Search

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

An early genetic diagnosis can guide the time-sensitive treatment and care of individuals with genetic epilepsies. However, identification of a genetic cause often occurs long after onset of these disorders. Here, we aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy by systematic large-scale analysis of clinical information from full-text patient notes in the electronic medical records (EMR).From the EMR of 32,112 individuals with childhood epilepsy, we retrieved 4,572,783 clinical notes spanning 203,369 total patient-years. A subcohort of 1,925 individuals had a known or presumed genetic epilepsy with 738 genetic diagnoses spanning 271 genes. We employed a customized natural language processing (NLP) pipeline to extract 89 million time-stamped standardized clinical annotations from free text of the retrieved clinical notes. Our analyses identified 47,641 clinical associations with a genetic cause at distinct ages prior to diagnosis. Notable among these associations were:SCN1Awith status epilepticus between 9 and 12 months of age (PSTXBP1with muscular hypotonia between 6 and 9 months (P=3.4×10−4, 95% CI=3.08-102);SCN2Awith autism between 1.5 and 1.75 years (PDEPDC5with focal-onset seizure between 5.75 and 6 years (PIQSEC2with myoclonic seizure between 2.75 and 3 years (P=2.5×10−4, 95% CI=11.3-1.15×104). We also identified associations between clinical terms and gene groups. Variants in ion channel gating mechanisms were associated with myoclonus between 3 and 6 months of age (PPKCNT1with migrating focal seizures from at 0 to 1.75 years (P15). A neurodevelopmental abnormality presenting between 6 and 9 months of age was strongly associated with an individual having any genetic diagnosis (PPP=5.5×10−3, 95% CI=1.23-3.35).In summary, we identified key clinical features that precede genetic diagnosis, leveraging EMR data at scale from a large cohort of individuals with genetic epilepsies. Our findings demonstrate that automated EMR analysis may assist clinical decision making, leading to earlier diagnosis and more precise prognostication and treatment of genetic epilepsies in the precision medicine era.

Purpose Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype–phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. Methods We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the NaV1.2 protein. Results We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. Conclusion Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype–phenotype correlations along a multidimensional spectrum.

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans, at the relevant time period in utero. To address this, we established an in vitro assay to study the impact of gene variants on the developing human brain by using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14–17 post-conception week brain tissue (www.hdbr.org). We were able to maintain cultures for several months, during which time the gross anatomical structures of the cortical plate, subplate and marginal zone persisted, while neurons continued to develop morphologically and form new synaptic networks. This preparation thus permits the study of genetic manipulations and their downstream effects on an intact developing human cortical network. We focused on STXBP1 haploinsufficiency, which is among the most common genetic causes of developmental and epileptic encephalopathy. This was induced using shRNA interference, leading to impaired synaptic function and a reduced density of glutamatergic synapses. We thereby provide a critical proof-of-principle for how to study the impact of any gene of interest on the development of the human cortex.

The Human Phenotype Ontology (HPO) is a dictionary of more than 15,000 clinical phenotypic terms with defined semantic relationships, developed to standardize their representation for phenotypic analysis. Over the last decade, the HPO has been used to accelerate the implementation of precision medicine into clinical practice. In addition, recent research in representation learning, specifically in graph embedding, has led to notable progress in automated prediction via learned features. Here, we present a novel approach to phenotype representation by incorporating phenotypic frequencies based on 53 million full-text health care notes from more than 1.5 million individuals. We demonstrate the efficacy of our proposed phenotype embedding technique by comparing our work to existing phenotypic similarity-measuring methods. Using phenotype frequencies in our embedding technique, we are able to identify phenotypic similarities that surpass the current computational models. In addition, we show that our embedding technique aligns with domain experts’ judgment at a level that exceeds their agreement. We show that our proposed technique efficiently represents complex and multidimensional phenotypes in HPO format, which can then be used as input for various downstream tasks that require deep phenotyping, including patient similarity analyses and disease trajectory prediction.

Neurology 99(3), e221-e233 (2022). doi:10.1212/WNL.0000000000200715, Published by Wolters Kluwer, Philadelphia, Pa.

