Perspectives of clinical genetics professionals toward genome sequencing and incidental findings: a survey study

The introduction of clinical genome‐wide sequencing raises complex issues regarding the management of incidental findings. However, there is a lack of empirical studies assessing views of providers involved in potential disclosure of such findings. In an anonymous survey of 279 clinical genetics professionals, we found that the vast majority of participants agreed that they were interested in knowing about clinically actionable incidental findings in themselves (96%) and their child (99%), and they reported that these types of findings should be disclosed in adult (96%) and minor (98%) patients. Approximately three‐fourths agreed that they were personally interested in knowing about an adult‐onset clinically actionable disease (78%) and a childhood‐onset non‐clinically actionable disease (75%) in their child. A similar percentage of participants (70%) felt that these two types of findings should be disclosed to patients. Forty‐four percent of participants wanted to know about an incidental finding that indicates an adult‐onset non‐clinically actionable condition in themselves and 31% wanted to know about this type of information in their child. Findings from this study revealed participants' views highly dependent on clinical actionability. Further research is needed with a broader population of geneticists to increase generalizability, and with diverse patients to assess their perspectives about results disclosure from clinical sequencing.     

Metabolic syndrome among 13 year old adolescents: prevalence and risk factors

Background

Obesity and metabolic syndrome is prevalent among Malaysian adolescents and has been associated with certain behavioural factors such as duration of sleep, screen time and physical activity. The aim of the study is to report the prevalence of overweight/obesity, metabolic syndrome and its risk factors among adolescents.

Methods

A multi-staged cluster sampling method was used to select participants from urban and rural schools in Selangor, Perak and Wilayah Persekutuan Kuala Lumpur. Participants underwent anthropometric measurement and physical examination including blood pressure measurement. Blood samples were taken for fasting glucose and lipids and participants answered a self-administered questionnaire. Overweight and obesity was defined using the extrapolated adult body mass index (BMI) cut-offs of >25 kg/m² and >30 kg/m², according to the International Obesity Task Force (IOTF) criteria. Metabolic syndrome was defined based on International Diabetes Federation (IDF) 2007 criteria.

Results

Data were collected from 1361 participants. After excluding incomplete data and missing values for the variables, we analysed a sample of 1014 participants. Prevalence of overweight and obesity in this population was 25.4% (N = 258). The prevalence of metabolic syndrome was 2.6% in the population and 10% among the overweight and obese adolescents. Participants who slept between 7 and 9 hours a day has a lower risk of developing metabolic syndrome OR 0.38(0.15-0.94).

Conclusion

Our results provide the prevalence of metabolic syndrome in Malaysian adolescents. Adequate sleep between 7 and 9 hours per day reduces the risk of developing metabolic syndrome.

     

A Preliminary Parasitological Survey of Hepatozoon Spp. Infection in Dogs in Mashhad,Iran

Background

We attempted to determine the prevalence of Hepatozoon spp. infection in Mashhad, northeast of Iran, via blood smear parasitology.

Methods

The prevalence was investigated by examination of blood smear parasitology, using blood samples collected from 254 dogs (51 strays and 203 privately owned-dogs).

Results

Two stray dogs (2/51; 3.92%) and two privately-owned dogs (2/203; 0.98%) were infected with Hepatozoon spp. Therefore, as per blood smear parasitology, the prevalence of Hepatozoon spp. infection was 1.57% (4/254). Sixteen out of 254 dogs (6.29%) were infested with ticks; all of which were Rhipicephalus sanguineus. One of the dogs infected with Hepatozoon spp. exhibited ticks at the time of examination. Concurrent infection with Ehrlichia canis and Leishmania infantum was not detected in the four Hepatozoon spp. infected dogs.

Conclusion

This is the first epidemiological study on the prevalence of Hepatozoon spp. infection in dogs in Iran.     

