Acidification and solar drying of manure-based digestate to produce improved fertilizing products.

The increase in energy and fertilizer consumption makes it necessary to develop sustainable alternatives for agriculture. Anaerobic digestion and digestates appeared to be suitable options. However, untreated digestates still have high water content and can increase greenhouse gas emissions during storage and land application. In this study, manure-derived digestate and solid fraction of digestate after separation were treated with a novel solar drying technology to reduce their water content, combined with acidification to reduce the gaseous emissions. The acidified digestate and acidified solid fraction of digestate recovered more nitrogen and ammonia nitrogen than their respective non-acidified products (1.5-1.3 times for TN; 14 times for TAN). Ammonia and methane emissions were reduced up to 94% and 72% respectively, compared to the non-acidified ones, while N2O increased more than 3 times. Dried digestate and dried acidified digestate can be labeled as NPK organic fertilizer regarding the European regulation, and the dried solid fraction and the improved dried acidified solid fraction can be labeled as N or P organic fertilizer. Moreover, plant tests showed that N concentrations in fresh lettuce leaves were within the EU limit with all products in all the cases. However, zinc concentration appeared to be a limitation in some of the products as their concentration exceeded the European legal limits.

[Impact of the COVID-19 pandemic above a universal electronic consultation program (e-consultation) between general practitioners and cardiologists]. / Impacto de la pandemia por COVID-19 sobre un programa de consulta electrónica universal (e-consulta) entre médicos de Atención Primaria y cardiólogos.

Blackground and objective: Virtual healthcare models, usually between healthcare professionals and patients, have developed strongly during the coronavirus disease 2019 (COVID-19) pandemic, but there are not data of models between clinicians. Our objective is to analyse the impact of the COVID-19 pandemic on the activity and health outcomes of the universal e-consultation program for patient referrals between primary care physicians and the Cardiology Department in our area. Methods: Patients with at least one e-consultation between 2018 and 2021 were selected. We analysed the impact of the COVID-19 pandemic on activity and waiting time for care, hospitalizations and mortality, taking as a reference the consultations carried out during 2018. Results: We analysed 25,121 patients. Through logistic regression analysis, it was observed that a shorter delay in care and resolution of the e-consultation without the need for face-to-face care were associated with a better prognosis. The COVID-19 pandemic periods (2019-2020 and 2020-2021) were not associated with worse health outcomes compared to 2018. Conclusions: The results of our study show a significant reduction in e-consult referrals during the first year of the COVID-19 pandemic with a subsequent recovery in the demand for care without the pandemic periods being associated with worse outcomes. The reduction in the time elapsed for solving the e-consult and no need for in-person visit were associated with better outcomes.

Adsorption of Organic Dyes on Magnetic Iron Oxide Nanoparticles. Part II: Field-Induced Nanoparticle Agglomeration and Magnetic Separation.

This paper (part II) is devoted to the effect of molecular adsorption on the surface of magnetic iron oxide nanoparticles (IONP) on the enhancement of their (secondary) field-induced agglomeration and magnetic separation. Experimentally, we use Methylene Blue (MB) cationic dye adsorption on citrate-coated maghemite nanoparticles to provoke primary agglomeration of IONP in the absence of the field. The secondary agglomeration is manifested through the appearance of needlelike micron-sized agglomerates in the presence of an applied magnetic field. With the increasing amount of adsorbed MB molecules, the size of the field-induced agglomerates increases and the magnetic separation on a magnetized micropillar becomes more efficient. These effects are mainly governed by the ratio of magnetic-to-thermal energy α, suspension supersaturation Δ0, and Brownian diffusivity Deff of primary agglomerates. The three parameters (α, Δ0, and Deff) are implicitly related to the surface coverage θ of IONP by MB molecules through the hydrodynamic size of primary agglomerates exponentially increasing with θ. Experiments and developed theoretical models allow quantitative evaluation of the θ effect on the efficiency of the secondary agglomeration and magnetic separation.

