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PubMed2025

A Digital Tool for Clinical Evidence-Driven Guideline Development by Studying Properties of Trial Eligible and Ineligible Populations: Development and Usability Study.

BACKGROUND: Clinical guideline development preferentially relies on evidence from randomized controlled trials (RCTs). RCTs are gold-standard methods to evaluate the efficacy of treatments with the highest internal validity but limited external validity, in the sense that their findings may not always be applicable to or generalizable to clinical populations or population characteristics. The external validity of RCTs for the clinical population is constrained by the lack of tailored epidemiological data analysis designed for this purpose due to data governance, consistency of disease or condition definitions, and reduplicated effort in analysis code. OBJECTIVE: This study aims to develop a digital tool that characterizes the overall population and differences between clinical trial eligible and ineligible populations from the clinical populations of a disease or condition regarding demography (eg, age, gender, ethnicity), comorbidity, coprescription, hospitalization, and mortality. Currently, the process is complex, onerous, and time-consuming, whereas a real-time tool may be used to rapidly inform a guideline developer's judgment about the applicability of evidence. METHODS: The National Institute for Health and Care Excellence-particularly the gout guideline development group-and the Scottish Intercollegiate Guidelines Network guideline developers were consulted to gather their requirements and evidential data needs when developing guidelines. An R Shiny (R Foundation for Statistical Computing) tool was designed and developed using electronic primary health care data linked with hospitalization and mortality data built upon an optimized data architecture. Disclosure control mechanisms were built into the tool to ensure data confidentiality. The tool was deployed within a Trusted Research Environment, allowing only trusted preapproved researchers to conduct analysis. RESULTS: The tool supports 128 chronic health conditions as index conditions and 161 conditions as comorbidities (33 in addition to the 128 index conditions). It enables 2 types of analyses via the graphic interface: overall population and stratified by user-defined eligibility criteria. The analyses produce an overview of statistical tables (eg, age, gender) of the index condition population and, within the overview groupings, produce details on, for example, electronic frailty index, comorbidities, and coprescriptions. The disclosure control mechanism is integral to the tool, limiting tabular counts to meet local governance needs. An exemplary result for gout as an index condition is presented to demonstrate the tool's functionality. Guideline developers from the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network provided positive feedback on the tool. CONCLUSIONS: The tool is a proof-of-concept, and the user feedback has demonstrated that this is a step toward computer-interpretable guideline development. Using the digital tool can potentially improve evidence-driven guideline development through the availability of real-world data in real time.

Humans↗

PubMedDate not supplied

General types of relationships between the development of the organism and the development of the subsystems of the organism.

There are elementary and complex types (combined elementary types): of temporospatial relations between the pattern of development of the organism and the patterns of development of individual subsystems; of influences exercised by the development of the organism upon the development of the subsystems of the organism; of influences exercised by the development of individual subsystems upon individual development; of temporospatial relations between the stability of the line of individual development and the stability of the line of development of individual subsystems; of mutual influence between the stability and variation of the line of individual development, on the one hand, and the stability and variation of the line of development of the individual subsystems, on the other.

Environment↗

PubMed1979

Golgi studies on Purkinje cell development in the frog during spontaneous metamorphosis. II. Details of dendritic development.

The development of Purkinje cell dendrites was studied in the bullfrog from premetamorphic tadpoles to 10-week-old postmetamorphic frog-lets by the Golgi-Kopsch method. In this species two distinct patterns of arbor formation may be seen, which appear to be related to differences in the timing of initial dendritic development. In Purkinje cells that begin development in early tadpole stages, the dendritic tree is elaborated by continuous and concomitant growth and branching, a process by which the developing arbor expands in both height and width. Arbor formation in Purkinje cells that begin development in metamorphosing tadpoles proceeds in two separate steps. Initially, dendrites of such cells elongate, but form only a few poorly developed branches; only when the arbor reaches near-adult height does branching become extensive. Additional differences present in Purkinje cells are reflected in the paucity of growth cones and filopodia in the tadpole, and numerous filopodia and growth cones in the metamorphic period. An interesting feature of dendritic development in this species is a tendency to alter the arboreal domain by the formation of extra-arboreal dendrites, and possibly by the occasional resorbtion of other partially formed dendrites. The pattern of dendritic development in the frog is different than in mammals and is difficult to interpret. Such unusual development may be due to disturbances in the timing of the formation of Purkinje cell dendrites and of the establishment of the external granular layer (EGL).

