registered for the treatment of stage IIIB/C‐IVM1a unresectable locally advanced melanoma. Here the authors evaluated the response to this drug in 26 patients with a follow up longer than 6 months. They demonstrate promising response rates, with 61.5% of their treated patients achieving a CR. This indicates a strong potential of this novel drug in the rapidly developing field of immunotherapeutic treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background: Voice outcome was assessed in patients with extended T1 and limited T2 glottic carcinoma, treated with a unilateral type III or a bilateral type II resection according to the European Laryngological Society (ELS) classification. Methods: Objective evaluation (acoustic and aerodynamic parameters), perceptual evaluation (GRBAS), and patients' self‐assessment (voice handicap index [VHI]) were performed before and 1 year after treatment. Results were evaluated according to ELS resection type and the involvement of the anterior commissure. Results: The majority of voice parameters in all resection subgroups showed an improvement of the mean score 1 year postoperatively. Grade of dysphonia varied between 1.15 and 1.66 postoperatively and VHI score varied from 23.3 to 24.5. Conclusion: Voice outcome after ELS unilateral type III or a bilateral type II resection for extended T1 and limited T2 glottic carcinoma is good with mild to very moderate perceptive dysphonia and low self‐reported voice impairment. [ABSTRACT FROM AUTHOR]

Although radiation therapy has traditionally been delivered with external beam or brachytherapy, intraoperative radiation therapy (IORT) represents an alternative that may shorten the course of therapy, reduce toxicities, and improve patient satisfaction while potentially lowering the cost of care. At this time, there are limited evidence-based guidelines to assist clinicians with patient selection for IORT. As such, the American Brachytherapy Society presents a consensus statement on the use of IORT. Physicians and physicists with expertise in intraoperative radiation created a site-directed guideline for appropriate patient selection and utilization of IORT. Several IORT techniques exist including radionuclide-based high-dose-rate, low-dose-rate, electron, and low-energy electronic. In breast cancer, IORT as monotherapy should only be used on prospective studies. IORT can be considered in the treatment of sarcomas with close/positive margins or recurrent sarcomas. IORT can be considered in conjunction with external beam radiotherapy for retroperitoneal sarcomas. IORT can be considered for colorectal malignancies with concern for positive margins and in the setting of recurrent gynecologic cancers. For thoracic, head and neck, and central nervous system malignancies, utilization of IORT should be evaluated on a case-by-case basis. The present guidelines provide clinicians with a summary of current data regarding IORT by treatment site and guidelines for the appropriate patient selection and safe utilization of the technique. High-dose-rate, low-dose-rate brachytherapy methods are appropriate when IORT is to be delivered as are electron and low-energy based on the clinical scenario. [ABSTRACT FROM AUTHOR]

Purpose: Cost-effectiveness analyses (CEAs) of screening can be highly sensitive to the health-related quality of life (HRQoL) effects of screen tests and subsequent treatment. Accordingly, accurate assessment of HRQoL is essential. We reviewed the literature regarding HRQoL in cervical prevention and management in order to appraise the current evidence regarding this important input to CEA.Methods: We searched the MEDLINE, Scopus and EconLit databases for studies that estimated HRQoL in cervical cancer prevention and management published January 1995-December 2015. The primary inclusion criterion was for studies that assess HRQoL using the EQ-5D. Data were abstracted from eligible studies on setting, elicitation group, sample size, elicitation instruments, health state valuations, study design and follow-up. We assessed the quality and comparability of the studies with a particular focus on the HRQoL reported across states and groups.Results: Fifteen papers met the inclusion criteria. Most used patient elicitation groups (n = 11), 2 used the general public and 2 used a mix of both. Eight studies were cross-sectional and seven were longitudinal. Six studies used both the EQ-5D-3L and the EQ-VAS together with other measures of overall HRQoL or condition-specific instruments. Extensive heterogeneity was observed across study characteristics.Conclusions: Our results reveal the challenges of sourcing reliable estimates of HRQoL for use in CEAs of cervical cancer prevention and treatment. The EQ-5D appears insufficiently sensitive for some health states. A more general problem is the paucity of HRQoL estimates for many health states and their change over time. [ABSTRACT FROM AUTHOR]

Recent advances in cytotoxic therapies for pancreatic ductal adenocarcinoma (PDA) are overshadowed by stalled clinical progress of more targeted strategies, the vast majority of which have failed in clinical trials. Inability to translate preclinical promise into clinical efficacy derives, in part, from imperfect disease modeling and mismatches between preclinical and clinical study design and execution. Into these gaps fall our patients who enter the clinical trial landscape expectantly and bear the brunt of its inadequacies. If improving patient survival is paramount, then it must be acknowledged that the failure of a phase III trial represents a larger failure of all of the work that preceded it. Repeated failures suggest a need to reappraise the current preclinical-to-clinical apparatus. Exceptional models of PDA are now available to researchers, and the first steps toward a new era of success can begin with improved selection and application of these systems. We discuss the key features of the major preclinical platforms for PDA and propose a paradigm for rigorous interrogation of prospective therapies. [ABSTRACT FROM AUTHOR]

