Spina bifida

Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa

Optical mesoscopy, machine learning and computational microscopy enable high information content diagnostic imaging of blood films

Automated image-based assessment of blood films has tremendous potential to support clinical haematology within overstretched healthcare systems. To achieve this, efficient and reliable digital capture of the rich diagnostic information contained within a blood film is a critical first step. However, this is often challenging, and in many cases entirely unfeasible, with the microscopes typically used in haematology due to the fundamental trade-off between magnification and spatial resolution. To address this, we investigated three state-of-the-art approaches to microscopic imaging of blood films which leverage recent advances in optical and computational imaging and analysis to increase the information capture capacity of the optical microscope: optical mesoscopy, which uses a giant microscope objective (Mesolens) to enable high resolution imaging at low magnification; Fourier ptychographic microscopy, a computational imaging method which relies on oblique illumination with a series of LEDs to capture high resolution information; and deep neural networks which can be trained to increase the quality of low magnification, low resolution images. We compare and contrast the performance of these techniques for blood film imaging for the exemplar case of Giemsa-stained peripheral blood smears. Using computational image analysis and shape-based object classification we demonstrate their use for automated analysis of red blood cell morphology and visualization and detection of small blood borne parasites such as the malarial parasite Plasmodium falciparum. Our results demonstrate that these new methods greatly increase the information capturing capacity of the light microscope with transformative potential for haematology and more generally across digital pathology. This article is protected by copyright. All rights reserved

Factors associated with the desire for orthodontic treatment among Brazilian adolescents and their parents

<p>Abstract</p> <p>Background</p> <p>In the period of adolescence physical appearance takes on significant importance in the construction of personal identity, including one's relationship with one's own body. A variety of social, cultural, psychological and personal factors influences the self-perception of dental appearance and the decision to undergo orthodontic treatment. Adolescents who seek orthodontic treatment are concerned with improving their appearance and social acceptance. The aim of the present study was to determine factors associated to the desire for orthodontic treatment among Brazilian adolescents and their parents.</p> <p>Methods</p> <p>The sample consisted of 403 subjects aged 14 to 18 years, selected randomly from a population of 182,291 schoolchildren in the same age group. The outcome variable "desire for orthodontic treatment" was assessed through a questionnaire. Self-perception of dental aesthetics was assessed using the Oral Aesthetic Subjective Impact Scale (OASIS) and the Dental Aesthetic Index (DAI) was used for clinical assessment. Statistical analysis involved the chi-square test as well as both simple and multiple logistic regression analyses.</p> <p>Results</p> <p>The majority (78%) of the Brazilian adolescents desired orthodontic treatment and 69% of the parents reported that their children were not in orthodontic treatment due to the high costs involved. There was significant association (p ≤ 0.05) between the desire for orthodontic treatment and most types of malocclusion. However, there was no significant association between the desire for orthodontic treatment and the variables gender and age.</p> <p>Conclusions</p> <p>The following were considered factors associated to the desire for treatment: upper anterior crowding ≥ 2 mm and parents' perception of their child's need for treatment.</p

Helical Chirality: a Link between Local Interactions and Global Topology in DNA

DNA supercoiling plays a major role in many cellular functions. The global DNA conformation is however intimately linked to local DNA-DNA interactions influencing both the physical properties and the biological functions of the supercoiled molecule. Juxtaposition of DNA double helices in ubiquitous crossover arrangements participates in multiple functions such as recombination, gene regulation and DNA packaging. However, little is currently known about how the structure and stability of direct DNA-DNA interactions influence the topological state of DNA. Here, a crystallographic analysis shows that due to the intrinsic helical chirality of DNA, crossovers of opposite handedness exhibit markedly different geometries. While right-handed crossovers are self-fitted by sequence-specific groove-backbone interaction and bridging Mg2+ sites, left-handed crossovers are juxtaposed by groove-groove interaction. Our previous calculations have shown that the different geometries result in differential stabilisation in solution, in the presence of divalent cations. The present study reveals that the various topological states of the cell are associated with different inter-segmental interactions. While the unstable left-handed crossovers are exclusively formed in negatively supercoiled DNA, stable right-handed crossovers constitute the local signature of an unusual topological state in the cell, such as the positively supercoiled or relaxed DNA. These findings not only provide a simple mechanism for locally sensing the DNA topology but also lead to the prediction that, due to their different tertiary intra-molecular interactions, supercoiled molecules of opposite signs must display markedly different physical properties. Sticky inter-segmental interactions in positively supercoiled or relaxed DNA are expected to greatly slow down the slithering dynamics of DNA. We therefore suggest that the intrinsic helical chirality of DNA may have oriented the early evolutionary choices for DNA topology

Secular Evolution and the Formation of Pseudobulges in Disk Galaxies

We review internal processes of secular evolution in galaxy disks, concentrating on the buildup of dense central features that look like classical, merger-built bulges but that were made slowly out of disk gas. We call these pseudobulges. As an existence proof, we review how bars rearrange disk gas into outer rings, inner rings, and gas dumped into the center. In simulations, this gas reaches high densities that plausibly feed star formation. In the observations, many SB and oval galaxies show central concentrations of gas and star formation. Star formation rates imply plausible pseudobulge growth times of a few billion years. If secular processes built dense central components that masquerade as bulges, can we distinguish them from merger-built bulges? Observations show that pseudobulges retain a memory of their disky origin. They have one or more characteristics of disks: (1) flatter shapes than those of classical bulges, (2) large ratios of ordered to random velocities indicative of disk dynamics, (3) small velocity dispersions, (4) spiral structure or nuclear bars in the bulge part of the light profile, (5) nearly exponential brightness profiles, and (6) starbursts. These structures occur preferentially in barred and oval galaxies in which secular evolution should be rapid. So the cleanest examples of pseudobulges are recognizable. Thus a large variety of observational and theoretical results contribute to a new picture of galaxy evolution that complements hierarchical clustering and merging.Comment: 92 pages, 21 figures in 30 Postscript files; to appear in Annual Review of Astronomy and Astrophysics, Vol. 42, 2004, in press; for a version with full resolution figures, see http://chandra.as.utexas.edu/~kormendy/ar3ss.htm

