Distinct responses from bacterial, archaeal and fungal streambed communities to severe hydrological disturbances.

Stream microbes that occur in the Mediterranean Basin have been shown to possess heightened sensitivity to intensified water stress attributed to climate change. Here, we investigate the effects of long-term drought (150 days), storms and rewetting (7 days) on the diversity and composition of archaea, bacteria and fungi inhabiting intermittent streambed sediment (surface and hyporheic) and buried leaves. Hydrological alterations modified the archaeal community composition more than the bacterial community composition, whereas fungi were the least affected. Throughout the experiment, archaeal communities colonizing sediments showed greater phylogenetic distances compared to those of bacteria and fungi, suggesting considerable adaptation to severe hydrological disturbances. The increase in the class abundances, such as those of Thermoplasmata within archaea and of Actinobacteria and Bacilli within bacteria, revealed signs of transitioning to a drought-favoured and soil-like community composition. Strikingly, we found that in comparison to the drying phase, water return (as sporadic storms and rewetting) led to larger shifts in the surface microbial community composition and diversity. In addition, microhabitat characteristics, such as the greater capacity of the hyporheic zone to maintain/conserve moisture, tended to modulate the ability of certain microbes (e.g., bacteria) to cope with severe hydrological disturbances.

Chromatic and achromatic visual fields in relation to choroidal thickness in patients with high myopia: A pilot study.

PURPOSE: To analyse the relationship between the choroidal thickness and the visual perception of patients with high myopia but without retinal damage. METHODS: All patients underwent ophthalmic evaluation including a slit lamp examination and dilated ophthalmoscopy, subjective refraction, best corrected visual acuity, axial length, optical coherence tomography, contrast sensitivity function and sensitivity of the visual pathways. RESULTS: We included eleven eyes of subjects with high myopia. There are statistical correlations between choroidal thickness and almost all the contrast sensitivity values. The sensitivity of magnocellular and koniocellular pathways is the most affected, and the homogeneity of the sensibility of the magnocellular pathway depends on the choroidal thickness; when the thickness decreases, the sensitivity impairment extends from the center to the periphery of the visual field. CONCLUSIONS: Patients with high myopia without any fundus changes have visual impairments. We have found that choroidal thickness correlates with perceptual parameters such as contrast sensitivity or mean defect and pattern standard deviation of the visual fields of some visual pathways. Our study shows that the magnocellular and koniocellular pathways are the most affected, so that these patients have impairment in motion perception and blue-yellow contrast perception.

Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort.

OBJECTIVES: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. METHODS: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. RESULTS: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. CONCLUSIONS: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Sensitivity of laccase activity to the fungicide tebuconazole in decomposing litter.

The present study investigates the sensitivity of laccase activity to the fungicide tebuconazole (TBZ) in order to seek for new functional toxicity descriptors in aquatic microbial communities associated to decomposing litter. With this aim, we analyzed the sensitivity of laccase from the different microbial components (fungi and bacteria growing separately and in co-existence), as well as that of their corresponding enzyme fractions (cell bound and diffusible), forming microbial communities in Alnus glutinosa leaves. Results show that fungi are pivotal for laccase activity in leaves and that their activity is repressed when they co-exist with bacteria. The sensitivity of laccase activity to the TBZ was only detectable in leaves colonized by fungi separately (Alatospora acuminata populations), but absent in those colonized by bacteria separately and/or mixed fungi plus bacteria. Specifically, the increase of TBZ concentration enhances laccase activity in Alatospora acuminata populations but decreases ergosterol concentration as well as the amount of 18S RNA gene copies. This activity response suggests a detoxification mechanism employed by the fungus in order to reduce TBZ toxicity. Besides, enzyme fractioning showed that laccase activity in the cell bound fraction (76% of the total activity) was sensitive to the fungicide, but not that in the diffusible fraction (24% of total activity). Hence, TBZ would influence laccase activity in the presence of fungal cells but not in enzymes already synthesized in the extracellular space. The present study highlights the importance of the biological complexity level (i. e. population, community, ecosystem) when seeking for appropriate functional ecotoxicity descriptors in aquatic microbial communities.

Photoprotection and photoreception of intraocular lenses under xenon and white LED illumination.

