Rare and Common Variants Conferring Risk of Tooth Agenesis.

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Impact of California Fires on Local and Regional Air Quality: The Role of a Low-Cost Sensor Network and Satellite Observations.

PM2.5, or fine particulate matter, is a category of air pollutant consisting of particles with effective aerodynamic diameter equal to or less than 2.5 µm. These particles have been linked to human health impacts as well as regional haze, visibility, and climate change issues. Due to cost and space restrictions, the U.S. Environmental Protection Agency monitoring network remains spatially sparse. To increase the spatial resolution of monitoring, previous studies have used satellite data to estimate ground-level PM concentrations, despite these estimates being associated with moderate to large uncertainties when relating a column measure of aerosol (aerosol optical depth) with surface measurements. To this end, we discuss a low-cost air quality monitor (LCAQM) network deployed in California. In this study, we present an application of LCAQM and satellite data for quantifying the impact of wildfires in California during October 2017. The impacts of fires on PM2.5 concentration at varying temporal (hourly, daily, and weekly) and spatial (local to regional) scales have been evaluated. Comparison between low-cost air quality sensors and reference-grade air quality instruments shows expected performance with moderate to high uncertainties. The LCAQM measurements, in the absence of federal equivalent method data, were also found to be very useful in developing statistical models to convert aerosol optical depth into PM2.5 with performance of satellite-derived PM2.5, similar to that obtained using the federal equivalent method data. This paper also highlights challenges associated with both LCAQM and satellite-based PM2.5 measurements, which require further investigation and research.

Risk of cancer in relatives of patients with myotonic dystrophy: a population-based cohort study.

BACKGROUND AND PURPOSE: Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted. METHODS: DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed). RESULTS: In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71-1.12) overall, and in stratified analyses 0.68 (0.37-1.12) before age 50 and 0.96 (0.74-1.23) at age 50 or older. CONCLUSIONS: The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

[Hidden diseases: tuberculosis in a woman with a severe mental illness]. / Tbc bij een vrouw met een ernstige psychiatrische aandoening.

Patients with severe mental illness often have only limited access to health care for physical symptoms. They have difficulty in organising their thoughts and articulating their requests for medical help; in addition, they often have a reduced perception of stimuli like physical pain. There may also be a language barrier and sometimes a cultural barrier. The case that we present demonstrates that these are not separate causes but they are interrelated in a complex manner. Screening for a latent disease such as tuberculosis reduces the risk of a delayed diagnosis stemming from the patient's inability to articulate a request for medical help. The physical symptoms of patients with severe mental illness can only be reliably interpreted when there is close cooperation between physicians and psychiatrists.

Genome-wide association scan for childhood caries implicates novel genes.

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

Genetic analysis of resistance to yellow rust in hexaploid wheat using a mixture model for multiple crosses.

DNA-based molecular markers have been used in numerous studies for tagging specific genes in wheat for subsequent use in marker-assisted selection. Usually in plant breeding, procedures for mapping genes are based on analysis of a single segregating population. However, breeding programmes routinely evaluate large numbers of progeny derived from multiple-related crosses with some parental lines shared. In most such related crosses, the number of progeny is quite small. Thus, statistical techniques for detecting quantitative trait loci (QTLs) using data from conventional multi-cross breeding programmes are interesting. The objective of this study is to present a mixture model for QTL mapping in crosses of multiple inbred varieties with non-normal phenotype distributions and to use this model to map QTLs for yellow rust resistance in elite wheat breeding material. Three doubled haploid populations consisting of 41, 42 and 55 lines, respectively, originating from four parental varieties were studied. Multi-cross QTL analysis with three specific pathogen isolates of Puccinia striiformis f. sp. tritici and a mixture of the isolates revealed QTLs for resistance at four different genomic locations. These QTLs were found on chromosome 2AL, 2AS, 2BL and 6BL and explained between 21 and 41% of the phenotypic variation. Two of these QTLs, one on the long arm of chromosome 2A and one on the short arm of chromosome 2A were identical to the known yellow rust resistance genes Yr32 and Yr17, respectively, whereas the QTLs located on the long arms of chromosomes 2B and 6B may reflect types of resistance to yellow rust, which have not previously been mapped.

