A hybrid approach: a safe option for surgical treatment of early-stage cervical cancer.

OBJECTIVE: The aim of the study was to describe the surgical treatment of early-stage cervical cancer (CC) via minimally invasive surgery (MIS) and a sequential hybrid approach combining MIS and mini-Pfannenstiel. Evaluate sentinel lymph node (SLN) detection using a hybrid tracer (ICG-99m Tc nanocolloid). PATIENTS AND METHODS: Prospective, observational, descriptive, single-center study conducted at Son Espases University Hospital between January 2019 and September 2021. Patients with early-stage CC (FIGO 2018 IA1 with ILV-IIA1) who underwent surgical treatment with a follow-up of at least one year were included. RESULTS: Thirty early-stage CC patients were included, of whom four (13.3%) were upstaged due to positive SLNs. In these cases, laparotomy was avoided, and paraaortic lymphadenectomy was performed via MIS approach. Twenty-six patients had a radical hysterectomy: 15 underwent a hybrid approach, 10 laparoscopy, and one laparotomy. Patients undergoing laparoscopic surgery had a smaller estimated tumor size than those undergoing the hybrid approach. The overall SLN detection rate was 96.1%, with 88.5% of cases occurring bilaterally. Five out of 26 patients (19.2%) presented SLN macrometastases, and five (19.2%) had atypical drainage. Surgery refined staging in 33.3% (10/30) of cases. No recurrences were reported after an average follow-up of 32 months. CONCLUSIONS: MIS for SLN avoids laparotomy leading to rapid recovery and early adjuvant treatment initiation in nodal metastasis. In our study, tumor size is an important clinical implication in the surgical approach to be used. The hybrid tracer provided a high detection rate and combined the advantages of the two tracers. The hybrid approach has a quick recovery and optimal results.

Five years' experience of the clinical exome sequencing in a Spanish single center.

Nowadays, exome sequencing is a robust and cost-efficient genetic diagnostic tool already implemented in many clinical laboratories. Despite it has undoubtedly improved our diagnostic capacity and has allowed the discovery of many new Mendelian-disease genes, it only provides a molecular diagnosis in up to 25-30% of cases. Here, we comprehensively evaluate the results of a large sample set of 4974 clinical exomes performed in our laboratory over a period of 5 years, showing a global diagnostic rate of 24.62% (1391/4974). For the evaluation we establish different groups of diseases and demonstrate how the diagnostic rate is not only dependent on the analyzed group of diseases (43.12% in ophthalmological cases vs 16.61% in neurological cases) but on the specific disorder (47.49% in retinal dystrophies vs 24.02% in optic atrophy; 18.88% in neuropathies/paraparesias vs 11.43% in dementias). We also detail the most frequent mutated genes within each group of disorders and discuss, on our experience, further investigations and directions needed for the benefit of patients.

Nationwide paediatric cohort study of a protective association between allergy and complicated appendicitis.

BACKGROUND: In a nationwide cohort the potentially protective association between allergy and complicated appendicitis was analysed, and the influence of seasonal antigens, antihistamine treatment, and timing of allergy onset assessed. METHODS: Some 1 112 571 children born between 2000 and 2010 were followed from birth until the end of 2014. A cross-sectional analysis of appendicitis cases, with comparison of allergic versus non-allergic children for absolute risk and odds of complicated appendicitis was first undertaken. This was followed by a longitudinal analysis of children with allergy and matched controls who had never had an allergy, for incidence rate and hazard of subsequent complicated or simple appendicitis. RESULTS: Of all children, 20.4 per cent developed allergy and 0.6 per cent had appendicitis during follow-up. Among children with appendicitis, complicated appendicitis was more common among non-allergic children (18.9 per cent, 948 of 5016) than allergic children (12.8 per cent, 173 of 1351) (P < 0.001), and allergic children had a lower adjusted odds of complicated appendicitis (adjusted odds ratio (OR) 0.80, 95 per cent c.i. 0.67 to 0.96; P = 0.021 ). The risk of complicated appendicitis among children with manifest allergy was reduced by one-third in the longitudinal analysis (incidence rate 0.13 versus 0.20 per 1000 person-years; hazard ratio (HR) 0.68, 95 per cent c.i. 0.58 to 0.81; P < 0.001), whereas the risk of simple appendicitis remained unchanged (incidence rate 0.91 versus 0.91; HR 1.00, 0.94 to 1.07; P = 0.932 ). Seasonal antigen exposure was a protective factor (adjusted OR 0.82, 0.71 to 0.94; P = 0.004) and ongoing antihistamine medication a risk factor (adjusted OR 2.28, 1.21 to 4.28; P = 0.012). CONCLUSION: Children with allergy have a lower risk of complicated appendicitis, but the same overall risk of simple appendicitis. Seasonal antigen exposure reduced, and antihistamine treatment increased, the risk of complicated disease.

