Introduction and validation of the open symptom framework: a public domain modular framework for patient-reported measurement of symptoms related to cancer and its treatment.

PURPOSE: We provide an initial description and validation of some public domain patient-reported outcome (PRO) items to assess cancer symptom burden to address immediate barriers to symptom assessment use in clinical practice and facilitate future research. METHODS: We created the Open Symptom Framework (OSF), a flexible tool for clinical cancer-related symptom assessment. The items comprise six components: recall period, concept, symptom, qualifier(s), a definition, and a 5-point Likert-type response. We recruited patients receiving cancer therapy in the United States and United Kingdom. We assessed external construct validity by comparing OSF scores to the PRO-CTCAE measure and assessed reliability, scalability, dimensionality, and item ordering within a non-parametric item response theory framework. We tested differential item functioning for country, age, gender, and level of education. RESULTS: We developed a framework alongside clinical and psychometric experts and debrieifed with 10 patients. For validation, we recruited 331patients. All items correlated with the PRO-CTCAE equivalents (r = 0.55-0.96, all p < 0.01). Mokken analysis confirmed the scalability and unidimensionality of all symptom scales with multiple items at the scale (Ho = 0.61-0.75) and item level (Hi = 0.60-0.76). Items are interpreted consistently between demographic groups (Crit = 0 for all groups). CONCLUSION: The public domain OSF has excellent psychometric properties including face, content, and criterion validity and can facilitate the development of flexible, robust measurements to fulfil stakeholder need. The OSF was designed specifically to support clinical assessment but will function well for research. Further work is planned to increase the number of symptoms and number of questions per symptom within the framework.

Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X(7), encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X(7) has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004

Single-Crystal 40Ar/39Ar Dating of the Eocene-Oligocene Transition in North America.

Explanations for the causes of climatic changes and associated faunal and floral extinctions at the close of the Eocene Epoch have long been controversial because of, in part, uncertainties in correlation and dating of global events. New single-crystal laser fusion (SCLF) (40)Ar/(39)Ar dates on tephra from key magnetostratigraphic and fossilbearing sections necessitate significant revision in North American late Paleogene chronology. The Chadronian-Orellan North American Land Mammal "Age" boundary, as a result, is shifted from 32.4 to 34.0 Ma (million years ago), the Orellan-Whitneyan boundary is shifted from 30.8 to 32.0 Ma, and the Whitneyan-Arikareean boundary is now approximately 29.0 Ma. The new dates shift the correlation of Chron C12R from the Chadronian to within the Orellan-Whitneyan interval, the Chadronian becomes late Eocene in age, and the North American Oligocene is restricted to the Orellan, Whitneyan, and early Arikareean. The Eocene-Oligocene boundary, and its associated climate change and extinction events, as a result, correlates with the Chadronian-Orellan boundary, not the Duchesnean-Chadronian boundary.

Age of the earliest known hominids in Java, Indonesia.

40Ar/39Ar laser-incremental heating of hornblende separated from pumice recovered at two hominid sites in Java, Indonesia, has yielded well-defined plateaus with weighted mean ages of 1.81 +/- 0.04 and 1.66 +/- 0.04 million years ago (Ma). The hominid fossils, a juvenile calvaria of Pithecanthropus and a partial face and cranial fragments of Meganthropus, commonly considered part of the Asian Homo erectus hypodigm, are at least 0.6 million years older than fossils referred to as Homo erectus (OH-9) from Olduvai Gorge, Tanzania, and comparable in age with the oldest Koobi Fora Homo cf. erectus (Homo ergaster) in Kenya. These ages lend further credence to the view that Homo erectus may have evolved outside of Africa. If the ancestor of Homo erectus ventured out of Africa before 1.8 Ma, the dispersal would have predated the advent of the Acheulean culture at 1.4 Ma, possibly explaining the absence of these characteristic stone cleavers and hand axes in East Asia.

Latest Homo erectus of Java: potential contemporaneity with Homo sapiens in southeast Asia.

Hominid fossils from Ngandong and Sambungmacan, Central Java, are considered the most morphologically advanced representatives of Homo erectus. Electron spin resonance (ESR) and mass spectrometric U-series dating of fossil bovid teeth collected from the hominid-bearing levels at these sites gave mean ages of 27 +/- 2 to 53.3 +/- 4 thousand years ago; the range in ages reflects uncertainties in uranium migration histories. These ages are 20,000 to 400,000 years younger than previous age estimates for these hominids and indicate that H. erectus may have survived on Java at least 250,000 years longer than on the Asian mainland, and perhaps 1 million years longer than in Africa. The new ages raise the possibility that H. erectus overlapped in time with anatomically modern humans (H. sapiens) in Southeast Asia.

