A pilot randomised double blind controlled trial of the efficacy of purified fatty acids for the treatment of women with endometriosis-associated pain (PurFECT):study protocol

Abstract Background Endometriosis affects 6–10% of women and is associated with debilitating pelvic pain. It costs the UK > £2.8 billion per year in loss of productivity. Endometriosis can be managed by surgical excision or medically by ovarian suppression. However, ~ 75% symptoms recur after surgery and available medical treatments have undesirable side effects and are contraceptive. Omega-3 purified fatty acids (PUFA) have been shown in animal models to reduce factors that are thought to lead to endometriosis-associated pain, have minimal side effects, and no effects on fertility. This paper presents a protocol for a two-arm, pilot parallel randomised controlled trial (RCT) which aims to inform the planning of a future multicentre trial to evaluate the efficacy of Omega-3 PUFA in the management of endometriosis-associated pain in women. Methods The study will recruit women with endometriosis over a 12-month period in the National Health Service (NHS) Lothian, UK, and randomise them to 8 weeks of treatment with Omega-3 PUFA or comparator (olive oil). The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness/acceptability to participants of the proposed methods of recruitment/randomisation/treatments/questionnaires, to inform the sample size calculation and to refine the research methodology for a future large randomised controlled trial. Response to treatment will be monitored by pain scores and questionnaires assessing physical and emotional function compared at baseline and 8 weeks. Discussion We recognise that there may be potential difficulties in mounting a large randomised controlled trial for endometriosis to assess Omega-3 PUFA because they are a dietary supplement readily available over the counter and already used by women with endometriosis. We have therefore designed this pilot study to assess practical feasibility and following the ‘Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials’ recommendations for the design of chronic pain trials. Trial registration ISRCTN4420234

Evo-devo of human adolescence: beyond disease models of early puberty

Despite substantial heritability in pubertal development, much variation remains to be explained, leaving room for the influence of environmental factors to adjust its phenotypic trajectory in the service of fitness goals. Utilizing evolutionary development biology (evo-devo), we examine adolescence as an evolutionary life-history stage in its developmental context. We show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence and maturation toward youth and adulthood. Using the evolutionary theory of socialization, we show that familial psychosocial stress fosters a fast life history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. Here we explore implications of an evolutionary-developmental-endocrinological-anthropological framework for theory building, while illuminating new directions for research

Contemporary Trends of Systemic Neoadjuvant and Adjuvant Intravesical Chemotherapy in Patients With Upper Tract Urothelial Carcinomas Undergoing Minimally Invasive or Open Radical Nephroureterectomy: Analysis of US Claims on Perioperative Outcomes and Health Care Costs

Introduction: New evidence indicates that minimally invasive surgery (MIS) (laparoscopic or robotic-assisted [LNU, RANU]) reaches oncologic equivalence compared with Open Radical Nephroureterectomy (ORNU) for high-risk upper-tract urothelial carcinoma (UTUC). Recently, European Association of Urology (EAU) Guidelines suggested implementing neoadjuvant chemotherapy (NAC) to standard treatment to improve oncologic outcomes of high-risk UTUC. We aimed (1) To explore contemporary trends of MIS for RNU in the United States and to compare perioperative outcomes and costs with that of ORNU. (2) To determine the trends of NAC and postoperative intravesical chemotherapy (PIC) administration for high-risk UTUC and to assess their contribution to perioperative outcomes and costs. Patients and methods: The Optum Clinformatics Data Mart de-identified database was queried from 2003 to 2018 to retrospectively examine patients who had undergone LNU/RANU or ORNU with or without NAC and PIC. We evaluated temporal adoption trends, complications, and health care cost analyses. We obtained descriptive statistics and utilized multivariable regression modeling to assess outcomes. Results: A total of n = 492 ORNU and n = 1618 LNU/RANU procedures were reviewed. The MIS approach was associated with a statistically significant lower risk of intraoperative complications (adjusted Odds Ratio [aOR], 0.48, 95% CI:0.24-0.96), risk of hospitalization costs (aOR: 0.62, 95% CI:0.49-0.78), and shorter hospital stay (aOR: 0.20, 95% CI:0.15-0.26) when compared to ORNU. Overall, adoption of NAC and PIC accounted for only n = 81 and n < 37 cases respectively. The implementation of NAC and higher number of cycles were associated with an increased probability of any complication rate (aOR: 2.06, 95% CI:1.26-3.36) and hospital costs (aOR: 2.12, 95% CI:1.33-3.38). Conclusion: MIS has become the approach of choice for RNU in the US. Although recommended by guidelines, neither NAC nor postoperative bladder instillation of chemotherapy has been routinely incorporated into the clinical practice of patients with UTUC