Summary More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with “complex febrile seizures” (HP: 0011172; p = 2.1 × 10−5) and “focal clonic seizures” (HP: 0002266; p = 8.9 × 10−6), STXBP1 with “absent speech” (HP: 0001344; p = 1.3 × 10−11), and SLC6A1 with “EEG with generalized slow activity” (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans,in utero. To address this, we established anin vitroassay to study the impact of gene variants on the developing human brain, using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14-17 post conception week brain tissue (www.hdbr.org). We were able to maintain cultures for several months, during which time, the gross anatomical structures of the cortical plate, subplate and marginal zone persisted, while neurons continued to develop morphologically, and form new synaptic networks. This preparation thus permits the study of genetic manipulations, and their downstream effects upon an intact developing human cortical network. We focused upon STXBP1 haploinsufficiency, which is among the most common genetic causes of developmental and epileptic encephalopathy. This was induced using shRNA interference, leading to impaired synaptic function and a drop in the number of glutamatergic synapses. We thereby provide a critical proof-of-principle for how to study the impact of any gene of interest on the development of the human cortex.

ObjectiveTo describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy.MethodsWe investigated by Sanger and targeted resequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened.ResultsIn all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed SYN1 variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common.ConclusionBathing epilepsy is genetically distinct reflex epilepsy caused mainly by SYN1 mutations.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

Collaborative studies exploit large data sets to discover new associations with diseases. However, analyses of clinical features struggle with big data. Beyond sheer volume, the challenge is in harmonisation of terminology and the level of detail of information provided for analysis by different sources; in epilepsy this is most pertinent to seizures.We applied two ontologies (representations of the relationship between different types of seizure) to the same sparse details from 82 individuals. We compared the amount of information imputed using the Human Phenotype Ontology (HPO, a reference of clinical phenotypes widely used by geneticists) and an ontology of seizures created by the Epilepsiome Task Force of the International League Against Epilepsy Genetics Commission (based upon ILAE classifications).We translated each individual’s seizure descriptions into 2 terms (median) from each ontology. Imputa- tion generated 2 additional terms per individual using the HPO and 4 using the Epilepsiome ontology. The Epilepsiome ontology was able to increase the amount of information available for analysis by two- thirds compared to the HPO.Well-designed ontologies can be used to impute descriptions of complex clinical features at multiple less specific levels of precision, addressing a major limiting step in harmonisation of data for collabora- tion or re-use.rhys.thomas@ncl.ac.uk

While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.

Alien limb refers to movements that seem purposeful but are independent of patients’ reported intentions. Alien limb often co-occurs with apraxia in the corticobasal syndrome, and anatomical and phenomenological comparisons have led to the suggestion that alien limb and apraxia may be causally related as failures of goal-directed movements. Here, we characterised the nature of alien limb symptoms in patients with the corticobasal syndrome (n = 30) and their relationship to limb apraxia. Twenty-five patients with progressive supranuclear palsy Richardson syndrome served as a disease control group. Structured examinations of praxis, motor function, cognition and alien limb were undertaken in patients attending a regional specialist clinic. Twenty-eight patients with corticobasal syndrome (93%) demonstrated significant apraxia and this was often asymmetrical, with the left hand preferentially affected in 23/30 (77%) patients. Moreover, 25/30 (83%) patients reported one or more symptoms consistent with alien limb. The range of these phenomena was broad, including changes in the sense of ownership and control as well as unwanted movements. Regression analyses showed no significant association between the severity of limb apraxia and either the occurrence of an alien limb or the number of alien limb phenomena reported. Bayesian estimation showed a low probability for a positive association between alien limb and apraxia, suggesting that alien limb phenomena are not likely to be related to severity apraxia. Our results shed light on the phenomenology of these disabling and as yet untreatable clinical features, with relevance to theoretical models of voluntary action.

Seizures are a common feature of many acquired and genetic syndromes and the predominant feature of some illnesses. We discuss the evidence for the genetic basis of epilepsy and the current knowledge of the genetic architecture of epilepsy. Genetic causes are varied, and so for an effective testing strategy, you must first understand the clinical scenario as clearly as possible; testing for progressive myoclonus epilepsy is different from severe myoclonic epilepsy of infancy. A variety of structural genomic, de novo dominant, repeat expansion, and mitochondrial mutations can cause epilepsy, and these are discussed in detail. Working in a multidisciplinary team for planning testing and interpreting results is increasingly important for returning clinically significant results.

