The influence of the menstrual cup on female pelvic floor muscles variables: a prospective case series.

The aim was to assess and report the effects of menstrual cup on pelvic floor muscles (PFM) function and tone, as well as check the acceptability after a period of three menstrual cycles in healthy young women. The data collected in assessments and reassessments included the International Consultation on Incontinence Questionnaire - Vaginal Symptoms (ICIQ-VS) questionnaire, evaluation of PFM function through PERFECT Scheme, PFM muscle tone, and PFM manometry (Peritron 9300®). A diary regarding the overall colletor acceptability and satisfaction was collected. Ten healthy young women completed the study. There was an improvement in the mean values of maximal voluntary contraction (MVC) (p = 0.032), a decrease in the vaginal resting pressure (VRP) (p = 0.05), and an increase in the number of repetitions of sustained muscle contractions (p = 0.042). Seven women reported some discomfort while using the vaginal cup only in the first cycle while three revealed discomfort during the whole experiment. This study provides preliminary case-based evidence that the use of the vaginal cup for a period of three menstrual cycles changes the VRP, MVC, and PFM tone, as well as improves the repetitions of PFM assessed by digital palpation. Moreover, the women reported the use of vaginal cup as a positive experience.

Qualitative study of return to work following breast cancer treatment.

BACKGROUND: After 5 years' sick leave in Brazil, employees must retire due to disability. The duration from breast cancer surgery to the end of treatment should be ~9 months. However, diagnosis alone can take 6 months. Surveys administered soon after returning to work have highlighted problems regarding the slow speed of the treatment process and lack of protective legislation. AIMS: To assess the barriers and facilitators experienced and the coping strategies adopted by Brazilian women 30 days after return to work following breast cancer treatment. METHODS: A qualitative study of 12 women treated for breast cancer. The interviews were recorded, transcribed verbatim and independently analysed by two researchers using a standardized method of analysis. RESULTS: Women took an average of 583 days to return to work following breast cancer treatment. The return-to-work experience was considered good, with the physical barriers being fatigue and problems with the arms, and the work environmental barriers being related to discrimination from employers and overprotection from colleagues. Facilitators included social and emotional support given by colleagues/relatives/employers and jobs requiring more cognitive effort than physical exertion. Coping strategies were related to job role adjustments and reduction in tasks and working hours. CONCLUSIONS: Results were similar to those reported by previous studies, with the exception of the facilitators. Cognitive effort is commonly considered a barrier. However, the present study had an unusually long duration before return to work, possibly reducing the acute effects of chemotherapy on cognition.

Education and training of clinical research professionals and the evolution of the Joint Task Force for Clinical Trial Competency.

Clinical research professionals play a critical role in the design, conduct, and oversight of clinical trials, and they must have the knowledge, skills, and abilities to ensure that trials are conducted ethically, safely, and in accordance with regulatory requirements. As clinical research has evolved from being a necessary activity for the development and regulatory approval of new medicines to an accredited academic discipline and, more recently, to a globally recognized profession, the methods of education and training of professionals have also evolved. Initially, on-the-job informal coaching and specialized training organizations led to formalized and accredited academic degree programs and, more recently, to international competency standards and competency maintenance through continuous professional development. The Joint Task Force (JTF) for Clinical Trial Competency is a multidisciplinary, international group of experts who came together to aggregate and refine competency standards for clinical research professionals, first published in 2014. The 8 domains and 49 specific core competencies of the JTF Framework have become a globally recognized standard upon which education and training programs, role descriptions, and upward mobility criteria for professionals are now based. The JTF meets regularly and, through its workgroups, continues to evolve in response to the changing needs of the profession. The JTF is committed to continuous improvement to ensure that clinical research professionals have the competence necessary to conduct safe, ethical, and high-quality clinical research.

Anti-inflammatory action of geopropolis produced by stingless bees on human peripheral blood mononuclear cells.

Natural products have been used to treat inflammatory reactions and led to the discovery of new anti-inflammatory drugs. Geopropolis (GEO) is produced by stingless bees and has been used by indigenous people to improve the immune functions. Here, a possible synergism between GEO and dexamethasone (DEX) was assessed on human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS). PBMC viability was evaluated by the MTT, apoptosis/necrosis by flow cytometry, cytokine and eicosanoids production by ELISA, and intracellular pathways by polymerase chain reaction. GEO and DEX alone or in combination did not affect cell viability. GEO in combination with lower concentrations of DEX inhibited cytokine production (TNF-α, IL-1ß, and IL-10). No effects were seen on eicosanoids nor in intracellular pathways. Despite not always being more efficient than the isolated treatments, GEO + DEX seemed to be promising and allow the use of DEX in lower concentrations, reducing adverse effects.