Animals↗

PubMed1978

Golgi studies on Purkinje cell development in the frog during spontaneous metamorphosis. I. General pattern of development.

The development of Purkinje cells was studied in the bullfrog from prometamorphic tadpoles to 10-week-old postmetamorphic froglets by the Golgi-Kopsch method. In this species, the rate of Purkinje cell development is unusually slow and proceeds in two waves. The first wave of development begins prior to the establishment of the external granular layer (EGL), and proceeds slowly for two to three months during the formation of the EGL; then accelerating as metamorphosis is being completed, the cells reach near-adult dimensions a month later. Even prior to the formation of the EGL these cells are already present in the stage of dendritic orientation and flattening which, however, varies from the norm. The second wave of Purkinje cell development begins during metamorphosis and proceeds at a more rapid pace until two months after metamorphosis, at which time they appear to have reached adult dimensions. In these cells the development of the apical dendrite does not always coincide with the stellate stage but may proceed directly to the stage of dendritic orientation and flattening which, in accordance with the norm, is towards the pia and in the sagittal plane. Many variations are present in the dendritic trees and orientation of the dendritic branches of Purkinje cells throughout their development. These variations are similar to those seen in mammals, however, since the frog cerebellum consists of a simple plate, they cannot be attributed to a Cartesian transformation of dendrites to accomodate the curvatures of a folial pattern. Similarly, since these morphological variations occur in the course of normal development they cannot be attributed to a reaction to, or recovery from, injury during development.

Animals↗

PubMed1978

[Light microscopic studies on the development of Theileria annulata (Dschunkowsky and Luhs, 1904) in Hyalomma anatolicum excavatum (Koch, 1844). II. The development in haemolymph and salivary glands (author's transl)].

Fully differentiated kinetes, average length 17.6 micrometer, appeared in the haemolymph of engorged nymphs usually 17 to 20 days after repletion. Kinetes were observed at first in the salivary glands on day 18 after repletion. The kinetes then transformed into fission bodies of about 10 micrometer in diameter, mainly in type III alveoli and less frequently in type II alveoli. The fission bodies grew up to a size of about 20 micrometer after several divisions of their nucleus. At this time the ticks moulted and no further development occurred until activation. Shortly before infestation the salivary glands began to proliferate, and rapid growth of the fission bodies was observed, especially in young ticks where development of 'infective particles' ('sporozoites') was concluded within two days. Development in feeding adult ticks apparently occurred in four major steps: (1) Division of primary fission bodies (sporonts) into numerous secondary fission bodies ('primary sporoblasts'), (2) division of secondary fission bodies into tertiary fission bodies ('secondary sporoblasts'), (3) production of particles ('sporozoites') by tertiary fission bodies and release of particles into the saliva, and (4) degeneration of fission bodies and their host cell but further release of particles. The host cell was stimulated to giant growth, thus its diameter increased, on average, from 15 to 110 micrometer. Heavy infections resulting from parasitaemias of greater than 40% caused disease and mortality in the tick population. Development was much retarded by aging. In ticks starved for six months 'sporozoites' did not develop before day five to seven of infestation. 'Sporozoites' did not develop before day five to seven of infestation. 'Sporozoites' may not develop at all in six to nine month old female ticks during the infestation period. The significance of the described developmental stages of T. annulata was discussed and a sexual generation postualted. The hypothetic development of T. annulata in its tick vector was illustrated.

Animals↗

PubMed1991

The Minnesota Child Development Inventory: validity and reliability for assessing development in infancy.