The Ischigualasto Tetrapod Assemblage (Late Triassic, Argentina) and 40Ar/39Ar Dating of Dinosaur Origins.

(40)Ar/(39)Ar dating of sanidine from a bentonite interbedded in the Ischigualasto Formation of northwestern Argentina yielded a plateau age of 227.8 +/- 0.3 million years ago. This middle Carnian age is a direct calibration of the Ischigualasto tetrapod assemblage, which includes some of the best known early dinosaurs. This age shifts last appearances of Ischigualasto taxa back into the middle Carnian, diminishing the magnitude of the proposed late Carnian tetrapod extinction event. By 228 million years ago, the major dinosaurian lineages were established, and theropods were already important constituents of the carnivorous tetrapod guild in the Ischigualasto-Villa Unión Basin. Dinosaurs as a whole remained minor components of tetrapod faunas for at least another 10 million years.

Pliocene paleoclimate and East antarctic ice-sheet history from surficial ash deposits.

The preservation, age, and stratigraphic relation of an in situ ashfall layer with an underlying desert pavement in Arena Valley, southern Victoria Land, indicate that a cold-desert climate has persisted in Arena Valley during the past 4.3 million years. These data indicate that the present East Antarctic Ice Sheet has endured for this time and that average temperatures during the Pliocene in Arena Valley were no greater than 3 degrees C above present values. One implication is that the collapse of the East Antarctic Ice Sheet due to greenhouse warming is unlikely, even if global atmospheric temperatures rise to levels last experienced during mid-Pliocene times.

Coeval 40Ar/39Ar Ages of 65.0 Million Years Ago from Chicxulub Crater Melt Rock and Cretaceous-Tertiary Boundary Tektites.

(40)Ar/(39)Ar dating of drill core samples of a glassy melt rock recovered from beneath a massive impact breccia contained within the 180-kilometer subsurface Chicxulub crater in Yucatán, Mexico, has yielded well-behaved incremental heating spectra with a mean plateau age of 64.98 +/- 0.05 million years ago (Ma). The glassy melt rock of andesitic composition was obtained from core 9 (1390 to 1393 meters) in the Chicxulub 1 well. The age of the melt rock is virtually indistinguishable from (40)Ar/(39)Ar ages obtained on tektite glass from Beloc, Haiti, and Arroyo el Mimbral, northeastern Mexico, of 65.01 +/- 0.08 Ma (mean plateau age for Beloc) and 65.07 +/- 0.10 Ma (mean total fusion age for both sites). The (40)Ar/(39)Ar ages, in conjunction with geochemical and petrological similarities, strengthen the recent suggestion that the Chicxulub structure is the source for the Haitian and Mexican tektites and is a viable candidate for the Cretaceous-Tertiary boundary impact site.

Earliest Pleistocene hominid cranial remains from Dmanisi, Republic of Georgia: taxonomy, geological setting, and age.

Archaeological excavations at the site of Dmanisi in the Republic of Georgia have uncovered two partial early Pleistocene hominid crania. The new fossils consist of a relatively complete cranium and a second relatively complete calvaria from the same site and stratigraphic unit that yielded a hominid mandible in 1991. In contrast with the uncertain taxonomic affinity of the mandible, the new fossils are comparable in size and morphology with Homo ergaster from Koobi Fora, Kenya. Paleontological, archaeological, geochronological, and paleomagnetic data from Dmanisi all indicate an earliest Pleistocene age of about 1.7 million years ago, supporting correlation of the new specimens with the Koobi Fora fossils. The Dmanisi fossils, in contrast with Pleistocene hominids from Western Europe and Eastern Asia, show clear African affinity and may represent the species that first migrated out of Africa.

Identification of QRS complex in non-stationary electrocardiogram of sick infants.