Background: Serum bactericidal antibody titres that correlate with protection against invasive meningococcal disease have been characterised. However, titres that are associated with protection against acquisition of pharyngeal carriage of Neisseria meningitidis are not known. Methods: Sera were obtained from the members of a household in seven countries of the African meningitis belt in which a pharyngeal carrier of N. meningitidis had been identified during a cross-sectional survey. Serum bactericidal antibody titres at baseline were compared between individuals in the household of the carrier who became a carrier of a meningococcus of the same genogroup during six months of subsequent follow-up and household members who did not become a carrier of a meningococcus of this genogroup during this period. Results: Serum bacterial antibody titres were significantly higher in carriers of a serogroup W or Y meningococcus at the time of recruitment than in those who were not a carrier of N. meningitidis of the same genogroup. Serum bactericidal antibody titres to a strain of N. meningitis of the same genogroup as the index cases were no different in individuals who acquired carriage with a meningococcus of the same genogroup as the index case than in those who did not become a carrier during six months of follow-up. Conclusion: Serum bacterial antibody titres to N. meningitidis of genogroup W or Y in the range of those acquired by natural exposure to meningococci of these genogroups, or with cross-reactive bacteria, are not associated with protection against acquisition of carriage with meningococci of either of these genogroups. [ABSTRACT FROM AUTHOR]

This was an observational study investigating the efficacy and side effects associated with ulipristal acetate (UPA), a progesterone receptor modulator, and the possible benefits to women who have co-existing pre-menstrual syndrome (PMS). 80 women returned a questionnaire on the bleeding, menstrual pain and side effects, and changes on PMS were recorded. 67 women (84%) showed improvement in their menses. 54 women (67%) became amenorrhoeic. Of those, 67% were within 10 days of commencing UPA. Menses returned in 33 amenorrhoeic women within 4 weeks of stopping UPA. 58 women (70%) reported an improvement in their pain score but 41 women had a return of their pain after stopping UPA. The majority of the women had no or infrequent side effects. 80% had demonstrable improvement in their PMS symptoms. UPA is effective in controlling symptoms due to uterine fibroids with infrequent side effects. Our data also showed new evidence of a concurrent dramatic improvement in PMS in these women. Impact statement The observational study explored the drug profile of ulipristal acetate (UPA), a selective progesterone receptor modulator, which has been licenced as pre-treatment for surgical therapies of fibroids since 2012. We aimed to investigate the efficiency and side effects of UPA. Since the introduction of UPA in clinical practice, there has yet to be a study looking at the drug profile outside a research setting. We have also decided to investigate the effect of UPA on pre-menstrual syndrome (PMS) in this group of women with symptomatic fibroids. As such this case report should be of interest to a broad readership including those interested in the medical management of symptomatic fibroids. [ABSTRACT FROM AUTHOR]

Background: Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics.Methods: We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided.Results: One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P <  .001). PRB-H tumors showed increased tumor size ( P <  .001), Ki-67 levels ( P <  .001), human epidermal growth factor receptor 2 expression ( P =  .04), high grades ( P =  .03), and decreased total PR ( P =  .004) compared with PRA-H tumors. MUC-2 ( P <  .001) and KRT6A ( P =  .02) were also overexpressed in PRB-H tumors.Conclusion: The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer. [ABSTRACT FROM AUTHOR]

Topical antiseptics are widely used for wound treatment, with the goal of disrupting biofilm capacity. We analysed the effectiveness of a variety of antiseptics to inhibit various stages of biofilm formation and to remove biofilms in vitro as well as the agents' cytotoxic effects on fibroblasts. We found that the chlorine-releasing agents exhibited immediate anti-biofilm effects in the short term, with lesser cytotoxicity than agents prepared from more stable compounds, such as biguanide or modified diallyl disulfide-oxide, which, conversely, have better long-term effectiveness. Among the examined organisms, Gram-positive bacteria and Candida albicans were the most sensitive to the antiseptics, whereas Pseudomonas aeruginosa and Acinetobacter baumannii were relatively resistant to them. Formulations whose mechanisms of action involve the release of chemically active chlorine were more effective when administered in solution than the gel form, likely because of the stability of the active ingredients during or after preparation of the formula. Interestingly, hypochlorous acid and some superoxidation solutions were effective in preventing biofilm formation within a short time period and showed virtually no toxicity. Our study indicates that most antiseptics remain effective long enough to prevent biofilm formation; thus, even brief application of an antiseptic agent during initial wound treatment can lead to better wound management outcomes. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to explore factors affecting efficacy of treatment of common cold symptoms with an over-the-counter ibuprofen/pseudoephedrine combination product.Methods: Data from an anonymous survey among 1770 pharmacy customers purchasing the combination product for treatment of own common cold symptoms underwent post-hoc descriptive analysis. Scores of symptoms typically responsive to ibuprofen (headache, pharyngeal pain, joint pain and fever), typically responsive to pseudoephedrine (congested nose, congested sinus and runny nose), considered non-specific (sneezing, fatigue, dry cough, cough with expectoration) and comprising all 11 symptoms were analysed. Multiple regression analysis was applied to explore factors associated with greater reduction in symptom intensity or greater probability of experiencing a symptom reduction of at least 50%.Results: After intake of first dose of medication, typically ibuprofen-sensitive, pseudoephedrine-responsive, non-specific and total symptoms were reduced by 60.0%, 46.3%, 45.4% and 52.8%, respectively. A symptom reduction of at least 50% was reported by 73.6%, 55.1%, 50.9% and 61.6% of participants, respectively. A high baseline score was associated with greater reductions in symptom scores but smaller probability of achieving an improvement of at least 50%. Across both multiple regression approaches, two tablets at first dosing were more effective than one and (except for ibuprofen-sensitive symptoms) starting treatment later than day 2 of the cold was generally less effective.Discussion and Conclusions: Efficacy of an ibuprofen/pseudoephedrine combination in the treatment of common cold symptoms was dose-dependent and greatest when treatment started within the first 2 days after onset of symptoms. [ABSTRACT FROM AUTHOR]