The concurrent validity and reliability of the Minnesota Child Development Inventory (MCDI) was assessed by comparing the MCDI general development index score, and each of the seven subscale scores, with the mental and psychomotor age equivalents achieved on the Bayley Scales of Infant Development. In addition, the co-positivity, co-negativity, positive and negative predictive values of the MCDI in identifying infants with a mental development index (MDI), or psychomotor development index (PDI) of greater than 2 SD below the mean were assessed. Subjects were 101 infants (8 to 19 months old) who were seen at a neonatal developmental follow-up clinic after discharge from the neonatal intensive care unit. Correlations were obtained for the entire sample as well as for the two chronological age groups (i.e., 8 to 10 months and 17 to 19 months) within the sample. A strong correlation between the MCDI scales and the Bayley Mental and Psychomotor Scales was documented for the entire population as well as for the individual age groups. The overall validity of the MCDI in identifying infants with a MDI or PDI of greater than 2 SD below the mean was limited due to relatively poor co-positivity and positive predictive value. Although the MCDI may yield consistent information about the development of an infant's skills, this research suggests the MCDI has limited capacity to discern infants having delayed development.

Aptitude↗

PubMed1991

The development of traffic and traffic safety in six developed countries.

Two models are presented, describing the development of traffic and traffic safety. Traffic volumes, measured by the total amount of vehicle kilometers per year, are expected to follow a sigmoid saturation curve over time. The logistic function is used to model this development. The fatality rate, the number of fatalities per vehicle kilometer, is chosen to measure safety. The (negative) exponential function is selected to model the fatality rates over time. It is argued that these two aspects of the traffic system are fundamental and that the development of the number of fatalities results by multiplication. Given this assumption, the fall in the number of fatalities, noticed in almost all developed countries after a steady increase until 1970, does not need a special explanation. It follows from the combination of the monotonically increasing traffic volumes and the monotonically decreasing fatality rates. The two parsimonious models fit the data fairly well for six developed countries. The parameters differ substantially between countries, but also show common features. It is found from the parameters of the logistic function, that for all countries the points of maximum increase in traffic volume coincide just after 1970, the moment of the energy crisis. It is concluded from this finding that the energy crisis was caused by the cumulating demands of the oil-consuming countries, resulting in a reaction of the oil-producing countries. From the parameters of the exponential function, it is found that there also is a common point of intersection for fatality rates around 1980. It is shown that the development of safety is directly related to the development of traffic. The ten-year delay is interpreted as the time necessary for planning and implementation of safety measures. Finally, a striking relation is found between the volume parameters and the fatality-rate parameters, suggesting that the number of fatalities is a function of the derivative of the amount of traffic in the mathematical sense.

Accidents, Traffic↗

PubMed1992

Spatial distribution of "tissue-specific" antigens in the developing human heart and skeletal muscle. III. An immunohistochemical analysis of the distribution of the neural tissue antigen G1N2 in the embryonic heart; implications for the development of the atrioventricular conduction system.

A monoclonal antibody raised against an extract from the Ganglion Nodosum of the chick and designated G1N2 proves to bind specifically to a subpopulation of cardiomyocytes in the embryonic human heart. In the youngest stage examined (Carnegie stage 14, i.e., 4 1/2 weeks of development) these G1N2-expressing cells are localized in the myocardium that surrounds the foramen between the embryonic left and right ventricle. In the lesser curvature of the cardiac loop this "primary" ring occupies the lower part of the wall of the atrioventricular canal. During subsequent development, G1N2-expressing cells continue to identify the entrance to the right ventricle, but the shape of the ring changes as a result of the tissue remodelling that underlies cardiac septation. During the initial phases of this process the staining remains recognizable as a continuous band of cells in the myocardium that surrounds the developing right portion of the atrioventricular canal, subendocardially in the developing interventricular septum and around the junction of the embryonic left ventricle with the subaortic portion of the outflow tract. During the later stages of cardiac septation, the latter part of the ring discontinues to express G1N2, while upon the completion of septation, no G1N2-expressing cardiomyocytes can be detected anymore. The topographic distribution pattern of G1N suggests that the definitive ventricular conduction system derives from a ring of cells that initially surrounds the "primary" interventricular foramen. The results indicate that the atrioventricular bundle and bundle branches develop from G1N2-expressing myocytes in the interventricular septum, while the "compact" atrioventricular node develops at the junction of the band of G1N2-positive cells in the right atrioventricular junction (the right atrioventricular ring bundle) and the ("penetrating") atrioventricular bundle. A "dead-end tract" represents remnants of conductive tissue in the anterior part of the top of the interventricular septum. The location of the various components of the avian conduction system is topographically homologous with that of the G1N2-ring in the human embryonic heart, indicating a phylogenetically conserved origin of the conduction system in vertebrates.