Sanger sequencing is no longer always necessary based on a single-center validation of 1109 NGS variants in 825 clinical exomes.

Despite the improved accuracy of next-generation sequencing (NGS), it is widely accepted that variants need to be validated using Sanger sequencing before reporting. Validation of all NGS variants considerably increases the turnaround time and costs of clinical diagnosis. We comprehensively assessed this need in 1109 variants from 825 clinical exomes, the largest sample set to date assessed using Illumina chemistry reported. With a concordance of 100%, we conclude that Sanger sequencing can be very useful as an internal quality control, but not so much as a verification method for high-quality single-nucleotide and small insertion/deletions variants. Laboratories might validate and establish their own thresholds before discontinuing Sanger confirmation studies. We also expand and validate 23 copy number variations detected by exome sequencing in 20 samples, observing a concordance of 95.65% (22/23).

Association between heavy metals and metalloids in topsoil and mental health in the adult population of Spain.

BACKGROUND AND OBJECTIVES: Despite the biological plausibility of the association between heavy metal exposure and mental health disorders, epidemiological evidence remains scarce. The objective was to estimate the association between heavy metals and metalloids in soil and the prevalence of mental disorders in the adult population of Spain. METHODS: Individual data came from the Spanish National Health Survey 2011-2012, 18,073 individuals residing in 1772 census sections. Mental health was measured with the 12-item General Health Questionnaire. The concentration estimates of heavy metal and metalloid levels in topsoil (upper soil horizon) came from the Geochemical Atlas of Spain based on 13,317 soil samples. Levels of lead (Pb), arsenic (As), cadmium (Cd) and manganese (Mn) were estimated in each census section by "ordinary Kriging". Odds ratios (OR) were calculated by multilevel logistic regression models. RESULTS: Compared with the lowest Pb concentration levels quartile, the OR for the second quartile was 1.29 (95%CI: 1.11-1.50), increasing progressively to 1.37 (95%CI: 1.17-1.60) and 1.51 (95%CI: 1.27-1.79) in the third and fourth quartiles, respectively. For As, the association was observed in the third and fourth quartiles: 1.21 (95%CI: 1.04-1.41) and 1.42 (95% CI: 1.21-1.65), respectively. Cd was associated also following a gradient from the second quartile: 1.34 (95%CI: 1.15-1.57) through the fourth: 1.84 (95%CI: 1.56-2.15). In contrast, Mn only showed a positive association at the second quartile. Additionally, individuals consuming vegetables > once a day the OR for the fourth quartile of Pb concentration, vs. the first, increased to 2.93 (95%CI: 1.97-4.36); similarly for As: 3.00 (95%CI: 2.08-4.31), and for Cd: 3.49 (95%CI: 2.33-5.22). CONCLUSIONS: Living in areas with a higher concentration of heavy metals and metalloids in soil was associated with an increased probability of having a mental disorder. These relationships were strengthened in individuals reporting consuming vegetables > once a day.

Long-term evaluation of the efficacy on the podalic support and postural control of a new elastic functional orthopaedic device for the correction of Class III malocclusion.

AIM: Correlations between occlusion and posture are open to new perspectives, which include treatment of functional alterations traditionally approached separately. The aim of this study is to evaluate whether the treatment of Class III malocclusion, through an innovative elastic functional orthopaedic device, allows an overall improvement of the podalic support. MATERIALS AND METHODS: A 5½-year-old patient with Angle Class III malocclusion and c anterior ross bite in deciduous dentition has been treated for 7 years with a functional orthopaedic device (MSB Class III). Assessment of frontal and lateral postural plumb line was performed with stabilo-baro-podometric platform analysis, in order to record the podalic support discrepancy between feet, both in static phase and in dynamic phase. The patient has been posturally re-evaluated at nine and twelve years old. RESULTS: The functional device allowed the restoration of the correct intermaxillary relationship, favourably conditioning also the posture. In particular, the correction of the valgus flat foot and a significative reduction of the podalic support discrepancy between feet has been obtained. CONCLUSIONS: A global approach to the patient can successfully address both malocclusion and postural alterations.

An extended core nanocoax pillar architecture for enhanced molecular detection.

