The association of fear of falling and physical and mental Health-Related Quality of Life (HRQoL) among community-dwelling older persons; a cross-sectional study of Urban Health Centres Europe (UHCE).

BACKGROUND: The share of people over 80 years in the European Union is estimated to increase two-and-a-half-fold from 2000 to 2100. A substantial share of older persons experiences fear of falling. This fear is partly associated with a fall in the recent past. Because of the associations between fear of falling, avoiding physical activity, and the potential impact of those on health, an association between fear of falling and low health-related quality of life, is suggested. This study examined the association of fear of falling with physical and mental Health-Related Quality of Life (HRQoL) among community-dwelling older persons in five European countries. METHODS: A cross-sectional study was conducted using baseline data of community-dwelling persons of 70 years and older participating in the Urban Health Centers Europe project in five European countries: United Kingdom, Greece, Croatia, the Netherlands and Spain. This study assessed fear of falling with the Short Falls Efficacy Scale-International and HRQoL with the 12-Item Short-Form Health Survey. The association between low, moderate or high fear of falling and HRQoL was examined using adjusted multivariable linear regression models. RESULTS: Data of 2189 persons were analyzed (mean age 79.6 years; 60.6% females). Among the participants, 1096 (50.1%) experienced low fear of falling; 648 (29.6%) moderate fear of falling and 445 (20.3%) high fear of falling. Compared to those who reported low fear of falling in multivariate analysis, participants who reported moderate or high fear of falling experienced lower physical HRQoL (ß = -6.10, P < 0.001 and ß = -13.15, P < 0.001, respectively). In addition, participants who reported moderate or high fear of falling also experienced lower mental HRQoL than those who reported low fear of falling (ß = -2.31, P < 0.001 and ß = -8.80, P < 0.001, respectively). CONCLUSIONS: This study observed a negative association between fear of falling and physical and mental HRQoL in a population of older European persons. These findings emphasize the relevance for health professionals to assess and address fear of falling. In addition, attention should be given to programs that promote physical activity, reduce fear of falling, and maintain or increase physical strength among older adults; this may contribute to physical and mental HRQoL.

Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population.

STUDY QUESTION: Is anogenital distance (AGD) associated with semen quality and reproductive hormones in men from the general population? SUMMARY ANSWER: Short AGD measured from the anus to the base of scrotum (AGDAS) was associated with reduced sperm counts and morphology but not with sperm motility or reproductive hormones. WHAT IS KNOWN ALREADY: AGD is longer in males than in females. In rodents, AGD is a well-established and sensitive marker of disruption during the masculinization programming window in utero and it has been suggested to be so in humans as well. Therefore, the average AGD would be expected to be shorter in men with poor semen quality, which some studies have confirmed while others have not. STUDY DESIGN, SIZE, DURATION: This cross-sectional population-based study was of 1106 men included between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men from the general Danish population (median age 19 years), unselected with regard to fertility status and semen quality, delivered a semen sample, had a blood sample drawn, which was analyzed for concentrations of reproductive hormones, and answered a comprehensive questionnaire. They also had a physical examination performed including determination of AGD measured as the distance between anus and scrotum (AGDAS) and penis (AGDAP). Odds ratios (OR) and 95% CI were estimated for a man having abnormal semen parameters according to the World Health Organization's reference values or a low/high concentration of reproductive hormones (defined as the lowest or highest 10%) depending on AGD. AGD was categorized in four strata: ≤10th percentile, 10th-30th percentile, 30th-50th percentile and >50th percentile. MAIN RESULTS AND THE ROLE OF CHANCE: Men with the 10% shortest AGDAS had a more than doubled risk (OR: 2.19, 95% CI: 1.40-3.42) of being in the subfertile range for either sperm concentration (<15 million/mL) or sperm morphology (<4%) compared to men with AGDAS above the median (reference). Men in the 10th-30th percentile also had an increased OR of 1.48 (95% CI: 1.06-2.08) but not men in the 30th-50th percentile (OR: 1.14, 95% CI: 0.81-1.62). AGDAP was only weakly related to semen quality. AGD was not associated with testicular volume or any of the reproductive hormones. LIMITATIONS, REASONS FOR CAUTION: Limitations include the potential non-differential misclassification of reproductive outcomes based on a single semen and blood sample and some between-examiner differences in AGD measurements which introduces noise and may result in an underestimation of observed associations. WIDER IMPLICATIONS OF THE FINDINGS: Our study of men from the general population confirmed associations between AGD and semen quality, supporting the hypothesis that AGD in humans could be a marker of fetal testicular development. This suggests that the low semen quality in Danish men may partly be explained by prenatal factors. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion (L.P.); the Research fund of Rigshospitalet, Copenhagen University Hospital (N.J.); Grants R01ES016863-04 and R01ES016863-02S4; National Institute of Environmental Health Sciences (NIEHS) and National Institute of Environmental Health Sciences grant (P30ES023515) (S.S.); the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Repeating Vertebral Fracture Assessment: 2019 ISCD Official Position.