Blended e-learning and certification for medicines development professionals: results of a 7-year collaboration between King's College, London and the GMDP Academy, New York.

Introduction: The field of Medicines Development faces a continuous need for educational evolution to match the interdisciplinary and global nature of the pharmaceutical industry. This paper discusses the outcomes of a 7-year collaboration between King's College London and the Global Medicines Development Professionals (GMDP) Academy, which aimed to address this need through a blended e-learning program. Methods: The collaboration developed a comprehensive curriculum based on the PharmaTrain syllabus, delivered through a combination of asynchronous and synchronous e-learning methods. The program targeted a diverse range of professionals serving in areas related to Medical Affairs. Results: Over seven annual cohorts, 682 participants from eighty-six countries were enrolled in the program. The program's effectiveness was assessed using Kirkpatrick's model, showing elevated levels of satisfaction (over 4.0 on a five-point scale), suggesting significant gains in competence at the cognitive level and leveraged performance. Notably, 70% of responding alumni reported significant improvement in their functions, corroborated by 30% of their supervisors. The further long-term impact of the program on their respective organization has not been established. Discussion: The GMDP Academy's program has significantly contributed to life-long learning in Medicines Development, addressing educational gaps and fostering interdisciplinary collaboration. Its success highlights the importance of continuous education in keeping pace with the industry's evolving demands and underscores the potential of blended learning in achieving educational objectives in pharmaceutical medicine.

Solid Lipid Nanoparticles Based on Babassu Oil and Copaiba Oleoresin: A Promising Approach for Prostate Cancer Therapy.

Solid lipid nanoparticles (SLNs) represent promising nanostructures for drug delivery systems. This study successfully synthesized SLNs containing different proportions of babassu oil (BBS) and copaiba oleoresin (COPA) via the emulsification-ultrasonication method. Before SLN synthesis, the identification and quantification of methyl esters, such as lauric acid and ß-caryophyllene, were performed via GC-MS analysis. These methyl esters were used as chemical markers and assisted in encapsulation efficiency experiments. A 22 factorial design with a center point was employed to assess the impact of stearic acid and Tween 80 on particle hydrodynamic diameter (HD) and polydispersity index (PDI). Additionally, the effects of temperature (8 ± 0.5 °C and 25 ± 1.0 °C) and time (0, 7, 15, 30, 40, and 60 days) on HD and PDI values were investigated. Zeta potential (ZP) measurements were utilized to evaluate nanoparticle stability, while transmission electron microscopy provided insights into the morphology and nanometric dimensions of the SLNs. The in vitro cytotoxic activity of the SLNs (10 µg/mL, 30 µg/mL, 40 µg/mL, and 80 µg/mL) was evaluated using the MTT assay with PC-3 and DU-145 prostate cancer cell lines. Results demonstrated that SLNs containing BBS and COPA in a 1:1 ratio exhibited a promising cytotoxic effect against prostate cancer cells, with a percentage of viable cells of 68.5% for PC-3 at a concentration of 30 µg/mL and 48% for DU-145 at a concentration of 80 µg/mL. These findings underscore the potential therapeutic applications of SLNs loaded with BBS and COPA for prostate cancer treatment.

Use of In silico Methodologies to Predict the Bioavailability of Oral Suspensions: A Regulatory Approach.

BACKGROUND: Oral suspensions are heterogeneous disperse systems, and the particle size distribution, crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters that control the drug dissolution rate and its bioavailability. OBJECTIVE: The aim of this work was to develop a discriminative dissolution test, which, in association with in silico methodologies, can make it possible to safely anticipate bioavailability problems. METHODS: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards, particle size distribution (0.1 to 360 µm), dissolution profile, and in vitro permeability in Caco-2 cell of commercial suspensions, were determined. These parameters were used as input for the establishment of the in vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo- Riegelmann deconvolution approach. RESULTS: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960, 0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%. CONCLUSION: In this work, we have performed a complete study combining in vitro/in silico approaches with the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory tool for this category of products in a faster and more economical way.

Common carotid artery intima-media thickness: the Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study results.