Biosensors that incorporate nanomaterials and nanofabrication techniques enable molecular detection of chemical and biological macromolecules with a high degree of specificity and ultrasensitivity. Here, we present a novel fabrication process that yields a nanostructure capable of detecting biological macromolecules. The extended core nanocoax (ECC) structure builds on a previously reported nanocoaxial-based sensor. The fabrication of the device incorporates an extended inner pillar, with controllable extension above the annulus and into the surrounding solution. This new design eliminates structural constraints inherent in the original nanocoax architecture. We also provide results demonstrating improvement in biosensing capability. Specifically, we show the capability of the new architecture to detect the B subunit of the Vibrio cholerae toxin at improved sensitivity (100 pg/ml) in comparison to optical enzyme-linked immunosorbant assay (1 ng/ml) and previously reported coaxial nanostructures (2 ng/ml).

Espectro mutacional de la distrofia muscular de Duchenne en España: estudio de 284 casos / Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases

Introducción: La distrofia muscular de Duchenne (DMD) es una enfermedad neuromuscular grave que afecta a uno de cada 3.500 varones nacidos y sigue un patrón de herencia ligada al cromosoma X. En esta enfermedad se observa una ausencia total de la distrofina, generalmente debida a mutaciones en el gen DMD, que altera la pauta de lectura y en torno al 80% de los casos son debidos a deleciones y duplicaciones de uno o más exones. Métodos: Se han revisado 284 casos de varones diagnosticados genéticamente de DMD entre los años 2007 y 2014. Estos pacientes provienen de 8 hospitales españoles de referencia que cubren la mayor parte del territorio español. Para la identificación de las mutaciones se realizaron las técnicas de reacción en cadena de la polimerasa multiplex, MLPA y secuenciación. Resultados: Los pacientes con DMD presentan en su mayoría grandes deleciones (46,1%) o grandes duplicaciones (19,7%) en el gen de la distrofina. El restante 34,2% corresponde al conjunto de mutaciones puntuales, destacando las sustituciones nucleotídicas tipo nonsense que aparecen en la mitad de los casos. Este estudio permitió identificar 23 nuevas mutaciones en DMD: 7 grandes deleciones y 16 mutaciones puntuales. Conclusiones: El algoritmo de diagnóstico genético aplicado por los centros participantes es el más adecuado para genotipificar a los pacientes con DMD. La especificidad genética de las distintas terapias en desarrollo pone de manifiesto la importancia de conocer la mutación de cada paciente, siendo un 38,7% de ellos susceptibles de participar en los ensayos clínicos actuales (AU)

Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. Methods: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. Results: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. Conclusions: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials (AU)

Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. / Espectro mutacional de la distrofia muscular de Duchenne en España: estudio de 284 casos.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. METHODS: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. RESULTS: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. CONCLUSIONS: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials.

Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz.

BACKGROUND: Fundación Jiménez Díaz (FJD) is a reference center for genetic diagnosis of Gaucher disease (GD) in Spain. Genetic analyses of acid ß-glucosidase (GBA) gene using different techniques were performed to search for new mutations, in addition to those previously and most frequently found in the Spanish population. Additionally, the study of the chitotriosidase (CHIT1) gene was used to assess the inflammatory status of patients in the follow-up of enzyme replacement therapy (ERT). We present the genetic data gathered during the last nine years at FJD. METHODS: Blood samples from patients with suspected GD were collected for enzymatic and genetic analyses. The genetic analysis was performed on DNA from 124 unrelated suspected cases and 57 relatives from 2007 to 2015, starting with a mutational screening kit, followed by Sanger sequencing of the entire gene and other techniques to look for deletions. CHIT1 was also studied to assess the reliability of this biomarker. RESULTS: In 46 out of 93 GD patients (49.5%) the two mutant alleles were found. We detected 21 different mutations. The most common mutation was N370S (c.126A > G; p.Asp409Ser current nomenclature) (in 50.5% of patients), followed by L444P (c.1448T > C; p.Leu483Pro current nomenclature) (in 24.7%). The most common heterozygous compound genotype observed (18.3%) was c.1226A > G/c.1448T > C (N370S/L444P). Two novel mutations were found (del. Ex.4-11 and c.1296G > T; pW432C), as well as p.S146L, only once previously reported. Two patients showed the homozygous state for the duplication of CHIT1. CONCLUSION: N370S and L444P are the most common mutations and other mutations associated to Parkinson's disease have been observed. This should be taken into account in the genetic counseling of GD patients.