Vertebral fracture (VF) is the most common type of osteoporotic fracture. VFs are associated with a decline in quality of life and high morbidity and mortality. The presence of a VF is a significant risk factor for developing another fracture; however, most VFs are not clinically recognized and diagnosed. Vertebral fracture assessment by dual-energy X-ray absorptiometry is a low cost, low radiation, convenient, and reliable method to identify VFs. The finding of a previously unrecognized VF may change the assessment of fracture risk, diagnostic classification, and treatment strategies. Vertebral fracture assessment or radiographic lateral spine imaging should be repeated in patients with continued high risk for fracture (e.g., historical height loss >4 cm [>1.5 inches], self-reported but undocumented vertebral fracture, or glucocorticoid therapy equivalent to ≥5 mg of prednisone or equivalent per day for greater than or equal to 3 months).

Bone Densitometry in Transgender and Gender Non-Conforming (TGNC) Individuals: 2019 ISCD Official Position.

The indications for initial and follow-up bone mineral density (BMD) in transgender and gender nonconforming (TGNC) individuals are poorly defined, and the choice of which gender database to use to calculate Z-scores is unclear. Herein, the findings of the Task Force are presented after a detailed review of the literature. As long as a TGNC individual is on standard gender-affirming hormone treatment, BMD should remain stable to increasing, so there is no indication to monitor for bone loss or osteoporosis strictly on the basis of TGNC status. TGNC individuals who experience substantial periods of hypogonadism (>1 yr) might experience bone loss or failure of bone accrual during that time, and should be considered for baseline measurement of BMD. To the extent that this hypogonadism continues over time, follow-up measurements can be appropriate. TGNC individuals who have adequate levels of endogenous or exogenous sex steroids can, of course, suffer from other illnesses that can cause osteoporosis and bone loss, such as hyperparathyroidism and steroid use; they should have measurement of BMD as would be done in the cisgender population. There are no data that TGNC individuals have a fracture risk different from that of cisgender individuals, nor any data to suggest that BMD predicts their fracture risk less well than in the cisgender population. The Z-score in transgender individuals should be calculated using the reference data (mean and standard deviation) of the gender conforming with the individual's gender identity. In gender nonconforming individuals, the reference data for the sex recorded at birth should be used. If the referring provider or the individual requests, a set of "male" and "female" Z-scores can be provided, calculating the Z-score against male and female reference data, respectively.

First and second trimester urinary metabolic profiles and fetal growth restriction: an exploratory nested case-control study within the infant development and environment study.

BACKGROUND: Routine prenatal care fails to identify a large proportion of women at risk of fetal growth restriction (FGR). Metabolomics, the comprehensive analysis of low molecular weight molecules (metabolites) in biological samples, can provide new and earlier biomarkers of prenatal health. Recent research has suggested possible predictive first trimester urine metabolites correlating to fetal growth restriction in the third trimester. Our objective in this current study was to examine urinary metabolic profiles in the first and second trimester of pregnancy in relation to third trimester FGR in a US population from a large, multi-center cohort study of healthy pregnant women. METHODS: We conducted a nested case-control study within The Infant Development and the Environment Study (TIDES), a population-based multi-center pregnancy cohort study. We identified 53 cases of FGR based on the AUDIPOG [Neonatal growth - AUDIPOG [Internet]. [cited 29 Nov 2016]. Available from: http://www.audipog.net/courbes_morpho.php?langue=en ] formula for birthweight percentile considering maternal height, age, and prenatal weight, as well as infant sex, gestational age, and birth rank. Cases were matched to 106 controls based on study site, maternal age (± 2 years), parity, and infant sex. NMR spectroscopy was used to assess concentrations of four urinary metabolites that have been previously associated with FGR (tyrosine, acetate, formate, and trimethylamine) in first and second trimester urine samples. We fit multivariate conditional logistic regression models to estimate the odds of FGR in relation to urinary concentrations of these individual metabolites in the first and second trimesters. Exploratory analyses of custom binned spectroscopy results were run to consider other potentially related metabolites. RESULTS: We found no significant association between the relative concentrations of each of the four metabolites and odds of FGR. Exploratory analyses did not reveal any significant differences in urinary metabolic profiles. Compared with controls, cases delivered earlier (38.6 vs 39.8, p < 0.001), and had lower birthweights (2527 g vs 3471 g, p < 0.001). Maternal BMI was similar between cases and controls. CONCLUSIONS: First and second trimester concentrations of urinary metabolites (acetate, formate, trimethylamine and tyrosine) did not predict FGR. This inconsistency with previous studies highlights the need for more rigorous investigation and data collection in this area before metabolomics can be clinically applied to obstetrics.

