Effect of prematurely elevated late follicular progesterone on pregnancy outcomes following ovarian stimulation-intrauterine insemination for unexplained infertility: secondary analysis of the AMIGOS trial.

STUDY QUESTION: What is the relationship between late follicular phase progesterone levels and clinic pregnancy and live birth rates in couples with unexplained infertility undergoing ovarian stimulation with IUI (OS-IUI)? SUMMARY ANSWER: Late follicular progesterone levels between 1.0 and <1.5 ng/ml were associated with higher live birth and clinical pregnancy rates while the outcomes in groups with higher progesterone levels did not differ appreciably from the <1.0 ng/ml reference group. WHAT IS KNOWN ALREADY: Elevated late follicular progesterone levels have been associated with lower live birth rates after fresh embryo transfer following controlled ovarian stimulation and egg retrieval, but less is known about whether an association exists with outcomes in OS-IUI cycles. Existing studies are few and have been limited to ovarian stimulation with gonadotrophins, but the use of oral agents, such as clomiphene citrate and letrozole, is common with these treatments and has not been well studied. STUDY DESIGN, SIZE, DURATION: The study was a prospective cohort analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial. Frozen serum was available for evaluation from 2121 cycles in 828 AMIGOS participants. The primary pregnancy outcome was live birth per cycle, and the secondary pregnancy outcome was clinical pregnancy rate per cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples with unexplained infertility in the AMIGOS trial, for whom female serum from day of trigger with hCG was available in at least one cycle of treatment, were included. Stored frozen serum samples from day of hCG trigger during treatment with OS-IUI were evaluated for serum progesterone level. Progesterone level <1.0 ng/ml was the reference group for comparison with progesterone categorized in increments of 0.5 ng/ml up to ≥3.0 ng/ml. Unadjusted and adjusted risk ratios (RR) and 95% CI were estimated using cluster-weighted generalized estimating equations to estimate modified Poisson regression models with robust standard errors. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the reference group with 110/1363 live births (8.07%), live birth rates were significantly increased in cycles with progesterone 1.0 to <1.5 ng/ml (49/401 live births, 12.22%) in both the unadjusted (RR 1.56, 95% CI 1.14, 2.13) and treatment-adjusted models (RR 1.51, 95% CI 1.10, 2.06). Clinical pregnancy rates were also higher in this group (55/401 clinical pregnancies, 13.72%) compared to reference group with 130/1363 (9.54%) (unadjusted RR 1.46, 95% CI 1.10, 1.94 and adjusted RR 1.42, 95% CI 1.07, 1.89). In cycles with progesterone 1.5 ng/ml and above, there was no evidence of a difference in clinical pregnancy or live birth rates relative to the reference group. This pattern remained when stratified by ovarian stimulation treatment group but was only statistically significant in letrozole cycles. LIMITATIONS, REASONS FOR CAUTION: The AMIGOS trial was not designed to answer this clinical question, and with small numbers in some progesterone categories our analyses were underpowered to detect differences between some groups. Inclusion of cycles with progesterone values above 3.0 ng/ml may have included those wherein ovulation had already occurred at the time the IUI was performed. These cycles would be expected to experience a lower success rate but pregnancy may have occurred with intercourse in the same cycle. WIDER IMPLICATIONS OF THE FINDINGS: Compared to previous literature focusing primarily on OS-IUI cycles using gonadotrophins, these data include patients using oral agents and therefore may be generalizable to the wider population of infertility patients undergoing IUI treatments. Because live births were significantly higher when progesterone ranged from 1.0 to <1.5 ng/ml, further study is needed to clarify whether this progesterone range may truly represent a prognostic indicator in OS-IUI cycles. STUDY FUNDING/COMPETING INTEREST(S): Oklahoma Shared Clinical and Translational Resources (U54GM104938) National Institute of General Medical Sciences (NIGMS). AMIGOS was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, and U10HD055925. Research made possible by the funding by American Recovery and Reinvestment Act. Dr Burks has disclosed that she is a member of the Board of Directors of the Pacific Coast Reproductive Society. Dr Hansen has disclosed that he is the recipient of NIH grants unrelated to the present work, and contracts with Ferring International Pharmascience Center US and with May Health unrelated to the present work, as well as consulting fees with May Health also unrelated to the present work. Dr Diamond has disclosed that he is a stockholder and a member of the Board of Directors of Advanced Reproductive Care, Inc., and that he has a patent pending for the administration of progesterone to trigger ovulation. Dr Anderson, Dr Gavrizi, and Dr Peck do not have conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Small Fiber Neuropathy.