Genetic discovery in epilepsies has focussed on cohorts of children who typically have severe and intractable seizures. Now that genetic testing for adults with epilepsy has entered routine clinical practice, we are able to learn about the developmental trajectory of these epilepsies.Undiagnosed patients with epilepsy and intellectual disability were offered gene panel testing in an NHS epilepsy clinic. We present the clinical features of eight adults found to carry variants in paediatric epilepsy genes during re-investigation. All are amongst the oldest cases described. In six cases (CHD2, CNTNAP2, KCN1A, KCNT1, SCN2A, SCN8A) the onset was typical of published cases and we describe the evolution of their syndromes into adulthood including EEG and imaging. In two (SMC1A, NEXMIF) the onset was significantly later than published cases and we hypothesise that the phenotypic spectrum is broader than first thought for these disorders.Rare variants in genes associated with developmental and epileptic encephalopathies occur in adults with epilepsy. Stratifying patients with regards to syndromic diagnosis will facilitate more precise personalised prognostication and ultimately molecularly stratified treatment strategies. To maximise this potential it will become more important over the coming years for adult neurologists to undertake and understand genetic testing and collaborate with longitudinal observational studies of cohorts defined by molecular features.

Objective: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy. Methods: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. Results: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. Conclusions: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1.

The original reports of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies describe a predominant association with acute disseminated encephalomyelitis in children and with neuromyelitis optica spectrum disease (NMOSD) in adults. More recent studies broaden the spectrum of associated disorders to include recurrent optic neuritis and a picture similar to CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids). We performed a retrospective case note review of the presentation, imaging, laboratory findings and response to treatment of a group of 12 patients, aged 3–55 years, with CNS demyelinating disease, who tested positive (out of 117 tests) at a single centre. Our series shows a frequent biphasic pattern of illness. In over 75% there was an acute, often multifocal and highly steroid responsive first phase. In over half this was followed by a second phase, typically single or recurrent episodes of optic neuritis. Adult patients appear more likely to develop limited forms of the disease such as isolated recurrent optic neuritis or monophasic forms, though with significantly adverse outcomes in some cases. This pattern of disease following a suggestive initial presentation may have important implications for guiding both when to test for anti-MOG antibody and decisions on further therapy.

Mutations in the MICU1 gene have been shown to cause a condition with overlapping clinical and pathological features between muscular dystrophy, congenital myopathy and mitochondrial disease. The molecular defect results in mitochondrial dysfunction secondary to disruption of calcium uptake. We present the clinical/pathological features in a cohort of 18 patients. Patients presented between birth and 8 years with a mild, relatively static, proximal myopathy associated with high Creatinine Kinase (2000–10,000 iu/L), learning difficulties and frequent microcephaly. At follow up (5–28 yrs), all remained ambulant but variable extrapyramidal symptoms had developed in the majority by the end of the 1st decade. Other features suggestive of mitochondrial dysfunction included peripheral neuropathy, icthyosis, stroke like episodes, episodic weakness, ataxia and cataracts. Cardiomyopathy was not seen. Serum and CSF lactate were normal where tested. Two had low free carnitine. Other metabolic investigations were normal. One had abnormal signal change in globus pallidus on MRI at 10 yrs. All had abnormal muscle biopsies, with myopathic features; diffuse variation in fibre size, increased internal and central nuclei and clusters of regenerating fibres without pronounced fibrosis or fatty infiltration. Necrotic fibers were rare and fibre typing was preserved. Focal areas devoid of mitochondria (minicores) were observed in both type I and type II fibres. Respiratory chain enzyme activity, where tested, was normal. All had mutations in the MICU1 gene, 2 different homozygous splice site mutations (12 and 4 cases respectively) and a deletion in a kindred of 2 cases. Although the numbers are small, there appears to be some correlation between genotype and phenotype. Testing for MICU1 mutations should be considered in children with a static proximal myopathy associated with a high CK and CNS involvement when immunohistochemical studies do not identify a protein defect.