Anogenital distance and reproductive parameters in young men.

The purpose of this study was to assess the relationship between anogenital distance (AGD) measures and semen quality and serum reproductive hormone levels in Caucasian young men from southern Spain. Two variants of AGD [from the anus to the posterior base of the scrotum (AGD(AS)) and to the cephalad insertion of the penis (AGD(AP))] were assessed in 215 university students. Semen parameters (semen volume, sperm concentration, total sperm counts, motility and morphology) and serum reproductive hormones (follicle stimulating hormone, luteinising hormone, inhibin B, testosterone, calculated free testosterone, oestradiol and sex hormone-binding globulin) were also determined. Associations between AGD measures and the semen quality and reproductive hormone levels were tested using multiple regression analyses. Overall, median sperm concentration was 44.0 × 10(6) ml(-1) (5th-95th percentiles: 8.9-129 × 10(6 ) ml(-1)), median total sperm count was 121 × 10(6) (18.0-400 × 10(6)), and mean (SD) testosterone level was 21.7 nmol/l (6.9). Mean (SD) AGD(AS) and AGD(AP) measures were 48.3 mm (11.6) and 128 mm (12.0) respectively. In the multivariable analysis, AGD measures were not associated with any semen parameters or any of the reproductive hormone levels, which is in contrast to results of studies of US young men or infertile men. Further research is warranted to confirm these findings.

First trimester phthalate exposure and anogenital distance in newborns.

STUDY QUESTION: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? SUMMARY ANSWER: Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. WHAT IS KNOWN ALREADY: AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. STUDY DESIGN, SIZE, DURATION: The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. MAIN RESULTS AND THE ROLE OF CHANCE: Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (ß, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 (-2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. LIMITATIONS, REASONS FOR CAUTION: Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical. STUDY FUNDING/COMPETING INTERESTS: Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest.

Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men.

STUDY QUESTION: Is consumption of sugar-sweetened beverages (SSB) associated with semen quality? SUMMARY ANSWER: Higher consumption of SSB was associated with lower sperm motility among healthy, young men. WHAT IS KNOWN ALREADY: The existing literature on the potential role of SSBs on male reproductive function is scarce and primarily focused on the relation between caffeinated beverages and semen quality. However, a rodent model suggests that SSBs may hamper male fertility. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study; a cross-sectional study of 189 healthy young men carried out at the University of Rochester during 2009-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18-22 years provided semen and blood samples, underwent a physical examination and completed a previously validated food frequency questionnaire (FFQ). Linear regression was used to analyze the association of SSBs with sperm parameters and reproductive hormone levels while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: SSB intake was inversely related to progressive sperm motility. Men in the highest quartile of SSB intake (≥1.3 serving/day) had 9.8 (95% CI: 1.9,17.8) percentage units lower progressive sperm motility than men in the lowest quartile of intake (<0.2 serving/day) (P, trend = 0.03). This association was stronger among lean men (P, trend = 0.005) but absent among overweight or obese men (P, trend = 0.98). SSB intake was unrelated to other semen quality parameters or reproductive hormones levels. LIMITATIONS, REASONS FOR CAUTION: As in all cross-sectional studies, causal inference is limited. An additional problem is that only single semen sample was obtained from each subject. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the relation between SSB intake and low semen quality beyond the contribution of caffeinated beverages. While our findings are in agreement with recent experimental data in rodents, more studies are required to draw conclusions on the relation of SSB with semen quality or male infertility. STUDY FUNDING/COMPETING INTEREST(S): Supported by the European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 and T32HD060454 from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

Metacognitive awareness of cognitive problems in schizophrenia: exploring the role of symptoms and self-esteem.