A 12-month-old healthy girl presented with a chronic diaper rash. Physical examination demonstrated crusting of the scalp, erythematous papules with surrounding petechiae on the lower abdomen, and an intraoral palatal ulcer. Further imaging demonstrated bone involvement. Histopathologic examination of involved skin and the intraoral ulcer demonstrated epithelioid histiocytes with "coffee bean-shaped" nuclei, staining positive for CD1a and langerin by immunohistochemistry, consistent with Langerhans cell histiocytosis (LCH). LCH is a disease entity of unknown etiology characterized by histiocytic proliferation that most commonly presents in young children. The cutaneous findings of LCH include a seborrheic dermatitis-like and/or red-brown papular eruption. Intraoral examination is crucial as oral mucosal and maxillofacial skeletal disease can also be seen in LCH. When a child presents with a recalcitrant seborrheic dermatitis-like eruption or chronic diaper rash, the clinician should be alerted to the possibility of LCH. Timely recognition and diagnosis of LCH is important for oncologic referral, evaluation, and treatment. [ABSTRACT FROM AUTHOR]

Treatment efficacy of a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, was determined in xenograft models of non-small-cell lung carcinoma. The short-term impact of local hyperthermia (HT) on tumor morphology, microvessel density and local inflammatory response was also evaluated. The HTLC formulation in combination with local HT resulted in a significant advantage in therapeutic effect in comparison with free drug and a non-thermosensitive liposome formulation of CDDP (i.e. LipoplatinTM) when administered at their maximum tolerated doses. Local HT-induced widespread cell necrosis and a significant reduction in microvessel density in the necrotic regions of tumors. CD11b-expressing innate leukocytes were demonstrated to infiltrate and reside preferentially at the necrotic rim of tumors, likely as a means to phagocytose-damaged tissue. Colocalization of CD11b with a marker of DNA damage (i.e. γH2AX) revealed a small portion of CD11b-expressing leukocytes that were possibly undergoing apoptosis as a result of HT-induced damage and/or the short lifespan of leukocytes. Overall, HT-induced tissue damage (i.e. at 24-h post-treatment) alone did not result in significant improvements in treatment effect, rather, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Burns can have both physical and psychological effects on individuals. Pressure garments and silicone gels are used to improve the aesthetic appearance and functions of the skin, but these treatments have been associated with various physical, emotional, sexual and social difficulties. Interpretative phenomenological analysis (IPA) was used to explore participants' experiences of scar management. IPA examines individual experiences before comparing results across cases, and is suited to capture the different ways in which individuals experience a phenomena as well as cautiously looking at patterns across cases. Eight burn patients who had experienced scar management, including pressure garments, were interviewed. Two superordinate themes were identified: Assimilation of Pressure Garment Identity, and Psychosocial Functions of the Pressure Garments. The findings offered insight into the positive and negative experiences of scar management, describing the diverse personal and social functions of the pressure garments and how they became integrated into participants' identities. By understanding the individual nature of these experiences, healthcare professionals can enhance support around these issues and potentially aid adherence to treatment. Further research with different demographic groups as well as for other burn treatments would be useful to develop and contextualise these findings. [ABSTRACT FROM AUTHOR]

Background. High prevalence of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae has been reported in long-term acute care hospitals (LTACHs), in part because of frequent readmissions of colonized patients. Knowledge of the duration of colonization with KPC is essential to identify patients at risk of KPC colonization upon readmission and to make predictions on the effects of transmission control measures. Methods. We analyzed data on surveillance isolates that were collected at 4 LTACHs in the Chicago region during a period of bundled interventions, to simultaneously estimate the duration of colonization during an LTACH admission and between LTACH (re)admissions. A maximum-likelihood method was used, taking interval-censoring into account. Results. Eighty-three percent of patients remained colonized for at least 4 weeks, which was the median duration of LTACH stay. Between LTACH admissions, the median duration of colonization was 270 days (95% confidence interval, 91-∞). Conclusions. Only 17% of LTACH patients lost colonization with KPC within 4 weeks. Approximately half of the KPC-positive patients were still carriers when readmitted after 9 months. Infection control practices should take prolonged carriage into account to limit transmission of KPCs in LTACHs. [ABSTRACT FROM AUTHOR]

Aims: To describe the drug utilisation patterns of aspirin, antihypertensives, vasodilators, and statins in a cohort of newly treated type 2 diabetes subjects previously unexposed to CVD agents.Methods: A population-based retrospective cohort study was conducted using a national pharmacy claims database of newly treated type 2 diabetes subjects aged 40 years or older. Data on the use of aspirin, antihypertensives, vasodilators, and statins 1 year after antidiabetic agent initiation were analysed. Poisson regression with a robust error variance was used to estimate adjusted relative risk (RRadj) and 95% CIs between socio-demographic and treatment factors on CVD agent use.Results: Over a 2-year period (2008-2009), 6093 subjects were identified. One year after antidiabetic agent initiation, 82% of the study population received at least one CVD agent, with 54% receiving aspirin, 64% receiving antihypertensives, 6% vasodilators, and 62% receiving statins. Subjects aged 40-49 years were significantly less likely than those aged 60-69 years to receive CVD agents (RRadj 0.83, 95% CI 0.80-0.87). Over 40% of subjects received antihypertensives without aspirin and statins, while 30% of subjects on statins did not receive aspirin.Conclusions: Substantial CVD agent utilisation was noted 1 year after antidiabetic agent initiation. Being aged younger than 60-69 years was associated with decreased utilisation of CVD agents. [ABSTRACT FROM AUTHOR]

