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.

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.

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.

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.

DNA quantification of exfoliated colonocytes as a novel screening tool for colorectal cancer.

AIMS: Colorectal cancer (CRC) sheds viable cells in the mucocelluar layer overlaying the colonic mucosa which travels distally alongside the faecal stream. These cells can be retrieved from the surface of the rectal mucosa. DNA quantification of these cells may be a marker of CRC, assessment of which was aim of this study. METHODS: A prospective double-blinded study of 467 consecutive patients referred with symptoms suggestive of CRC. Cells were collected from the surface of the rectal mucosa and total DNA quantified. DNA scores were compared with outcome after subjects had completed bowel investigations. Analysis of receiver operating characteristic (ROC) curves was performed to determine the optimum cut-off point for a positive result. RESULTS: 107 of the 467 patients were excluded due to; excessive faecal contamination of samples (n = 84); declined investigations (n = 17); inappropriate referral (n = 5); unfit (n = 1). 263 patients had lower GI endoscopy; 89 CT colonography and 8 barium enema. The diagnosis were; CRC (n = 23), inflammatory bowel disease (IBD) (n = 7), adenomatous polyps (AP) (n = 20) and no significant abnormality detected (n = 310). ROC analysis revealed that sensitivities at a specificity of 60% for detecting CRC were 91.3%; for CRC and IBD 86.7%; and for CRC, IBD and AP 72.0%. CONCLUSION: In symptomatic patients DNA quantification of cells retrieved from the surface of the rectal mucosa is sensitive for the detection of CRC. Although faecal contamination is a limitation of this technique, refinement and application of other molecular tests hold promise for a better non invasive method for the detection of CRC.

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.

Please Touch: Object Properties that Invite Touch.

Touch has received increasing interest in marketing, given research indicating that contact with products influences evaluation and the tendency to purchase. However, little is known from the marketing or psychophysical literature about visible attributes of objects that elicit touch for hedonic purposes. In these studies, participants rated the tendency of pictured objects to invite touch, or "touch-ability." Rated touch-ability varied reliably with structural attributes of objects, and the structural influences were distinct from those on other ratings such as attractiveness and apparent expense. Although the trends varied across object sets, touch-ability generally declined as surface textures became markedly rough and shape complexity became extreme. Holding stimulus factors constant, touch-ability also varied with the specific hand movements that were anticipated. Finally, mean touch-ability ratings were correlated across participants with the "Need for Touch" scale, which measures an individual's tendency to touch products. The studies point to touch-ability as a potential factor that might be incorporated into product design.

Atlantic forcing of persistent drought in West Africa.

Although persistent drought in West Africa is well documented from the instrumental record and has been primarily attributed to changing Atlantic sea surface temperatures, little is known about the length, severity, and origin of drought before the 20th century. We combined geomorphic, isotopic, and geochemical evidence from the sediments of Lake Bosumtwi, Ghana, to reconstruct natural variability in the African monsoon over the past three millennia. We find that intervals of severe drought lasting for periods ranging from decades to centuries are characteristic of the monsoon and are linked to natural variations in Atlantic temperatures. Thus the severe drought of recent decades is not anomalous in the context of the past three millennia, indicating that the monsoon is capable of longer and more severe future droughts.

The frequency of the perfect genotype in a population subject to pleiotropic mutation.

We consider a large population of asexual organisms characterised by a number of quantitative traits that are subject to stabilising selection. Mutation is taken to act pleiotropically, with every mutation generally changing all of the traits under selection. We focus on the equilibrium distribution of the population, where mutation and selection are in balance. It has been previously established that the equilibrium distribution of genotypic effects may be anomalous, as it may contain a singular spike--a Dirac delta function--corresponding to a non-zero proportion of the population having exactly optimal genotypic values. In the present work, we present exact results for the case where three traits are under selection. These results give the equilibrium genetic variance of the population, and the proportion of the population that have the optimal genotype. This is achieved for two different spherically symmetric distributions of mutant effects. Additionally, a simple and robust numerical approach is also presented that allows the treatment of some other mutation distributions, where there are an arbitrary number of selected traits.

A one locus, biased mutation model and its equivalence to an unbiased model.

Experimental data suggests that for some continuously-varying characters under stabilising selection, mutation may cause a mean change in the value of the character. A one locus, mathematical model of a continuously-varying biological character with this property of biased mutation is investigated. Via a mathematical transformation, the equilibrium equation describing a large population of individuals is reduced to the equilibrium equation describing a mutationally unbiased problem. Knowledge of an unbiased problem is thus sufficient to determine all equilibrium properties of the corresponding biased problem. In the biased mutation problem, the dependence of the mean equilibrium value of the character, as a function of the mutational bias, is non-monotonic and remains small, for all levels of mutational bias. The analysis presented in this work sheds new light on Turelli's House of Cards Approximation.