BACKGROUND: People with a diagnosis of schizophrenia have limited metacognitive awareness of their symptoms. This is also evident for cognitive difficulties when neuropsychological assessments and self-reports are compared. Unlike for delusions and hallucinations, little attention has been given to factors that may influence the mismatch between objective and subjectively reported cognitive problems. Symptom severity, and also self-esteem and social functioning, can have an impact on cognitive problem perception and help to explain the gap between objective and subjective cognitive assessments in psychosis. METHOD: One-hundred participants with a diagnosis of schizophrenia were recruited and assessed with a comprehensive neuropsychological battery, a measure of awareness of cognitive problems and measures of psychotic symptoms, social and behavioural functioning and self-esteem. Regression was used to investigate the influence of symptoms, social functioning and self-esteem, and patients with different levels of cognitive problem awareness were contrasted. RESULTS: Simple correlation analysis replicated the lack of association between objective cognitive measures and metacognitive awareness of cognitive problems. However, the results of the regression analyses highlight that self-esteem and negative symptoms predict metacognitive awareness. When significant predictors were controlled, individuals with better awareness had more impaired working memory but higher IQ. CONCLUSIONS: Poor self-esteem and high negative symptoms are negatively associated with metacognitive awareness in people with schizophrenia. Interventions that aim to improve cognition should consider that cognitive problem reporting in people with schizophrenia correlates poorly with objective measures and is biased not only by symptoms but also by self-esteem. Future studies should explore the causal pathways using longitudinal designs.

Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men.

STUDY QUESTION: Is increased consumption of dairy foods associated with lower semen quality? SUMMARY ANSWER: We found that intake of full-fat dairy was inversely related to sperm motility and morphology. These associations were driven primarily by intake of cheese and were independent of overall dietary patterns. WHAT IS KNOWN ALREADY: It has been suggested that environmental estrogens could be responsible for the putative secular decline in sperm counts. Dairy foods contain large amounts of estrogens. While some studies have suggested dairy as a possible contributing factor for decreased semen quality, this finding has not been consistent across studies. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study (n = 189) was a cross-sectional study conducted between 2009 and 2010 at the University of Rochester. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18-22 years were included in this analysis. Diet was assessed via food frequency questionnaire. Linear regression was used to analyze the relation between dairy intake and conventional semen quality parameters (total sperm count, sperm concentration, progressive motility, morphology and ejaculate volume) adjusting for age, abstinence time, race, smoking status, body mass index, recruitment period, moderate-to-intense exercise, TV watching and total calorie intake. MAIN RESULTS AND THE ROLE OF CHANCE: Total dairy food intake was inversely related to sperm morphology (P-trend = 0.004). This association was mostly driven by intake of full-fat dairy foods. The adjusted difference (95% confidence interval) in normal sperm morphology percent was -3.2% (-4.5 to -1.8) between men in the upper half and those in the lower half of full-fat dairy intake (P < 0.0001), while the equivalent contrast for low-fat dairy intake was less pronounced [-1.3% (-2.7 to -0.07; P= 0.06)]. Full-fat dairy intake was also associated with significantly lower percent progressively motile sperm (P= 0.05). LIMITATIONS, REASONS FOR CAUTION: As it was a cross-sectional study, causal inference is limited. WIDER IMPLICATIONS OF THE FINDINGS: Further research is needed to prove a causal link between a high consumption of full-fat dairy foods and detrimental effects on semen quality. If verified our findings would mean that intake of full-fat dairy foods should be considered in attempts to explain secular trends in semen quality and that men trying to have children should restrict their intake. STUDY FUNDING/COMPETING INTEREST(S): European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

Latent factor regression models for grouped outcomes.

We consider regression models for multiple correlated outcomes, where the outcomes are nested in domains. We show that random effect models for this nested situation fit into a standard factor model framework, which leads us to view the modeling options as a spectrum between parsimonious random effect multiple outcomes models and more general continuous latent factor models. We introduce a set of identifiable models along this spectrum that extend an existing random effect model for multiple outcomes nested in domains. We characterize the tradeoffs between parsimony and flexibility in this set of models, applying them to both simulated data and data relating sexually dimorphic traits in male infants to explanatory variables.

Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being.

BACKGROUND: Cannabis varies considerably in levels of its two major constituent cannabinoids - (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Recently, we found evidence that those who smoked cannabis containing detectable levels of CBD had fewer psychotic-like symptoms than those whose cannabis had no CBD. The present study aimed, first, to replicate those findings and, second, to determine whether protective effects of CBD may extend to other harms of cannabis, such as memory impairment and reduced psychological well-being. METHOD: A total of 120 current cannabis smokers, 66 daily users and 54 recreational users were classified into groups according to whether analysis of their hair revealed the presence or absence of CBD and high versus low levels of THC. All were assessed on measures of psychosis-like symptoms, memory (prose recall; source memory) and depression/anxiety. RESULTS: Lower psychosis-like symptoms were found in those whose hair had CBD compared with those without. However, this was seen only in recreational users, who had higher levels of THC in their hair. Higher THC levels in hair were associated with increased depression and anxiety. Prose recall and source memory were poorer in daily users with high THC levels in hair while recognition memory was better in individuals with CBD present in hair. CONCLUSIONS: CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as 'skunk' (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.

Associations between urinary metabolites of di(2-ethylhexyl) phthalate and reproductive hormones in fertile men.

Widely used man-made chemicals, including phthalates, can induce hormonal alterations through a variety of cellular and molecular mechanisms. A number of rodent and observational studies have consistently demonstrated the anti-androgenic effect of several phthalates. However, there are only limited data on the relationship between exposure to these chemicals and reproductive hormone levels in men. All men (n=425) were partners of pregnant women who participated in the Study for Future Families in five US cities and provided urine and serum samples on the same day. Eleven phthalate metabolites were measured in urine and serum samples were analysed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone, testosterone, inhibin B and oestradiol and sex hormone-binding globulin (SHBG). Pearson correlations and parametric tests were used for unadjusted analyses, and multiple linear regression analysis was performed controlling for appropriate covariates. We observed weak or no associations with urinary phthalates other than di(2-ethylhexyl) phthalate (DEHP). All measures of testosterone [total, calculated free testosterone and the free androgen index (FAI)] were inversely correlated with the urinary concentrations of four DEHP metabolites. After adjustment by appropriate covariates, there was no longer an association between urinary DEHP metabolite concentrations and total testosterone levels; however, FAI was significantly associated with the urinary concentrations of several DEHP metabolites. SHBG was positively related to the urinary concentrations of mono(2-ethylhexyl) phthalate, but not with other DEHP metabolites, an association that was attenuated after adjustment. Our results suggest that DEHP exposure of fertile men is associated with minor alterations of markers of free testosterone.

Pharmacokinetics and safety of multiple doses of daptomycin 6 mg/kg in noninfected adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis.

AIMS: The purpose of this study was to characterize the pharmacokinetics and tolerability of daptomycin in subjects undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). METHOD: 16 noninfected adults on stable dialysis regimens were enrolled. Daptomycin 6 mg/kg was administered after HD during a 48 h - 48 h - 72 h dialysis week or before a CAPD dwell time over a 48 h - 48 h - 48 h dialysis week. Pharmacokinetic parameters were described, and adverse events were monitored. RESULTS: Daptomycin had mean half-lives in HD subjects of 28.0 and 35.9 h on Days 1 and 5, with corresponding values of 25.8 and 26.7 h in CAPD subjects. Steady state was reached by Day 5 in both groups. At steady state, HD subjects had a mean peak plasma concentration (Cmax) of 81.6 µg/ml and a mean trough concentration of 15.3 µg/ml (on Day 8). In CAPD subjects, Cmax was 93.9 µg/ml and the trough was 20.7 µg/ml (on Day 7). Adverse events were experienced by 71.4% and 66.7% of HD and CAPD subjects, respectively. Most of these were mild or moderate in intensity; however, 2 subjects experienced muscle spasms and mild creatine phosphokinase elevations although neither event was considered to be related to study drug. CONCLUSIONS: The pharmacokinetics of daptomycin 6 mg/kg support a dosing regimen of every 48 h in CAPD and thrice-weekly dosing in HD.

Pharmacokinetics and pharmacodynamics of tonapofylline in subjects with severe renal impairment and in elderly subjects.