This paper aims to provide a critical analysis of key concepts associated with post-natal depression (PND) to facilitate healthcare professionals with improving standards of care. Post-natal depression is often inadequately understood by healthcare professionals. The objective was to clarify and present understandings of PND. Post-natal depression may result in referral to Community Mental Health Teams and although initial contact and management is usually through Primary Care, increasingly there is involvement of liaison mental health nurses. A literature review and synthesis of research papers on PND was conducted. Using the keywords post-natal depression, post-partum, puerperium, perinatal, therapy, trial, review, systematic, 135 articles were yielded and limited to 57, which were critically reviewed and categorized into key concepts and themes. Synthesis of literature in relation to PND has facilitated construction of an evidence-based contemporary picture of clinical manifestation, aetiology, methods of screening, preventing, treating and managing PND. The veracity of the evidence surrounding the aetiology and treatment of PND is variable. Interventions are often ineffective and a vacuum in the evidence base exists leaving a dynamic environment for researchers to identify more successful ways of predicting, detecting, treating and managing PND. [ABSTRACT FROM AUTHOR]

The Dublin Declaration on Partnership to fight HIV/AIDS in Europe and Central Asia is the key policy document on HIV/AIDS in the European Region as a whole Among the Declaration's 33 actions for governments are many that apply to prison populations. Based upon an analysis of these commitments, and a review of the current status of states in meeting those targets, it is clear that the scale-up of HIV/AIDS prevention and treatment programmes and services in prisons lags far behind what is needed, what is available outside of prisons, and what is mandated within the Declaration itself. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre-clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro , the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo , PDT was applied on an orthotopic mouse tumor model with illumination at 1 h post-injection of the nanobody–PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody–PS conjugate, with illumination performed 24 h post-injection. Importantly, EGFR targeted nanobody–PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24 h after PDT. Overall, results show that these EGFR targeted nanobody–PS conjugates are selective and able to induce tumor cell death in vivo . Additional studies are now needed to assess the full potential of this approach to improving PDT. [ABSTRACT FROM AUTHOR]

Context Emm1- type group A Streptococcus (GAS), or Streptococcus pyogenes , is mostly responsible for invasive infections such as necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS). The recommended treatment of severe invasive GAS infections is a combination of clindamycin and penicillin. Until 2012, almost all emm1 isolates were susceptible to clindamycin. Objectives We aimed to identify the phenotypic and genotypic characteristics of emm 1 GAS clone resistant to clindamycin. Methods GAS strains were characterized by emm sequence typing, detection of genes encoding pyrogenic exotoxins or superantigens. Cluster analysis was performed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Antibiotic susceptibility was assessed using disk diffusion and resistance genes were detected by PCR. Results A total of 1321 GAS invasive isolates were analyzed between January 2011 and December 2012. The overall number of invasive isolates resistant to clindamycin was 52 (3.9%); seven of them were emm1 isolates. All isolates had the same genomic markers: macrolide resistance due to the presence of the erm (B) gene, emm subtype 1.0, the same toxin or superantigen profile, PFGE pattern and sequence type. Conclusion This is the first description of highly virulent GAS emm1 isolates resistant to clindamycin in France. This article strengthens the need for monitoring the epidemiology of invasive GAS strains as they could lead to changes in treatment guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the mechanisms by which bupropion promotes smoking cessation may lead to more effective treatment. To the extent that reduced smoking reinforcement is one such mechanism, a longer duration of pre quit bupropion treatment should promote extinction of smoking behavior. We evaluated whether 4 weeks of pre quit bupropion (extended run-in) results in greater pre quit reductions in smoking rate and cotinine and, secondarily, greater short-term abstinence, than standard 1 week of pre quit bupropion (standard run-in).Methods: Adult smokers (n = 95; 48 females) were randomized to a standard run-in group (n = 48; 3-week placebo, then 1-week bupropion pre quit) or an extended run-in group (4-week pre quit bupropion; n = 47). Both groups received group behavioral counseling and 7 weeks of post quit bupropion. Smoking rate (and craving, withdrawal, and subjective effects) was collected daily during the pre quit period; biochemical data (cotinine and carbon monoxide) were collected at study visits.Results: During the pre quit period, the extended run-in group exhibited a greater decrease in smoking rate, compared to the standard run-in group, interaction p = .03. Cigarette craving and salivary cotinine followed a similar pattern, though the latter was evident only among women. Biochemically verified 4-week continuous abstinence rates were higher in the extended run-in group (53%) than the standard run-in group (31%), p = .033.Conclusions: The extended use of bupropion prior to a quit attempt reduces smoking behavior during the pre quit period and improved short-term abstinence rates. The data are consistent with an extinction-of-reinforcement model and support further investigation of extended run-in bupropion therapy for smoking cessation. [ABSTRACT FROM AUTHOR]