Antigens↗

PubMed1992

Direct-developing sea urchins and the evolutionary reorganization of early development.

The evolution of development can be made accessible to study by exploiting closely related species that exhibit distinct ontogenies. The direct-developing sea urchin Heliocidaris erythrogramma is closely related to indirect-developing sea urchins that develop via a feeding larval stage. Superficial consideration would suggest that simple heterochronies resulting in loss of larval features and acceleration of adult features could explain the substitution of direct for indirect development. However, our experiments show that early development has in fact been extensively remodeled, with modified localization of maternal determinants coupled with dissociation of cell cleavage from axis formation resulting in novel patterns of cell lineage differentiation and fate map. Gene expression has undergone concomitant changes.

Animals↗

PubMed1976

The effects of experimental unilateral anotia on skull development in the chick embryo. III. Chondrocranial development in anotic embryos of 7-20 days of incubation.

The study of the development of of the chondrocranium in chick embryos with unilateral (right-sided) anotia revealed the following main characteristics. 1. The median axes of the chordal and the prechordal part of the cranial base are not in a straight line but show a deviation toward the right side. The angle between the two axes has its vertex in the region of the foramen hypophyseos. 2. The metotic cartilage and the foramina of the IXth and Xth cranial nerves are normal in position. 3. The tectum synoticum develops later and to a lesser extent than normal. 4. Between the basal plate, the metotic cartilage, the occipital arch and the supracapsular cartilage a foramen is formed which, later in development, is closed by outgrowths of the metotic cartilage and the basal plate. 5. The "optic area" shows a practically normal appearance which indicates that the cartilaginous ventral wall of the lagenal capsule is of basal plate origin. 6. The pro-otic process develops practically normal and, hence, is independent of the ear capsule. 7. The quadrate cartilage and the right lower jaw are displaced ventro-posteriorward. The earliest development of the perichondral bones shows some particularities which are closely correlated with the development of the various cartilaginous structures.

Animals↗

PubMed1979

[Medical development cooperation in the Confederation. The international framework and the important place of public health in Swiss development cooperation].

The systematic organization of health services in the developing countries to benefit the majority of the population is seen as an important contribution toward the general economic and social development of these countries. This view is uncontested today, but was given less importance in the early years of Swiss development aid. The Swiss Development Cooperation's support of health services is now integrated into its overall program to satisfy the basic needs of the people of the developing countries.

Developing Countries↗

PubMed1992

Insulin and insulinlike growth factors in embryonic development. Effects of a biologically inert insulin (guinea pig) on rat embryonic growth and development in vitro.