Using lod scores to detect sex differences in male-female recombination fractions.

Human recombination fraction (RF) can differ between males and females, but investigators do not always know which disease genes are located in genomic areas of large RF sex differences. Knowledge of RF sex differences contributes to our understanding of basic biology and can increase the power of a linkage study, improve gene localization, and provide clues to possible imprinting. One way to detect these differences is to use lod scores. In this study we focused on detecting RF sex differences and answered the following questions, in both phase-known and phase-unknown matings: (1) How large a sample size is needed to detect a RF sex difference? (2) What are "optimal" proportions of paternally vs. maternally informative matings? (3) Does ascertaining nonoptimal proportions of paternally or maternally informative matings lead to ascertainment bias? Our results were as follows: (1) We calculated expected lod scores (ELODs) under two different conditions: "unconstrained," allowing sex-specific RF parameters (theta(female), theta(male)); and "constrained," requiring theta(female) = theta(male). We then examined the DeltaELOD (identical with difference between maximized constrained and unconstrained ELODs) and calculated minimum sample sizes required to achieve statistically significant DeltaELODs. For large RF sex differences, samples as small as 10 to 20 fully informative matings can achieve statistical significance. We give general sample size guidelines for detecting RF differences in informative phase-known and phase-unknown matings. (2) We defined p as the proportion of paternally informative matings in the dataset; and the optimal proportion p(circ) as that value of p that maximizes DeltaELOD. We determined that, surprisingly, p(circ) does not necessarily equal (1/2), although it does fall between approximately 0.4 and 0.6 in most situations. (3) We showed that if p in a sample deviates from its optimal value, no bias is introduced (asymptotically) to the maximum likelihood estimates of theta(female) and theta(male), even though ELOD is reduced (see point 2). This fact is important because often investigators cannot control the proportions of paternally and maternally informative families. In conclusion, it is possible to reliably detect sex differences in recombination fraction.

Video-speed electronic paper based on electrowetting.

In recent years, a number of different technologies have been proposed for use in reflective displays. One of the most appealing applications of a reflective display is electronic paper, which combines the desirable viewing characteristics of conventional printed paper with the ability to manipulate the displayed information electronically. Electronic paper based on the electrophoretic motion of particles inside small capsules has been demonstrated and commercialized; but the response speed of such a system is rather slow, limited by the velocity of the particles. Recently, we have demonstrated that electrowetting is an attractive technology for the rapid manipulation of liquids on a micrometre scale. Here we show that electrowetting can also be used to form the basis of a reflective display that is significantly faster than electrophoretic displays, so that video content can be displayed. Our display principle utilizes the voltage-controlled movement of a coloured oil film adjacent to a white substrate. The reflectivity and contrast of our system approach those of paper. In addition, we demonstrate a colour concept, which is intrinsically four times brighter than reflective liquid-crystal displays and twice as bright as other emerging technologies. The principle of microfluidic motion at low voltages is applicable in a wide range of electro-optic devices.

[Intracerebral tuberculomas in a pregnant Somalian woman]. / Intracerebrale tuberculomen bij een zwangere Somalische.

A pregnant Somalian woman aged 28 years, in the Netherlands for the last five years, suffered from a progressive hemiparesis, epilepsia, behavioural problems and low fever. Brain MRI showed multiple lesions with contrast enhancement. Extensive serologic and parasitologic tests on serum and cerebrospinal fluid did not disclose any cause. A brain biopsy revealed only necrosis, but bacterial culture and polymerase chain reaction (PCR) supplied the diagnosis of 'tuberculosis'. PCR on the cerebrospinal fluid remained negative. In the meantime the chest X-ray showed miliary tuberculosis and a spine MRI thoracic spondylodiscitis and a large paravertebral abscess. Subsequently the patient was treated successfully with tuberculostatic agents. Her healthy child which was born by caesarean section was treated with the tuberculostatic agents as well.