During a large hospital outbreak of OXA-48 producing bacteria, most K. pneumoniaeOXA-48 isolates were phenotypically resistant to meropenem or imipenem, whereas most E. coliOXA-48 isolates were phenotypically susceptible to these antibiotics. In the absence of molecular gene-detection E. coliOXA-48 could remain undetected, facilitating cross-transmission and horizontal gene transfer of blaOXA-48. Based on 868 longitudinal molecular microbiological screening results from patients carrying K. pneumoniaeOXA-48 (n = 24), E. coliOXA-48 (n = 17), or both (n = 40) and mathematical modelling we determined mean durations of colonisation (278 and 225 days for K. pneumoniaeOXA-48 and E. coliOXA-48, respectively), and horizontal gene transfer rates (0.0091/day from K. pneumoniae to E. coli and 0.0015/day vice versa). Based on these findings the maximum effect of horizontal gene transfer of blaOXA-48 originating from E. coliOXA-48 on the basic reproduction number (R0) is 1.9%, and it is, therefore, unlikely that phenotypically susceptible E. coliOXA-48 will contribute significantly to the spread of blaOXA-48. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma ( OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase ( COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid ( ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg−1 ZOL twice weekly, 0.3 mg kg−1 meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC. [ABSTRACT FROM AUTHOR]

The article discusses the 2015 British Association of Dermatologists (BAD) and British Photodermatology Group (BPG) guidelines on ultraviolet (UV) radiation level dosimetry in UV phototherapy. Topics explored include the methodology observed in the development of these guidelines, clinical and biological factors that need to be considered in the application of phototherapy, and the proper use and management of UV phototherapy equipment and tools.

A New Algorithm to Reduce Inappropriate Therapy Introduction The subcutaneous ICD system (S-ICD) has been shown to be a safe and effective treatment for patients at risk for sudden cardiac death. This device reliably detects ventricular tachyarrhythmias with a low incidence of inappropriate shocks for supraventricular arrhythmias. However, T-wave oversensing (TWOS) is more common with the S-ICD compared with transvenous systems. We developed a novel discrimination algorithm to reduce TWOS without compromising tachyarrhythmia discrimination. Methods and Results The algorithm was developed using a database of recorded episodes, including 244 appropriate therapies for ventricular arrhythmias and 133 episodes with an inappropriate detection due to TWOS, and using a computer model that simulates the S-ICD system. An independent set of data of 161 TWOS episodes, 137 ventricular and 328 supraventricular episodes, was used to validate the algorithm on actual device hardware. The S-ICD performance with the new algorithm was compared with the S-ICD without the new algorithm. Development results showed a decrease in inappropriate charge due to TWOS by 30.7 ± 18%. All ventricular arrhythmias were appropriately detected and the time to appropriate charge initiation was not increased. System validation showed that the new algorithm avoided an inappropriate charge due to TWOS by 39.8 ± 11.4%. No decrease in ventricular arrhythmia sensitivity and no significant change in supraventricular specificity were observed. Conclusions A new algorithm that uses correlation of the existing complex to previous complexes reduced TWOS episodes by approximately 40%. The algorithm has potential for a clinically meaningful decrease in inappropriate shocks. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Serrated polyps of the colon comprise a heterogeneous group of lesions with distinct histological and malignant features. The presence of serrated polyps has been associated with synchronous advanced neoplasia, although the magnitude of this relationship is unclear.METHODS:Using studies identified from systematic literature search up to February 2014, we performed a systematic review and meta-analysis to estimate the pooled prevalence of serrated polyps and their association with synchronous advanced neoplasia. Random-effects models were used to combine estimates from heterogeneous studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented.RESULTS:Nine studies with 34,084 participants were included. The mean age of subjects was 59.9±6.6 years and 52.5% of the subjects were male. Pooled prevalence of serrated polyps was 15.6% (95% CI, 10.3-22.9%). The pooled OR of advanced neoplasia in individuals with serrated polyps was 2.05 (95% CI, 1.38-3.04). Pooled analysis showed that the presence of proximal serrated polyps (OR=2.77, 95% CI, 1.71-4.46) and large serrated polyps (OR=4.10, 95% CI, 2.69-6.26) was associated with an increased risk of synchronous advanced neoplasia. The pooled OR for advanced neoplasia in individuals with proximal and large serrated polyps was 3.35 (95% CI, 2.51-4.46). Considerable heterogeneity was observed in most analyses.CONCLUSIONS:Our meta-analysis showed that serrated polyps are associated with a more than twofold increased risk of detection of synchronous advanced neoplasia. Individuals with proximal and large serrated polyps have the highest risk. These individuals deserve surveillance colonoscopy. [ABSTRACT FROM AUTHOR]

Objectives: To explore awareness of human papillomavirus (HPV) and use of HPV vaccines (Gardasil and Cervarix) by college students.Participants: The sample was composed of 817 undergraduates at 2 northeastern US universities; they participated between February and May 2010.Methods: Students were provided with a link to an anonymous, self-administered, Web-based survey comprised of 76 questions. The survey included questions about health behaviors, awareness, and knowledge of HPV and the 2 HPV vaccines, and vaccine uptake.Results: Results indicate high levels of awareness of HPV as well as marked sex differences related to vaccine awareness and uptake. Both sexes are largely unaware of Cervarix and the differences between Cervarix and Gardasil.Conclusion: The study affirms the importance of a clinician's recommendation for HPV vaccination. Public health messaging should become more inclusive of adolescent and young adult males. College students’ awareness of HPV vaccine options mirrors Gardasil's market dominance in the United States. [ABSTRACT FROM AUTHOR]