Congenital anomalies occur up to four times more frequently in diabetic pregnancy than in the nondiabetic population. Although past work has shown that maternal hyperglycemia and hyperketonemia may increase embryonic abnormalities, recent experimental evidence suggests that low insulin levels may also contribute to diabetic embryopathy. This study investigated the effects of guinea pig serum (whose insulin is inactive in rat systems) on rat embryonic growth and development in culture. Supplementation of guinea pig serum with pork insulin at low (1 ng/ml) and high (5 ng/ml) physiological concentrations and insulinlike growth factors (IGF) I and II were also studied. Culture of rat embryos from the early headfold stage in guinea pig serum resulted in poor embryonic growth and development with a 92% rate of anomalies. Supplementation of guinea pig serum with zinc-binding pork insulin significantly improved rat embryonic growth and development (46% anomaly rate) especially between the first 5 and 21 h of the period of organogenesis. This evidence supports our most recent findings that low insulin levels, as encountered in untreated diabetic pregnancy, may contribute to the increased risk of congenital abnormality. Insulin at low physiological concentrations improved growth, whereas higher physiological concentrations were required to increase growth and development. IGF-I or IGF-II supplementation improved rat embryonic growth and development but failed to match that of the controls, indicating that other growth factors including insulin may also be required.

Abnormalities, Drug-Induced↗

PubMed1992

The health transition in developing countries: a role for internists from the developed world.

Demographic and epidemiologic changes that have occurred in the past five decades in many developing countries provide new opportunities for internists from developed countries to contribute to improvements in international health. These changes, called the "health transition," are characterized by major growth in the number and proportion of middle-aged and elderly persons and in the frequency of the chronic diseases that occur in these age groups. The health transition is the result of concentrated national and international efforts to improve maternal and child health by emphasizing primary care and community-organized outreach services. In many developing countries, such efforts have been responsible for a decrease in the birth rate; reduced maternal mortality; improved preventive services; and a vigorous therapeutic approach to infantile diarrhea and respiratory infection, which, in turn, have resulted in the reduced infant mortality and the increased life expectancy that defines the health transition. These changes, often accompanied by increasing urbanization and industrialization, are creating health problems similar to those seen in the "developed" world but are occurring in countries that have far fewer resources. Internists interested in working in developing countries can therefore bring their skills, experience, and perspective to bear on these problems, primarily by working within well-structured programs, the aim of which is to strengthen the capacity of the organizations and institutions within these countries to cope with the rising tide of chronic adult diseases.

Delivery of Health Care↗

PubMed1992

Development shows some backbone. HFSP Workshop on Genetic Control of Vertebrate Development cosponsored by the Human Frontier Science Program, European Science Foundation, and European Molecular Biology Organization, Les Diablerets, Switzerland, May 26-30, 1991.

This meeting aptly illustrated the power of a combined analysis of development in a range of vertebrate systems. Each system has its own inherent strengths: the mouse has gene transfer technology and targeted mutagenesis, the frog and chick have experimental embryology, and the zebrafish has genetics. It is the synergistic effect of considering all of these systems in combination that is without measure. In the past, the study of vertebrate development has been relegated to a largely descriptive phase. Initially, this was through analysis of morphological changes taking place during development. More recently, this has taken the form of cataloging the expression patterns of genes transcribed in development. It is clear that we are now entering an era when a functional analysis of development can get underway.

Animals↗

PubMed1992

A comparison between the disease status of hospitalized dogs from developed and those from developing communities.

The health status of canine populations within developed and those within developing communities was studied in a retrospective survey and compared. There were significant differences in the prevalence of disease amongst the hospitalised dogs from the 2 communities. Dogs from developing communities were mainly young cross-bred dogs which suffered from infectious diseases (44%), trauma (22%) and parasitic diseases (11%). There was a high mortality rate (30%) and 82% of these patients suffered from diseases that could have been prevented. The dogs from developed communities were mainly adult or old pure-bred dogs that suffered mainly from organ diseases (57%). There was a low mortality rate (10%) while only 31% suffered from diseases that could have been prevented. Based on the epidemiological findings, it was evident that owners of dogs in the developing communities required education in primary and secondary prevention of disease.

Animals↗

PubMed1990

Development of the interferon system. I. In chicken cells development in ovo continues on time in vitro.