Cross-cultural adaptation and validation of the neurogenic bladder symptom score for Spanish speakers.

AIM: To perform a cross-cultural adaptation and validation of the Neurogenic Bladder Symptom Score (NBSS) to Spanish in patients with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: The questionnaire was culturally adapted according to international guidelines. It was applied, twice in a range of 14-28 days. Psychometric properties were tested such as content validity, construct validity, internal consistency, and test-retest reliability. RESULTS: A total of 82 patients between 18 and 78 years old (mean age of 43.9) participated in the study, and completed the first NBSS assessment; only 39 (32.19%) performed the test-retest study. The internal consistency was tested by Cronbach α with a result of 0.86 (95% CI, 0.81-0.90). The reliability was tested by interclass correlation coefficient with a result of 0.91 [0.87-0.95] (p < 0.0001). The construct validity was tested by Pearson correlation between NBSS and Qualiveen-SF, which showed a moderate correlation with a result of 0.57 (p < 0.0001). One-way analysis of variance with trend analysis demonstrated that patients who reported having a more severe problem with their bladder function had a higher NBSS total score (p < 0.001). CONCLUSION: The results of this study demonstrated that the Spanish version of the NBSS has a good internal consistency and reliability, proving its applicability.

The determination of fertiliser quality of the formed struvite from a WWTP.

Struvite from nutrient-rich wastewaters has been identified as a potential substitute for commercial mineral fertilisers, with the added benefit of reducing threats to global food security by prolonging phosphate rock reserves. A fertilisation test using grass (Brachiaria brizantha Marandú) and a sand column leaching test was conducted to determine the agronomic effectiveness of struvite precipitates produced from the supernatant of dewatered sewage sludge (centrate) from a municipal Wastewater Treatment Plant (WWTP). The performance of this struvite as a fertiliser was compared with biosolids and commercial fertilisers (Urea and Triple15). The results show that the concentration of heavy metals in struvite was lower than in biosolids and below the limits of Colombia and European fertiliser regulations. Struvite increased the uptake of N and P in grass, resulting in crop yields similar to other treatments tested. Struvite use as an effective slow-release fertiliser is highly dependent on the size of crystal particles, particularly in achieving low P losses, but resulted in high N loss in the sand columns tested; N loses from struvite were higher than in the commercial fertilisers due to the struvite small particle size. Therefore, struvite represents a suitable opportunity to recover and recycle nutrients from municipal sewage sludge, facilitating the effective reuse of P and N in agriculture and uptake by plants.

Solar drying in the vineyard: a sustainable technology for the recovery of nutrients from winery organic waste.

The present study describes a pilot-scale experimental validation of a forced-convection greenhouse solar dryer, combined with a biofilter, for controlled atmospheric emissions. This set-up was applied to the dewatering of sewage sludge from a biological plant that treated process wastewater in a commercial Mediterranean winery. Experiments were performed after the harvest, from September onwards, during the peak generation of sludge. The average drying rate during the first 10 days of operation ranged from 1.17 to 2.24 kg m-2 d-1, depending on the measurement method, during which the water content of the sludge was reduced from 90% down to 67%. Biofiltration was quite inefficient against greenhouse gases (methane and dinitrous oxide), and direct emissions during the drying process were on average 57 g CO2-eq m-2 d-1. Ammonia and volatile organic compounds were removed with average efficiencies of 71% and 35%, but ammonia losses through volatilization represented less than 2% of the initial nitrogen content. The sludge was dried further during November, to the lowest possible water content of 14%. Both the intermediate and final sludge dried materials were characterized for their agronomical value as organic fertilizers.

Prevalence of oral side effects of chemotherapy and its relationship with periodontal risk: a cross sectional study.