OBJECTIVE: To analyze the photoprotection and phototransmission that various intraocular lenses (IOLs) provide under the illumination of a xenon (Xe) lamp and white LEDs (light emitting diode). METHODS: The spectral transmission curves of six representative IOLs were measured using a Perkin-Elmer Lambda 35 UV/VIS spectrometer. Various filtering simulations were performed using a Xe lamp and white LEDs. The spectral emissions of these lamps were measured with an ILT-950 spectroradiometer. RESULTS: The IOLs analyzed primarily show transmission of nearly 100% in the visible spectrum. In the ultraviolet (UV) region, the filters incorporated in the various IOLs did not filter equally, and some of them let an appreciable amount of UV through. The Xe lamp presented a strong emission of ultraviolet A (UVA), and its emission under 300nm was not negligible. The white LED did not present an appreciable emission under 380nm. CONCLUSIONS: The cut-off wavelength of most filters is between 380 and 400nm (Physiol Hydriol60C(®), IOLTECH E4T(®), Alcon SA60AT(®), Alcon IQ SN60WF(®)), so that their UV protection is very effective. Nonetheless, the IOL OPHTEC Oculaid(®) contains a filter that, when a Xe lamp is used, lets through up to 20% for 350nm and up to 15% for 300nm, which at this point is ultraviolet B (UVB). The OPHTEC(®) Artisan IOL has a transmission peak below 300nm, which must be taken into account under Xe illumination. White LEDs do not emit energy below 380nm, so no special protection is required in the UV region.

Manejo diagnóstico del cólico renal / Diagnostic management of renal colic

El cólico renal es un motivo frecuente de consulta en los Servicios de Urgencias y la imagen diagnóstica se ha convertido en una herramienta fundamental del diagnóstico y manejo clínico. La ecografía y, fundamentalmente, la tomografía computarizada sin contraste permiten diagnosticarlo con un rendimiento elevado. El manejo radiológico va a depender de la disponibilidad del centro y de las características de la población. Es imprescindible usar técnicas de baja dosis de radiación en la tomografía computarizada y técnicas alternativas como la ecografía en embarazadas y niños. En este artículo hacemos una revisión epidemiológica, clínica, radiológica y del manejo clínico de la litiasis ureteral (AU)

Renal colic is a common reason for presentation to emergency departments, and imaging has become fundamental for the diagnosis and clinical management of this condition. Ultrasonography and particularly noncontrast computed tomography have good diagnostic performance in diagnosing renal colic. Radiologic management will depend on the tools available at the center and on the characteristics of the patient. It is essential to use computed tomography techniques that minimize radiation and to use alternatives like ultrasonography in pregnant patients and children. In this article, we review the epidemiology, clinical and radiologic presentations, and clinical management of ureteral lithiasis (AU)

Diagnostic management of renal colic.

Renal colic is a common reason for presentation to emergency departments, and imaging has become fundamental for the diagnosis and clinical management of this condition. Ultrasonography and particularly noncontrast computed tomography have good diagnostic performance in diagnosing renal colic. Radiologic management will depend on the tools available at the center and on the characteristics of the patient. It is essential to use computed tomography techniques that minimize radiation and to use alternatives like ultrasonography in pregnant patients and children. In this article, we review the epidemiology, clinical and radiologic presentations, and clinical management of ureteral lithiasis.

Spectral transmission of the pig lens: effect of ultraviolet A+B radiation.

OBJECTIVE: To determine the spectral transmission curve of the crystalline lens of the pig. To analyse how this curve changes when the crystalline lens is irradiated with ultraviolet A+B radiation similar to that of the sun. To compare these results with literature data from the human crystalline lens. PROCEDURES: We used crystalline lenses of the common pig from a slaughterhouse, i.e. genetically similar pigs, fed with the same diet, and slaughtered at six months old. Spectral transmission was measured with a Perkin-Elmer Lambda 35 UV/VIS spectrometer. The lenses were irradiated using an Asahi Spectra Lax-C100 ultraviolet source, which made it possible to select the spectral emission band as well as the intensity and exposure time. RESULTS: The pig lens transmits all the visible spectrum (95%) and lets part of the ultraviolet A through (15%). Exposure to acute UV (A+B) irradiation causes a decrease in its transmission as the intensity or exposure time increases: this decrease is considerable in the UV region. CONCLUSIONS: We were able to determine the mean spectral transmission curve of the pig lens. It appears to be similar to that of the human lens in the visible spectrum, but different in the ultraviolet. Pig lens transmission is reduced by UV (A+B) irradiation and its transmission in the UV region can even disappear as the intensity or exposure time increases. An adequate exposure intensity and time of UV (A+B) radiation always causes an anterior subcapsular cataract (ASC).

Comparative sensitivity to the fungicide tebuconazole of biofilm and plankton microbial communities in freshwater ecosystems.

Stream and lake ecosystems in agricultural watersheds are exposed to fungicide inputs that can threaten the structure and functioning of aquatic microbial communities. This research analyzes the impact of the triazole fungicide tebuconazole (TBZ) on natural biofilm and plankton microbial communities from sites presenting different degrees of agricultural contamination. Biofilm and plankton communities from less-polluted (LP) and polluted (P) sites were exposed to nominal concentrations of 0 (control), 2 and 20 µg TBZ L(-1) in 3-week microcosm experiments. Descriptors of microbial community structure (bacterial density and chlorophyll-a concentration) and function (bacterial respiration and production and photosynthesis) were analyzed to chart the effects of TBZ and the kinetics of TBZ attenuation in water during the experiments. The results showed TBZ-induced effects on biofilm function (inhibition of substrate-induced respiration and photosynthetic activity), especially in LP-site communities, whereas plankton communities experienced a transitory stimulation of bacterial densities in communities from both LP and P sites. TBZ attenuation was stronger in biofilm (60-75%) than plankton (15-18%) experiments, probably due to greater adsorption on biofilms. The differences between biofilm and plankton responses to TBZ were likely explained by differences in community structure (presence of extracellular polymeric substances (EPS) matrix) and microbial composition. Biofilm communities also exhibited different sensitivity levels according to their in-field pre-exposure to fungicide, with P-site communities demonstrating adaptation capacities to TBZ. This study indicates that TBZ toxicity to non-targeted aquatic microbial communities essentially composed by microalgae and bacteria was moderate, and that its effects varied between stream and lake microbial communities.

Ultraviolet radiation at Mediterranean latitudes and protection efficacy of intraocular lenses.

PURPOSE: After determining the mean intensity of ultraviolet radiation to which the human eye is exposed at Mediterranean latitudes, this data is used to evaluate the efficacy of the ultraviolet filters incorporated into various intraocular lenses. METHODS: Ultraviolet radiation measured at Mediterranean latitudes was used as a reference for the theoretical calculation of the amount of radiation to which the human eye is exposed. The spectral transmission curve from 290 to 380 nm was measured for 10 IOLs using a UV/VIS Perkins-Elmer Lambda 800 spectrometer. RESULTS: At Mediterranean latitudes, at sea level, with a mean annual solar irradiation of 50 j/cm(2), the human eye receives a quantity of UVA and UVB that is lower than the threshold toxic dose for the rabbit crystalline lens (93 j/cm(2) for UVA and 6.45 j/cm(2) for UVB). However, at higher altitudes and with albedo approaching 0.9 (fresh snow), the amount of radiation increases, with duration of exposure potentially playing a significant role. The UV filters incorporated into the IOLs studied are, in general, protective against such levels of radiation. CONCLUSION: At Mediterranean latitudes, at sea level, the amount of UV radiation to which our eyes are exposed is insufficient to damage the crystalline lens; however, at higher altitudes, the risk of such damage exists. UV filters incorporated into intraocular lenses are generally effective, since they filter all radiation with wavelengths under 380 nm.

Phosphorus use by planktonic communities in a large regulated Mediterranean river.

The regulation of large rivers to meet human requirements (e.g. hydroelectricity production, flood prevention, recreation activities) alters the longitudinal distribution of plankton communities and may affect their capacity to use nutrients and organic matter. Here we analyzed phosphorus (P) availability and use by phytoplankton and bacterioplankton in 6 upstream and 5 downstream sites from a reservoir system in the Ebro River (N Spain). Alkaline phosphatase activity (APA) was related to nutrient availability and biomass of both phytoplankton and bacterioplankton. During dry periods phytoplankton and bacterioplankton APA was inversely correlated to P availability in the water, but these patterns became less clear during wet periods. The phosphorus-APA patterns were more consistent in the upstream sites and especially during dry periods. Although phytoplankton APA was 6-40 times greater than that of bacterioplankton, APA per unit of biomass suggested that bacterioplankton was more efficient at utilizing dissolved organic phosphorus (DOP) in the upstream section during dry periods. Imbalanced N:P ratios in the particulate (N:P ranging 133-170) and dissolved (N:P ranging 301-819) water fractions confirmed the strong P limitation in these upstream communities. The phosphorus-APA patterns were weaker in the downstream section and during wet periods. The reservoirs caused a change in the downstream dynamics, where bacterioplankton biomass was positively correlated to APA but APA per unit of biomass decreased. Our findings reveal that river regulation drives changes in plankton use of organic phosphorus, especially during extreme dry periods.

Adaptive behaviour in Angelman syndrome: its profile and relationship to age.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder usually caused by an anomaly in the maternally inherited chromosome 15. The main features are severe intellectual disability, speech impairment, ataxia, epilepsy, sleep disorder and a behavioural phenotype that reportedly includes happy disposition, attraction to/fascination with water and hypermotoric behaviour. METHOD: We studied the level of adaptive behaviour and the adaptive behavioural profile in the areas of 'motor skills', 'language and communication', 'personal life skills' and 'community life skills' in a group of 25 individuals with genetically confirmed AS, to determine whether there is a specific adaptive behaviour profile. RESULTS AND CONCLUSIONS: None of the individuals, whatever their chronological age, had reached a developmental age of 3 years. A specific adaptive behaviour profile was found, with 'personal life skills' emerging as relative strengths and 'social and communication skills' as weaknesses.

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

Comparison of gastrointestinal tolerability and patient preference for treatment with the 625 mg and 250 mg nelfinavir tablet formulations.

OBJECTIVES: To compare gastrointestinal (GI) tolerability and patient preference for the new 625 mg formulation of nelfinavir (NFV) and the marketed 250 mg tablets (Viracept) in HIV-1-infected patients. METHODS: Virologically controlled patients (n=126) treated with a nelfinavir (NFV) 250 mg-containing regimen for > or =8 weeks completed a stool diary for 14 days to assess baseline bowel function. After switching to the NFV 625 mg formulation [1250 mg twice a day (bid)] for 28 days, patients continued their stool diaries and at study completion answered a questionnaire regarding formulation preferences. RESULTS: The incidence and mean weekly duration of GI upset over a 2-week period were lower with NFV 625 mg than with NFV 250 mg (79.8% vs. 84.9% of patients and 2.1 vs. 3.0 days, respectively). Fewer patients experienced moderate or severe diarrhoea with NFV 625 mg (6.5% vs. 11.1%), and the incidence of investigator-assessed diarrhoea also decreased with NFV 625 mg. Importantly, there was a significant improvement overall in the incidence of diarrhoea (any grade) when patients switched to NFV 625 mg [38 of 124 (31%) improving, 69 of 124 (56%) stable and 17 of 124 (14%) worsening on NFV 625 mg; P<0.01]. At study completion, most patients expressed a preference to continue treatment with NFV 625 mg [112 of 122 (91.8%); P<0.0001], with only one patient (0.8%) preferring to resume treatment with NFV 250 mg. The new formulation was well tolerated with no new safety concerns. CONCLUSIONS: The new NFV 625 mg formulation is better tolerated and preferred by patients switching from NFV 250 mg tablets. By reducing the daily pill count and improving GI tolerability, the NFV 625 mg formulation may enhance patient adherence to NFV-containing antiretroviral regimens and thus potentially improve virological outcomes.

Analysis and identification of several apple varieties using ISFETs sensors.

There are a number of variables that are useful to determine the optimal moment for the fruit collection such as starch content, sugar content, acidity and firmness. Other variables, including calcium and potassium concentrations, may establish better the state of ripeness of fruit and can help to optimise the collection process as well as augmenting the nutritional value of fruits. At present, these novel parameters cannot be used for the control of fruit collection due to the slow standard methods required. The need for in situ and in real-time ion measurements calls for fast response sensors and simpler and portable instrumentation. Solid-state sensors respond to these requirements. This work describes the application of ISFET sensors to analyse calcium, potassium and nitrates in several apple varieties, both in juice and in situ fruit. Results show that the analysis of potassium, calcium and nitrate permits to distinguish among apple varieties and can also be used to determine correctly the concentrations of these ions.

Proyecto PASSVEN de Venezuela, un modelo de cooperacón integradora / PASSVEN project of Venezuela, a model for integrating co-operation

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[Periodic movements of the limbs during sleep in childhood]. / Movimientos periódicos de las extremidades durante el sueño en la infancia.

INTRODUCTION: Periodic movements of the limbs (PML) whilst sleeping is a disorder included in the group of intrinsic dysomnias which cause problems of insomnia and somnolence during the day. It is usually associated with the restless legs syndrome (it occurs in 80% of the patients with this syndrome) although PML may occasionally be an isolated finding. The prevalence of the disease is of 11%. It usually occurs in patients aged over 50 years, and the frequency increase with age. It is uncommon in persons aged under 30 years. In children it is almost unknown. When it does occur in this age group it is usually associated with the restless legs syndrome. OBJECTIVE: To obtain data regarding this disorder in childhood, in view of the scarcity of information available in the literature and the importance of the neuropsychological problems and difficulty with learning that affected children have. CLINICAL CASES: We report two cases of PML occurring in girls of under 7 years of age. They had severe associated neuropsychological disorders (disorders of behavior and feeding, psychotic episodes, etc.). The effect on performance at school led to complete failure in one case. We describe the clinical course of the two girls, emphasizing the variability, and both diagnostic and therapeutic difficulties. CONCLUSIONS: Although this condition is uncommon in childhood, it should always be borne in mind in cases of children with sleep disorders, since early diagnosis will prevent major behavior and learning problems.

Movimientos periódicos de las extremidades durante el sueño en la infancia / Periodic movements of the limbs during sleep in childhood

Introducción. Los movimientos periódicos de las extremidades (MPE) durante el sueño constituyen un trastorno incluido dentro de las disomnias intrínsecas, que provoca problemas de insomnio y somnolencia diurna. Suele asociarse al síndrome de las piernas inquietas (ya que aparece en un 80 por ciento de los pacientes con este síndrome), aunque en ocasiones los MPE se manifiestan de forma aislada. La prevalencia de la enfermedad es de un 11 por ciento. Habitualmente se presenta en mayores de 50 años, aumentando su prevalencia con la edad. Su presentación en menores de 30 años es infrecuente, siendo las descripciones en niños casi inexistentes y habitualmente asociadas al síndrome de piernas inquietas. Objetivo. Aportar datos sobre esta entidad en la infancia, dada la escasez de datos publicados sobre esta patología en edades tempranas, y la trascendencia de los problemas neuropsicológicos y del aprendizaje que provoca esta entidad en los niños afectos. Casos clínicos. Presentamos dos casos de MPE de aparición en niñas menores de 7 años, y mostramos los graves trastornos neuropsicológicos asociados (trastornos de conducta, alimentación, episodios psicóticos, etc.), y la influencia sobre el rendimiento escolar, que llegó a provocar fracaso del mismo en una de las pacientes. Se detalla la evolución de ambas niñas, y se hace hincapié en su variabilidad, la dificultad diagnóstica y terapéutica. Conclusiones. A pesar de su infrecuencia en la infancia, esta entidad debe estar siempre presente ante todo niño con trastornos del sueño, ya que su diagnóstico temprano evita importantes problemas de conducta y de aprendizaje (AU)

Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease.

Congenital disorders of glycosylation (CDG) and mitochondrial diseases are multisystem disorders with clinical characteristics that may overlap. We present four patients with CDG whose phenotypes suggested the diagnosis of a mitochondrial disease. Patients 1 and 2 are siblings with hemiplegic headache, stroke-like episodes, lactic acidaemia and history of maternal migraine; their initial clinical diagnosis was MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes). Patient 3 suffers from ataxia, neuropathy, ophtalmoplegia and retinitis pigmentosa suggestive of NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. Patient 4 presented with neurological regression mimicking Leigh disease, with ptosis, myoclonus, ataxia and brainstem and cerebellar atrophy. Screening for mitochondrial disease including enzyme and mtDNA investigations on muscle biopsy were performed on Patients 1, 2 and 4 with normal results. However, evidence for a glycosylation disorder was substantiated by an increased carbohydrate deficient transferrin (CDT). The isoelectric focussing pattern of serum sialotransferrin was typical of CDG type I in Patients 1, 2 and 3 and was shifted towards the less sialylated bands in case 4. A deficiency of phosphomanomutase (PMM) confirmed the diagnosis of CDG-Ia in Patients 1, 2 and 3, who are compound heterozygous for mutations R141H/T237M (Patients 1 and 2) and R141H/P113L (Patient 3). In Patient 4, PMM activity was normal, and further enzymatic and molecular studies are underway. As the search for the primary defect in mitochondrial diseases is often unsuccessful, the pool of mitochondrial patients that remain without definite diagnosis might include CDG cases. Routine screening for CDG may avoid precocious invasive investigations.