Hot electron plasmon-protected solar cell.

A solar cell based on a hot electron plasmon protection effect is proposed and made plausible by simulations, non-local modeling of the response, and quantum mechanical calculations. In this cell, a thin-film, plasmonic metamaterial structure acts as both an efficient photon absorber in the visible frequency range and a plasmonic resonator in the IR range, the latter of which absorbs and protects against phonon emission the free energy of the hot electrons in an adjacent semiconductor junction. We show that in this structure, electron-plasmon scattering is much more efficient than electron-phonon scattering in cooling-off hot electrons, and the plasmon-stored energy is recoverable as an additional cell voltage. The proposed structure could become a prototype of a new generation of high efficiency solar cells.

Angle dependence of the interaction distance in the shear force technique.

We study the interaction distance in the lateral force detection, using a standard quartz tuning fork as a force transducer. That is the distance at which the interaction sample-probe starts to be detected. We study in particular the dependence on the approaching angle. For angles smaller than 0.366 radians, we found an exponential behavior of the interaction distance as a function of the approaching angle. We show an equation that adjusts well with the experimental data, and discuss the possible phenomena.

Psychotropic drugs and falling accidents among the elderly: a nested case control study in the whole population of Scania, Sweden.

STUDY OBJECTIVE: The objective of this study was to investigate the associations between medication with psychotropic drugs and falling accidents in the whole population aged 65 years and older in the county of Scania, Sweden. DESIGN: A population based nested case control study was performed. SUBJECTS: Cases were persons registered in the Region Healthcare database after a falling accident during the year 2006 (n=10 482). One control was matched to each case based on age, sex, date of the falling accident, living area and propensity score (based on prevalent disease). MAIN RESULTS: Using psychotropic drugs within 3 months before the fall was associated with a more than doubled odds for a falling accident among both men (2.14, 95% CI 1.87 to 2.44) and women (2.21, 95% CI 2.04 to 2.39). The use of psychotropic drugs during the week before the accident occurred was associated with an even higher odds for a falling accident among both men (OR=5.61; 95% CI 2.54 to 12.41) and women (OR=3.40; 95% CI 2.24 to 5.17). A similar pattern of association was seen for specific groups of psychotropic drugs: opioids, antidepressants and anxiolytics/hypnotics/sedatives. CONCLUSIONS: The use of psychotropic drugs increased the odds for a falling accident among persons 65 years and older. Generally, patients using psychotropic drugs seemed to have the highest odds for falling accidents immediately after initiating therapy. Since these medications are extensively used among the elderly, the increased risk for falls associated with these kinds of drugs is an important public health problem that could be tackled by a more rational medication use.

Context and disease when disease risk is low: the case of type 1 diabetes in Sweden.

BACKGROUND: Several European studies have found significant small area variation in the risk of childhood onset (type 1) diabetes (T1D) which has been interpreted as evidence for contextual determinants of T1D. However, this conclusion may be fallacious since the limited number of newborn infants and the low risk for T1D is a source of spurious variability not properly handled by usual statistical methods. This study investigates the existence of contextual effects in the genesis of T1D, compares conclusions in previous reports with results obtained in a multilevel regression framework and highlights analysis of variance as a useful approach in public health. METHODS: All singletons born in Sweden between 1987 and 1991 were identified in the Medical Birth Registry (n=560 766) and followed for diabetes until age 14 using the Hospital Discharge Registry. Area variation in the cumulative incidence of T1D was estimated by different statistical methods including multilevel logistic regression. RESULTS: The risk of T1D ranged from 4.3 to 6.5 per 1000 newborns across the counties (n=24) and from 0.0 to 19.2 per 1000 newborns across the municipalities (n=284). These differences were significant in standard statistical tests (counties, p=0.02; municipalities, p=0.007). However, according to multilevel analyses, the risk of T1D ranged from 4.7 to 5.7 and from 4.4 to 6.0 per 1000 newborns in counties and municipalities, respectively, and the area variation was small and without practical relevance (counties, sigma(2)=0.006; municipalities, sigma(2)=0.017). CONCLUSIONS: Previous reports based on standard statistical tests are misleading. According to multilevel analysis, administrative areas have minor relevance for individual risk of T1D in Sweden.

Individual and collective bodies: using measures of variance and association in contextual epidemiology.