PURPOSE: To determine the prevalence of professionally reported oral side effects of chemotherapy and the self-reported oral side effects and whether both prevalences could be related to the periodontal risk of the patients. METHODS: A cross-sectional study with patients undergoing chemotherapy treatment was carried out. Demographic, oral hygiene habits, and cancer-related data were collected while the patient was receiving the chemotherapy infusion. Patient's oral status, measured according to the oral-assessment guide for patients in hospital environments, patient-related outcomes (PROMs), measured by a visual analogue scale, and patient's periodontal risk were analyzed using validated questionnaires. Data was reported in means and standard deviations (SD) in quantitative variables and in counts, prevalence, and 95% confidence intervals (CI) in qualitative variables. ANOVA test and chi-squared tests were used to compare oral side effects among different periodontal risk groups. RESULTS: Three hundred sixty-nine patients were included in the study. The prevalence of professionally reported oral side effects was 86.99% (95% confidence interval CI 83.54%; 90.44%). The prevalence of self-reported oral side effects was 89.70% (95% CI 86.59; 92.82). The most common oral side effects were xerostomia (73.4%), dysgeusia (61.8%), and dry lips (54.2%). More oral alterations were found in patients with worse periodontal risk (p < 0.001). CONCLUSIONS: The prevalence of oral side effects (professional or self-reported) is higher than 85% in patients undergoing chemotherapy. This prevalence increases as the risk of developing periodontal disease does.

Effectiveness of a multimodal training programme to improve general practitioners' burnout, job satisfaction and psychological well-being.

BACKGROUND: The changes in the models of care for mental disorders towards a community focus and deinstitutionalisation might have risen General practitioners' (GPs) workload, increasing their mental health concerns and the need for solutions. Pragmatic research into improving GPs' work-related health and psychological well-being is limited by focusing mainly on stressors and through not providing systematic attention to the development of positive mental health via interventions that develop psychological resources and capacities. The aim of this study was twofold: a) to determine the effectiveness of an intensive multimodal training programme for GPs designed to improve their management of mental-health patients; and b) to ascertain if the program could be also useful to improve the GPs management of their own burnout, job satisfaction and psychological well-being. METHOD: Eighteen GPs constituted a control group that underwent the routine clinical Mental health support programme for primary care. An experimental group (N = 20) additionally received a Multimodal training programme (MTP) with an Integrated Brief Systemic Therapy (IBST) approach. Through questionnaires and a clinical interview, level of burnout, professional satisfaction, psychopathological state and various indicators of the quality of administrative and healthcare management were analysed at baseline and 10 months after the programme. RESULTS: In relation to government of mental-health patients indicators, on the one hand MTP group showed statistically significant improvements in certain administrative health parameters, but on the other it did not improve opinions and attitudes towards mental illness. Regarding GPs management of their own burnout, job satisfaction and psychological well-being assessments, the MTP presented better scores on global psychopathological state and better evolution of satisfaction at work; psychopharmacology use dropped in both groups; in contrast, the MTP did not improve burnout levels. CONCLUSIONS: Findings of this preliminary study are promising for the MTP (with an IBST approach) practice in primary care. More research evidence is required from larger samples and randomized controlled trials to support both the hypothetical adoption of MTP (with an IBST approach) as a part of a continuing professional-training programme for GPs' management of mental-health patients and its positive effects on work-related health factors.

Characterization of microbial community dynamics during the anaerobic co-digestion of thermally pre-treated slaughterhouse wastes with glycerin addition.

Microbial community dynamics during the anaerobic co-digestion of pig manure, pasteurized slaughterhouse waste and glycerin were studied in a lab-scale CSTR. The feed composition was optimized through progressive co-substrate additions for enhanced methane production and organic matter removal without accumulation of intermediate compounds. Microbial community structure of biomass samples was studied by means of qPCR and DGGE profiling of 16S rRNA genes (Bacteria and Archaea), and genus-specific qPCR of the methyl coenzyme M reductase gene (mcrA), which encodes for an enzyme universally involved in methanogenesis. The composition of the dominant bacterial populations remained relatively stable, when compared to those in the influent, but the highest changes were observed upon the introduction of glycerin. Biodiversity of archaea was restricted to a few representatives of the genera Methanosaeta and Methanosarcina, but Methanospirillum sp. was detected only when glycerin was introduced in the feeding. Glycerin supplementation coincided with the strongest increase in methane yield (from 0.22 to 0.64 m3CH4 m-3 d-1).