Quality assessment and quality control of radiographic units using simple tests. Experiences and results from Egypt.

To assess the image quality of radiographic units we developed a set of three relatively simple tests. With this set we investigated the performance of two small film x-ray units and seven dark rooms in chest disease clinics in Egypt. As a reference we performed the same tests at the Consultation Bureau for Tuberculosis and at the Radiology Department of the Medical Centre, Leeuwarden, The Netherlands. The tests revealed deficiencies during several phases of the production of radiographs at the chest disease clinics in Egypt, as well as at the Consultation Bureau for Tuberculosis, Leeuwarden, The Netherlands. The results of the tests were used to advise the radiology units tested on how to improve their quality. We believe, that this set of tests can be applied to any radiography unit to find ways for image quality improvement.

A new ventilation inhomogeneity index from multiple breath indicator gas washout tests in mechanically ventilated patients.

OBJECTIVES: a) To determine the validity of a new method to analyze indicator gas washout tests on mechanically ventilated patients. This method takes into account the difference between the end-expiratory gas fraction and the mean gas fraction in the lung and provides the end-expiratory lung volume and a new index of ventilation inhomogeneity called volumes regression index. b) To determine the validity of this index as a predictor of chronic obstructive pulmonary disease. c) To compare this index with the moment ratio index and Becklake index. DESIGN: Prospective study of diagnostic test. Criterium standards: Closed-circuit indicator gas dilution technique and Tiffeneau index. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: A total of 38 mechanically ventilated postoperative patients, divided into two groups: the obstructive group (n = 21) and the nonobstructive group (n = 17), based on their preoperative lung function. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: a) The mean coefficient of variation of all lung volume measurements in a group of nine healthy volunteers was 5%, and the difference between this technique and the closed-circuit helium dilution measurements was -2 +/- 5%. In patients, the mean coefficient of variation of the lung volume measurements was 3.5%. The volumes regression index was measured as 0.02 +/- 0.04 in a dummy lung, 0.37 +/- 0.08 in the healthy volunteers, 0.64 +/- 0.23 in the nonobstructive patients, and 1.1 +/- 0.3 in the obstructive patients. The volumes regression index provided a better correlation (r2 = .46) with preoperatively determined Tiffeneau index than the Becklake index (r2 = .11) or the moment ratio index (r2 = .18). CONCLUSION: The proposed technique provides a means for accurate measurement of the end-expiratory lung volume and the amount of ventilation inhomogeneity in mechanically ventilated intensive care unit patients.

PDPS: a pulmonary data processing system for assessment of gas exchange properties by multiple gas wash-out.

A data acquisition and processing system for the analysis of inert gas wash-out tests is described. The described system is in clinical use on spontaneously breathing patients as well as on mechanically ventilated Intensive Care patients. It combines several analysis techniques with an aim to provide a deeper insight into the nature of existing ventilation inhomogeneity than the individual techniques alone can provide. The signals measured are the respiratory flow, the fractions of one or two indicator gases washing out and the fractions of the metabolic gases oxygen and carbon dioxide. Analysis of these signals provides information concerning the end-expiratory lung-volume, distribution of ventilation and perfusion in the lung, the role of diffusion in the ventilation process and the metabolic oxygen uptake and CO2 release. This article describes the algorithms used and the results that are presented.

Assessment of energy expenditure by indirect calorimetry in healthy subjects and patients with liver cirrhosis.