BACKGROUND: Due to the high-frequency of routine interventions in an intensive care setting, electrocardiogram (ECG) recordings from sick infants are highly non-stationary, with recurrent changes in the baseline, alterations in the morphology of the waveform, and attenuations of the signal strength. Current methods lack reliability in identifying QRS complexes (a marker of individual cardiac cycles) in the non-stationary ECG. In the current study we address this problem by proposing a novel approach to QRS complex identification. METHOD: Our approach employs lowpass filtering, half-wave rectification, and the use of instantaneous Hilbert phase to identify QRS complexes in the ECG. We demonstrate the application of this method using ECG recordings from eight preterm infants undergoing intensive care, as well as from 18 normal adult volunteers available via a public database. We compared our approach to the commonly used approaches including Pan and Tompkins (PT), gqrs, wavedet, and wqrs for identifying QRS complexes and then compared each with manually identified QRS complexes. RESULTS: For preterm infants, a comparison between the QRS complexes identified by our approach and those identified through manual annotations yielded sensitivity and positive predictive values of 99% and 99.91%, respectively. The comparison metrics for each method are as follows: PT (sensitivity: 84.49%, positive predictive value: 99.88%), gqrs (85.25%, 99.49%), wavedet (95.24%, 99.86%), and wqrs (96.99%, 96.55%). Thus, the sensitivity values of the four methods previously described, are lower than the sensitivity of the method we propose; however, the positive predictive values of these other approaches is comparable to those of our method, with the exception of the wqrs approach, which yielded a slightly lower value. For adult ECG, our approach yielded a sensitivity of 99.78%, whereas PT yielded 99.79%. The positive predictive value was 99.42% for both our approach as well as for PT. CONCLUSIONS: We propose a novel method for identifying QRS complexes that outperforms common currently available tools for non-stationary ECG data in infants. For stationary ECG our proposed approach and the PT approach perform equally well. The ECG acquired in a clinical environment may be prone to issues related to non-stationarity, especially in critically ill patients. The approach proposed in this report offers superior reliability in these scenarios.

Real-time high dynamic range laser scanning microscopy.

In conventional confocal/multiphoton fluorescence microscopy, images are typically acquired under ideal settings and after extensive optimization of parameters for a given structure or feature, often resulting in information loss from other image attributes. To overcome the problem of selective data display, we developed a new method that extends the imaging dynamic range in optical microscopy and improves the signal-to-noise ratio. Here we demonstrate how real-time and sequential high dynamic range microscopy facilitates automated three-dimensional neural segmentation. We address reconstruction and segmentation performance on samples with different size, anatomy and complexity. Finally, in vivo real-time high dynamic range imaging is also demonstrated, making the technique particularly relevant for longitudinal imaging in the presence of physiological motion and/or for quantification of in vivo fast tracer kinetics during functional imaging.

Autism and mental retardation: neuropathologic studies performed in four retarded persons with autistic behavior.

Four persons who exhibited prominent autistic features throughout life died when 4, 14, 27, and 33 years old. All were mentally retarded. One had documented phenylketonuria, but the cause of mental retardation and autistic behavior was undefined in three. At the time of autopsy, brain weights were within 2 SDs of the norm for age. Complete neuropathologic examination, including analysis of cortical neurons impregnated with the rapid Golgi method, failed to provide clues as to cause or the pathoanatomic substrate of autistic behavior in these cases.

Cerebro-ocular dysgenesis (Walker-Warburg syndrome): neuropathologic and etiologic analysis.

We studied three cases (two of them siblings) with ocular and cerebral dysgenesis (Walker-Warburg syndrome). The histologic changes suggest that the disorder results from a sclerosing meningoencephalitis active through the second and third trimesters, but different from that typically encountered with known congenital pathogens. This illness was encountered first in the 1930s and has been reported with increasing frequency since 1970. The risk of recurrence among siblings exceeds 50%, with a predilection for involving consecutive siblings, a high incidence of reproductive failure, and no transmission across generations. The evidence suggests that an acquired agent may be transmitted transplacentally through consecutive pregnancies.

The effects of diphenhydramine and SR142948A on periaqueductal gray neurons and on the interactions between the medial preoptic nucleus and the periaqueductal gray.

