From the Cover: Deep phenotyping to predict live birth outcomes in in vitro fertilization

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVF_BT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003–2006, followed by external validation with 634 cycles from 2007–2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVF_BT, that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p < 0.05), and increased discrimination by receiver–operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVF_BT provided predictions that were more accurate for ∼83% of C1 and ∼60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.     

Sensory Impairment Among Older US Workers

We used 1997–2004 National Health Interview Survey data to evaluate the prevalence of sensory impairment among US workers 65 years and older. Hearing impairment prevalence was 3 times that of visual impairment (33.4% vs 10.2%), and 38% of older workers reported experiencing either impairment. Farm operators, mechanics, and motor vehicle operators had the highest prevalence of sensory impairment. Workplace screening and accommodations, including sensory protection devices for older workers, are warranted given the greater risk for injuries among the sensory impaired.Americans are living longer and are delaying retirement. As a result, the number of older US workers is increasing rapidly, with more than 40 million American workers 65 years and older projected to be in the workforce by 2012.¹ Older age is associated with a higher prevalence of sensory impairment,^2,3 which in turn is associated with an increased risk of occupational injury.^4–6 One public health implication of an increasingly older workforce is a continued rise in workplace injuries. An estimated 3.9 million cases of workplace injuries were reported in 2006,⁷ a disproportionate amount of which were among older employed men.⁸ Research on the prevalence of sensory impairment by occupational and industrial worker groups is needed to identify older US workers in greatest need of workplace accommodations. We examined the prevalence of vision and hearing impairment among older workers with data from a nationally representative sample of US worker groups.     

A sea change ahead for recreational water quality criteria

The United States Environmental Protection Agency is committed to developing new recreational water quality criteria for coastal waters by 2012 to provide increased protection to swimmers. We review the uncertainties and shortcomings of the current recreational water quality criteria, describe critical research needs for the development of new criteria, as well as recommend a path forward for new criteria development. We believe that among the most needed research needs are the completion of epidemiology studies in tropical waters and in waters adversely impacted by urban runoff and animal feces, as well as studies aimed to validate the use of models for indicator and pathogen concentration and health risk predictions.     

A novel CCR5-specific pharmacodynamic assay in whole blood using phosphoflow cytometry highlights different ligand-dependent responses but similar properties of antagonists in CD8+ and CD4+ T lymphocytes

Chemokine CC motif receptor (CCR) 5 is a major drug target for both inflammation and virology indications. The primary function of CCR5 is to mediate the trafficking of CCR5-expressing lymphocytes to any of the CCR5 ligands, which are often increased during inflammatory responses. In addition, CCR5 is a coreceptor for HIV, mediating R5 tropic HIV infection of CCR5-expressing CD4 T cells. We report the use of a novel method to assay the pharmacodynamic (PD) properties of small-molecule and antibody inhibitors of CCR5 ligand-induced activation by measuring phosphorylation of serine residue 349 in the cytoplasmic tail of human CCR5 using phosphoflow cytometry in whole blood. This assay is highly specific and measures CCR5 phosphorylation in both CD8(+) and CD4(+) T cells and allows the calculation of inhibitor IC(50) values from both lymphocyte subsets in the presence of CCR5 antagonists. In addition, this assay is cross-reactive to nonhuman primates and allows PD analysis in whole blood from rhesus and cynomolgus macaque. Using this assay, we identified different ligand-dependent response properties between CD8(+) and CD4(+) T cells, although CCR5 antagonists behave with similar properties against both cell types. The use of this assay may be of particular benefit to monitor PD effects of CCR5 inhibitors during drug development, preclinical in vivo studies, and in patients currently being treated for HIV or CCR5-mediated inflammatory diseases with CCR5 inhibitors. Similar phosphoflow approaches to other GPCR targets on circulating lymphocytes may prove to be the most reliable PD assay for preclinical and potentially clinical development.     

The Costs of Respiratory Illnesses Arising from Florida Gulf Coast Karenia brevis Blooms

Background

Algal blooms of Karenia brevis, a harmful marine algae, occur almost annually off the west coast of Florida. At high concentrations, K. brevis blooms can cause harm through the release of potent toxins, known as brevetoxins, to the atmosphere. Epidemiologic studies suggest that aerosolized brevetoxins are linked to respiratory illnesses in humans.

Objectives

We hypothesized a relationship between K. brevis blooms and respiratory illness visits to hospital emergency departments (EDs) while controlling for environmental factors, disease, and tourism. We sought to use this relationship to estimate the costs of illness associated with aerosolized brevetoxins.

Methods

We developed a statistical exposure–response model to express hypotheses about the relationship between respiratory illnesses and bloom events. We estimated the model with data on ED visits, K. brevis cell densities, and measures of pollen, pollutants, respiratory disease, and intra-annual population changes.

Results

We found that lagged K. brevis cell counts, low air temperatures, influenza outbreaks, high pollen counts, and tourist visits helped explain the number of respiratory-specific ED diagnoses. The capitalized estimated marginal costs of illness for ED respiratory illnesses associated with K. brevis blooms in Sarasota County, Florida, alone ranged from $0.5 to $4 million, depending on bloom severity.