Mechanical resilience and cementitious processes in Imperial Roman architectural mortar

The pyroclastic aggregate concrete of Trajan’s Markets (110 CE), now Museo Fori Imperiali in Rome, has absorbed energy from seismic ground shaking and long-term foundation settlement for nearly two millenia while remaining largely intact at the structural scale. The scientific basis of this exceptional service record is explored through computed tomography of fracture surfaces and synchroton X-ray microdiffraction analyses of a reproduction of the standardized hydrated lime–volcanic ash mortar that binds decimeter-sized tuff and brick aggregate in the conglomeratic concrete. The mortar reproduction gains fracture toughness over 180 d through progressive coalescence of calcium–aluminum-silicate–hydrate (C-A-S-H) cementing binder with Ca/(Si+Al) ≈ 0.8–0.9 and crystallization of strätlingite and siliceous hydrogarnet (katoite) at ≥90 d, after pozzolanic consumption of hydrated lime was complete. Platey strätlingite crystals toughen interfacial zones along scoria perimeters and impede macroscale propagation of crack segments. In the 1,900-y-old mortar, C-A-S-H has low Ca/(Si+Al) ≈ 0.45–0.75. Dense clusters of 2- to 30-µm strätlingite plates further reinforce interfacial zones, the weakest link of modern cement-based concrete, and the cementitious matrix. These crystals formed during long-term autogeneous reaction of dissolved calcite from lime and the alkali-rich scoriae groundmass, clay mineral (halloysite), and zeolite (phillipsite and chabazite) surface textures from the Pozzolane Rosse pyroclastic flow, erupted from the nearby Alban Hills volcano. The clast-supported conglomeratic fabric of the concrete presents further resistance to fracture propagation at the structural scale.The builders of the monuments of Imperial Rome (from 27 BCE, when Octavian became Emperor Augustus, through the fourth century CE) used pyroclastic volcanic rock to create unreinforced concrete structures with dramatic vaulted spans, as at the Markets of Trajan (110 CE) (1, 2) (Fig. 1A). The concrete foundations, walls, and vaulted ceilings are composed of decimeter-sized volcanic tuff and brick coarse aggregate (caementa) bound by volcanic ash–lime mortar (Fig. 1B). The conglomeratic fabric of the concretes is analogous to sedimentary rocks made of coarse rock fragments and a matrix of finer grained material. The concretes have resisted structural scale failure during moderate-magnitude earthquakes (<8 on the Mercalli–Cancani–Sieberg intensity scale) associated with slip on Appennine fault systems 80–130 km to the northeast, as well as chemical decay associated with repeated inundations of foundations and walls by Tiber River floods (3–5). To date, at least six episodes of moment magnitude 6.7–7 ground shaking and damage to monuments have been recorded since 508 CE (4). The concrete structures contain common macroscale fractures, with rough surfaces that link by complex segment overlap and bridging, and either follow or traverse caementa interfacial zones (Fig. 1C). Many monuments remain in active use as residences, offices, museums, and churches. In addition to the Markets of Trajan, these include the Theater of Marcellus (44–13 BCE), Mausoleum of Hadrian (123–39 CE), Pantheon (ca. 126 CE), and Baths of Diocletian (298–306 CE). The monuments that did undergo sectional failure, for example at the Colosseum (70–90 CE), Baths of Caracalla (ca. 215 CE), and Basilica of Maxentius (ca. 313 CE), mainly did so in Late Antiguity or the Middle Ages, when they were several centuries old and had become vulnerable through subsurface instabilities; problematic structural design; removal of marble and travertine dimension stone, columns, and cladding; and lack of regular maintenance (4, 6, 7).Open in a separate windowFig. 1.Markets of Trajan concretes. (A) Great Hall, vaulted ceiling and brick-faced concrete walls; reprinted with permission from Archives, Museo Fori Imperiali. (B) Drill core with Pozzolane Rosse volcanic ash (harena fossicia) mortar and conglomeratic aggregate (caementa). (C) Fractures in vaulted ceiling, Grande Emiciclo: 1, crack follows caementa perimeter; 2, crack traverses caementa. Wall concrete contains ∼88 vol % pyroclastic rock: 45–55% tuff (and brick) as caementa, ∼38% volcanic ash pozzolan, and ∼12% lime paste, with 3:1 ash:lime volumetric ratio (de Architectura 2.5.1) in the mortar (18).The pozzolanic mortar perfected by Roman builders during first century BCE (8) is key to the durability of concrete components in structurally sound monuments well maintained over two millennia of use. [Pozzolans, named after pumiceous ash from Puteoli (now, Pozzuoli) in the Campi Flegrei volcanic district, react with lime in the presence of moisture to form binding cementitious hydrates (9)]. By the Augustan era (27 BCE–14 CE), after experimenting with ash mixtures for >100 y, Romans had a standardized mortar formulation using scoriaceous ash of the mid-Pleistocene Pozzolane Rosse pyroclastic flow (Fig. S1) that substantially improved the margin of safety associated with increasingly daring structural designs (10, 11). They used this mortar formulation in the principal Imperial monuments constructed in Rome through early fourth century CE (8). Pozzolane Rosse erupted at 456 ± 3 ka from nearby Alban Hills volcano (12), filling valleys and covering topographic plateaus across the Roman region; the ash has a highly potassic tephritic composition (13). Romans made the architectural mortars by calcining limestone at ∼900 °C to produce quicklime [CaO], hydrating the quicklime to form portlandite [Ca(OH)₂], a trigonal calcium hydroxide] putty, and laboriously incorporating granular Pozzolane Rosse ash. This is the red and black excavated sand (harena fossicia) described by the Roman architect Vitruvius in first century BCE (de Architectura 2.4.1–2.4.3; 2.5.1–2.5.3) (14). The strongly alkaline portlandite solution attacks the surfaces of the scoriaceous pozzolan; volcanic glass and silicate mineral textures dissociate; their alkali ions dissolve in the liquid phase; and calcium is adsorbed on the scoria surfaces, forming cementitious hydrates (9). These phases are regarded as central to the chemical durability that is an essential component of the impressive record of survival of many monuments, but their role in resisting mechanical degradation through obstructing microcrack propagation has never been examined.Fracture-mechanical properties offer important insight into a cementitious material’s long-term survivability (i.e., its ability to absorb energy from applied loads without failing catastrophically). Two common properties are uniaxial tensile strength [f_t (megapascals)], which refers to the stress at which a macrocrack initiates, and fracture energy [G_F (joules per square meter)], the amount of mechanical work required to propagate a macrocrack to create one square unit of new surface area (15). Experimental characterization of the fracture behavior of the Imperial-age mortar through tests of ancient material is difficult, because it occurs in narrow, irregular zones that are bonded to caementa (Fig. 1B), and the heterogeneous fabric of the concrete requires large test dimensions (16). We therefore duplicated the Imperial-age mortar using the volcanic ash–quicklime proportions described by Vitruvius (de Architectura 2.4–2.5) (14) and petrographic and mineralogical characterization of mortar samples from the Great Hall of Trajan’s Markets (17) to formulate a mix design that closely mimics the Trajanic formulation. Fracture-mechanical properties, as well as Young’s modulus, were previously determined at 28, 90, and 180 d hydration via an innovative arc-shaped three-point bending test (18) that reproduced half-slices of hollow 20-cm-diameter drill cores from the Great Hall (Fig. 1B), so that the behavior of the mortar reproduction can be compared with that of Trajanic concrete in a future experimental testing program. All measured properties increase with age, with the 180-d mortar producing values for Young’s modulus and uniaxial tensile strength around 1/10 of modern structural concrete, whereas fracture energy is close to one-half (Fig. S2) of the crack arrays in the reproduction at 28, 90, and 180 d hydration provide visualization of millimeter-scale fracture processes to which macroscale toughness associated with previously published G_F values are attributed (18). X-ray microdiffraction experiments with synchroton radiation are a critical analytic component, because they provide very fine-scale identifications of the cementitious mineral assemblage that evolved over 1,900 y. The Markets of Trajan concrete provides a proven prototype for innovations in monolithic concretes (19) that are reinforced by a clast-supported conglomeratic fabric at the macroscale and an enduring crystalline fabric at the microscale. New concrete materials formulated with pyroclastic aggregate based on the Imperial Roman prototype could reduce carbon emissions, produce crystalline cementitious reinforcements over long periods of time, enhance durability in seismically active regions, and extend the service life of environmentally sustainable buildings.