BACKGROUND: Measurement of far wall common carotid artery intima-media thickness (CCAIMT) has emerged as a predictor of incident cardiovascular events. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study was the first large-scale population-based assessment of both CCAIMT and cardiovascular risk factor prevalence in 7 Latin American cities; the relationship between CCAIMT and cardiovascular risk markers was assessed in these urban Latin American centers. METHODS: CARMELA was a cross-sectional, population-based, observational study using stratified, multistage sampling. The participants completed a questionnaire, were evaluated in a clinical visit and underwent carotid ultrasonography. Clinical measurements were obtained by health personnel trained, certified and supervised by CARMELA investigators. Mannheim intima-media thickness consensus guidelines were followed for measurement of CCAIMT. RESULTS: In all cities and for both sexes, CCAIMT increased with higher age. CCAIMT was greater in the presence of cardiovascular risk factors than in their absence. In all cities, there was a statistically significant linear trend between increasing CCAIMT and a growing number of cardiovascular risk factors (p < 0.001). After adjustment for age and sex, metabolic syndrome was strongly associated with increased CCAIMT (p < 0.001 in all cities), as were hypercholesterolemia, obesity and diabetes (p < 0.001 in most cities). By multivariate analysis, hypertension was independently associated with an increase in CCAIMT in all cities (p < 0.01). CONCLUSIONS: CARMELA was the first large-scale population study to provide normal CCAIMT values according to age and sex in urban Latin American populations and to show CCAIMT increases in the presence of cardiovascular risk factors and metabolic syndrome.

Propolis antiviral and immunomodulatory activity: a review and perspectives for COVID-19 treatment.

OBJECTIVES: Viral outbreaks are a frequent concern for humans. A great variety of drugs has been used to treat viral diseases, which are not always safe and effective and may induce adverse effects, indicating the need for new antiviral drugs extracted from natural sources. Propolis is a bee-made product exhibiting many biological properties. An overview of viruses, antiviral immunity, propolis safety and its immunomodulatory and antiviral action is reported, as well as perspectives for coronavirus disease 2019 (COVID-19) treatment. PubMed platform was used for data collection, searching for the keywords "propolis", "virus", "antiviral", "antimicrobial" and "coronavirus". KEY FINDINGS: Propolis is safe and exerts antiviral and immunomodulatory activity; however, clinical trials should investigate its effects on individuals with viral diseases, in combination or not with antiviral drugs or vaccines. SUMMARY: Regarding COVID-19, the effects of propolis should be investigated directly on the virus in vitro or on infected individuals alone or in combination with antiviral drugs, due to its immunomodulatory and anti-inflammatory action. Propolis administration simultaneously with vaccines should be analyzed, due to its adjuvant properties, to enhance the individuals' immune response. The search for therapeutic targets may be useful to find out how propolis can help to control COVID-19.

Dyslipidemia in seven Latin American cities: CARMELA study.

OBJECTIVE: The objective of this study was to describe the prevalence of dyslipidemia in the CARMELA study population. METHODS: CARMELA was a cross-sectional study of cardiovascular risk conducted between September 2003 and August 2005 in adults (aged 25 to 64 years) living in Barquisimeto (n=1,824), Bogotá (n=1,511), Buenos Aires (n=1,412), Lima (n=1,628), Mexico City (n=1,677), Quito (n=1,620), and Santiago (n=1,605). Dyslipidemia was defined as the presence of one or more of the following conditions: triglycerides>/=200 mg/dL, or total cholesterol (TC)>/=240 mg/dL, or HDL cholesterol<40 mg/dL, or LDL cholesterol=not optimal, or currently taking antilipemic agents. RESULTS: Prevalence rates of dyslipidemia in men and women were: 75.5% (CI: 71.9-79.1) and 48.7% (CI: 45.4-51.9) in Barquisimeto; 70% (CI: 66.2-73.8) and 47.7% (CI: 43.9-51.5) in Bogotá; 50.4% (CI: 46.8-54.0) and 24.1% (CI: 21.0-27.2) in Buenos Aires; 73.1% (CI: 69.3-76.8) and 62.8% (CI: 59.2-66.5) in Lima; 62.5% (CI: 58.5-66.5) and 37.5% (CI: 33.5-41.6) in Mexico City; 52.2% (CI: 47.9-56.5) and 38.1% (CI: 34.5-41.7) in Quito; and, 50.8% (CI: 47.1-54.4) and 32.8% (CI: 29.3-36.3) in Santiago. CONCLUSIONS: Dyslipidemia was disturbingly prevalent and varied across cities. The most frequent dyslipidemia was low HDL-C followed by high triglycerides. The high TC/HDL-C ratios and non-HDL-C levels suggest a high risk of cardiovascular disease.