In contrast to the articulating and taper surfaces of failed total hip replacements, volumetric wear analysis of trunnions is not routinely performed. Metal wear particles from the trunnion may contribute not only to the failures of metal-on-metal total hip replacements but also to all hip replacements utilising metal trunnions. A validation study was performed with the material removed in stages from the trunnions of an Exeter V40 stem, a Corail stem and an Accolade stem to simulate different magnitudes of wear. The material loss from the trunnions was measured both volumetrically with a coordinate measuring machine and gravimetrically with a high-precision balance. A cohort of 28 ex vivo trunnions was also measured using the coordinate measuring machine. The maximum error between the two methods was found to be 0.13 mm3. This result was comparable with the coordinate measuring machine method for the taper surface (0.2 mm3). The ex vivo trunnions had a median wear volume of 0.14mm3 (range: 0.04–0.28 mm3). This is the first study to determine the accuracy of volumetric wear measurements of trunnions by comparing against gravimetric measurements. Volumetric wear analysis of trunnions may provide additional insights into failures of modular total hip prostheses and will be performed routinely at our centre. [ABSTRACT FROM AUTHOR]

Multimorbidity has become the norm worldwide as populations age. It remains, however, infrequently researched. This study evaluated factors associated with multimorbidity in a predominantly Chinese hypertensive population. We included all adult patients prescribed their first antihypertensive agents in the entire public sector in Hong Kong from a validated database. Multimorbidity was defined as having one or more medical conditions (cardiovascular diseases; respiratory diseases; diabetes or impaired fasting glucose; renal disease) in addition to hypertension. We studied the prevalence of multimorbidity and performed multinomial regression analyses to evaluate factors independently associated with multimorbidity. 223,286 hypertensive patients (average age of 59.9 years, SD 17.6) were included. The prevalence of having 0, 1 and ≥ 2 additional conditions was 59.6%, 32.8% and 7.5%, respectively. The most common conditions were cardiovascular disease (24.2%) and diabetes (23.0%), followed by respiratory disorders (14.6%) and renal disease (10.9%). Older age (> 50 years), male sex, lower household income, receipt of social security allowance and suboptimal blood pressure control (> 140 mmHg or > 90 mmHg; > 130 mmHg or > 80 mmHg for diabetes patients; AOR = 3.38-4.49) were significantly associated with multimorbidity. There exists a synergistic effect among these variables as older (≥ 70 years), male patients receiving security allowance had substantially higher prevalence of multimorbidity (19.9% vs 7.5% among all patients). Multimorbidity is very common in hypertensive patients and its prevalence increased markedly with the presence of risk factors identified in this study. Hypertensive patients with multimorbidities should receive more meticulous clinical care as their blood pressure control tends to be poorer. [ABSTRACT FROM AUTHOR]

Background Perindopril and lisinopril are two common ACE inhibitors prescribed for management of hypertension. Few studies have evaluated their comparative effectiveness to reduce mortality. This study compared the all-cause and cardiovascular related mortality among patients newly prescribed ACE inhibitors. Methods All adult patients newly prescribed perindopril or lisinopril from 2001 to 2005 in all public clinics or hospitals in Hong Kong were retrospectively evaluated, and followed up until 2010. Patients prescribed the ACE inhibitors for less than a month were excluded. The all-cause mortality and cardiovascular-specific (i.e. coronary heart disease, heart failure and stroke) mortality were compared. Cox proportional hazard regression model was used to assess the mortality, controlling for age, sex, socioeconomic status, patient types, the presence of comorbidities, and medication adherence as measured by the proportion of days covered. An additional model using propensity scores was performed to minimize indication bias. Results A total of 15,622 patients were included in this study, in which 6910 were perindopril users and 8712 lisinopril users. The all-cause mortality (22.2% vs. 20.0%, p < 0.005) and cardiovascular mortality (6.5% vs. 5.6%, p < 0.005) were higher among lisinopril users than perindopril users. From regression analyses, lisinopril users were 1.09-fold (95% C.I. 1.01-1.16) and 1.18-fold (95% C.I. 1.02-1.35) more likely to die from any-cause and cardiovascular diseases, respectively. Age-stratified analysis showed that this significant difference was observed only among patients aged > 70 years. The additional models controlled for propensity scores yielded comparable results. Conclusions The long-term all-cause and cardiovascular related mortality rates of lisinopril users was significantly different from those of perindopril users. These findings showed that intra-class variation on mortality exists among ACE inhibitors among those aged 70 years or older. Future studies should consider a longer, large-scale randomized controlled trial to compare the effectiveness between different medications in the ACEI class, especially among the elderly. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival of children with Wilms tumor is excellent. However, treatment-related complications may occur, requiring treatment at the pediatric intensive care unit (PICU). The aim of our retrospective study was to assess the frequency, clinical characteristics, and outcome of 175 children with Wilms tumor requiring treatment at the PICU in the Netherlands. Thirty-three patients (almost 20%) required unplanned PICU admission during their disease course. Younger age at diagnosis, intensive chemotherapy regimens, and bilateral tumor surgery were risk factors for these unplanned PICU admissions. Three children required renal replacement therapy, two of which continued dialysis after PICU discharge. Two children died during their PICU stay. During follow up, hypertension and renal dysfunction were frequently observed, which justifies special attention for kidney function and blood pressure monitoring during and after treatment of these children. Survival rates are excellent for children with Wilms tumor (WT), yet tumor and treatment-related complications may require pediatric intensive care unit (PICU) admission. We assessed the frequency, clinical characteristics, and outcome of children with WT requiring PICU admissions in a multicenter, retrospective study in the Netherlands. Admission reasons of unplanned PICU admissions were described in relation to treatment phase. Unplanned PICU admissions were compared to a control group of no or planned PICU admissions, with regard to patient characteristics and short and long term outcomes. In a multicenter cohort of 175 children with an underlying WT, 50 unplanned PICU admissions were registered in 33 patients. Reasons for admission were diverse and varied per treatment phase. Younger age at diagnosis, intensive chemotherapy regimens, and bilateral tumor surgery were observed in children with unplanned PICU admission versus the other WT patients. Three children required renal replacement therapy, two of which continued dialysis after PICU discharge (both with bilateral disease). Two children died during their PICU stay. During follow-up, hypertension and chronic kidney disease (18.2 vs. 4.2% and 15.2 vs. 0.7%) were more frequently observed in unplanned PICU admitted patients compared to the other patients. No significant differences in cardiac morbidity, relapse, or progression were observed. Almost 20% of children with WT required unplanned PICU admission, with young age and treatment intensity as potential risk factors. Hypertension and renal impairment were frequently observed in these patients, warranting special attention at presentation and during treatment and follow-up. [ABSTRACT FROM AUTHOR]