Conclusions

Blooms of K. brevis lead to significant economic impacts. The costs of illness of ED visits are a conservative estimate of the total economic impacts. It will become increasingly necessary to understand the scale of the economic losses associated with K. brevis blooms to make rational choices about appropriate mitigation.     

Elastic fiber depletion in the supporting ligaments of the gastroesophageal junction: a structural basis for the development of hiatal hernia

BACKGROUND: The position of the gastroesophageal junction is maintained by a complex of fibroelastic ligaments. The purpose of this study was to characterize and compare the histology of these ligaments in patients with gastroesophageal reflux disease (GERD) and hiatal hernia (HH) versus GERD alone, with emphasis on the elastin morphology. STUDY DESIGN: Thirteen patients were examined at the time of laparoscopic fundoplication for symptomatic GERD; nine had no significant HH and four had large diaphragmatic hernias (GERD/HH). Tissue biopsies were obtained from the gastrohepatic ligament (GHL, n=5 and n=3, GERD and GERD/HH, respectively), the phrenoesophageal ligament (n=7 and n=4, respectively), and the gastrophrenic ligament (n=6 and n=4, respectively). Sections of fixed tissue were stained with hematoxylin and eosin, Masson's trichrome, and resorcin-fuchsin for analysis of elastic fibers by light microscopy, and elastin area was quantified and expressed as a percentage of the imaged tissue. RESULTS: Elastin and collagen fibers were prominent in all ligaments in patients with GERD alone. In patients with GERD/HH, there was fragmentation and distortion of elastin in the phrenoesophageal ligament and gastrohepatic ligament, and to a lesser degree, in the gastrophrenic ligament. Compared with patients with GERD alone, the presence of hiatal hernia was associated with a reduction in elastin area by more than 50% in the phrenoesophageal ligament ([mean +/- SEM] 31.0%+/-3.3% versus 15.1%+/-1.3%, p < 0.01) and gastrohepatic ligament (26.9% +/- 0.5% versus 12.5%+/-0.1%, p < 0.008). There was no decrease with respect to elastin in the gastrophrenic ligament. CONCLUSIONS: The periesophageal ligaments in patients with GERD are characterized by prominent elastic fibers. In contrast, GERD/HH is associated with depletion of elastic fibers in two of three ligaments supporting the gastroesophageal junction. Elastic fiber depletion in the periesophageal ligaments thereby provides a structural basis for the development of HH. It remains unclear if this represents a primary (etiologic) alteration or if it is a secondary phenomenon.     

Design, feasibility, and acceptability of an intervention using personal digital assistant-based self-monitoring in managing type 2 diabetes

BackgroundThe information processing demands associated with behavioral self-management of diabetes are extensive. Pairing personal digital assistant (PDA)-based self-monitoring with a behavioral self-management intervention may improve adherence and patient outcomes.MethodsENHANCE is a randomized controlled trial to test an intervention designed to improve regimen adherence in adults with type 2 diabetes. The intervention, based on Social Cognitive Theory (SCT), is paired with PDA-based self-monitoring. In this paper we describe the: (a) manner in which PDA-based self-monitoring is integrated within the SCT-based intervention, (b) feasibility and acceptability of PDA-based dietary self-monitoring, and (c) issues encountered in teaching participants to self-monitor using a PDA.ResultsDuring the first 30 months of this 5-year study, 232 participants were screened and 151 were randomized. To date, 6 cohorts have completed the study. The retention rate is 85% (n = 129). Of those randomized to the intervention (n = 74) and completing the study (n = 61), 88% reported understanding the usefulness of PDA-monitoring, 85% reported ease in entering foods into the device, 70% reported ease in interpreting feedback graphs, and 82% indicated that they would continue to use the PDA for self-monitoring after the study concluded. Assuming 3 meals per day, participants entered an average of 58% of their meals in their PDA, and 43% were entered assuming 4 meals per day. If we eliminate from the analysis those individuals who entered less than 10% of their expected meals (n = 12), the average rate of self-monitoring was 69% assuming 3 meals per day, and 52% assuming 4 meals per day.ConclusionsPDA-based dietary monitoring is perceived by participants to be useful and acceptable. The approach used to instruct participants in use of the PDA and lessons learned are discussed. PDA technology shows promise as a tool for assisting those with type 2 diabetes in their efforts to manage their disease.     

Melanocortin receptors as targets in the treatment of obesity

The central melanocortin system plays a critical role in energy homeostasis. It is well established that melanocortin-containing neurons are nutritionally regulated and that genetic alterations in the melanocortin system produce profound effects on food intake, energy expenditure, and body weight. Within the brain, melanocortin-producing neurons originate in the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the brainstem and project to various nuclei modulating energy balance. A large body of pharmacological and genetic evidence implicates the central melanocortin 4 receptors (MC4Rs) in the effects of melanocortin peptides on ingestive behaviour, energy expenditure, and body weight. Preclinical studies with endogenous and synthetic melanocortin ligands demonstrate that they produce potent effects on food intake and energy expenditure. Clinical studies thus far have been somewhat less successful and have been hampered by the induction of side effects, which present obstacles to the development of successful therapeutic agents. However, various promising strategies are being pursued to overcome these limitations, including the synthesis of more selective and potent melanocortin analogs.