PURPOSE OF REVIEW: This narrative review aims to summarize advances in the field of small fiber neuropathy made over the last decade, with emphasis on novel research highlighting the distinctive features of SFN. RECENT FINDINGS: While the management of SFNs is ideally aimed at treating the underlying cause, most patients will require pain control via multiple, concurrent therapies. Herein, we highlight the most up-to-date information for diagnosis, medication management, interventional management, and novel therapies on the horizon. Despite the prevalence of small fiber neuropathies, there is no clear consensus on guidelines specific for the treatment of SFN. Despite the lack of specific guidelines for SFN treatment, the most recent general neuropathic pain guidelines are based on Cochrane studies and randomized controlled trials (RCTs) which have individually examined therapies used for the more commonly studied SFNs, such as painful diabetic neuropathy and HIV neuropathy. The recommendations from current guidelines are based on variables such as number needed to treat (NNT), safety, ease of use, and effect on quality of life.

How well can levator ani muscle morphology on 3D pelvic floor ultrasound predict the levator ani muscle function?

INTRODUCTION AND HYPOTHESIS: The aim of our study was to assess the performance of levator ani muscle deficiency (LAD) evaluated by 3D endovaginal ultrasound (EVUS) to detect pelvic floor muscle function as assessed by digital examination. METHODS: This cross-sectional study was conducted among 77 patients referred to our urogynecology clinic for pelvic floor dysfunction symptoms. Patients underwent physical examinations including digital pelvic muscle strength assessment using the Modified Oxford scale (MOS). EVUS volumes were evaluated and levator ani muscles were scored according to a validated LAD scoring system. MOS scores were categorized as nonfunctional (scores 0-1) and functional (scores 2-5). RESULTS: Mean age of participants was 56 (SD ± 12.5) and 71% were menopausal. Overall, 32.5% had nonfunctional muscle strength and 44.2% were classified as having significant LAD. LAD identified by ultrasound had a sensitivity of 60% (95% CI 41 -79%) for detecting nonfunctional muscle and a specificity of 63% (95% CI 50 -77%) for detecting functional muscle. Overall, LAD demonstrated fair ability to discriminate between patients with and those without poor muscle function (area under the ROC curve = 0.70 [95% CI 0.58-0.83]). Among patients with an LAD score of 16-18, representing almost total muscle avulsion, 70% had nonfunctional MOS scores, whereas in patients with normal/minimal LAD (scores of 0-4), 89.5% had functional MOS scores. CONCLUSIONS: Levator ani deficiency and MOS scales were moderately negatively correlated. Among patients with normal morphology or the most severe muscle deficiency, LAD scores can identify the majority of patients with functional or nonfunctional MOS scores respectively.

Associations between early alcohol and tobacco use and prolonged time to puberty in boys.

BACKGROUND: Previous research has demonstrated a relationship between prepubertal alcohol and tobacco use and delayed pubertal characteristics in girls. Although, laboratory research indicates that alcohol and tobacco use inhibits sexual maturation in male rats, human research in this area is lacking. To address this question among boys, we conducted a study to explore the association between early use of alcohol and tobacco and time to development of secondary sexual characteristics. METHODS: The study population included 3199 boys interviewed between the ages of 11 and 21. Participants reported the ages at which they first experienced body hair growth, deepening of the voice and facial hair growth. Early alcohol and tobacco use were defined as first use preceding the age of pubertal development among those reporting regular consumption patterns. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. RESULTS: Early alcohol use was associated with longer time to body hair growth (HR 0.77; 95% CI 0.69-0.87), voice changes (HR 0.72; 95% CI 0.64-0.82) and facial hair growth (HR 0.77; 95% CI 0.68-0.86), after adjusting for tobacco use and age at interview. Tobacco use was not independently associated with the puberty indicators after controlling for alcohol use and age at interview. CONCLUSIONS: Our findings are consistent with the hypothesis that alcohol may inhibit puberty onset in boys, an association that has been previously observed among young girls. Thus, alcohol may be an exposure deserving more scrutiny as a disruptor to normal pubertal development.