The treatment of invasive candidiasis associated with growing numbers of immunocompromised patients remains a major challenge complicated by increasing drug resistance. A novel class of branched histidine-lysine (bHK) peptides has promising antifungal activity, and exhibits a mechanism similar to natural histatins, and thus may avoid drug resistance. The present studies evaluate ligand targeting of bHK peptides to fungal surface integrins by determining whether a cyclic RGD (cRGD) peptide with a large PEG linker could enhance bHK peptide antifungal activity. Whereas conjugates containing only the PEG linker reduced bHK peptide activity, conjugates with the cRGD-PEG ligand resulted in marked enhancement of activity against Candida albicans. This study provides the first demonstration of benefit from ligand targeting of antifungal agents to fungal surface receptors. [ABSTRACT FROM AUTHOR]

Background Ventricular arrhythmias (VAs) in the months following continuous-flow left ventricular assist devices (LVADs) implantation are common and associated with increased morbidity and mortality. We sought to evaluate for changes in implantable cardioverter defibrillator (ICD) performance following LVAD implantation. Methods We retrospectively reviewed the ICD interrogation reports and medical records of patients who received a continuous-flow LVAD at the University of Chicago Medical Center between January 2008 and December 2010. Patients who did not have an ICD prior to LVAD implantation were excluded. Results Forty-four patients were included. Median right ventricular lead sensing amplitude decreased from 10.0 (interquartile range 7.6-13.6) mV prior to LVAD to 7.9 (5.9-9.3) mV after LVAD implantation (P < 0.01). Significant reductions in sensing threshold were associated with smaller lead diameters, smaller pace/sense electrode surface areas, and Medtronic ICD leads (Medtronic Inc., Minneapolis, MN, USA). Lead impedance and capture threshold did not change significantly. ICD-related adverse events occurred in 30% of patients and led to ICD modification in 18% of patients. Conclusions Implantation of a continuous-flow LVAD is associated with changes in the performance of preexisting ICDs. ICD-related adverse events were encountered following LVAD implantation in this cohort, and at times resulted in invasive and noninvasive ICD system modification. Reductions in ICD sensing threshold after LVAD implantation may adversely affect ICD function. Formal ICD interrogation in addition to the regular follow-up testing is warranted post-LVAD. [ABSTRACT FROM AUTHOR]

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups. [ABSTRACT FROM AUTHOR]

Changes in serotonin2C receptor (5-HTR2c) editing, splicing and density were found in conditions such as depression and suicide, but mechanisms explaining the changes in 5-HTR2c function are unknown. Thus, mice expressing only the fully edited VGV isoform of 5-HTR2c, in which clinically relevant behavioral changes are associated with alterations in splicing and receptor density, were studied. VGV mice displayed enhanced anxiety-like behavior in response to a preferential 5-HTR2c agonist in the social interaction test. Nearly half of interactions between pairs of VGV congeners consisted of fighting behaviors, whereas no fighting occurred in wild-type (WT) mice. VGV mice also exhibited a striking increase in freezing behaviors in reaction to an innately aversive ultrasonic stimulus. This behavioral phenotype occurred in conjunction with decreased brain 5-HT turnover during stress. These functional data were put in relation with the 5-HTR2c mRNA splicing process generating a truncated protein (5-HTR2c-Tr) in addition to the full-length receptor (5-HTR2c-Fl). 5-HTR2c-Tr mRNA was less abundant in many brain regions of VGV mice, which concomitantly had more 5-HTR2c than WT mice. Fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies in transfected living HEK293T cells showed that 5-HTR2c-Tr interacts with 5-HTR2c-Fl. The 5-HTR2c-Tr was localized in the endoplasmic reticulum where it retained 5-HTR2c-Fl, preventing the latter to reach the plasma membrane. Consequently, 5-HTR2c-Tr decreased 3H-mesulergine binding to 5-HTR2c-Fl at the plasma membrane in a concentration-dependent manner and more strongly with edited 5-HTR2c-Fl. These results suggest that 5-HTR2c pre-mRNA editing and splicing are entwined processes determining increased 5-HTR2c levels in pathological conditions through a deficit in 5-HTR2c-Tr. [ABSTRACT FROM AUTHOR]

The article presents a study on the effect of an immunomodulatory treatment in delaying the secondary progression (SP) of relapsing-remitting multiple sclerosis (RRMS). Methods used include survival analysis, Gothenburg Incidence Cohort (GIC), and Cox regression models. Result shows that disease modifying drugs (DMDs) slows the SP process of RRMS.