The reliability of resting energy expenditure (REE) measurements by indirect calorimetry with a ventilated hood was investigated in 50 healthy controls and 10 patients with liver cirrhosis. In each subject basal energy expenditure (BEE) was determined once and REE three times (morning REE1, noon REE2, afternoon REE3). In controls and patients the first 5-minute BEE and first 5-minute REE (controls also second 5-minute REE) were higher than in the remainder of the 30-minute recording. Only the last 20 minutes of recordings were used to calculate BEE (1645 +/- 315, mean +/- SD, in kilocalories per day), REE1 (1880 +/- 365), REE2 (1782 +/- 384), and REE3 (1775 +/- 316) in controls, and in cirrhotics: BEE (1530 +/- 235), REE1 (1714 +/- 267), REE2 (1715 +/- 238), and REE3 (1779 +/- 275). REE was higher than BEE in controls and cirrhotics (p less than 0.05). The REE variation coefficient was 5 +/- 3% in controls and 5 +/- 2% in cirrhotics. No systematic difference between REE1, REE2, and REE3 was found. Energy expenditure predicted by the Harris-Benedict equation differed up to 21% from measured BEE in individual controls; group mean BEE, however, was correctly predicted. In cirrhotics differences between measured and predicted BEE up to 26% occurred, while measured BEE was higher than predicted BEE (p = 0.06). It is concluded that REE can be reliably assessed by indirect calorimetry with a ventilated hood system in controls and patients at any time of the day, when values obtained in the first 10 minutes are deleted.(ABSTRACT TRUNCATED AT 250 WORDS)

Independent oxygen uptake and oxygen delivery in septic and postoperative patients.

Previous studies reporting pathologic oxygen supply dependency calculated VO2 as CO x C(a-v)O2. We investigated whether pathologic oxygen supply dependency exists in septic and postoperative patients if VO2 and DO2 are assessed independently. In septic patients, VO2 was 164 +/- 31 and DO2 was 633 +/- 209 ml/min/m2. The slope (b) of the VO2-DO2 regression line VO2 = b x DO2 + a ranged from -0.10 to 0.08 (mean, 0.02 +/- 0.01, p less than 0.05) and was statistically significant in two patients (b = 0.05 and b = 0.08, p less than 0.05). In postoperative patients VO2 was 136 +/- 19 and DO2 was 481 +/- 160 ml/min/m2; b ranged from -0.07 to 0.09 (mean, 0.04 +/- 0.01, p less than 0.001) and was statistically significant in one patient (b = 0.09, p less than 0.01). The lack of a close relationship between independently measured VO2 and DO2 may indicate that septic and postoperative patients in stable hemodynamic condition have no pathologic oxygen supply dependency. Analysis of the VO2-DO2 relationship may not be useful to guide therapy or predict outcome.

Oxygen delivery and oxygen uptake in postoperative and septic patients.

Pathologic dependency of VO2 on DO2 has been reported in postoperative and septic patients. We studied the influence of an artifact due to calculation of VO2 from CO and AV content difference. In 13 postoperative and seven septic patients, the relationships between DO2 and cVO2 and between DO2 and mVO2 were analyzed by linear regression. In ten patients, cVO2 and DO2 were significantly correlated, but in only two of these patients mVO2 also correlated with DO2. In two patients, there was a significant correlation between mVO2 and DO2. The main contribution to the correlation and to the slope of the regression line between cVO2 and DO2 may be due to mathematic coupling of cVO2 and DO2. With cVO2, erroneous conclusions concerning the VO2-DO2 relationship may be drawn. In four patients, DO2 and mVO2 were significantly related, reflecting either physiologic coupling or pathologic supply dependency of VO2.

Design and validation of an indicator gas injector for multiple gas washout tests in mechanically ventilated patients.

A device to produce a stepwise indicator gas fraction variation to initiate a washout test in mechanically ventilated patients is described. The device, which can be used in conjunction with the commonly used Siemens-Elema series 900 ventilators, is based on simple, off-the-shelf technology. It features the simultaneous use of two indicator gases (so that the influence of diffusion processes in the gas exchange to the patient can be measured) and maintains a nearly constant FIO2 during a washout procedure. With this indicator gas injector, the transition time of the indicator gas fraction at the beginning of a washout proved to be short enough to detect ventilation inhomogeneity by visual inspection of the washout curves. Functional residual capacity measurements using this device are presented on a test lung with known volume, on healthy volunteers, and on critically ill patients.