Non-invasive fetal genotyping for maternal alleles with droplet digital PCR: A comparative study of analytical approaches

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.OBJECTIVES: To develop a flexible droplet digital PCR (ddPCR) workflow to perform non-invasive prenatal diagnosis via relative mutation dosage (RMD) for maternal pathogenic variants with a range of inheritance patterns, and to compare the accuracy of multiple analytical approaches. METHODS: Cell free DNA (cfDNA) was tested from 124 archived maternal plasma samples: 88 cases for sickle cell disease and 36 for rare Mendelian conditions. Three analytical methods were compared: sequential probability ratio testing (SPRT), Bayesian and z-score analyses. RESULTS: The SPRT, Bayesian and z-score analyses performed similarly well with correct prediction rates of 96%, 97% and 98%, respectively. However, there were high rates of inconclusive results for each cohort, particularly for z-score analysis which was 31% overall. Two samples were incorrectly classified by all three analytical methods; a false negative result predicted for a fetus affected with sickle cell disease and a false positive result predicting the presence of an X-linked IDS variant in an unaffected fetus. CONCLUSIONS: ddPCR can be applied to RMD for diverse conditions and inheritance patterns, but all methods carry a small risk of erroneous results. Further evaluation is required both to reduce the rate of inconclusive results and explore discordant results in more detail.National Institute for Health and Care Research (NIHR

Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review

Background: Urinary tract infection (UTI) is one of the most common sources of infection in children under five. Prompt diagnosis and treatment is important to reduce the risk of renal scarring. Rapid, cost-effective, methods of UTI diagnosis are required as an alternative to culture. Methods: We conducted a systematic review to determine the diagnostic accuracy of rapid tests for detecting UTI in children under five years of age. Results: The evidence supports the use of dipstick positive for both leukocyte esterase and nitrite (pooled LR+ = 28.2, 95% CI: 17.3, 46.0) or microscopy positive for both pyuria and bacteriuria (pooled LR+ = 37.0, 95% CI: 11.0, 125.9) to rule in UTI. Similarly dipstick negative for both LE and nitrite (Pooled LR- = 0.20, 95% CI: 0.16, 0.26) or microscopy negative for both pyuria and bacteriuria (Pooled LR- = 0.11, 95% CI: 0.05, 0.23) can be used to rule out UTI. A test for glucose showed promise in potty-trained children. However, all studies were over 30 years old. Further evaluation of this test may be useful. Conclusion: Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation

Assessment of severity and frequency of self-reported hypoglycemia on quality of life in patients with type 2 diabetes treated with oral antihyperglycemic agents: A survey study

<p>Abstract</p> <p>Background</p> <p>Some oral antihyperglycemic agents may increase risk of hypoglycemia and thereby reduce patient quality of life. Our objective was to assess the impact of the severity and frequency of self-reported hypoglycemia on health-related quality of life (HRQoL) among patients with type 2 diabetes treated with oral antihyperglycemic agents.</p> <p>Findings</p> <p>A follow-up survey was conducted in participants with self-reported type 2 diabetes treated with oral antihyperglycemic agents from the US National Health and Wellness Survey 2007. Data were collected on the severity and frequency of hypoglycemic episodes in the 6 months prior to the survey, with severity defined as mild (no interruption of activities), moderate (some interruption of activities), severe (needed assistance of others), or very severe (needed medical attention). HRQoL was assessed using the EuroQol-5D Questionnaire (EQ-5D) US weighted summary score (utility) and Worry subscale of the Hypoglycemia Fear Survey (HFS). Of the participants who completed the survey (N = 1,984), mean age was 58 years, 57% were male, 72% reported an HbA_1c<7.0%, and 50% reported treatment with a sulfonylurea-containing regimen. Hypoglycemic episodes were reported by 63% of patients (46% mild, 37% moderate, 13% severe and 4% very severe). For patients reporting hypoglycemia, mean utility score was significantly lower (0.78 versus 0.86, p < 0.0001) and mean HFS score was significantly higher (17.5 versus 6.2, p < 0.0001) compared to patients not reporting hypoglycemia. Differences in mean scores between those with and without hypoglycemia increased with the level of severity (mild, moderate, severe, very severe) for utility (0.03, 0.09, 0.18, 0.23) and HFS (6.1, 13.9, 20.1, 25.6), respectively. After adjusting for age, gender, weight gain, HbA_1c, microvascular complications, and selected cardiovascular conditions, the utility decrement was 0.045 (by level of severity: 0.009, 0.055, 0.131, 0.208), and the HFS increase was 9.6 (by severity: 5.3, 12.4, 17.6, 23.2). HRQoL further decreased with greater frequency of hypoglycemic episodes.</p> <p>Conclusions</p> <p>Self-reported hypoglycemia is independently associated with lower HRQoL, and the magnitude of this reduction increases with both severity and frequency of episodes in patients with type 2 diabetes treated with oral antihyperglycemic agents.</p