Cardiovascular risk awareness, treatment, and control in urban Latin America.

Effective prevention and treatment of cardiovascular diseases require regular screening for risk factors, high awareness of the condition, effective treatment of the identified risk factors, and adherence to the prescribed treatment. The Cardiovascular Risk Factor Multiple Evaluation in Latin America study was a cross-sectional, population-based, observational study of major cardiovascular risk factors-including hypertension, diabetes, and hypercholesterolemia-in 7 Latin American cities. This report presents data on assessment, diagnosis, extent, and effectiveness of treatment, adherence to treatment, and reasons for nonadherence. Data were collected through household questionnaire-based interviews administered to 5383 men and 6167 women, 25-64 years of age, living in the following cities: Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. Participants also completed a clinic visit for anthromorphometric and laboratory assessments. Rates of prior diagnosis of hypertension and diabetes were high (64% and 78% of affected individuals, respectively) but relatively low for hypercholesterolemia (41%). The majority of affected individuals (hypercholesterolemia 88%, diabetes 67%, and hypertension 53%) were untreated. Among individuals who were receiving pharmacologic treatment, targets for control of hypertension, diabetes, and hypercholesterolemia were achieved by 51%, 16%, and 52%, respectively. Adherence to treatment was observed in 69% of individuals with hypertension, 63% with diabetes, and 66% with hypercholesterolemia. Forgetfulness was the major cause of nonadherence for all 3 conditions. There is a substantial need for increasing patient education, diagnosis, treatment, adherence, and control of cardiovascular risk factors in the 7 Latin American cities.

Development and Use of Gene Therapy Orphan Drugs-Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society.

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15-20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

Evolution of the Development of Core Competencies in Pharmaceutical Medicine and Their Potential Use in Education and Training.

The evolution of postgraduate vocational education and training in pharmaceutical medicine is described alongside the growth of this scientific-medical discipline and profession for the development of new medicines. Over the past 50 years, whilst the training of competent professionals for their work has been paramount, this has paralleled the need to engage with the rapid and complex changes in R&D technologies, patient and healthcare system needs, and the ethical and regulatory obligations applied to the development of medicines throughout their lifecycle. The move from unstructured training to formal programs with syllabus, curricula and assessments for certification, has been accompanied by educational changes to outcomes-based, learner-centered, competency-based programs. The evolution of education and training along with the development of the set of 57 core competencies for professional practitioners in pharmaceutical medicine are described within the competence framework of seven domains: discovery of medicines and early development; clinical development and clinical trials; medicines regulation; drug safety and surveillance; ethics and subject protection; healthcare marketplace; communication and management. The application of the core competencies in a harmonized, international platform of education and training in medicines development at the undergraduate, postgraduate and continuing professional development levels would invigorate the potential for having a competent workforce with the intent to provide faster access to better and appropriate medicines for patients worldwide.

Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

Expansion of data-driven research in the 21st century has posed challenges in the evolution of the international agreed framework of research ethics. The World Medical Association (WMA)'s Declaration of Helsinki (DoH) has provided ethical principles for medical research involving humans since 1964, with the last update in 2013. To complement the DoH, WMA issued the Declaration of Taipei (DoT) in 2016 to provide additional principles for health databases and biobanks. However, the ethical principles for secondary use of data or material obtained in research remain unclear. With such a perspective, the Working Group on Ethics (WGE) of the International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine (IFAPP) suggests a closer scientific linkage in the DoH to the (Declaration of Taipei) DoT focusing specifically on areas that will facilitate data-driven research, and to further strengthen the protection of research participants.

Corrigendum: Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

[This corrects the article DOI: 10.3389/fphar.2020.579714.].

Prevalence of the metabolic syndrome in Latin America and its association with sub-clinical carotid atherosclerosis: the CARMELA cross sectional study.

BACKGROUND: Metabolic syndrome increases cardiovascular risk. Limited information on its prevalence in Latin America is available. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study included assessment of metabolic syndrome in 7 urban Latin American populations. METHODS: CARMELA was a cross-sectional, population-based, observational study conducted in Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. The prevalence of metabolic syndrome, defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and associated carotid atherosclerosis were investigated in 11,502 participants aged 25 to 64 years. RESULTS: Across CARMELA cities, metabolic syndrome was most prevalent in Mexico City (27%) and Barquisimeto (26%), followed by Santiago (21%), Bogota (20%), Lima (18%), Buenos Aires (17%), and Quito (14%). In nondiabetic participants, prevalence was slightly lower but followed a comparable ranking. Overall, 59%, 59%, and 73% of women with high triglycerides, hypertension, or glucose abnormalities, respectively, and 64%, 48% and 71% of men with abdominal obesity, hypertension, or glucose abnormalities, respectively, had the full metabolic syndrome. Prevalence of metabolic syndrome increased with age, markedly so in women. Mean common carotid artery intima-media thickness (CCAIMT) and prevalence of carotid plaque increased steeply with increasing numbers of metabolic syndrome components; mean CCAIMT was higher and plaque more prevalent in participants with metabolic syndrome than without. CONCLUSION: The prevalence of metabolic syndrome and its components by NCEP ATP III criteria was substantial across cities, ranging from 14% to 27%. CARMELA findings, including evidence of the association of metabolic syndrome and carotid atherosclerosis, should inform appropriate clinical and public health interventions.

International Perception of Competence, Education, and Training Needs Among Biomedical Professionals Involved in Medicines Development.

The development of new medicines today, requires a multi-professional workforce, both in industry and the clinical research arena. Pharmaceutical physicians (PPs) and medicines development scientists (MDS) need a certain level of competence, achieved through on-the-job experience, with a postgraduate education foundation and continuous professional development programs. In order to assess the self-perception of competence, education and training needs, an on-line questionnaire based on the seven domains of competence, developed by IFAPP-PharmaTrain, was prepared and distributed among PPs and MDS members of IFAPP's affiliated professional associations in countries with facilities for postgraduate education. The data collection was run over a fixed period of three months in Japan, Italy, Brazil, and Spain during 2017. Results indicate low but variable levels of perceived competence for the various domains as well as seniority in the job. All respondents declared a significant need for continuing professional development in all domains. These results corroborate and support the continuous efforts, put in place by IFAPP and the PharmaTrain Federation, to foster the development of accredited education and training among professionals involved in medicines development.

The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams.

The complexity of developing and applying increasingly sophisticated new medicinal products has led to the participation of many non-medically qualified scientists in multi-disciplinary non-clinical and clinical drug development teams world-wide. In this introductory paper to the "IFAPP International Ethics Framework for Pharmaceutical Physicians and Medicines Development Scientists" it is argued that all members of such multidisciplinary teams must share the scientific and ethical responsibilities since they all influence directly or indirectly both the outcome of the various phases of the medicines development projects and the safety of the research subjects involved. The participating medical practitioner retains the overriding responsibility and the final decision to stop a trial if the well-being of the research subjects is seriously endangered. All the team members should follow the main ethical principles governing human research, the respect for autonomy, justice, beneficence and non-maleficence. Nevertheless, the weighing of these principles might be different under various conditions according to the specialty of the members.

Female sexual function and urinary incontinence in nulliparous athletes: An exploratory study.

OBJECTIVES: To estimate the prevalence of Female Sexual Dysfunction (FSD) and Urinary Incontinence (UI) symptom in nulliparous athletes and analyze the risk factors for these dysfunctions. DESIGN: A cross-sectional study. SETTING: The International Consultation on Incontinence Questionnaire-Short Form (ICIQ-UI-SF) and the Female Sexual Function Index (FSFI) were applied to assess the UI and the FSD. PARTICIPANTS: 50 athletes with ≥18 years old. RESULTS: We found a prevalence of 48% of UI and 44% of FSD among nulliparous athletes. The rate of athletes having concomitant FSD and UI was 24%. We found a significant difference between high and low impact sports in the ICIQ-UI-SF score (p = 0.028). Hours of training (p = 0.007; R2 = 0.21) was found to be a risk factor for UI. Incontinent athletes demonstrated a Relative Risk of 2.7 to develop sexual desire problem when compared to the continents (p = 0.04; 95% CIs: 1.50-4.89). CONCLUSIONS: This study found a high prevalence of both UI and FSD among nulliparous athletes. Furthermore, nulliparous athletes practicing high-impact modalities are the most susceptible to UI. The hours of training per day was considered a risk factor to develop UI, and incontinent athletes have more chances of showing difficulties in sexual desire.