Tuning Electroluminescence from a Plasmonic Cavity-Coupled Silicon Light Source.

The combination of Moore's law and Dennard's scaling rules have constituted the fundamental guidelines for the silicon-based semiconductor industry for decades. Furthermore, the enormous growth of global data volume has pushed the demand for complex and densely packed devices. In recent years, it has become clear that wired interconnects impose increasingly severe speed and power limitations onto integrated circuits as scaling slows toward a halt. To overcome these limitations, there is a clear need for optical data processing. Despite significant progress in the development of silicon photonics, light sources remain challenging owing to the indirect bandgap of group IV materials. It is therefore highly desirable to develop new concepts for a silicon light source that meets efficiency and footprint requirements similar to their electronic counterparts. Here, we demonstrate an electrically driven and tunable silicon light source by matching the resonant modes of a silver nanocavity with the hot luminescence spectrum of an avalanching p-n junction. The cavity significantly enhances phonon-assisted recombination of hot carriers by tailoring the local density of states at the size-tunable resonance. Such tunable nanoscale emitter may be of great interest for short-reach communications, microdisplays or lab-on-chip applications.

Monolithic Axial and Radial Metal-Semiconductor Nanowire Heterostructures.

The electrical and optical properties of low-dimensional nanostructures depend critically on size and geometry and may differ distinctly from those of their bulk counterparts. In particular, ultrathin semiconducting layers as well as nanowires have already proven the feasibility to realize and study quantum size effects enabling novel ultrascaled devices. Further, plasmonic metal nanostructures attracted recently a lot of attention because of appealing near-field-mediated enhancement effects. Thus, combining metal and semiconducting constituents in quasi one-dimensional heterostructures will pave the way for ultrascaled systems and high-performance devices with exceptional electrical, optical, and plasmonic functionality. This Letter reports on the sophisticated fabrication and structural properties of axial and radial Al-Ge and Al-Si nanowire heterostructures, synthesized by a thermally induced exchange reaction of single-crystalline Ge-Si core-shell nanowires and Al pads. This enables a self-aligned metallic contact formation to Ge segments beyond lithographic limitations as well as ultrathin semiconducting layers wrapped around monocrystalline Al core nanowires. High-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, and µ-Raman measurements proved the composition and perfect crystallinity of these metal-semiconductor nanowire heterostructures. This exemplary selective replacement of Ge by Al represents a general approach for the elaboration of radial and axial metal-semiconductor heterostructures in various Ge-semiconductor heterostructures.

Two-dimensional and shear wave elastography ultrasound: A reliable method to analyse spastic muscles?

INTRODUCTION: Few data exist on the feasibility and reliability of measuring muscular atrophy in 2 dimensions (2D) by ultrasonography (US) and elasticity with shear wave elastography (SWE) in spastic muscles. METHODS: Fourteen patients with chronic stroke took part in 2 intersession reliability experiments performed with 1-week intervals between sessions. Pennation angle (PA), muscle thickness (MT), and shear elastic modulus (µ) were measured in spastic gastrocnemius medialis (GM) muscles at rest and at maximal passive stretching in paretic and nonparetic legs. RESULTS: On the paretic side, the coefficient of variation (CV) in GM was 6.30% for MT and 6.40% for PA at rest and was 7.53% and 8.26% for MT and PA, respectively, at maximal passive stretching. The reliability of the µ measurement was good only for GM at rest on the paretic side (CV = 9.86%). DISCUSSION: 2D US associated with SWE shows promise for assessing structural changes in muscles. With some methodological adaptations, this approach could help guide spasticity treatment. Muscle Nerve 57: 222-228, 2018.