Diagnosing HIV infection in patients presenting with glandular fever-like illness in primary care: are we missing primary HIV infection?

OBJECTIVES: The aim of the study was to examine the prevalence of HIV infection in patients presenting in primary care with glandular fever (GF)-like illness. METHODS: Samples from primary care submitted for a GF screen between April 2009 and June 2010 were identified. Samples without an HIV request were anonymized and retrospectively tested using a 4th-generation HIV antigen/antibody screening test. Reactive samples were further confirmed by an HIV antibody only test, with or without a p24 antigen assay. Antibody avidity testing based on the Recent HIV Infection Testing Algorithm (RITA) was used to identify individuals with evidence of recent acquisition (within 4-5 months). RESULTS: Of 1046 GF screening requests, concomitant HIV requests were made in 119 patients. Excluding one known positive patient, 2.5% (three of 118) tested HIV positive. Forty-five (4.3%) had a subsequent HIV test through another consultation within 1 year; of these, 4.4% (two of 45) tested positive. Of the remaining 882 patients, 694 (78.7%) had samples available for unlinked anonymous HIV testing, of which six (0.9%) tested positive. The overall HIV prevalence was 1.3% (11 of 857), with 72.7% (eight of 11) of cases missed at initial primary care presentation. Four of the nine (44.4%) available positive samples had evidence of recent acquisition, with three (75.0%) missed at initial primary care presentation. CONCLUSION: Low levels of HIV testing in patients presenting in primary care with GF-like illness are resulting in a significant number of missed HIV and seroconversion diagnoses. Local policy should consider adopting an opt-out strategy to include HIV testing routinely within the GF-screening investigation panel.

Pleiotropy and the preservation of perfection.

A mathematical model is presented in which a single mutation can affect multiple phenotypic characters, each of which is subject to stabilizing selection. A wide range of mutations is allowed, including ones that produce extremely small phenotypic changes. The analysis shows that, when three or more characters are affected by each mutation, a single optimal genetic sequence may become common. This result provides a hypothesis to explain the low levels of variation and low rates of substitution that are observed at some loci.

Kin selection and the evolution of monogamy.

A two-locus genetic model is studied in which one locus controls the tendency of individuals to act altruistically toward siblings and the other locus controls the mating habits of females. It is demonstrated that genetic variation at the altruism locus is often sufficient to induce an increase in the frequency of genes that cause females to produce all of their offspring with a single mate. This occurs because of nonrandom associations that develop between genes that cause altruism and those that affect female mating behavior. The results provide a new explanation for the evolution of monogamy, and they suggest a previously unexplored mechanism for the evolution of a variety of other behavioral traits as well.

Protection against heat-induced cell killing by polyols in vitro.

The polyols erythritol and adonitol reduced 45 degrees heat killing in asynchronous Chinese hamster ovary cells. Heat protection by glycerol and erythritol increased with the apparent intracellular concentration, as inferred from cell volume measurements, and the number of hydroxyl groups per alcohol molecule. The nonlinear tetrahydroxy alcohol pentaerythritol did not protect but sensitized to heat killing. On cell survival curves, the reduced cell killing of protected cells was expressed by an increased Do for the pentahydroxy alcohol adonitol (0.3 M), whereas equimolar concentrations of glycerol increased primarily the Dq (quasithreshold dose) with little increase in Do. The distribution of Chinese hamster ovary cells within the cell cycle was unaffected by the presence of 0.3 M glycerol in the culture medium. However, the polyols erythritol and sorbitol caused a small but significant loss of cells from the heat-resistant G1 compartment. The cell cycle redistribution with prolonged incubation (6 hr) in polyol-supplemented medium is expected to increase the heat sensitivity of the perturbed cell population; the observed heat protection by polyols suggests that heat resistance in the presence of polyols is not an artifact of an asynchronous cell system. Instead, the data identify a family of heat-protective compounds that may occur naturally in mammalian cells.

