Frontiers in hormone therapy for male infertility.

For a significant number of couples worldwide, infertility is a harsh reality. As specialists in male infertility, much of our armamentarium lacks definitive, evidence-based therapies. For years, we have relied on manipulation of the male hormonal axis to treat those men who help carry the burden of infertility in their partnerships. Indeed, male factor infertility is the sole component of infertility in at least 20% of couples. Further compounding this dilemma is that 25% to 50% of males with infertility have no identifiable etiology and thus present a true management conundrum. This manuscript is an attempt to clarify what therapies exist for the treatment of male factor infertility. We have reviewed the relevant infertility literature honing, our focus on hormonal anomalies and their subsequent impact on fertility. Many of the therapies discussed have been utilized in practice for generations. Thus, this article attempts to provide the evidence-based literature to support the continued use of the current treatment paradigm. Furthermore, we recognize that any review beckons a discussion of what challenges and therapies await on the horizon. For instance, there has been significant interest in restoring spermatogenesis after testosterone replacement therapy (TRT). We explore the adverse long-term spermatogenic outcomes associated with TRT, which with the widespread use of TRT, will inevitably present a great challenge for male infertility specialists. Moreover, we discuss the role of varicocelectomy in the treatment of hypogonadism and infertility, review the association between growth hormone (GH) and male fertility and address the challenges presented by the rising prevalence of obesity.

Enhanced transdermal delivery with less irritation by magainin pore-forming peptide with a N-lauroylsarcosine and sorbitan monolaurate mixture.

Transdermal drug delivery is advantageous over other conventional drug administration routes. However, it can be inefficient because of the natural barrier of the stratum corneum which is the uppermost layer of the skin. A previous study verified that the treatment of magainin pore-forming peptide with N-lauroylsarcosine (NLS) on human skin can increase skin permeability by 47-fold. However, NLS is well known as a potential skin irritant. The irritation potential of NLS is known to decrease when mixed with sorbitan monolaurate (S20). Encouraged by these results, we combined S20 with magainin-NLS to enhance transdermal drug transport with less skin irritation. In this study, nine groups with magainin and NLS:S20 mixtures at different concentrations and weight fractions were screened to maximize their synergistic effect. To quantify the efficacy to toxicity ratio of each formulation, we defined the ratio as the "enhancement ratio/irritation potential (ER/IP)." The ER was observed by Franz cell diffusion of the target drug fluorescein, and the IP was measured by the cytotoxicity of the NIH/3T3 mouse fibroblast cell line. As a result, the magainin with the NLS:S20 mixture increased the permeability of porcine skin as well as decreased the toxicity. Among the various combinations, a formulation of 2% (w/v) NLS:S20 with a weight fraction of 0.6:0.4 had the largest ER/IP. ATR-FTIR spectroscopy of the formulations and skin was done to analyze the interactions in the formulations themselves and between the formulations and the skin. Both the intercellular lipidic route and transcellular route through the stratum corneum protein were involved in the delivery of fluorescein. This study turned pore-forming peptides into an efficient and safe penetration enhancer by combining them with other chemical penetration enhancers. Moreover, this discovery could be a possible method for enabling the transdermal delivery of macromolecules.

A 3D Human-Machine Integrated Design and Analysis Framework for Squat Exercises with a Smith Machine.

In this paper, we propose a three-dimensional design and evaluation framework and process based on a probabilistic-based motion synthesis algorithm and biomechanical analysis system for the design of the Smith machine and squat training programs. Moreover, we implemented a prototype system to validate the proposed framework. The framework consists of an integrated human-machine-environment model as well as a squat motion synthesis system and biomechanical analysis system. In the design and evaluation process, we created an integrated model in which interactions between a human body and machine or the ground are modeled as joints with constraints at contact points. Next, we generated Smith squat motion using the motion synthesis program based on a Gaussian process regression algorithm with a set of given values for independent variables. Then, using the biomechanical analysis system, we simulated joint moments and muscle activities from the input of the integrated model and squat motion. We validated the model and algorithm through physical experiments measuring the electromyography (EMG) signals, ground forces, and squat motions as well as through a biomechanical simulation of muscle forces. The proposed approach enables the incorporation of biomechanics in the design process and reduces the need for physical experiments and prototypes in the development of training programs and new Smith machines.

Bullying and lower urinary tract symptoms: why the pediatric urologist should care about school bullying.

PURPOSE: Bullying has become a social plague associated with various deleterious outcomes. We hypothesized that pediatric lower urinary tract symptoms could be associated with exposure to bullying. MATERIALS AND METHODS: We assessed exposure to school bullying via the Setting the Record Straight bullying questionnaire in children 8 to 11 years old being evaluated for lower urinary tract symptoms at our pediatric urology clinic. Lower urinary tract symptoms were quantified with the Vancouver Symptom Score. Children 8 to 11 years old presenting for pediatric well visits also completed the questionnaires. Linear regression assessed the relationship between Vancouver Symptom Score and bullying score. Categorical variables were compared by chi-square test, while continuous variables were compared using the Student t-test. RESULTS: A total of 113 children at the urology clinic and 63 children in the primary care setting consented to participate. There were significant differences between the 2 populations, including gender and race, with significantly more perpetrators of bullying in the primary care group (7.9% vs 0.9%, p = 0.02). When looking specifically at the urology group, there was a significant association between Vancouver Symptom Score and self-perceived (p <0.001) and peer perceived (p <0.001) victimization scores. In the primary care group there was also a significant association between Vancouver Symptom Score and self-perceived (p = 0.01) and peer perceived (p = 0.001) bullying perpetrator scores. Of children seen at the primary care office 33% had a significant Vancouver Symptom Score. CONCLUSIONS: Although bullying exposure is multifactorial, we found that Vancouver Symptom Score can be associated with bullying victimization and perpetrator scores.