Day-to-day variability of energy expenditure in critically ill surgical patients.

To determine whether the total energy expenditure (TEE) determined on a single day reliably estimates TEE on subsequent days of a patient's ICU stay, day-to-day variability of TEE and its relation to clinical condition were assessed. TEE was measured by indirect calorimetry in 60 mechanically ventilated critically ill surgical patients during a 2 to 7-day period. Clinical condition was scored by daily determination of the simplified acute physiology score (SAPS). Day-to-day variation of TEE was significantly (p less than .0001) influenced by body temperature, but not by SAPS or day of measurement. In the individual patient, day-to-day variability of TEE may be large. When TEE on day 1 is used to estimate TEE on subsequent days, errors of up to 31% of actual TEE occurred. Addition of a temperature correction reduced the maximum error to 25%. If a balance between caloric supply and demand is intended, it is advised to adapt the caloric supply to the result of daily TEE measurement by indirect calorimetry.

Accuracy of intermittent metabolic gas exchange recordings extrapolated for diurnal variation.

In the treatment of critically ill patients, it may be important to know the values of total diurnal O2 consumption and CO2 production. Often, diurnal values are obtained by extrapolation from the easily obtained short interval values. However, both stochastic and systematic errors can be introduced. This study analyzes the systematic influence of a possible diurnal variation of gas exchange and quantifies the extrapolation accuracy of 16 commonly used recording protocols (one to four times a day for 5, 15, 30, and 60 min). Continuous gas exchange measurements were performed for 24 h in 50 ventilated patients and compared to extrapolated results. Only a small diurnal variation was found, and extrapolation accuracy depended on the duration and, especially, the number of recording periods. In clinical practice, 24-h values can be estimated with sufficient accuracy by extrapolation from two 15-min measurements per day.

Assessment of peripheral vascular obliterative disease by transcutaneous oxygen tension tests.

By repeated measurements in each of ten normal subjects and ten patients with mild intermittent claudication, the performance of three transcutaneous oxygen tension (PtcO2) test in the diagnosis of obliterative peripheral arterial disease was studied. PtcO2 resting value, PtcO2 response to oxygen breathing and PtcO2 reperfusion response after tourniquet obstruction were all measured on the dorsum of the foot. We found that PtcO2 resting values were not different between patients and controls, while responses to 100% oxygen breathing and reperfusion responses differed significantly between the two groups. The most prominent difference between the two groups was observed in the latency of PtcO2 rise after reperfusion. Therefore the reperfusion response test may have a place in the assessment of claudication by PtcO2 measurement.

Outcome prediction in critically ill patients by means of oxygen consumption index and simplified acute physiology score.

Both oxygen consumption index (VO2-index) and simplified acute physiology score (SAPS) are reported to be reliable predictors of the ultimate outcome in critically ill patients. The purpose of this study was to verify whether survivors and nonsurvivors have different VO2-indices and whether the prognostic potency of SAPS can be improved by addition of VO2-index as a supplemental physiological variable. In 50 mechanically ventilated surgical ICU patients with heterogeneous underlying diseases, SAPS was calculated and VO2-index was determined by continuous 24-h measurement of oxygen consumption. The VO2-indices of survivors and nonsurvivors were not significantly different (p greater than 0.05), which is in contrast to the results of earlier studies. This contrast may be explained by a difference both in methods of VO2-measurement and in study populations. SAPS was significantly lower in survivors than in nonsurvivors (p less than 0.005) and was able to classify the patients correctly into groups of increasing probability of death. However, SAPS failed to be a helpful prognosticator in the individual patient. The addition of VO2-index to SAPS as a supplemental physiological variable did not substantially improve the prognostic potency. Because a higher VO2-index did not necessarily indicate a better survival chance, there is no argument for therapeutic interventions aimed exclusively at increasing VO2-index, as suggested previously.