When confluent monolayers of cells derived from chicken embryos of different gestational age were cultured for several days without a medium change, a condition termed in vitro aging, the cells' developed an increased capacity to express the interferon (IFN) system. The capacity to both produce IFN and to respond to its antiviral action were enhanced up to 1000- and 100-fold, respectively. Remarkably, the programmed development of the IFN system in these cells seemed to continue virtually uninterrupted after monodispersion of the cells and seeding at high cell density. Cells prepared from young embryos required more time to develop the IFN system than cells from older embryos with the yield of IFN, and sensitivity to its action, related directly to the total in ovo and in vitro age of the cells in culture. For example, essentially the same yields of IFN were obtained from cell cultures made from 5-d-old embryos "aged" for 10 d in vitro, as were obtained from 10-d-old embryos whose cells were aged in vitro for 5 d. In contrast, inducibility of 2'-5' oligoadenylate synthetase by IFN and the induction of heat shock genes by elevated temperature are not enhanced with in vitro aging. The programmed development of the IFN system that starts in ovo seems to continue on schedule in vitro, making the development of the IFN system in chick embryo cells appear as a time-dependent process.

2',5'-Oligoadenylate Synthetase↗

PubMed1992

Development of cerebral arterial innervation: synchronous development of neuropeptide Y (NPY)- and vasoactive intestinal polypeptide (VIP)-containing fibers and some observations on growth cones.

The pre- and postnatal development of sympathetic fibers containing neuropeptide Y (NPY) and parasympathetic fibers containing vasoactive intestinal polypeptide (VIP) supplying the cerebral arteries were studied with immunohistochemistry in rats. The innervation patterns and densities of NPY and VIP fibers were similar at all stages of development and similar to that previously reported for norepinephrine (NE). There was a striking reorganization of the innervation pattern of all three fiber systems between the first and second postnatal weeks. At all stages of development prior to the first postnatal week, growth cones were present on individual fibers at the distal part of major cerebral arteries and the middle segment of the basilar artery. The growth cones had a range of shapes from blunt to stellate, lanceolate or filiform. NPY and VIP immunoreactive granules were commonly present. The present results taken with our earlier developmental study of NE fibers (J. Comp. Neurol., 271 (1988) 435-444), demonstrate that: (1) both sympathetic and parasympathetic perivascular nerves on immature cerebral vessels develop with similar sequences: first longitudinal fibers and fiber bundles are present; these transform to a meshwork pattern and finally transform again into the mature, predominantly circumferential pattern; (2) both the classical (NE) and peptidergic transmitters (NPY) within the sympathetic system appear to develop identically in terms of time of appearance, innervation patterns, densities and reorganization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗

PubMed1975

[Role of the somitic mesoderm in the development of the rib cage of bird embryos. I. Origin of the sternal component and conditions for the development of the ribs (author's transl)].

The developmental origin of the sternal component of the ribs and the conditions for the development of the rib cage have been elucidated in bird embryos. Experiments consisted in homo- or heterospecific transplantations of 2-day-old quail or chick embryo somitic mesoderm into chick hosts of the same age in ortho- or heterotopic position along the cephalo-caudal axis. Results show that vertebral halves, ribs (not only their vertebral segment, but also their sternal component when they possess one), the trunk and intercostal muscles, as well as at least part of the scapula originate exclusively from the somitic material, while the sternum, ventral muscles and the other parts of the pectoral girdle are derived from the somatopleural mesoderm. The development of the rib basket is subjected to following rules: -only the somitic mesoderm of the prospective thoracic region (somites 19-26) is able to give rise to ribs. -only the somitic mesoderm of the posterior thoacic region (somites 22-26) is able to develop ribs with a sternal component. -the vertebral component of ribs can develop outside the thoracic region. -contrariwise, the sternal component can form only in the vicinity of the sternal anlage, i.e. within about three somites in front and rear of the normal limits of the thoracic region. It is concluded that the somitic mesoderm is already regionalized at a stage slightly preceding its metamerization and that the somatopleural territory of the sternum plays a morphogenetic role in the development of the sternal component of ribs, although it does not make a cellular contribution to their construction.

Animals↗