OBJECTIVE: The study was conducted to characterize the pharmacokinetics and pharmacodynamics of tonapofylline in subjects with severe renal impairment and in elderly subjects. METHOD: Subjects with severe renal impairment were matched demographically with healthy subjects. Elderly subjects with normal renal function for their ages were also enrolled. All subjects (n = 8 per group) received a single intravenous administration of tonapofylline at 1 mg/kg. RESULTS: The pharmacokinetics of tonapofylline was not significantly different in subjects with severe renal impairment, or in elderly subjects, as compared to healthy subjects. Among all pharmacokinetic parameters, the only statistically significant difference was observed for Cmax between the healthy and the severe renal impairment groups, which was 21% and considered clinically insignificant. Pharmacodynamic assessment demonstrated the natriuretic effects of tonapofylline across groups, with little accompanying kaliuresis. No change in renal function occurred after single dose of tonapofylline, despite substantial increases in excretion of urinary sodium. Single 1 mg/kg intravenous administration of tonapofylline was generally safe. CONCLUSION: The pharmacokinetics of tonapofylline in subjects with severe renal impairment and elderly subjects with normal renal function for age is similar to that in healthy subjects. It has been demonstrated in all groups that tonapofylline has natriuretic effects and is able to maintain renal function, which can be beneficial to patients with congestive heart failure.

Prenatal phthalate exposure and reduced masculine play in boys.

Foetal exposure to antiandrogens alters androgen-sensitive development in male rodents, resulting in less male-typical behaviour. Foetal phthalate exposure is also associated with male reproductive development in humans, but neurodevelopmental outcomes have seldom been examined in relation to phthalate exposure. To assess play behaviour in relation to phthalate metabolite concentration in prenatal urine samples, we recontacted participants in the Study for Future Families whose phthalate metabolites had been measured in mid-pregnancy urine samples. Mothers completed a questionnaire including the Pre-School Activities Inventory, a validated instrument used to assess sexually dimorphic play behaviour. We examined play behaviour scores (masculine, feminine and composite) in relationship to (log(10)) phthalate metabolite concentrations in mother's urine separately for boys (N = 74) and girls (N = 71). Covariates (child's age, mother's age and education and parental attitude towards atypical play choices) were controlled using multivariate regression models. Concentrations of dibutyl phthalate metabolites, mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) and their sum, were associated with a decreased (less masculine) composite score in boys (regression coefficients -4.53,-3.61 and -4.20, p = 0.01, 0.07 and 0.04 for MnBP, MiBP and their sum respectively). Concentrations of two urinary metabolites of di(2-ethylhexyl) phthalate (DEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the sum of these DEHP metabolites plus mono(2-ethylhexyl) phthalate were associated with a decreased masculine score (regression coefficients -3.29,-2.94 and -3.18, p = 0.02, 0.04 and 0.04) for MEHHP, MEOHP and the sum respectively. No strong associations were seen between behaviour and urinary concentrations of any other phthalate metabolites in boys, or between girls' scores and any metabolites. These data, although based on a small sample, suggest that prenatal exposure to antiandrogenic phthalates may be associated with less male-typical play behaviour in boys. Our findings suggest that these ubiquitous environmental chemicals have the potential to alter androgen-responsive brain development in humans.

Vitamin D status is not associated with reproductive parameters in young Spanish men.

BACKGROUND: Relatively low sperm count was reported among young Spanish men in 2013. Several potential culprits have been suggested as explanations for reported trends in sperm counts in Western men, including lifestyles. Although controversial, some studies suggest that semen parameters, such as low sperm motility or abnormal morphology, may be associated with low serum vitamin D levels. OBJECTIVES: To evaluate associations between semen parameters and reproductive hormones and serum 25-hydroxyvitamin D (25OHD) status in young Spanish men and to examine these associations in relation to dietary intake of vitamin D. MATERIALS AND METHODS: This cross-sectional study includes 198 university students recruited in 2010-2011 in southern Spain, who provided samples of blood and semen and food frequencies. Semen quality was evaluated by measuring volume, concentration, sperm counts, motility, and morphology, according to the WHO guidelines. Serum samples were analyzed for total 25OHD and reproductive hormones, including FSH, LH, testosterone, inhibin B, and estradiol. Dietary vitamin D intake was assessed using a validated food frequency questionnaire. Associations with semen quality and reproductive hormones were examined using linear regression, adjusting for potential confounders. RESULTS: Almost all men had adequate levels of serum vitamin D - only three men (1.5%) were vitamin D deficient (<30 nmol/L) and 17% were insufficient (<50 nmol/L). However, dietary vitamin D intakes were relatively low (below recommended 600 IU/day in 99% of men). Neither dietary intake nor serum vitamin D levels were associated with any sperm parameter or any reproductive hormone (all p ≥ 0.09). DISCUSSION: We did not observe an association between vitamin D status and any reproductive parameter in our study population. CONCLUSIONS: Our results suggest that serum vitamin D levels are sustained in Spanish men despite low dietary intake and therefore low vitamin D does not explain the poor semen quality previously observed in these young Spanish men.