Combined Patterns of IGHV Repertoire and Cytogenetic/Molecular Alterations in Monoclonal B Lymphocytosis versus Chronic Lymphocytic Leukemia

Background:Chronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis (MBL) with (MBLhi) or without (MBLlo) absolute B-lymphocytosis precedes most CLL cases,the specific determinants for malignant progression remaining unknown.Methodology/Principal Findings:For this purpose, simultaneous iFISH and molecular analysis of well-established cytogenetic alterations of chromosomes 11, 12, 13, 14 and 17 together with the pattern of rearrangement of the IGHV genes were performed in CLL-like cells from MBL and CLL cases. Our results based on 78 CLL-like MBL and 117 CLL clones from 166 subjects living in the same geographical area, show the existence of three major groups of clones with distinct but partially overlapping patterns of IGHV gene usage, IGHV mutational status and cytogenetic alterations. These included a group enriched in MBLloclones expressing specific IGHV subgroups (e.g. VH3-23) with no or isolated good-prognosis cytogenetic alterations, a second group which mainly consisted of clinical MBLhiand advanced stage CLL with a skewed but different CLL-associated IGHV gene repertoire (e.g. VH1-69), frequently associated with complex karyotypes and poor-prognosis cytogenetic alterations, and a third group of clones with intermediate features, with prevalence of mutated IGHV genes, and higher numbers of del(13q)+clonal B-cells.Conclusions/Significance:These findings suggest that the specific IGHV repertoire and IGHV mutational status of CLL-like B-cell clones may modulate the type of cytogenetic alterations acquired, their rate of acquisition and/or potentially also their clinical consequences. Further long-term follow-up studies investigating the IGHV gene repertoire of MBLloclones in distinct geographic areas and microenvironments are required to confirm our findings and shed light on the potential role of some antigen-binding BCR specificities contributing to clonal evolution

Compared Efficacy of Adjuvant Intravesical BCG-TICE vs. BCG-RIVM for High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC): A Propensity Score Matched Analysis

Background: Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC). The superiority of any BCG strain over another could not be demonstrated yet. Methods: Patients with NMIBCs underwent adjuvant induction ± maintenance schedule of intravesical immunotherapy with either BCG TICE or RIVM at two high-volume tertiary institutions. Only BCG-naïve patients and those treated with the same strain over the course of follow-up were included. One-to-one (1:1) propensity score matching (PSM) between the two cohorts was utilized to adjust for baseline demographic and tumor characteristics imbalances. Kaplan-Meier estimates and multivariable Cox regression models according to high-risk NMIBC prognostic factors were implemented to address survival differences between the strains. Sub-group analysis modeling of the influence of routine secondary resection (re-TUR) in the setting of the sole maintenance adjuvant schedule for the two strains was further performed. Results: 852 Ta-T1 NMIBCs (n = 719, 84.4% on TICE; n = 133, 15.6% on RIVM) with a median of 53 (24-77) months of follow-up were reviewed. After PSM, no differences at 5-years RFS, PFS, and CSS at both Kaplan-Meier and Cox regression analyses were detected for the whole cohort. In the sub-group setting of full adherence to European/American Urology Guidelines (EAU/NCCN), BCG TICE demonstrated longer 5-years RFS compared to RIVM (68% vs. 43%, p = 0.008; HR: 0.45 95% CI 0.25-0.81). Conclusion: When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to RIVM for RFS outcomes. However, no significant differences were detected for PFS and CSS, respectively

Sero-epidemiological evaluation of changes in Plasmodium falciparum and Plasmodium vivax transmission patterns over the rainy season in Cambodia