Table 1.

Mechanical properties of mortar reproductions

Toward a better understanding and quantification of methane emissions from shale gas development

The identification and quantification of methane emissions from natural gas production has become increasingly important owing to the increase in the natural gas component of the energy sector. An instrumented aircraft platform was used to identify large sources of methane and quantify emission rates in southwestern PA in June 2012. A large regional flux, 2.0–14 g CH₄ s⁻¹ km⁻², was quantified for a ∼2,800-km² area, which did not differ statistically from a bottom-up inventory, 2.3–4.6 g CH₄ s⁻¹ km⁻². Large emissions averaging 34 g CH₄/s per well were observed from seven well pads determined to be in the drilling phase, 2 to 3 orders of magnitude greater than US Environmental Protection Agency estimates for this operational phase. The emissions from these well pads, representing ∼1% of the total number of wells, account for 4–30% of the observed regional flux. More work is needed to determine all of the sources of methane emissions from natural gas production, to ascertain why these emissions occur and to evaluate their climate and atmospheric chemistry impacts.Methane is a very important component of the Earth’s atmosphere: it represents a significant component of the natural and anthropogenically forced greenhouse effect, with a global warming potential 28–34 times greater than CO₂ using a 100-y horizon and even greater on shorter time scales (1, 2). It also is an important sink for the hydroxyl radical, the dominant agent that defines the atmosphere’s cleansing capacity (3), has a significant impact on tropospheric ozone, and is one of the important sources of water vapor in the stratosphere, which in turn impacts stratospheric ozone and climate (4). The recent observation that global methane concentrations have begun increasing (5), after a decade of static or decreasing emissions in the late 1990s to ∼2007, has renewed interest in pinpointing the causes of global methane trends. Recently natural gas has been explored as a potential bridge to renewable energy, owing in part to the reduction in carbon emissions produced from electricity generation by natural gas compared with coal (6–9). Advances in drilling and well stimulation techniques have allowed access to previously locked reservoirs of natural gas, such as the Marcellus shale formation in Pennsylvania, which has led to a boom in natural gas production in the last decade (10). This has led to estimations of the carbon footprint of natural gas to examine the impact of increasing our reliance on natural gas for various energy needs (11–16). An important unresolved issue is the contribution of well-to-burner tip CH₄ emission to the greenhouse gas footprint of natural gas use. Given that CH₄ is a much more potent greenhouse gas than CO₂, quantifying CH₄ emissions has become critical in estimating the long- and short-term environmental and economic impacts of increased natural gas use. According to a recent study, if total CH₄ emissions are greater than approximately 3.2% of production, the immediate net radiative forcing for natural gas use is worse than for coal when used to generate electricity (8).The first estimates for CH₄ emissions from shale gas development were reported in late 2010 and are based on uncertain emission factors for various steps in obtaining the gas and getting it to market (17, 18). In the short time since these first estimates, many others have published CH₄ emission estimates for unconventional gas (including tight-sand formations in addition to shales), giving a range of 0.6–7.7% of the lifetime production of a well emitted “upstream” at the well site and “midstream” during processing and 0.07–10% emitted during “downstream” transmission, storage, and distribution to consumers (reviewed in refs. 18 and 19). The highest published estimates for combined upstream and midstream methane emissions (2.3–11.7%) are based on actual top-down field-scale measurements at specific regions (20, 21). Whereas a recent shale gas study (22) based on field sites across the United States to which the authors were given access scaled actual measurements up to the national level and found lower emissions than US Environmental Protection Agency (EPA) estimates, an equally recent study (23) used atmospheric measurements of greenhouse gases across the United States to inform a model and found CH₄ emissions, cumulatively and specifically from fossil fuel production activities, to be underestimated by the EPA.The current range of observed CH₄ emissions from US natural gas systems (2.3–11.7%), if it were representative of the national scale, applied to the reported 2011 unassociated gas production number yields a range of CH₄ emissions between 5.6 and 28.4 Tg CH₄, whereas the EPA reports 6.7 Tg CH₄ from natural gas systems in 2011 and only 28 Tg CH₄ total anthropogenic emissions (24). Natural gas systems are currently estimated to be the top source of anthropogenic CH₄ emission in the United States, followed closely by enteric fermentation, but the top-down observations suggest that natural gas may play a more substantial role than previously thought (24). Inadequate accounting of greenhouse gas emissions hampers efforts to identify and pursue effective greenhouse gas reduction policies.Although it is clear that analysis of the effect of natural gas use would benefit from better measurements of emissions from unconventional gas wells, the inaccessible and transient nature of these leaks makes them difficult to identify and quantify, particularly at a scale at which they are useful for bottom-up inventories or mitigation strategies (i.e., leak rates of individual components or activities). Previous techniques have used either bottom-up inventories of the smallest scale of contributions or top-down apportionment of observed large-scale regional enhancements over a complex area to identify the source of the enhancements (11, 17, 20–23, 25). Although the latter suggest that the leak rate may be higher than what bottom-up inventories have allocated, they give little to no information about where in the upstream production process these leaks occur, thus hampering the interpretation of these data for bottom-up inventories or mitigation purposes.Here we use an aircraft-based approach that enables sampling of methane emissions between the regional and component level scales and can identify plumes from single well pads, groups of well pads, and larger regional scales, giving more information as to the specific CH₄ emission sources. We implemented three types of flights over 2 d in June 2012: investigative (I), mass-balance flux (MB), and regional flux (RF). Details of each flight are presented in