Abstinence-Conflict Model: Toward an Optimal Animal Model for Screening Medications Promoting Drug Abstinence.

Drug addiction is a significant health and societal problem for which there is no highly effective long-term behavioral or pharmacological treatment. A rising concern are the use of illegal opiate drugs such as heroin and the misuse of legally available pain relievers that have led to serious deleterious health effects or even death. Therefore, treatment strategies that prolong opiate abstinence should be the primary focus of opiate treatment. Further, because the factors that support abstinence in humans and laboratory animals are similar, several animal models of abstinence and relapse have been developed. Here, we review a few animal models of abstinence and relapse and evaluate their validity and utility in addressing human behavior that leads to long-term drug abstinence. Then, a novel abstinence "conflict" model that more closely mimics human drug-seeking episodes by incorporating negative consequences for drug seeking (as are typical in humans, eg, incarceration and job loss) and while the drug remains readily available is discussed. Additionally, recent research investigating both cocaine and heroin seeking in rats using the animal conflict model is presented and the implications for heroin treatments are examined. Finally, it is argued that the use of animal abstinence/relapse models that more closely approximate human drug addiction, such as the abstinence-conflict model, could lead to a better understanding of the neurobiological and environmental factors that support long-term drug abstinence. In turn, this will lead to the development of more effective environmental and pharmacotherapeutic interventions to treat opiate addiction and addiction to other drugs of abuse.

Blood metal ion levels are not a useful test for adverse reactions to metal debris: A systematic review and meta-analysis.

OBJECTIVES: Alarm over the reported high failure rates for metal-on-metal (MoM) hip implants as well as their potential for locally aggressive Adverse Reactions to Metal Debris (ARMDs) has prompted government agencies, internationally, to recommend the monitoring of patients with MoM hip implants. Some have advised that a blood ion level >7 µg/L indicates potential for ARMDs. We report a systematic review and meta-analysis of the performance of metal ion testing for ARMDs. METHODS: We searched MEDLINE and EMBASE to identify articles from which it was possible to reconstruct a 2 × 2 table. Two readers independently reviewed all articles and extracted data using explicit criteria. We computed a summary receiver operating curve using a Bayesian random-effects hierarchical model. RESULTS: Our literature search returned 575 unique articles; only six met inclusion criteria defined a priori. The discriminative capacity of ion tests was homogeneous across studies but that there was substantial cut-point heterogeneity. Our best estimate of the "true" area under curve (AUC) for metal ion testing is 0.615, with a 95% credible interval of 0.480 to 0.735, thus we can state that the probability that metal ion testing is actually clinically useful with an AUC ≥ 0.75 is 1.7%. CONCLUSION: Metal ion levels are not useful as a screening test for identifying high risk patients because ion testing will either lead to a large burden of false positive patients, or otherwise marginally modify the pre-test probability. With the availability of more accurate non-invasive tests, we did not find any evidence for using blood ion levels to diagnose symptomatic patients.Cite this article: M. Pahuta, J. M. Smolders, J. L. van Susante, J. Peck, P. R. Kim, P. E. Beaule. Blood metal ion levels are not a useful test for adverse reactions to metal debris: a systematic review and meta-analysis. Bone Joint Res 2016;5:379-386. DOI: 10.1302/2046-3758.59.BJR-2016-0027.R1.

A ruby in the rubbish: beneficial mutations, deleterious mutations and the evolution of sex.

This study presents a mathematical model in which a single beneficial mutation arises in a very large population that is subject to frequent deleterious mutations. The results suggest that, if the population is sexual, then the deleterious mutations will have little effect on the ultimate fate of the beneficial mutation. However, if most offspring are produced asexually, then the probability that the beneficial mutation will be lost from the population may be greatly enhanced by the deleterious mutations. Thus, sexual populations may adapt much more quickly than populations where most reproduction is asexual. Some of the results were produced using computer simulation methods, and a technique was developed that allows treatment of arbitrarily large numbers of individuals in a reasonable amount of computer time. This technique may be of prove useful for the analysis of a wide variety of models, though there are some constraints on its applicability. For example, the technique requires that reproduction can be described by Poisson processes.