The midbrain periaqueductal gray contains both neurotensin type-1 and type-2 receptors. Behavioral studies have shown that the analgesic effect of neurotensin is mediated through its interaction with the type-2 receptors. These receptors specifically bind the type-1 histamine antagonist, levocabastine. Recently, it has been shown that another histamine-1 antagonist, diphenhydramine, blocks the analgesic effect of neurotensin. In addition, it has been shown that a non-peptide neurotensin antagonist, SR142948A, binds to both types of neurotensin receptors and blocks the analgesic effect of exogenously applied neurotensin. Major afferents to the periaqueductal gray arise from the medial preoptic nucleus of the hypothalamus. This region contains neurotensinergic neurons, and the expression of neurotensin mRNA in this region increases following cold-water swim stress that leads to opioid-independent analgesia. The goal of this study was to determine whether the responses of periaqueductal gray neurons to stimulation of the medial preoptic nucleus are modified by local injection of diphenhydramine and SR142948A. Because the cellular basis of the effects of diphenhydramine on periaqueductal gray neurons had not been reported, we also examined the effects of diphenhydramine on the baseline-firing rate and synaptic transmission using in vivo and in vitro methods. The results of the in vitro studies indicate that diphenhydramine concentrations above 500 nM significantly reduce the baseline firing of the periaqueductal gray neurons without a significant effect on the frequency of postsynaptic potentials. At concentrations below 100 nM, diphenhydramine has little effect on the baseline-firing rate but partially blocks the response to neurotensin. The results of the in vivo studies showed similar effects of diphenhydramine. At high concentrations it inhibited periaqueductal gray neurons, but at low concentrations it had no effect on the baseline-firing rate and it blocked the response to neurotensin and to medial preoptic nucleus stimulation. Unlike diphenhydramine, SR142948A had virtually no effect on the baseline-firing rate but blocked the response to neurotensin and to stimulation of the medial preoptic nucleus. It is concluded that: (1) SR142948A, at a dose that completely blocks the effect of exogenously applied neurotensin on periaqueductal gray neurons, has little effect on their baseline-firing rates. (2) Because of its effect on the baseline-firing rate, only low doses of diphenhydramine can be used as an antagonist of the neurotensin analgesic effect. (3) Responses of periaqueductal gray neurons to medial preoptic nucleus stimulation is, in part, mediated by a neurotensinergic network within the periaqueductal gray.

Treatment of children with posttraumatic transient loss of consciousness.

Recommendations for the treatment of asymptomatic children who have had a brief period of loss of consciousness due to blunt head trauma are anecdotal and vary greatly. The purpose of this study is to define the range of practice in treating children with uncomplicated loss of consciousness by determining: (1) the frequency of "routine" hospitalization for observation and (2) those criteria which, when present, result in hospitalization. A total of 957 pediatricians representing five groups of physicians responded to a nationwide questionnaire survey to determine current treatment practices for uncomplicated loss of consciousness. Of all directors of pediatric emergency rooms and pediatric chief residents, 44% routinely hospitalize all patients who have had loss of consciousness. Academic child neurologists and child neurologists in private practice hospitalize these patients least frequently, 29% and 31%, respectively (P less than 0.05). Of pediatricians in private practice, 38% admit all children with loss of consciousness. Pediatricians from all groups who do not routinely hospitalize all children with uncomplicated loss of consciousness showed similarity in the criteria they use for admission. These variables include: abnormal vital signs (97% to 100%), skull fracture (96% to 100%), suspicion of child abuse (93% to 100%), observation of a change in level of consciousness (92% to 99%), unreliable caretaker at home (91% to 98%), vomiting (90% to 99%), history of a change in level of consciousness (88% to 100%), duration of loss of consciousness (88% to 96%), seizure (77% to 94%), age of child (62% to 75%), child nearly back to normal (32% to 48%), dizziness (22% to 49%), witness of loss of consciousness not reliable (24% to 36%), headache (9% to 16%), and decision deferred to neurosurgeon (2% to 7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic and developmental outcome in treated congenital toxoplasmosis.