Fructose breath hydrogen tests

Fructose absorption was studied by the breath hydrogen test in 114 healthy children aged 0.1-6 years, given either 2 g/kg or 1 g/kg of fructose. All 57 children given 2 g/kg had peak breath hydrogen excretions > or = 20 ppm. At 1 g/kg only 25/57 (44%) showed incomplete absorption and the percentage incompletely absorbing fructose and the peak breath hydrogen value were significantly higher in children aged 1-3 years. Interestingly, this age distribution correlates with that of toddler diarrhoea.     

Bowel migration in the normal fetus: US detection

Ten fetuses underwent ultrasound scanning at 7-10 weeks gestational (postmenstrual) age. In all cases, an echogenic mass measuring 0.5-1.0 cm was demonstrated within the base of the umbilical cord at its insertion into the fetal abdomen. No area with echogenicity characteristic of the small bowel was identified within the lower part of the fetal abdomen. All fetuses were reexamined 4-12 weeks later, at which time the mass in the umbilical cord was no longer seen, and normal fetal bowel was visualized in the lower abdominal cavity of the fetus. This sequence of findings appears to represent the sonographic demonstration of normal fetal bowel migration early in gestation and should not be confused with defects of the abdominal wall such as omphalocele or gastroschisis.     

Clinico-epidemiological features of congenital nonbullous ichthyosiform erythroderma in the eastern province of Saudi Arabia

BACKGROUND: A total of 10 455 new dermatology patients were seen in the dermatology clinics of King Fahd Hospital of the University (KFHU), Al-Khobar, Eastern Saudi Arabia, between January 1990 and December 1995. We identified 21 patients with a histopathologically confirmed diagnosis of congenital nonbullous ichthyosiform erythroderma (CNBIE). We have reviewed the epidemiological and clinical features of these patients. OBJECTIVE: To document the epidemiological and clinical features of patients with CNBIE in eastern Saudi Arabia. METHODS: We used the dermatology outpatient department (OPD) logbooks to identify diagnosed cases of CNBIE from new patients presenting with different dermatological problems over a 6-year period. We used specifically designed data-collection protocol forms to extract epidemiological and clinical data from the patients' medical records. These were entered into a computer database and analysed using standard statistical software. RESULTS: A total of 21 patients (five males, 16 females) with a male : female ratio of 0.31 : 1 were identified from a total of 10 455 new patients seen in our dermatology clinics over the study period. The occurrence rate of CNBIE in our clinics was 0.2%, or two per 1000 new dermatology cases. Nineteen (90%) of 21 CNBIE patients were born with collodion membranes. Eighty-one per cent of our patients had a positive family history of CNBIE. Consanguinity among the parents of our CNBIE patients was significantly high at 95%. CONCLUSIONS: To the best of our knowledge, this preliminary study is the first report of its kind from Saudi Arabia (documenting the clinico-epidemiological features of CNBIE patients in the Eastern Province). The high rate of parental consanguinity among the parents of our Saudi CNBIE patients may account for the high incidence rate of this genodermatosis in eastern Saudi Arabia. In comparison with results of other studies that reported a low occurrence rate of CNBIE among dermatology patients, our results were of a significantly higher rate.