An Addisonian crisis marks an acute adrenocortical failure which can be caused by decompensation of a chronic insufficiency due to stress, an infarct or bleeding of the adrenal cortex and also abrupt termination of a long-term glucocorticoid medication. This article reports the case of a 25-year-old patient with Crohn's disease who suffered an Addisonian crisis with hypotension, hyponatriemia and hypoglycemia during an emergency laparotomy after he had terminated prednisolone medication on his own authority. This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. Under this treatment regimen hemodynamic stabilization was achieved. Reduction of the administration of hydrocortisone after 3 days resulted in cardiovascular insufficiency which required an escalation of the hydrocortisone substitution. [ABSTRACT FROM AUTHOR]

The article assesses the changes in the amygdala and the limbic-subcortical-prefrontal network as response to negative facial expressions after treatment of major depressive disorder (MDD) with paroxetine relative to responder status. Functional magnetic resonance imaging is cited to be conducted on patients with unipolar, MDD after six and 12 weeks of treatment. MDD patients are showed to have increased ventral/limbic, and decreased dorsal prefrontal activations in response to negative faces.

AIMS To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03-0.16), Kp,free (0.01-0.04) and CSF : free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10-6 cm s-1), moderate for 5-HMT (11.7 × 10-6 cm s-1) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10-6 cm s-1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine).CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study. [ABSTRACT FROM AUTHOR]

Abstract: β-Adrenoceptor stimulation can enhance the storage function of the urinary bladder by acting on detrusor smooth muscle tone, mediator release from the urothelium and/or afferent nerve activity. In humans this may occur predominantly if not exclusively via the β3-subtype. The effects of β-adrenoceptor agonists including several β3-selective agonists have been studied in vitro and in vivo, in healthy animals of both genders and various age groups and in a wide range of animal (mostly rat) models of genetic or acquired bladder dysfunction. Such models included bladder irritation by intravesical instillation of acetic acid or prostaglandin E2, bladder outlet obstruction, stroke, diabetes, spontaneously hypertensive rats, and NO synthase inhibition. Across all of these models β-adrenoceptor agonists had effects consistent with improved bladder storage function. β3-Adrenoceptor effects are resistant to agonist-induced desensitization in many cell types, but whether this also applies to the human bladder is unknown. The efficacy of β-adrenoceptor agonists appears to be largely unaffected by common polymorphisms of the β3-adrenoceptor gene. Taken together these findings suggest that β3-adrenoceptor agonists may become useful drugs for the treatment of bladder storage dysfunction, a view supported by recent phase III clinical studies for one such agent, mirabegron. [Copyright &y& Elsevier]

Summary: Objectives: Questions concerning nonretractile foreskin are frequently asked by parents in infant consultations. Topical steroid treatment could be a less expensive and less traumatizing alternative to surgery. Aim: To assess the effectiveness of topical steroid therapy in boys with phimosis. Methods: Literature review. All randomized controlled trials were selected, using the following research sources: Medline, Cochrane Library, Pascal, Embase, Blackwell Science, Google, Google scholar, SUDOC, international register of trials, and congress abstracts. Unpublished trials were also searched. The trials were analyzed using the ANAES guide from a therapeutic article. Results: Seven randomized controlled trials (n =714 patients) were in accordance with the inclusion criteria. The patients were between 1 and 12years old. The treatment lasted for 4–8weeks. The success rate at the end of the study was higher with the steroid (53.8–95%) than with the placebo (6.25–52%), P <0.05 for 6 randomized control trials. Discussion: According to the ANAES criteria, the level of scientific evidence is low (gradeC) because of the lack of power in clinical trials and numerous methodological shortcomings and biases, even when examining both randomized control trials and nonrandomized trials. Only a few local side effects were noted. Conclusion: The use of topical steroids can be recommended in first-intention treatment before surgery for the management of phimosis. [ABSTRACT FROM AUTHOR]

Abstract: Context: Individuals differ in their sensitivity to drug treatment, including that with muscarinic receptor antagonists used in the treatment of overactive bladder (OAB), due to a combination of pharmacodynamic and pharmacokinetic reasons. Objective: To discuss the variability in drug response among individual patients, the concept of the dose-response curve, and the selection of drug dosage as well as how these factors are integrated when optimising OAB treatment using the muscarinic receptor antagonist fesoterodine as an example. Evidence acquisition: Data sources were identified in 2010 using a nonsystematic search and included articles and abstracts selected using expert opinion of their relevance to drug response in OAB. Evidence synthesis: A given drug dose is unlikely to yield the same quantitative response in all patients, and undertreatment (too little efficacy) or overtreatment (too many side effects) may occur. The position and shape of the dose-response curve for a drug may differ between patients and within a patient for desired and adverse effects. The availability of two or more drug doses allows for titration (flexible dosing) to find the dose exhibiting the optimal clinical efficacy that is tolerable for an individual patient. Optimally, a patient would have symptom resolution with no adverse events (AEs). Realistically, an efficacy-to-tolerability ratio (therapeutic index) exists for each of the combinations of selected efficacy metrics and AE reports. Conclusions: Dose titration is important for selection of an effective dose of a treatment with minimal side effects. [Copyright &y& Elsevier]