Influence of the Mediterranean diet during pregnancy in the development of wheezing and eczema in infants in Pamplona, Spain.

BACKGROUND: This study examined the relationship between different food groups and the adherence to a Mediterranean diet during pregnancy and the risk of wheezing and eczema in children aged 12-15 months. METHODS: The study involves 1087 Spanish infants from the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). The study of the association of the different food consumption and Mediterranean diet with wheezing, recurrent wheezing and eczema was performed using different models of unconditional logistic regression to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: No association was found between a good adherence to the Mediterranean diet during pregnancy and the development of wheezing (p=0.372), recurrent wheezing (p=0.118) and eczema (p=0.315). The consumption once or twice a week of white fish (OR: 1.95[1.01-3.75]), cooked potatoes (OR: 1.75[1.22-2.51]) and industrial pastry (OR: 1.59[1.13-2.24]), and the consumption more than three times a week of industrial pastry (OR: 1.47 [1.01-2.13]) during pregnancy increases the risk of "wheezing" at 12 months. Instead, high fruit consumption during the pregnancy has a protective effect against "wheezing" in 12-month-old infants (OR: 0.44 [0.20-0.99]). No statistically significant differences were observed between food intake during pregnancy and "recurrent wheezing". No statistically significant differences were observed between the consumption of any food during pregnancy and the presence of eczema at 12 months. CONCLUSIONS: The present study showed that the consumption of Mediterranean diet during pregnancy did not have a protective effect for wheezing, recurrent wheezing or eczema.

Phenomenology of coupled nonlinear oscillators.

A recently introduced model of coupled nonlinear oscillators in a ring is revisited in terms of its information processing capabilities. The use of Lempel-Ziv based entropic measures allows to study thoroughly the complex patterns appearing in the system for different values of the control parameters. Such behaviors, resembling cellular automata, have been characterized both spatially and temporally. Information distance is used to study the stability of the system to perturbations in the initial conditions and in the control parameters. The latter is not an issue in cellular automata theory, where the rules form a numerable set, contrary to the continuous nature of the parameter space in the system studied in this contribution. The variation in the density of the digits, as a function of time is also studied. Local transitions in the control parameter space are also discussed.

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

Dicephalous v. diprosopus sharks: record of a two-headed embryo of Galeus atlanticus and review of the literature.

As far as is known, this paper gives the first description of a two-headed shark embryo belonging to an oviparous species, Galeus atlanticus (Carcharhiniformes: Scyliorhinidae). The specimen was detected among 797 embryos intended for cardiovascular studies, which represents a defect incidence of 0·13%. Each head had a mouth, two eyes, a brain, a notochord and five gill openings on each side. The two heads fused behind the gills. On the single body, there were four anticipated dorsal fins, two anterior, right and left and two posterior, right and left. Ventrally, the specimen possessed two pairs of pectoral fins, a pair of pelvic fins and one anal fin. Two adjacent notochords, two neural tubes and two dorsal aortas ran along the body, which bent 180° at its posterior portion. There were two hearts, two oesophaguses, two stomachs, two livers, but a single intestine with a spiral valve. Previous reports of conjoined twins in sharks are scarce and only refer to oviparous and ovoviviparous species. Seven dicephalous sharks reported so far were similar to the specimen described here, namely, with two totally separated heads on one body. Instead, only one case of diprosopus shark has been reported; it had a single body and a single head with partial duplication of the face. Two further cases described in the literature as dicephalous or simply as abnormal sharks should be better regarded as diprosopus, while another three cases, also considered dicephalous, showed a mixture of characteristics of diprosopia and dicephalia.

[Pleural cavity concerns]. / Los quebraderos de cabeza del espacio pleural.