A multiprotein bicarbonate dehydration complex essential to carboxysome function in cyanobacteria.

Carboxysomes are proteinaceous biochemical compartments that constitute the enzymatic "back end" of the cyanobacterial CO2-concentrating mechanism. These protein-bound organelles catalyze HCO3- dehydration and photosynthetic CO2 fixation. In Synechocystis sp. strain PCC6803 these reactions involve the beta-class carbonic anhydrase (CA), CcaA, and Form 1B ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). The surrounding shell is thought to be composed of proteins encoded by the ccmKLMN operon, although little is known about how structural and catalytic proteins integrate to form a functional carboxysome. Using biochemical activity assays and molecular approaches we have identified a catalytic, multiprotein HCO3- dehydration complex (BDC) associated with the protein shell of Synechocystis carboxysomes. The complex was minimally composed of a CcmM73 trimer, CcaA dimer, and CcmN. Larger native complexes also contained RbcL, RbcS, and two or three immunologically identified smaller forms of CcmM (62, 52, and 36 kDa). Yeast two-hybrid analyses indicated that the BDC was associated with the carboxysome shell through CcmM73-specific protein interactions with CcmK and CcmL. Protein interactions between CcmM73 and CcaA, CcmM73 and CcmN, or CcmM73 and itself required the N-terminal gamma-CA-like domain of CcmM73. The specificity of the CcmM73-CcaA interaction provided both a mechanism to integrate CcaA into the fabric of the carboxysome shell and a means to recruit this enzyme to the BDC during carboxysome biogenesis. Functionally, CcaA was the catalytic core of the BDC. CcmM73 bound H14CO3- but was unable to catalyze HCO3- dehydration, suggesting that it may potentially regulate BDC activity.

Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics.

CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19(+) B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4(+) or CD8(+) T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration.

Maternal and infant urinary phthalate metabolite concentrations: are they related?

BACKGROUND: Phthalates are synthetic chemicals that are ubiquitous in our society and may have adverse health effects in humans. Detectable concentrations of phthalate metabolites have been found in adults and children, but no studies have examined the relationship between maternal and infant phthalate metabolite concentrations. OBJECTIVE: We investigated the relationship between maternal and infant urinary phthalate metabolite concentrations. METHODS: We measured nine phthalate metabolites in urine samples from 210 mother/infant pairs collected on the same study visit day (1999-2005) and obtained demographic history from questionnaires. Using multivariate linear regression analyses, we examined the degree to which maternal urine phthalate metabolite concentration predicted infant phthalate metabolite concentration. All analyses were adjusted for infant age, creatinine concentration, and race. RESULTS: Correlation coefficients between phthalate metabolite concentrations in the urine of mothers and their infants were generally low but increased with decreasing age of infant. In multivariate analyses, mother's phthalate metabolite concentrations were significantly associated with infants' concentrations for six phthalate metabolites: monobenzyl phthalate, monoethyl phthalate, monoisobutyl phthalate, and three metabolites of di(2-ethylhexyl) phthalate: mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxy-hexyl) phthalate, and mono(2-ethyl-5-oxo-hexyl) phthalate (p-values for all coefficients <0.05). DISCUSSION: Mother's urine phthalate metabolite concentration is significantly associated with infant urine phthalate metabolite concentration for six phthalate metabolites. It is plausible that shared exposures to phthalates in the immediate surrounding environment accounted for these relationships, but other unidentified sources may also contribute to infants' phthalate exposures. This study indicates the importance of further identifying infant phthalate exposures that may be distinct from maternal exposures in order to decrease overall infant phthalate exposures.