Testing the Dose–Response Specification in Epidemiology: Public Health and Policy Consequences for Lead

Statistical evaluation of the dose–response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose–response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear–linear dose response) and natural-log–transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose–response relationship. We found that a log-linear lead–IQ relationship was a significantly better fit than was a linear–linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead–IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 μg/dL to 2.0 μg/dL) was 2.2 times ($319 billion) that calculated using a linear–linear dose–response function ($149 billion). The Centers for Disease Control and Prevention action limit of 10 μg/dL for children fails to protect against most damage and economic cost attributable to lead exposure

Short-Term Exposure to Warm Microhabitats Could Explain Amphibian Persistence with Batrachochytrium dendrobatidis

Environmental conditions can alter the outcomes of symbiotic interactions. Many amphibian species have declined due to chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd), but many others persist despite high Bd infection prevalence. This indicates that Bd's virulence is lower, or it may even be a commensal, in some hosts. In the Australian Wet Tropics, chytridiomycosis extirpated Litoria nannotis from high-elevation rain forests in the early 1990 s. Although the species is recolonizing many sites, no population has fully recovered. Litoria lorica disappeared from all known sites in the early 1990 s and was thought globally extinct, but a new population was discovered in 2008, in an upland dry forest habitat it shares with L. nannotis. All frogs of both species observed during three population censuses were apparently healthy, but most carried Bd. Frogs perch on sun-warmed rocks in dry forest streams, possibly keeping Bd infections below the lethal threshold attained in cooler rain forests. We tested whether short-term elevated temperatures can hamper Bd growth in vitro over one generation (four days). Simulating the temperatures available to frogs on strongly and moderately warmed rocks in dry forests, by incubating cultures at 33°C for one hour daily, reduced Bd growth below that of Bd held at 15°C constantly (representing rain forest habitats). Even small decreases in the exponential growth rate of Bd on hosts may contribute to the survival of frogs in dry forests

People’s understanding of verbal risk descriptors in patient information leaflets : a cross-sectional national survey of 18- to 65-year-olds in England

Introduction Evidence suggests the current verbal risk descriptors used to communicate side effect risk in patient information leaflets (PILs) are overestimated. Objectives The aim was to establish how people understand the verbal risk descriptors recommended for use in PILs by the European Commission (EC), and alternative verbal risk descriptors, in the context of mild and severe side effects. Methods A cross-sectional online survey was carried out by a market research company recruiting participants aged between 18 and 65 years living in England. Data were collected between 18 March and 1 April 2016. Participants were given a hypothetical scenario regarding the risk of mild or severe medication side effects and asked to estimate how many out of 10,000 people would be affected for each of the verbal risk descriptors being tested. Results A total of 1003 participants were included in the final sample. The risks conveyed by the EC recommended verbal risk descriptors were greatly overestimated by participants. Two distinct distributions were apparent for participant estimates of side effect risks: those for ‘high risk’ verbal descriptors (e.g. ‘common’, ‘likely’, ‘high chance’) and those for ‘low risk’ verbal descriptors (e.g. ‘uncommon’, ‘unlikely’, ‘low chance’). Within these two groups, the distributions were near to identical regardless of what adverb (e.g. very, high, fair) or adjective (e.g. common, likely, chance) was used. The EC recommended verbal risk descriptors were more likely to be understood in accordance with their intended meanings when describing severe side effects. Very few demographic or psychological factors were consistently associated with how well participants understood the EC recommended verbal risk descriptors. Discussion The current verbal risk descriptors used in PILs are ineffective at best and misleading at worst. Discontinuing the use of verbal risk descriptors would limit the likelihood of people overestimating the risk of side effects

A Reservoir Species for the Emerging Amphibian Pathogen Batrachochytrium dendrobatidis Thrives in a Landscape Decimated by Disease