Development and validation of a prediction model for diagnosing blood stream infections in febrile, non-neutropenic children with cancer.

BACKGROUND: Pediatric oncology patients are at increased risk for blood stream infections (BSI). Risk in the absence of severe neutropenia (absolute neutrophil count [ANC] ≥500/µl) is not well defined. PROCEDURE: In a retrospective cohort of febrile (temperature ≥38.0° for >1 hr or ≥38.3°) pediatric oncology patients with ANC ≥500/µl, a diagnostic prediction model for BSI was constructed using logistic regression modeling and the following candidate predictors: age, ANC, absolute monocyte count, body temperature, inpatient/outpatient presentation, sex, central venous catheter type, hypotension, chills, cancer diagnosis, stem cell transplant, upper respiratory symptoms, and exposure to cytarabine, anti-thymocyte globulin, or anti-GD2 antibody. The model was internally validated with bootstrapping methods. RESULTS: Among 932 febrile episodes in 463 patients, we identified 91 cases of BSI. Independently significant predictors for BSI were higher body temperature (Odds ratio [OR] 2.36 P < 0.001), tunneled external catheter (OR 13.79 P < 0.001), peripherally inserted central catheter (OR 3.95 P = 0.005), elevated ANC (OR 1.19 P = 0.024), chills (OR 2.09 P = 0.031), and hypotension (OR 3.08 P = 0.004). Acute lymphoblastic leukemia diagnosis (OR 0.34 P = 0.026), increased age (OR 0.70 P = 0.049), and drug exposure (OR 0.08 P < 0.001) were associated with decreased risk for BSI. The risk prediction model had a C-index of 0.898; after bootstrapping adjustment for optimism, corrected C-index 0.885. CONCLUSIONS: We developed a diagnostic prediction model for BSI in febrile pediatric oncology patients without severe neutropenia. External validation is warranted before use in clinical practice. Pediatr Blood Cancer 2015;62:262-268. © 2014 Wiley Periodicals, Inc.

Impact of complications and hospital-free days on health related quality of life 1 year after radical cystectomy.

PURPOSE: We determined the extent to which complications as well as number of hospital-free days within 30 and 90 days of surgery predicted health related quality of life 1 year after radical cystectomy. MATERIALS AND METHODS: We used data from a prospective health related quality of life study using a validated instrument, the Vanderbilt Cystectomy Index-15. Complications were graded by the Clavien system, and hospital length of stay and length of stay during readmissions were used to calculate 30 and 90-day hospital-free days, respectively. We compared the number of hospital-free days among patients with varying levels of complications. Multivariate analysis was performed to determine predictors of Vanderbilt Cystectomy Index-15 score 1 year after surgery adjusting for demographic (age, gender, comorbidities) and clinical variables (stage and diversion type). RESULTS: A total of 100 patients with complete baseline and 1-year followup health related quality of life data were included in the analysis. Median (IQR) 30 and 90-day hospital-free days were 24 (22-25) and 84 (82-85), respectively. Patients who experienced any complications had significantly fewer 30-day hospital-free days (22 vs 24 days, p <0.01) and 90-day hospital-free days (81 vs 84 days, p <0.01), and patients with higher grade complications had fewer hospital-free days than those with lower grade or no complications (p <0.01). On multivariate analysis female gender and baseline Vanderbilt Cystectomy Index-15 score independently predicted higher 1-year health related quality of life scores. CONCLUSIONS: Patients who experience complications after radical cystectomy have fewer 30 and 90-day hospital-free days. However, neither predicts health related quality of life at 1 year. Instead, long-term health related quality of life appears to be driven largely by baseline health related quality of life and gender.

Prevalence of 25-hydroxyvitamin D deficiency in child and adolescent patients undergoing hematopoietic cell transplantation compared to a healthy population.

BACKGROUND: Pediatric patients undergoing allogeneic hematopoietic cell transplant (HCT) are at risk for low bone mineral density, which may due, in part, to low 25-hydroxyvitamin D levels. PROCEDURE: We compared the serum 25-hydroxyvitamin D status of 22 pediatric HCT patients with 100 healthy pediatric controls. We determined the prevalence of and risk factors for 25-hydroxyvitamin D insufficiency and deficiency. RESULTS: Serum 25-hydroxyvitamin D levels were lower in the pediatric HCT patients at time of transplant than healthy pediatric controls (median 19.5 ng/ml vs. 31.0 ng/ml, P < 0.001). Of HCT patients, 27% were 25-hydroxyvitamin D deficient (<15 ng/dl) and 68% insufficient (15-29 ng/dl), compared with 4% and 40%, respectively, of healthy pediatric controls (P < 0.001). In multivariable analysis, treatment with HCT, decreased ambient ultraviolet light exposure, non-Caucasian race, and older age were associated with decreased serum 25-hydroxyvitamin D levels. No association was found between 25-hydroxyvitamin D levels and gender, body mass index, dietary vitamin D intake, or patient-reported vitamin D supplementation. Few patients in either group reported sunscreen use, vitamin D supplementation, or recommended dietary vitamin D intake. CONCLUSIONS: At time of transplant, pediatric HCT patients frequently have 25-hydroxyvitamin D insufficiency/deficiency, and this occurs more commonly than in the healthy pediatric population. HCT patients rarely follow recommended guidelines to take supplemental vitamin D, consume the Recommended Daily Allowance for vitamin D, or regularly use sunscreen. Further studies are needed to determine whether vitamin D insufficiency/deficiency persists long term in HCT patients and requires dietary and behavioral interventions.