Limited dispersal, deleterious mutations and the evolution of sex.

This study presents a mathematical model that allows for some offspring to be dispersed at random, while others stay close to their mothers. A single genetic locus is assumed to control fertility, and this locus is subject to the occurrence of deleterious mutations. It is shown that, at equilibrium, the frequency of deleterious mutations in the population is inversely related to the rate of dispersal. This is because dispersal of offspring leads to enhanced competition among adults. The results also show that sexual reproduction can lead to a decrease in the equilibrium frequency of deleterious mutations. The reason for this relationship is that sex involves the dispersal of genetic material, and thus, like the dispersal of offspring, sex enhances competition among adults. The model is described using the example of a hermaphroditic plant population. However, the results should apply to animal populations as well.

Sex and adaptation in a changing environment.

In this study we consider a mathematical model of a sexual population that lives in a changing environment. We find that a low rate of environmental change can produce a very large increase in genetic variability. This may help to explain the high levels of heritability observed in many natural populations. We also study asexuality and find that a modest rate of environmental change can be very damaging to an asexual population, while leaving a sexual population virtually unscathed. Furthermore, in a changing environment, the advantages of sexuality over asexuality can be much greater than suggested by most previous studies. Our analysis applies in the case of very large populations, where stochastic forces may be neglected.

The anomalous effects of biased mutation.

A model is presented in which alleles at a number of loci combine to influence the value of a quantitative trait that is subject to stabilizing selection. Mutations can occur to alleles at the loci under consideration. Some of these mutations will tend to increase the value of the trait, while others will tend to decrease it. In contrast to most previous models, we allow the mean effect of mutations to be nonzero. This means that, on average, mutations can have a bias, such that they tend to either increase or decrease the value of the trait. We find, unsurprisingly, that biased mutation moves the equilibrium mean value of the quantitative trait in the direction of the bias. What is more surprising is the behavior of the deviation of the equilibrium mean value of the trait from its optimal value. This has a nonmonotonic dependence on the degree of bias, so that increasing the degree of bias can actually bring the mean phenotype closer to the optimal phenotype. Furthermore, there is a definite maximum to the extent to which biased mutation can cause a difference between the mean phenotype and the optimum. For plausible parameter values, this maximum-possible difference is small. Typically, quantitative-genetics models assume an unconstrained model of mutation, where the expected difference in effect between a parental allele and a mutant allele is independent of the current state of the parental allele. Our results show that models of this sort can easily lead to biologically implausible consequences when mutations are biased. In particular, unconstrained mutation typically leads to a continual increase or decrease in the mean allelic effects at all trait-controlling loci. Thus at each of these loci, the mean allelic effect eventually becomes extreme. This suggests that some of the models of mutation most commonly used in quantitative genetics should be modified so as to introduce genetic constraints.

Imperfect genes, Fisherian mutation and the evolution of sex.

In this paper we present a mathematical model of mutation and selection that allows for the coexistence of multiple alleles at a locus with very small selective differences between alleles. The model also allows for the determination of fitness by multiple loci. Models of this sort are biologically plausible. However, some previous attempts to construct similar models have assumed that all mutations produce a decrease in fitness, and this has led to a tendency for the average fitness of population members to decline when population numbers are finite. In our model we incorporate some of the ideas of R. A. FISHER, so that both deleterious and beneficial mutations are possible. As a result, average fitness tends to approach a stationary distribution. We have used computer simulation methods to apply the Fisherian mutation model to the problem of the evolution of sex and recombination. The results suggest that sex and recombination can provide very large benefits in terms of average fitness. The results also suggest that obligately sexual species will win ecological competitions with species that produce a substantial fraction of their offspring asexually, so long as the number of sites under selection within the genomes of the competing species is not too small and the population sizes are not too large. Our model focuses on fertility selection in an hermaphroditic plant. However, the results are likely to generalize to a wide variety of other situations as well.

Treatment with carbamazepine may enhance alpha 2-noradrenergic autoreceptor sensitivity.