INTRODUCTION: Persistent air leak (PAL) is a common problem. We asses our experience in the management of these patients. MATERIAL AND METHODS: Retrospective review of patients with chest tubes after bronchopulmonary pneumothorax (due to lung resections, spontaneous pneumothorax, necrotizing pneumonia) from 2010 to 2015. We studied clinical data, PAL incidence, risk factors and treatment, considering PAL ≥ 5 days. RESULTS: Thirty-seven cases (28 patients) between 0-16years: 26 lung resections, 11 pneumothorax. We found no differences in the distribution of age, weight, indication or comorbidity, but we noticed a trend to shorter hospital stay in infants. Patients with staple-line reinforcement presented lower PAL incidence than patients with no mechanical suture (43% vs 37%), the difference is even apparent when applying tissue sealants (29% vs 50%) (p > 0.05). We encountered no relationship between the size of the tube (10-24 Fr) or the type of resection, with bigger air leaks the higher suction pressure. We performed 13 pleurodesis in 7 patients (2 lobectomies, 3 segmentectomies and 2 bronchopleural fistulas), with 70% effectiveness. We conducted 7 procedures with autologous blood (1.6 ml/kg), 2 with povidone-iodine (0.5 ml/kg), 2 mechanical thoracoscopic and 2 open ones. We repeated pleurodesis four times, 3 of them after autologous blood infusion: 2 infusions with the same dose (both effective) and the other 2 as thoracotomy in patients with bronchopleural fistulas. After instillation of blood 3 patients presented with fever. After povidone-iodine instillation, the patient suffered from fever and rash. CONCLUSIONS: Intraoperative technical aspects are essential to reduce the risk of PAL. Autologous blood pleurodesis, single or repeated, is a minimal invasive option, very safe and effective to treat the parenchymatous PAL.

INTRODUCCION: La fuga aérea persistente (FAP) es un problema común. Evaluamos nuestra experiencia en el manejo de estos pacientes. MATERIAL Y METODOS: Revisión retrospectiva 2010-2015 de pacientes con drenaje endotorácico por neumotórax broncopulmonar (resecciones pulmonares, neumotórax, neumonía necrotizante). Revisamos datos clínicos, incidencia de FAP, factores determinantes y tratamiento, considerando FAP ≥ 5 días. RESULTADOS: Treinta y siete casos (28 pacientes) con edades entre 0-16 años: 26 resecciones pulmonares, 11 neumotórax. No encontramos diferencias en distribución de edad, peso, indicación quirúrgica ni comorbilidad, aunque sí tendencia a menor estancia hospitalaria en lactantes. Los pacientes con sutura no mecánica presentaron más fugas que los pacientes con sutura mecánica (43 vs 37%), así como los pacientes a los que no se aplicaron sellantes tisulares (29 vs 50%) (ambos p > 0,05). No encontramos relación con el tamaño del tubo (10-24 Fr) ni con el tipo de resección, manteniendo más fuga aérea los de mayor presión de aspiración. Realizamos 13 pleurodesis en 7 pacientes (2 lobectomías, 3 segmentectomías y 2 fístulas broncopleurales), con efectividad del 70%. Realizamos 7 con sangre autóloga (1,6 ml/kg), 2 con povidona iodada (0,5 ml/kg), 2 mecánicas toracoscópicas y 2 abiertas. Se repitió la pleurodesis en 4 ocasiones, 3 de ellas tras sangre autóloga: dos con repetición de la misma dosis (ambas efectivas) y otras dos por toracotomía en los pacientes con fístula broncopleural. Tras la instilación de sangre 3 casos presentaron fiebre. Tras la de povidona iodada, fiebre y exantema. CONCLUSIONES: Los aspectos técnicos intraoperatorios son esenciales para disminuir el riesgo de FAP. La pleurodesis con sangre autóloga, única o repetida, es una opción poco invasiva, muy segura y efectiva para las FAP parenquimatosas en nuestra muestra.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.