BACKGROUND: Social epidemiology investigates both individuals and their collectives. Although the limits that define the individual bodies are very apparent, the collective body's geographical or cultural limits (eg "neighbourhood") are more difficult to discern. Also, epidemiologists normally investigate causation as changes in group means. However, many variables of interest in epidemiology may cause a change in the variance of the distribution of the dependent variable. In spite of that, variance is normally considered a measure of uncertainty or a nuisance rather than a source of substantive information. This reasoning is also true in many multilevel investigations, whereas understanding the distribution of variance across levels should be fundamental. This means-centric reductionism is mostly concerned with risk factors and creates a paradoxical situation, as social medicine is not only interested in increasing the (mean) health of the population, but also in understanding and decreasing inappropriate health and health care inequalities (variance). METHODS: Critical essay and literature review. RESULTS: The present study promotes (a) the application of measures of variance and clustering to evaluate the boundaries one uses in defining collective levels of analysis (eg neighbourhoods), (b) the combined use of measures of variance and means-centric measures of association, and (c) the investigation of causes of health variation (variance-altering causation). CONCLUSIONS: Both measures of variance and means-centric measures of association need to be included when performing contextual analyses. The variance approach, a new aspect of contextual analysis that cannot be interpreted in means-centric terms, allows perspectives to be expanded.

Socioeconomic position, macroeconomic environment and overweight among adolescents in 35 countries.

OBJECTIVE: It is important to understand levels and social inequalities in childhood overweight within and between countries. This study examined prevalence and social inequality in adolescent overweight in 35 countries, and associations with macroeconomic factors. DESIGN: International cross-sectional survey in national samples of schools. SUBJECTS: A total of 11-, 13- and 15-year-olds from 35 countries in Europe and North America in 2001-2002 (N=162 305). MEASUREMENTS: The main outcome measure was overweight based on self-reported height and weight (body mass index cut-points corresponding to body mass index of 25 kg/m(2) at the age of 18 years). Measures included family and school affluence (within countries), and average country income and economic inequality (between countries). RESULTS: There were large variations in adolescent overweight, from 3.5% in Lithuanian girls to 31.7% in boys from Malta. Prevalence of overweight was higher among children from less affluent families in 21 of 24 Western and 5 of 10 Central European countries. However, children from more affluent families were at higher risk of overweight in Croatia, Estonia and Latvia. In Poland, Lithuania, Macedonia and Finland, girls from less affluent families were more overweight whereas the opposite was found for boys. Average country income was associated with prevalence and inequality in overweight when considering all countries together. However, economic inequality as measured by the Gini coefficient was differentially associated with prevalence and socioeconomic inequality in overweight among the 23-high income and 10-middle income countries, with a positive relationship among the high income countries and a negative association among the middle income countries. CONCLUSION: The direction and magnitude of social inequality in adolescent overweight shows large international variation, with negative social gradients in most countries, but positive social gradients, especially for boys, in some Central European countries. Macroeconomic factors are associated with the heterogeneity in prevalence and social inequality of adolescent overweight.

Prenatal diagnosis of Huntington disease in maternal plasma: direct and indirect study.

BACKGROUND AND PURPOSE: The presence of cell-free fetal DNA in maternal plasma could allow performing a non-invasive prenatal diagnosis of Huntington disease (HD). The great advantage of this diagnosis is the absence of risk of fetal loss that it entails. METHODS: Maternal plasma from four pregnant women in their first trimester of gestation with a fetus at-risk was studied. In all the four cases, the father was affected. RESULTS: The diagnosis was performed both by a direct study of the mutation and an indirect haplotype study. By the direct analysis, three out of the four fetuses could be correctly diagnosed whilst the indirect analysis was only conclusive in one case. CONCLUSIONS: Non-invasive prenatal diagnosis of HD is possible by the analysis of fetal DNA in maternal plasma. Direct analysis of the mutation has shown higher accuracy than the haplotype analysis except for long expansions. Haplotype analysis would need to be improved for the study of Juvenile-onset HD. This diagnostic method would be limited to those couples with an affected male however this situation represents 80-90% of the pregnancies at-risk of HD. Moreover, it could be used as a confirmation test of healthy embryos transferred on pre-implantation genetic studies of HD.

Two non-contiguous duplications in the DMD gene in a Spanish family.

DMD and BMD are X-linked myopathy diseases in most cases caused by intragenic deletions, but duplications also appear in a significant number of cases. We present a complex duplication pattern detected by MLPA, a recently formulated method applied here to amplify the 79 exons of the DMD gene. We found a double-duplication in two DMD-affected brothers and in their carrier mother, which consist of two non-contiguous duplications encompassing exons 2 to 7 and exons 50 to 55. Different models are presented to explain formation of this genetic variant.