Chronic, not acute treatment with carbamazepine enhanced the hypothermic response to a dose of clonidine thought to exert its predominant effect on the presynaptic alpha 2-autoreceptor. This response was markedly elevated both during the course of and 10 days after the discontinuation of treatment with carbamazepine. Sensitivity to clonidine returned to baseline 10 to 21 days after the discontinuation of treatment. Carbamazepine is the first treatment for the disorders of mood that has been demonstrated to enhance a physiological response to clonidine. The authors discuss the theoretical relationship between increased sensitivity of the presynaptic alpha 2-autoreceptor and the usefulness of carbamazepine in the treatment of bipolar disorder.

Mean arterial pressure, pregnancy-induced hypertension, and preeclampsia: evaluation as independent risk factors and as surrogates for high maternal serum alpha-fetoprotein in estimating breast cancer risk.

Data from a nested case-control study were analyzed to examine high mean arterial pressure (MAP), hypertension of pregnancy, and preeclampsia as independent predictors and as surrogate markers for elevated alpha-fetoprotein (AFP) levels in evaluating breast cancer risk. Cases (n = 205) were identified by the California Cancer Registry from a cohort of pregnant women who were part of the Kaiser Health Plan and took part in the Child Health and Development Studies initiated by the University of California, Berkeley, from June 1959 to September 1966. Controls (n = 337) were selected by randomized recruitment from the same cohort probability matched to cases by distribution of birth dates of cases. High MAP was associated with breast cancer risk and is different across quartile of age at first full-term pregnancy as is high AFP. Odds ratios (OR) across quartiles for MAP were 0.24 [95% confidence interval (CI), 0.08-0.71], 0.84 (95% CI, 0.39-1.66), 1.00 (referent), and 2.50 (95% CI, 1.21-5.13), and for AFP were 0.34 (95% CI, 0.13-0.93), 0.77 (95% CI, 0.36-1.67), 1.00 (referent), and 2.38 (95% CI, 1.13-5.00). Neither diagnosed preeclampsia nor hypertension of pregnancy showed any association with breast cancer risk. When both high AFP and high MAP were entered into the same analysis, neither changed the OR for the other more than 8%. Additionally, AFP level was not a linear function of MAP. Although the pattern of ORs across quartiles of age at first full-term pregnancy was similar for the two variables, it cannot be concluded that high MAP is an adequate surrogate for high levels of maternal serum AFP, but rather represents some related process that is in and of itself a risk factor for breast cancer.

Change in the in vivo hyperthermic response resulting from the metabolic effects of temporary vascular occlusion.

Previous workers have reported that clamping of animal tumors in vivo enhanced the effect of hyperthermia; the enhancement has been attributed to pH and nutritional effects of vascular occlusion. It has not been clear, however, the degree to which improved heating patterns or effects on the tumor cells and vasculature from the clamping procedure itself might have contributed to the observed effect. In the experiments herein reported, care was taken to insure comparable heating of C3H mouse mammary tumors transplanted on the flank whether clamped or unclamped. Clamping for one hour with hyperthermia during the final 30 minutes caused a marked thermosensitization as measured by tumor control. The temperature at 30 minutes heating to control 50% of the tumors for 120 days (TCT 50-120) was reduced from 46.8 degrees C in controls to 43.5 degrees C in clamped tumors, a difference of 3.3 +/- 0.09 degrees C. No cytotoxicity from the clamping alone was evident by assessment of subsequent tumor growth and no lasting vascular effects could be detected by 133Xe washout and tumor growth. Since the techniques used produced essentially identical heating patterns, we conclude that the striking enhancement in hyperthermic response in clamped tumors can be attributed to the metabolic consequences of temporary vascular occlusion.

Frequency-dependent selection, beneficial mutations, and the evolution of sex.

This paper presents a mathematical model of a population in which multiple alleles at a particular locus are maintained by frequency-dependent selection. The results suggest that, if the population reproduces sexually, the benefit conferred on the population by beneficial mutations at other loci will typically be much larger than if the population reproduces by asexual means. In part, this is true because, in asexual populations, beneficial mutations can produce suboptimal distributions of the alleles that are subject to frequency-dependent selection. Another factor that produces an advantage for sex is that, in asexual populations, beneficial mutations that have achieved a high copy number may nevertheless be lost from the population. This is highly unlikely in sexual populations.