Mutation and selection in a large population.

In this paper we study a large, but finite population, in which mutation and selection occur at a single genetic locus in a diploid organism. We provide theoretical results for the equilibrium allele frequencies, their variances and covariances and their equilibrium distribution, when the population size is larger than the reciprocal of the mean allelic mutation rate. We are also able to infer that the equilibrium distribution of allele frequencies takes the form of a constrained multivariate Gaussian distribution. Our results provide a rapid way of obtaining useful information in the case of complex mutation and selection schemes when the population size is large. We present numerical simulations to test the applicability of our theoretical formulations. The results of these simulations are in very reasonable agreement with the theoretical predictions.

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.

Amine modulation of the transient potassium current in identified cells of the lobster stomatogastric ganglion.

The pyloric network of the stomatogastric ganglion of the lobster Panulirus interruptus is a model system used to understand how motor networks change their output to produce a variety of behaviors. The transient potassium current (I(A)) shapes the activity of individual pyloric neurons by affecting their rate of postinhibitory rebound and spike frequency. We used two electrode voltage clamp to study the modulatory effects of dopamine (DA), octopamine (OCT), and serotonin (5-HT) on I(A) in the anterior burster (AB), inferior cardiac (IC), and ventricular dilator (VD) neurons of the pyloric circuit. DA significantly reduced I(A) in the AB and IC neurons and shifted their voltages of activation (V(act)) and inactivation (V(inact)) in a depolarized direction. These ionic changes contribute to the depolarization and increased firing rate of the AB and IC neurons produced by DA. Likewise, 5-HT significantly reduced I(A) and shifted V(inact) in the depolarized direction in the IC neuron, consistent with 5-HT's enhancement of IC firing. None of the amines evoked significant changes in I(A) in the VD neuron, suggesting that other currents mediate the amine effects on this neuron.

Developing a synagis clinic for respiratory syncytial virus prophylaxis.

Respiratory Syncytial Virus (RSV) can be devastating to premature infants and children with chronic lung disease. Palivizumab (Synagis) is a monoclonal antibody that is administered monthly by injection to prevent RSV infection in infants at high risk. This article describes a nurse-run ambulatory clinic to provide RSV prophylaxis. Coordination with other agencies, including community neonatal intensive care units, was essential to the clinic's success. For each of its first 2 years of operation, 24 infants and their families attended the clinic once each month for 5 months throughout the RSV season. Outcomes for this patient population were compared to outcomes reported in the literature, and include reduced RSV-related hospitalizations and reduced days of hospitalization.

Comparison of carotid endarterectomy at high- and low-volume hospitals.

BACKGROUND: Population-based studies have demonstrated better outcomes for carotid endarterectomies at high-volume hospitals. METHODS: This is a 2-year retrospective review of carotid procedures at two low-volume hospitals (n = 156) and one high-volume hospital (n = 404) in the metropolitan area of Portland, Oregon. RESULTS: There were no significant differences in 30-day mortality and stroke rates for carotid endarterectomies when comparing low- and high-volume hospitals (P = 0.59). These were comparable rates despite the fact that the low-volume hospitals had significantly older patients (P <0.001), more smokers (P <0.001), more patients with an indication of a previous nondisabling stroke (P <0.01), and fewer patients who were asymptomatic (P <0.01). CONCLUSION: The regionalization of carotid endarterectomy into high-volume hospitals is not justified by the findings of this study. Carotid endarterectomy performed by well-trained, experienced surgeons in low-volume hospitals is a safe procedure.

Osteosarcoma of the patella with pulmonary metastases in a dog.

A 6-year-old neutered male Rottweiler was examined for a progressive right pelvic limb lameness. In radiographs of the right stifle, there was an osteolytic lesion with irregular new bone formation along the cranial aspect of the patella consistent with an aggressive bone lesion. In thoracic radiographs, there were multiple soft tissue nodular opacities throughout the lung fields, consistent with pulmonary metastases. Microscopically, fine needle aspirate samples from the right patella contained pleomorphic spindle cells with cytologic features of osteosarcoma. The presence of pulmonary metastases at the time of initial diagnosis in the dog described herein suggests that osteosarcoma of the patella has the potential for similar aggressive biologic behavior as that seen in dogs with appendicular osteosarcoma.