BACKGROUND: Earlier studies have shown that infants with untreated congenital toxoplasmosis and generalized or neurologic abnormalities at presentation almost uniformly develop mental retardation, seizures, and spasticity. Children with untreated subclinical disease at birth have developed seizures, significant cognitive and motor deficits, and diminution in cognitive function over time. OBJECTIVE: To determine neurologic, cognitive, and motor outcomes for children with congenital toxoplasmosis who were treated for approximately 1 year with pyrimethamine and sulfadiazine. DESIGN AND METHODS: Systematic, prospective, and longitudinal neurologic, cognitive, and motor evaluations were performed for 36 individuals with congenital toxoplasmosis. These infants were born between December 1981 and January 1991 and were treated with pyrimethamine and sulfadiazine for approximately 1 year beginning in the first months of life. Compliance with medications was documented. These individuals were evaluated in a standardized manner in a single center in the first months of life and at approximately 1, 3.5, 5, 7.5, and 10 years of age. Their cognitive function was compared with the cognitive function of a nearest-age, same-sex sibling when such siblings older than 3.5 years were available for study. RESULTS: Signs of active central nervous system infection (eg, cerebrospinal fluid [CSF] pleiocytosis, hypoglycorrhachia, elevated CSF protein, and, in some instances, seizures and motor abnormalities) resolved during therapy. Six of the 36 children had perinatal seizures. Four had their anticonvulsant therapy discontinued successfully within the first months of life, and two additional children developed new seizures at 3 and 5 years of age. Tone and motor abnormalities resolved by 1 year of age in 12 of 20 infants who exhibited abnormalities of tone and motor function at their initial neonatal evaluation. By February 1992, 29 of the 36 children had been evaluated when they were 1 year old, and 23 (79%) had a mean +/- standard deviation Mental Developmental Index (MDI) of 102 +/- 22 (range, 59 to 140). Six (21%) had a measure of their cognitive function that was less than 50. Results of sequential IQ tests, performed at 1.5 year intervals or greater, did not differ significantly over time (P > .05). Seven children with MDIs greater than 50 were compared with sibling controls; they had scores of 87 +/- 11 (range, 68 to 97) and their siblings had scores of 112 +/- 15 (range, 85 to 132) (P = .008). Seventeen of 18 children without hydrocephalus and six of eight children with obstructive hydrocephalus responsive to shunting had normal or near-normal neurologic and developmental outcomes. Children with hydrocephalus ex vacuo present at birth, with high CSF protein, and with lack of response to shunting have done less well. CONCLUSIONS: Neurologic and developmental outcomes were significantly better for most of these treated children than outcomes reported for untreated children or those treated for only 1 month (P < .001). Although the level of cognitive function for treated children was less than for their uninfected siblings (P < .008), there was no significant deterioration in neurologic and cognitive function of the treated children tested sequentially. These favorable treatment outcomes justify systematic identification and treatment of pregnant women with acute gestational Toxoplasma infection and young infants with congenital toxoplasmosis.

Myotonic pupils in Charcot-Marie-Tooth disease. Successful relief of symptoms with 0.025% pilocarpine.

Twenty-seven members of a family with dominantly inherited Charcot-Marie-Tooth disease (CMTD) were examined. Fifteen members had CMTD and 13 of these had varying amounts of myotonic pupillary abnormalities similar in some ways to Adie tonic pupil syndrome. Those with graver neurologic disease showed greater pupillary abnormalities. Ten of the 15 patients had pupillary constriction with methacholine chloride (Mecholyl) and some of these had extensive iris atrophy. Several affected patients received symptomatic relief from 0.025% pilocarpine. Seven other patients with CMTD who were not related to our initial family were checked for myotonic pupils; two had findings similar to our initial family. Pupillary abnormalities in certain patients with CMTD appear secondary to a parasympathetic denervation of the iris sphincter and ciliary muscle, as shown by a positive methacholine test, and probably represent part of the autonomic nervous system dysfunction associated with the polyneuropathy in CMTD.

Eye manifestations of congenital toxoplasmosis.

PURPOSE: To determine the natural history of treated and untreated congenital toxoplasmosis and impact of this infection on vision. METHODS: In this prospective, longitudinal study, 76 newborns were treated with pyrimethamine and sulfadiazine for approximately one year, and 18 individuals not treated during their first year of life entered the study after age 1 year (historical patients). RESULTS: Chorioretinal scars were the most common eye finding in all patients and were most common in the periphery (58% of treated and 82% of historical patients). Macular scars were present in 54% of the treated patients; 41% were bilateral. Macular scars were present in 76% of the historical patients; 23% were bilateral. Visual acuity in the presence of macular lesions ranged from 20/20 to 20/400. Of the patients followed up from the newborn period and treated, 29% had bilateral visual impairment, with visual acuity for the best eye of less than 20/40. Causes for this visual impairment in eyes with quiescent lesions included macular scars, dragging of the macula secondary to a peripheral lesion, retinal detachment, optic atrophy, cataract, amblyopia, and phthisis. There were recurrences in both treated (13%, 7/54) and previously untreated historical patients (44%, 8/18). The total, median, and range of years of follow-up during which recurrences were observed were, for treated patients, 189 years (total), five years (median) and three to ten years (range) and, for historical, untreated patients, 160 years (total), 11 years (median), and three to 24 years (range). New lesions occurred in previously normal retinas and also contiguous to older scars. Active lesions appeared to become quiescent within ten to 14 days after beginning pyrimethamine and sulfadiazine therapy. CONCLUSION: Many children with congenital toxoplasmosis have substantial retinal damage at birth and consequent loss of vision. Nonetheless, vision may be remarkably good in the presence of large macular scars. Active lesions become quiescent with treatment.