Introduction Patients with corticobasal degeneration (CBD) have well known difficulties in praxis and may experience alien limb phenomena (ALP). While cases of alien limb syndrome (ALS) with vascular or surgical aetiologies have received much attention, less is understood about ALS in CBD despite this being a diagnostic criterion. The ALS of CBD has been interpreted as a deficit in praxis. This study sought to establish whether this assumption is justified. Methods We reviewed the cases of 30 patients with CBD and 25 with the closely related tauopathy progressive supranuclear palsy (PSP) at a specialist neurology clinic. Consultations included a structured examination of praxis and 14 questions designed to elicit symptoms of ALS. Quantitative scores were allocated to each examination and questionnaire. Results 83% of CBD patients reported at least one possible ALP, 57% reported more than four. Only one PSP patient reported any ALP. Commonly reported ALP included spontaneous limb levitation (50%), the sense that the patient9s hand did not belong to them (50%), and reaching for objects against the patient9s will (30%). CBD patients with ALS rarely experienced a delusion of external control (17%). Importantly, no correlation was found between limb praxis and alien limb questionnaire scores among CBD patients (r=0.04, ns). Conclusions Symptoms of ALS are common in CBD, but do not occur in PSP. Our results cast doubt on the assumption that ALS in CBD is a manifestation of severe apraxia.

This paper examines the research strategies of stress and police work using the example of role conflict. The major problems are identified as the lack of adequate measurement and conceptual clarity. Given this rudimentary state, a causal approach to the problem is not recommended at this time. The serious public consequences of physical, mental, and behavioral police reactions to stress will result in an increasing number of treatment and preventive programs. The existing programs lack careful evaluation components. Adequate evaluations should be a part of every treatment or preventive program. The most important research need is to conduct a thorough descriptive study of the actual rates of illness and stress related behaviors among the police. Once the extent and nature of the problem are identified, causal analysis can be undertaken.

The discipline of sociology generally has not analyzed the differential productivity among graduates of doctoral programs. When such productivity has been assessed, quantity rather than quality of publications has been the basis for comparisons. The present study uses data compiled from the Social Science Citation Index to measure the differential contributions to sociology by the graduates of a number of long established and prestigious doctoral programs in the field. Based on these data, a number of interesting patterns emerge concerning the quality of graduates' productivity, both across departments and within various alumni cohorts of the same department.

Over the past decade, a sizeable body of literature has developed that examines police stress from a variety of perspectives. The vast majority of the literature is anecdotal in nature and that which is based on research is often inconsistent. As used in the literature, the term stress has widely differing meanings and its measurement has ranged from the artful to the sublime. But of greater importance than the measurement issue is the necessary complexity of any model that attempts to deal with the interrelationships thought to exist between stress and other factors. The variety and complexity of individual differences and the interplay between environmental conditions and the person's unique perception of both objective and subjective situations obscures any simple relationships. The purpose of this note is to examine the nature of stress, its sources and consequences among police, and to identify gaps in the conceptual model within which police stress is normally viewed.

While the available evidence suggests that at least some aspects of police work are stressful, our knowledge of the causes and consequences of that stress is based largely on conjecture. Stress research is exceedingly complex. After literally hundreds of studies on various facets of occupational stress, the results remain ambivalent and our knowledge meagre. Given that stress research is still in an exploratory stage, it is argued that the immediate attention of occupational stress studies among the police should focus on treatment and prevention strategies rather than on the sources or consequences of stress. Toward this end, this paper reviews a wide variety of programs aimed at preventing or alleviating police stress. The proposed strategies are classified here as either proactive or reactive. Proactive strategies are meant to prevent the development of stress through training and selection programs, better selection criteria, and a variety of administrative methods. The reactive strategies, such as counseling or rehabilitation programs, are aimed at alleviating the consequences of stress. Other direct relaxation techniques, e.g., biofeedback and meditation, are also reviewed along with the issue of disability compensation for stress related illnesses.

Durkheim argues that anomie occurs as a result of some temporary or longterm crisis that disturbs the collective order. Yet, at the individual level an event or events must be perceived as affecting immediate social relationships before anomia occurs. Previous victimization research reports suggest that crimes may cause interaction problems for the victims. This passibility was analyzed using two notional samples collected by the Notional Opinion Research Center in 1973 and 1974. Using regression to analyze the impact of robbery and burglary on anomia scores no significant relations were found. Bath are usually non-recurrent experiences that either do not have long-term effects on individuls, or anomia as measured here is too far removed to serve as an adequate measure.

Interest in the structure and dynamics of sociology as a discipline has led to recurrent attempts to measure the prestige, productivity, and quality of education of the various sociology departments. While several previous papers have suggested the potential value of the Science Citation Index (SCI) as a measure of scientific standing, few attempts have been made to utilize a citation-based measure of scientific prestige. This paper considers the meaning of the citation in science and in stratification theory. Procedures are described whereby citations to individual sociologists and journals are employed to yield rankings of departments of sociology and journals. The differences between these rankings and other rankings are discussed.