Chytridiomycosis, a disease caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is driving amphibian declines and extinctions in protected areas globally. The introduction of invasive reservoir species has been implicated in the spread of Bd but does not explain the appearance of the pathogen in remote protected areas. In the high elevation (>1500 m) Sierra Nevada of California, the native Pacific chorus frog, Pseudacris regilla, appears unaffected by chytridiomycosis while sympatric species experience catastrophic declines. We investigated whether P. regilla is a reservoir of Bd by comparing habitat occupancy before and after a major Bd outbreak and measuring infection in P. regilla in the field, monitoring susceptibility of P. regilla to Bd in the laboratory, examining tissues with histology to determine patterns of infection, and using an innovative soak technique to determine individual output of Bd zoospores in water. Pseudacris regilla persists at 100% of sites where a sympatric species has been extirpated from 72% in synchrony with a wave of Bd. In the laboratory, P. regilla carried loads of Bd as much as an order of magnitude higher than loads found lethal to sympatric species. Histology shows heavy Bd infection in patchy areas next to normal skin, a possible mechanism for tolerance. The soak technique was 77.8% effective at detecting Bd in water and showed an average output of 68 zoospores per minute per individual. The results of this study suggest P. regilla should act as a Bd reservoir and provide evidence of a tolerance mechanism in a reservoir species

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l−1, 1=C-reactive protein >10 mg l−1, and 2=C-reactive protein >10 mg l−1 and albumin<35 g l−1) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54–9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29–11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11–4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99–3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05–4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82–3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01–2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response

Monitoring of adherence to headache treatments by means of hair analysis

The aim of this study was to evaluate the potential of hair analysis to monitor medication adherence in headache patients undergoing chronic therapy. For this purpose, the following parameters were analyzed: the detection rate of 23 therapeutic drugs in headache patients' hair, the degree of agreement between the self-reported drug and the drug found in hair, and whether the levels found in hair reflected the drug intake reported by the patients

Acquired homotypic and heterotypic immunity against oculogenital Chlamydia trachomatis serovars following female genital tract infection in mice

BACKGROUND: Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen causing female genital tract infection throughout the world. Reinfection with the same serovar, as well as multiple infections with different serovars, occurs in humans. Using a murine model of female C. trachomatis genital tract infection, we determined if homotypic and/or heterotypic protection against reinfection was induced following infection with human oculogenital strains of C. trachomatis belonging to two serovars (D and H) that have been shown to vary significantly in the course of infection in the murine model. METHODS: Groups of outbred CF-1 mice were reinfected intravaginally with a strain of either serovar D or H, two months after initial infection with these strains. Cellular immune and serologic status, both quantitative and qualitative, was assessed following initial infection, and the course of infection was monitored by culturing vaginal samples collected every 2–7 days following reinfection. RESULTS: Serovar D was both more virulent (longer duration of infection) and immunogenic (higher level of circulating and vaginal IgG and higher incidence of IgA in vaginal secretions) in the mouse genital tract. Although both serovars induced cross-reacting antibodies during the course of primary infection, prior infection with serovar H resulted in only a slight reduction in the median duration of infection against homotypic reinfection (p ~ 0.10), while prior infection with serovar D resulted in significant reduction in the median duration of infection against both homotypic (p < 0.01) and heterotypic reinfection (p < 0.01) when compared to primary infection in age and conditions matched controls. CONCLUSION: Serovar D infection resulted in significant homotypic and heterotypic protection against reinfection, while primary infection with serovar H resulted in only slight homotypic protection. In addition to being the first demonstration of acquired heterotypic immunity between human oculogenital serovars, the differences in the level and extent of this immunity could in part explain the stable difference in serovar prevalence among human isolates

The relationship between the preoperative systemic inflammatory response and cancer-specific survival in patients undergoing potentially curative resection for renal clear cell cancer

The relationship between tumour stage, grade (Fuhrman), performance status (ECOG), a combined score (UCLA Integrated Staging System, UISS), systemic inflammatory response (elevated C-reactive protein concentration), and cancer-specific survival was examined in patients undergoing potentially curative resection for renal clear cell cancer (n=100). On univariate survival analysis, sex (P=0.050), tumour stage (P=0.001), Fuhrman grade (P<0.001), UISS (P<0.001), C-reactive protein (P=0.002) were significant predictors of survival. On multivariate analysis with sex, UISS and C-reactive protein entered as covariates, only UISS (HR 2.70, 95% CI 1.00–7.30, P=0.050) and C-reactive protein (HR 4.00, 95% CI 1.21–13.31, P=0.024) were significant independent predictors of survival. The presence of a preoperative systemic inflammatory response predicts poor cancer-specific survival in patients who have undergone potentially curative resection for renal clear cell cancer

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a\u27s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes