From cryptogenic to ESUS: Toward precision medicine?

Cryptogenic infarctions are infarctions without a defined cause, despite a complete work-up. They differ from infarctions of undetermined causes, which may involve overlapping causes or an incomplete investigation. It is also different from uncommon heritable and non-heritable causes. The term embolic stroke of undetermined source (ESUS) proposed in 2014 is defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources. The major advantage of this definition compared to cryptogenic definition is the proposition of a specific work-up. In a general population, frequent potential sources of embolism in patients with ESUS have been suggested since a long time and include: patent foramen ovale (PFO), covert atrial fibrillation (AF), complex aortic arch atheroma, large vessel atheroma with stenosis<50%, carotid web, atrial cardiomyopathy, thrombophilia associated with cancer. It took almost 30 years to show, in patients under 60 with a cryptogenic stroke and a PFO, that PFO occlusion was superior to medical treatment alone for recurrent stroke. PFO under 60 is therefore no longer a cryptogenic cause of infarction. The concept of cryptogenic stroke and its refinement in ESUS have been fruitful for the identification of PFO associated as a cause. Covert AF can be detected by different techniques but its risk significance for recurrent stroke might be different from the simple electrocardiographic detection of AF. With the development of direct oral anticoagulants (DOAs), randomized studies in patients with ESUS, were run for stroke prevention but no difference was observed between patients treated by DOA compared to aspirin. These studies showed however the heterogeneity of ESUS patients. Further ESUS classification should be considered as a tool to identify homogeneous groups. We propose to further split the ESUS group into different subgroups: ESU-PFO>60-year-old, ESUS-ATH with stenosis<50%, ESUS-AF (covert AF & atrial cardiomyopathy), ESUS-cancer and others. Precision medicine is the ability to make targeted healthcare decisions based on the specific risks of individual patients. One preliminary stage is therefore to identify homogeneous groups suitable in the future for new therapeutic trials and, at the end, for new specific treatments.

Estimated number of eligible patients for mechanical thrombectomy based on NIHSS and population-based Brest stroke registry.

BACKGROUND: Since 2015, mechanical thrombectomy (MT) is indicated as a treatment for patients with large vessel occlusion (LVO) at the acute phase of ischemic stroke. However, the number of stroke patients eligible for MT is poorly known. OBJECTIVE: The objective of our study was to estimate the number of patients eligible for thrombectomy within the first 24hours of an ischemic stroke, based on the clinical National Institute of Health Stroke Scale (NIHSS). METHOD: Our study concerned all ischemic strokes which occurred between January 2013 and December 2016 recorded in the population-based Brest Stroke Registry (BSR). Based on positive predictive value and negative predictive value from articles evaluating the performance of a defined NIHSS threshold to identify LVO, we first estimated the frequency of patients with LVO and then the frequency of patients eligible for MT depending on pre-stroke modified Rankin score (mRS). Our results were extrapolated to regions of metropolitan France. Two scenarios were considered: one called "stringent criteria" with mRS ≤1 and one called "real-life" criteria with mRS ≤2. RESULT: We analyzed data from 2,025 ischemic strokes with symptom onset ≤24hours. No statistical difference between patient characteristics according to the time of hospital admission (≤6H vs. 6-24H) was observed. Based on NIHSS scores, between 23.90% and 44.20% of ischemic strokes admitted within the first six hours had LVO clinical characteristics. Among them, 14.53% to 26.87% met the ``stringent eligibility'' criteria for MT and 16.9 to 31.25% for ``real-life'' criteria. Eligible patients represented 6.32% to 11.70% of all ischemic strokes, irrespective of admission time. In France, 75 to 162 persons per million inhabitants per year were eligible for endovascular therapy, depending on including criteria. Based on activity levels recorded by the French Neuroradiology Society (SFNR) in 2018, the estimated needed increase in MT showed a heterogeneous pattern region-by-region, with the greatest need in Brittany, Pays de la Loire, and Corsica. CONCLUSION: Based on NIHSS, our study provides coherent information concerning the estimated number of MT procedures to be performed in France: 4,877 to 10,494 ischemic strokes would be eligible each year in metropolitan France compared to the 6,596 thrombectomy procedures actually performed in 2018. Depending on the region, an estimated 10-20% to 90-100% increase in MT activity would be necessary to meet patient needs. These data suggest that there is still room for improvement in thrombectomy activity, particularly in certain regions of France, to allow equal access to MT to the entire French population.

High completeness of the brest stroke registry evidenced by analysis of sources and capture-recapture method.

BACKGROUND: Population-based stroke registries are necessary to evaluate the precise burden of stroke. The methodology used in the Brest Stroke Registry and an estimation of its completeness are described. METHODS: 'Hot pursuit' as well as 'cold pursuit' were used, and five sources of identification were included: emergency wards, brain imaging, practitioners, death certificates and hospital-based electronic research. Ascertainment for each case was certified by a neurologist. Inclusion criteria were: (1) age >15 years; (2) a stroke defined by WHO criteria or all neurological deficits lasting at least 1 h. Completeness was estimated using capture-recapture method. RESULTS: For 2008, 2009 and 2010, 851, 898, 823 patients were collected, respectively. The number of sources of identification per patient was as follows: one source: 30.8, 24.1 and 18.7%; two sources: 54.5, 42.9 and 31.0%; three sources: 13.4, 30.1 and 46%; four sources: 1.3, 3.0 and 3.8%. Capture-recapture analysis showed data completeness over 90%. Standardized cumulative first-ever stroke incidence using a world standard population was 87 in 2008, 87 in 2009 and 84 in 2010. CONCLUSIONS: Case ascertainment by a neurologist, numerous sources, as well as 'hot' and 'cold' pursuit can provide a reliably large data set suitable for further epidemiological studies.

Opalski syndrome detected on DWI MRI: A rare lateral medullary infarction. Case report and review.

INTRODUCTION: Wallenberg's syndrome and ipsilateral paresis due to combined infarction of the lateral medullary and cervical spinal infarction is known as Opalski syndrome. This rarely described syndrome was reported, to our knowledge, with DWI MRI, only once. CASE REPORT: We report the case of a 43-year-old man with autosomal dominant polycystic kidney disease who, after a brief episode of coma, developed Wallenberg syndrome and ipsilateral hemiparesis. Initial diffusion weighted-imaging MRI showed a high-intensity signal involving the lateral medulla oblongata and the spinal cord; but FLAIR MRI sequences showed bilateral high-intensity signals in the lateral medulla oblongata and spinal cord and high-intensity signals in the right and left cerebellar hemisphere in the PICA territories. MRI performed one year later showed an infarction involving the left medullary area and adjacent spinal segments alone. CONCLUSION: This observation illustrates a rare syndrome of lateral medullary infarction, associated with spinal cord infarction related to a possible transient basilar occlusion.

[Metered-dose inhaler with spacer vs nebulization for severe and potentially severe acute asthma treatment in the pediatric emergency department]. / Traitement aux urgences des crises d'asthme par nébulisations vs chambres d'inhalation.

OBJECTIVE: To compare treatment with beta 2 agonist delivered either by a spacer device or a nebulizer in children with severe or potentially severe acute asthma. METHODS: In this randomized trial, children 4 to 15 years, cared for in the emergency department for severe or potentially severe acute asthma, received 6 times either nebulizations of salbutamol (0.15mg/kg) or puffs of a beta 2 agonist (salbutamol 50 microg/kg or terbutaline 125 microg/kg). The primary outcome was the hospitalization rate. Secondary outcomes included percentage improvement in Bishop score, in PEF, SaO(2), respiratory and heart rates, side effects, length of stay and relapses 10 and 30 days later. RESULTS: Groups did not differ for baseline data. There were no significant differences between the 2 groups (nebulizer N=40, spacer N=39) for baseline characteristics before emergency department consultation except for length of acute asthma in the spacer group. Clinical evolution after treatment, hospitalization rate, relapse were similar including the more severe subgroup. In the spacer group, tachycardia was less frequent (P<0.02). The overall length of stay in the emergency department was significantly shorter (148+/-20 vs 108+/-13 min, P<10(-9)). CONCLUSIONS: The administration of beta 2 agonist using a metered-dose inhaler with spacer is an effective alternative to nebulizers for the treatment of children with severe or potentially severe acute asthma in the emergency department. Time gained can be used for asthma education.

Cryptogenic mechanism in ischaemic stroke patients is a predictor of 5-year survival: A population-based study.

INTRODUCTION: The present study sought to identify factors affecting mortality beyond 28 days in ischaemic stroke patients with whatever ischaemic mechanism. PATIENTS AND METHODS: A prospective population-based registry was set up in Brest County, Brittany, France. Demographic data, clinical presentation, vascular risk factors and mortality were collected from January 2008 to December 2012. At "home without help" was used as a surrogate marker for low Rankin (0-1) at discharge from the hospital. IS was classified on the TOAST classification. Overall mortality was calculated using the Kaplan-Meier method. Multivariate analysis of mortality beyond 28 days was implemented, using a Cox model, on significant risk factors identified on univariate analysis. RESULTS: About 3024 IS cases were followed up beyond 28 days. Overall mortality beyond 28 days was 38.49% at 60 months. On multivariate analysis, age (10 years: HR = 1.84; [1.66-2.02]), coronary artery disease (HR = 1.28; [1.05-1.56]), cardiac arrhythmia (HR = 1.36; [1.11-1.67]), peripheral artery disease (HR = 1.66 [1.29-2.13]) and incomplete assessment (HR = 1.39; [1.12-1.74]) were associated with higher mortality risk, whereas female gender (HR = 0.80; [0.68-0.94]), high Glasgow Coma Scale score (GCS > 12) (HR = 0.58; [0.45-0.76]), lacunar syndrome (HR = 0.82; [0.68-0.99], being 'at home without help' (HR = 0.50; [0.41-0.59]) and negative assessment (HR = 0.75; [0.58-0.97], compared to cardioembolism) were associated with better survival probability. DISCUSSION: Initial clinical status, prior cardiovascular diseases and age was associated with more risk of death: an increment of 10 years almost doubled mortality. Women had more survival probability than men, controlling for age. Ischaemic stroke mechanisms were predictors of late 5-year mortality. CONCLUSION: Patients with negative assessment, i.e. representing truly cryptogenic ischaemic stroke, had the best survival probability probably due to fewer atherosclerotic markers.

[Acute osteomyelitis and septic arthritis in children: one year experience]. / Infections bactériennes ostéoarticulaires du nourrisson et de l'enfant: expérience sur un an.

To describe bacteriologic epidemiology of bone and joint infections, a total of 52 osteomyelitis, 52 arthritis and 20 osteoarthritis of children aged one month to 15 years during a one-year period (2001) were included in a retrospective unicentric review. The mean age was 3,9 +/-3,6 years. Fever and pain were the most common clinical symptoms. The site of infection was single in 95%, involving lower extremities in 80%. Bone scintigraphy was abnormal in 71% of osteomyelitis. Positive cultures was obtained in 29% of all cases (blood cultures: 20%, aspiration cultures: 29%), but in 42% of cases which have both blood and aspiration cultures. Thirty-six bacteria were identified: 19 Staphylococcus (14 aureus), ten Streptococcus (four pneumoniae), three Salmonella, three Kingella kingae, one Moraxella. All the isolates were susceptible to the empiric antibiotic therapy. Outcome was good in 100% of osteomyelitis and in 96% of arthritis.

Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association.

Members of the trk gene family encode neurotrophin receptors. The trkC locus encodes multiple neurotrophin-3 catalytic and noncatalytic receptor isoforms. We report the molecular cloning and characterization of mouse cDNAs encoding two noncatalytic TrkC receptors: novel isoforms designated as TrkC NC1 and TrkC NC2, the mouse homologue of the TrkC truncated form previously identified in rat (Tsoulfas et al. [1993] Neuron 10:975-990; Valenzuela et al. [1993] Neuron 10:963-974). We extensively analyzed the transcription pattern of these two noncatalytic isoforms and that of the catalytic isoforms by Northern blotting and in situ hybridization. We did not detect trkC NC1 transcripts in embryos, but we found that trkC NC1 expression is restricted to specific areas in adult brain. In contrast, trkC NC2 transcripts are readily detected early during embryogenesis and are expressed predominantly in adult brain and gonads. We also provide the first evidence for the existence of TrkC NC2 protein by using polyclonal antibodies that specifically recognize this isoform. By using in situ hybridization, we show for the first time that trkC NC2 transcripts are found in differentiating fields of maturing neurons and in mature neurons of laminar structures of adult brain. We also report a similarity of localization between trkC NC2 transcripts and markers of oligodendrocyte progenitors in the embryonic spinal cord. Furthermore, our results also show that trkC NC2 and trkC catalytic transcripts could be either codistributed (in the central and peripheral nervous system) or independently expressed, especially outside the nervous system. These results suggest that the TrkC NC2 isoform acts either independently or in association with its catalytic counterpart. Finally, we show that TrkC NC2 is expressed in dendrites of pyramidal neurons of hippocampus and cerebral cortex. We propose that this receptor is involved in proliferation of oligodendrocyte progenitors, neuronal differentiation, and synaptic plasticity and that it may also play a fundamental role in mediating neurotrophin-3 effects outside the nervous system.

Brain infarction severity differs according to cardiac or arterial embolic source.

We compared clinical and radiologic features between 246 cardiac embolism (EMB) and 66 arterial embolic (tandem arterial pathology [TAP]) patients selected from the 1,273 patients with cerebral infarction in the Stroke Data Bank. Diagnostic definitions accounted for the increased frequency of cardiac disease among patients with EMB compared with TAP (78.4% versus 29.3%), while transient ischemic attacks (32.3% versus 13.1%) and carotid artery bruit (15.1% versus 3.3%) were more prevalent in TAP than in EMB. Multiple logistic regression differentiated TAP and EMB further. The probability of a TAP diagnosis was increased by the CT finding of a superficial infarct alone (odds ratio [OR] = 4.6; 95% CI = 1.5 to 13.7) or by a higher admission hematocrit. The probability of EMB was greater in patients with an initial decreased consciousness (OR = 39.2; 95% CI = 4.0 to 381.3) or with an abnormal first CT (OR = 3.2; 95% CI = 1.2 to 8.6). These findings indicate that the two infarct subtypes differ in the location and extent of the cortical infarction, which argues for a smaller particle size, with smaller and more distal infarction in embolism from an arterial source compared with cardiogenic embolism.

[Unilateral benign episodic mydriasis]. / Mydriase épisodique unilatérale bénigne.

Ophthalmoplegic migraine is a rare phenomenon. In this setting, extrinsic as well as intrinsic fibers of the third nerve are involved. We report 2 cases of isolated, unilateral, remitting, mydriasis and describe 23 other cases already published. CT scan, MRI and angiogram were always normal when performed. The pathophysiology of this syndrome is probably related to a migrainous manifestation.

[Assessing the cost of the first episode of bronchiolitis]. / Evaluation du coût du premier épisode de bronchiolite.

BACKGROUND: Each year, a quarter of the children younger than 24 months has respiratory syncytial virus bronchiolitis. The morbidity among high-risk infants and the possible association with the development of asthma lead to propose preventive measures whose cost-effectiveness relationship is unknown. The present work was aimed at measuring costs of a first attack of bronchiolitis. METHOD: For children less than two years visited in the emergency department, direct and indirect costs were measured according to the 'Sécurité Sociale' prices. Associated morbidity, the management of care (inpatient versus outpatient), outpatients' outcome two weeks after the visit, socioeconomic data were recorded. RESULTS: One hundred eighty three children have been studied. The length of stay for 40 hospitalizations was 7.6 +/- 4.3 days. Direct costs were 37,200 +/- 22,000 FF for inpatients, and 1286 +/- 633 F for outpatients. For 113 outpatients' families, indirect costs were 49 working days lost. The way the child was looked after and the unemployment rate in the study were similar to data provided by the National Institute of Statistics and Economic Studies. CONCLUSION: Because of the variability of the hospitalization rate from one setting to another, overall costs of the epidemic cannot be evaluated. For the policymaker, the greatest costs come from the outpatient care. Others studies will be necessary to evaluate the price of future preventive measures.

[Effect of racecadotril in the management of acute diarrhea in infants and children]. / Effet du racécadotril sur le recours aux soins dans le traitement des diarrhées aiguës du nourrisson et de l'enfant.

BACKGROUND: The treatment of diarrhoea relies on the maintenance or restoration of hydration with maintenance of an adequate nutritional intake. Racecadotril has been shown to reduce the stools output during acute diarrhoea. The present work was aimed at measuring the number of emergency department visits for acute diarrhoea either the children received racecadotril or not. METHOD: Racecadotril and rehydration were compared with rehydration alone in children aged three months to three years who had acute diarrhoea and were evaluated in the emergency department (ED). The primary end point was the number of medical exams during the week after starting treatment. Secondary end points were the number of stools during the first 48 hours, the duration of the diarrhoea and the weight on day 7. RESULTS: One hundred and sixty-six children were alternatively randomized to the treated and the control groups. There was no difference for age, degree of dehydration and length of illness before the first visit between the groups. Whatever type of rehydration (oral or i.v.), the treated group had a significant lower number of stools (p < 0.001) and a faster recovery (p < 10(-9)). The children receiving racecadotril needed less additional ED visits for the same episode (p < 0.05). There was no difference for the weight-gain on day 7. CONCLUSIONS: This study demonstrates the efficacy of racecadotril as adjuvant therapy to oral and i.v. rehydration in the treatment of acute diarrhoea and a fewer emergency department second visit before recovery.

[Benefits of ipratropium bromide in the management of asthmatic crises in the emergency department]. / Apport du bromure d'ipratropium dans la prise en charge des crises d'asthme aux urgences.

BACKGROUND: To determine if the addition of ipratropium bromide in the emergency department (ED) for the treatment of childhood asthma reduces rates of hospitalization and relapses for moderate and severe exacerbations. METHODS: Patients were given an oral corticosteroid treatment (2 mg/kg) and received every 20 minutes either three nebulizations with albuterol (0.15 mg/kg) and ipratropium bromide (250 micrograms) or six nebulizations with albuterol alone (control group). The primary end point was the need for hospitalization, additional nebulizations or a relapse during the following week. Secondary end point included the effect of age. RESULTS: One hundred and forty three children, two to 15 years old, were randomized to ipratropium or control groups and 121 were evaluated on day seven. As a whole, the control group was less often hospitalized or in relapse than those treated with three nebulizations of albuterol and ipratropium (17.5% vs 37.9%, p < 0.02). The ipratropium group reached the same result after three additional albuterol nebulizations. The benefit of anticholinergic therapy was observed for children less than six years of age who had a similar rate of success (73.5 vs 75.7%). CONCLUSION: The association of ipratropium bromide to the first three doses of the albuterol protocol for acute asthma did not act as well as six nebulizations of albuterol alone. The effect was age dependent and two to six years old children needed more attention. Nevertheless the hospitalization rate did not support the use of ipratropium compared with repeated albuterol nebulizations.

[Smoking and sudden infant death syndrome]. / Tabac et mort subite du nourrisson.

Assessment of the causation relationship between two phenomena requires the demonstration of an epidemiological association, a temporal and asymmetric sequence, and a biological gradient and identification of the biological mechanism(s). All epidemiological studies on sudden infant death syndrome (SIDS) and smoking have encountered major bias and difficult data interpretation but they all have estimated that maternal smoking caused a 2 to 3-fold increased risk of SIDS. Nicotine may interact with non-neuronal nicotinic receptors in the lung, peripheral nicotinic cholinergic and adrenergic chemoreceptors, and brainstem nuclei and has been largely studied. More accurate knowledge concerning the biochemistry and specific features of nicotinic receptors will be useful to explain the way nicotine alters breathing at rest and during hypoxia. Uncertainty about the casual relationship in no way means the fight against smoking is not warranted.

[Asomatognosia and oral drive: a psychoanalytical perspective]. / Asomatognosie et troubles de l'oralité. Une lecture psychanalytique.

OBJECTIVE: The psychoanalytic concept of specular image refers to the complex construction that associates the body image with the language coordinates of the individual, thus making him/her a human subject. The acquisition of this specular image implies the loss of corporeal exchanges between mother and child, i.e., the "neutralization" of those body parts or extensions where these exchanges take place. These conceptions of body image and subjectivity lead to the hypothesis that neurological disturbances of body schema may alter the patients' subjectivity and their relation to the lost "object" insofar as they alter body image. MATERIAL: In the present paper, we present two patients aged under 50, with a unique first ever stroke due to ischemia in the right middle cerebral artery territory and asomatognosia. METHODS: On one hand, Bisiach's protocol was used to assess hemiplegia, sensory troubles, visual troubles, hemineglect and anosognosia, and adapted to assess asomatognosia. On the other hand, subjective data were gathered during a semistructured interview and a self-portrait test. RESULTS: This showed that asomatognosia was accompanied by a destructuration of body image and aberrant oral manifestations involving the paralyzed hand. DISCUSSION-CONCLUSION: The psychological positive phenomena accompanying asomatognosia might correspond to the intrusion of the lost object in the patients' psychic reality, due to the alteration of body schema and body image.

[Asthma and the child below 5 years of age: diagnosis and treatment]. / Asthme de l'enfant avant 5 ans: diagnostic et traitement.

Asthma is the most frequent chronic disease in pediatrics and the increase in its prevalence is a major public health problem. Diagnosis may be difficult in the young child, symptomatology most often occurring following a viral infection. It is important not to ignore a foreign body in the airways or fibrocystic disease and asthma remains, particularly in infants, a diagnosis of elimination. Misdiagnosis or insufficient treatment of asthma may risk the development of irreversible histological lesions and also could compromise pulmonary growth and the child's lung reserve. Spacer devices and nebulisers enable inhaled therapy to be administered to very young children. The value of early diagnosis is to institute appropriate treatment notably in severe asthma with inhaled corticosteroid therapy, the aim being to reduce remodelling lesions of the airways. The minimal effective dose should be defined to minimalise side-effects. The treatment of asthma is not restricted to pharmacotherapy: attempts should be made to reduce intercurrent viral infections, domestic pollution (including smoking) and allergenic concentrations. However, as for all chronic diseases, the clinician will encounter poor compliance. The work of education and support of health professionals is fundamental to the management of asthma.

[Asthma in children below 5 years of age: diagnosis and treatment]. / Asthme de l'enfant avant 5 ans: diagnostic et traitement.

Asthma is the most frequent chronic disease in pediatrics and the increase in its prevalence is a major public health problem. Diagnosis may be difficult in the young child, symptomatology most often occurring following a viral infection. It is important not to ignore a foreign body in the airways or fibrocystic disease and asthma remains, particularly in infants, a diagnosis of elimination. Misdiagnosis or insufficient treatment of asthma may risk the development of irreversible histological lesions and also could compromise pulmonary growth and the child's lung reserve. Spacer devices and nebulisers enable inhaled therapy to be administered to very young children. The value of early diagnosis is to institute appropriate treatment notably in severe asthma with inhaled corticosteroid therapy, the aim being to reduce remodelling lesions of the airways. The minimal effective dose should be defined to minimalize side-effects. The treatment of asthma is not restricted to pharmacotherapy: attempts should be made to reduce intercurrent viral infections, domestic pollution (including smoking) and allergenic concentrations. However, as for all chronic diseases, the clinician will encounter poor compliance. The work of education and support of health professionals is fundamental to the management of asthma.

[An unusual foreign body. Report of a case of subcutaneous emphysema during an asthma attack]. / Un corps étranger hors du commun. À propos d'un cas d'emphysème sous-cutané lors d'une crise d'asthme.

Pneumomediastinum is an uncommon complication after an asthma attack. The essential clinical sign is the presence of subcutaneous emphysema. In the great majority of cases, the treatment of pneumomediastinum corresponds to that of asthma, with resorption over several days. The situation is very different when the development of pneumomediastinum and subcutaneous emphysema is secondary to an aspiration syndrome.

[Vertigo of vascular origin]. / Vertiges d'origine vasculaire.

The concept of vascular origin in vertigo and equilibrium disorders is only a pragmatic clinical tool used to initiate and direct complex, complementary clinical investigation to determine the location (peripheral, central or mixed), the pathophysiological mechanisms and the multiple etiologies of the vestibular disorder. The concept includes focal and systemic ischemic processes and haemorrhagic processes of the posterior fossa. If the vertigo is associated with central neurological signs, the method can lead to certain diagnosis. If such signs are not detected by neurological screening of all the intra-axial signs of the vertebrobasilar regions, the diagnosis is uncertain clinical. Screening associated CT scan and MRI is more reliable than neuro-otological quantification. The major diagnostic difficulty involves TIA. Vertebrobasilar appears to be more heterogeneous than carotid ischemia. Schematic distinction is possible to differentiate thrombo-embolic from hemodynamic TIA. It is based on methodic clinical analysis and complementary investigations that are of unequal value.