<p>Abstract</p> <p>Background</p> <p>In Cambodia, malaria transmission is low and most cases occur in forested areas. Sero-epidemiological techniques can be used to identify both areas of ongoing transmission and high-risk groups to be targeted by control interventions. This study utilizes repeated cross-sectional data to assess the risk of being malaria sero-positive at two consecutive time points during the rainy season and investigates who is most likely to sero-convert over the transmission season.</p> <p>Methods</p> <p>In 2005, two cross-sectional surveys, one in the middle and the other at the end of the malaria transmission season, were carried out in two ecologically distinct regions in Cambodia. Parasitological and serological data were collected in four districts. Antibodies to <it>Plasmodium falciparum </it>Glutamate Rich Protein (GLURP) and <it>Plasmodium vivax </it>Merozoite Surface Protein-1₁₉(MSP-1₁₉) were detected using Enzyme Linked Immunosorbent Assay (ELISA). The force of infection was estimated using a simple catalytic model fitted using maximum likelihood methods. Risks for sero-converting during the rainy season were analysed using the Classification and Regression Tree (CART) method.</p> <p>Results</p> <p>A total of 804 individuals participating in both surveys were analysed. The overall parasite prevalence was low (4.6% and 2.0% for <it>P. falciparum </it>and 7.9% and 6.0% for <it>P. vivax </it>in August and November respectively). <it>P. falciparum </it>force of infection was higher in the eastern region and increased between August and November, whilst <it>P. vivax </it>force of infection was higher in the western region and remained similar in both surveys. In the western region, malaria transmission changed very little across the season (for both species). CART analysis for <it>P. falciparum </it>in the east highlighted age, ethnicity, village of residence and forest work as important predictors for malaria exposure during the rainy season. Adults were more likely to increase their antibody responses to <it>P. falciparum </it>during the transmission season than children, whilst members of the Charay ethnic group demonstrated the largest increases.</p> <p>Discussion</p> <p>In areas of low transmission intensity, such as in Cambodia, the analysis of longitudinal serological data enables a sensitive evaluation of transmission dynamics. Consecutive serological surveys allow an insight into spatio-temporal patterns of malaria transmission. The use of CART enabled multiple interactions to be accounted for simultaneously and permitted risk factors for exposure to be clearly identified.</p

BALB/c Mice Infected with Antimony Treatment Refractory Isolate of Leishmania braziliensis Present Severe Lesions due to IL-4 Production

Leishmaniasis is a neglected disease that affects more than 12 million people worldwide. In Brazil, the cutaneous disease is more prevalent with about 28,000 new cases reported each year, and L. braziliensis is the main causative agent. The interesting data about the infection with this parasite is the wide variety of clinical manifestations that ranges from single ulcerated lesions to mucocutaneous and disseminated disease. However, experimental models to study the infection with this parasite are difficult to develop due to high resistance of most mouse strains to the infection, and the mechanisms underlying the distinct manifestations remain poorly understood. Here, the authors use a mouse experimental model of infection with different L. braziliensis isolates, known to induce diseases with distinct severity in the human hosts, to elucidate immune mechanisms that may be involved in the different manifestations. They showed that distinct parasite isolates may modulate host response, and increased IL-4 production and Arg I expression was related to more severe disease, resulting in longer length of disease with larger lesions and reduced parasite clearance. These findings may be useful in the identification of immunological targets to control L. braziliensis infection and potential clinical markers of disease progression

The bodily social self: a link between phenomenal and narrative selfhood

The Phenomenal Self (PS) is widely considered to be dependent on body representations, whereas the Narrative Self (NS) is generally thought to rely on abstract cognitive representations. The concept of the Bodily Social Self (BSS) might play an important role in explaining how the high level cognitive self-representations enabling the NS might emerge from the bodily basis of the PS. First, the phenomenal self (PS) and narrative self (NS), are briefly examined. Next, the BSS is defined and its potential for explaining aspects of social cognition is explored. The minimal requirements for a BSS are considered, before reviewing empirical evidence regarding the development of the BSS over the first year of life. Finally, evidence on the involvement of the body in social distinctions between self and other is reviewed to illustrate how the BSS is affected by both the bottom up effects of multisensory stimulation and the top down effects of social identification