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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Gaslighting is an understudied form of abuse wherein a sane and rational survivor is convinced of their own epistemic incompetence on false pretenses by a perpetrator. The current study aimed to characterize the features of gaslighting as well as test and verify common claims about gaslighting. We recruited participants (N = 65) who self-identified as having experienced gaslighting in romantic relationships to fill out a qualitative survey wherein they described instances of gaslighting, features of their relationships, and the consequences of gaslighting on their mental health. The age of participants in this study ranged from 18-69 (M = 29), most participants identified as female (48), and heterosexual (43). Gaslighting occurs within relationships that are typified by a combination of affectionate and abusive behaviors extended over the course of a relationship. Gaslighting victimization was associated with a diminished sense of self, mistrust of others, and on occasion, post-traumatic growth. Those who recovered from gaslighting often emphasized the importance of separation from the perpetrator, prioritization of healthier relationships, and engaging in meaningful and re-embodying activities. This study provides a basis for further research into gaslighting and recovery from gaslighting, which will contribute to prevention of and treatment for this type of abuse.

The State of Washington received a State Innovation Models (SIM) $65 million award from the federal Centers for MedicareMedicaid Services to improve population health and quality of care and reduce the growth of health care costs in the entire state, which has over 7 million residents. SIM is a "complex intervention" that implements several interacting components in a complex, decentralized health system to achieve goals, which poses challenges for evaluation. Our purpose is to present the state-level evaluation methods for Washington's SIM, a 3-year intervention (2016-2018). We apply the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) evaluation framework to structure our evaluation. We create a conceptual model and a plan to use multiple and mixed methods to study SIM performance in the RE-AIM components from a statewide, population-based perspective.

BACKGROUND: Jumping from a height is an uncommon but lethal means of suicide. Restricting access to means is an important universal or population‐based approach to suicide prevention with clear evidence of its effectiveness. However, the evidence with respect to means restriction for the prevention of suicide by jumping is not well established. OBJECTIVES: To evaluate the effectiveness of interventions to restrict the availability of, or access to, means of suicide by jumping. These include the use of physical barriers, fencing or safety nets at frequently‐used jumping sites, or restriction of access to these sites, such as by way of road closures. SEARCH METHODS: We searched the Cochrane Library, Embase, MEDLINE, PsycINFO, and Web of Science to May 2019. We conducted additional searches of the international trial registries including the World Health Organization International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov, to identify relevant unpublished and ongoing studies. We searched the reference lists of all included studies and relevant systematic reviews to identify additional studies and contacted authors and subject experts for information on unpublished or ongoing studies. We applied no restrictions on date, language or publication status to the searches. Two review authors independently assessed all citations from the searches and identified relevant titles and abstracts. Our main outcomes of interest were suicide, attempted suicide or self‐harm, and cost‐effectiveness of interventions. SELECTION CRITERIA: Eligible studies were randomised or quasi‐randomised controlled trials, controlled intervention studies without randomisation, before‐and‐after studies, or studies using interrupted time series designs, which evaluated interventions to restrict the availability of, or access to, means of suicide by jumping. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and three review authors extracted study data. We pooled studies that evaluated similar interventions and outcomes using a random‐effects meta‐analysis, and we synthesised data from other studies in a narrative summary. We summarised the quality of the evidence included in this review using the GRADE approach. MAIN RESULTS: We included 14 studies in this review. Thirteen were before‐and‐after studies and one was a cost‐effectiveness analysis. Three studies each took place in Switzerland and the USA, while two studies each were from the UK, Canada, New Zealand, and Australia respectively. The majority of studies (10/14) assessed jumping means restriction interventions delivered in isolation, half of which were at bridges. Due to the observational nature of included studies, none compared comparator interventions or control conditions. During the pre‐ and postintervention period among the 13 before‐and‐after studies, a total of 742.3 suicides (5.5 suicides per year) occurred during the pre‐intervention period (134.5 study years), while 70.6 suicides (0.8 suicides per year) occurred during the postintervention period (92.4 study years) ‐ a 91% reduction in suicides. A meta‐analysis of all studies assessing jumping means restriction interventions (delivered in isolation or in combination with other interventions) showed a directionality of effect in favour of the interventions, as evidenced by a reduction in the number of suicides at intervention sites (12 studies; incidence rate ratio (IRR) = 0.09, 95% confidence interval (CI) 0.03 to 0.27; P < 0.001; I(2) = 88.40%). Similar findings were demonstrated for studies assessing jumping means restriction interventions delivered in isolation (9 studies; IRR = 0.05, 95% CI 0.01 to 0.16; P < 0.001; I(2) = 73.67%), studies assessing jumping means restriction interventions delivered in combination with other interventions (3 studies; IRR = 0.54, 95% CI 0.31 to 0.93; P = 0.03; I(2) = 40.8%), studies assessing the effectiveness of physical barriers (7 studies; IRR = 0.07, 95% CI 0.02 to 0.24; P < 0.001; I(2) = 84.07%), and studies assessing the effectiveness of safety nets (2 studies; IRR = 0.09, 95% CI 0.01 to 1.30; P = 0.07; I(2) = 29.3%). Data on suicide attempts were limited and none of the studies used self‐harm as an outcome. There was considerable heterogeneity between studies for the primary outcome (suicide) in the majority of the analyses except those relating to jumping means restriction delivered in combination with other interventions, and safety nets. Nevertheless, every study included in the forest plots showed the same directional effects in favour of jumping means restriction. Due to methodological limitations of the included studies, we rated the quality of the evidence from these studies as low. A cost‐effectiveness analysis suggested that the construction of a physical barrier on a bridge would be a highly cost‐effective project in the long term as a result of overall reduced suicide mortality. AUTHORS' CONCLUSIONS: The findings from this review suggest that jumping means restriction interventions are capable of reducing the frequency of suicides by jumping. However, due to methodological limitations of included studies, this finding is based on low‐quality evidence. Therefore, further well‐designed high‐quality studies are required to further evaluate the effectiveness of these interventions, as well as other measures at jumping sites. In addition, further research is required to investigate the potential for suicide method substitution and displacement effects in populations exposed to interventions to prevent suicide by jumping.

Glucocorticoid administration has been shown to exert complex effects on cognitive and emotional processing. In the current study we investigated the effects of glucocorticoid administration on attention towards emotional words, using an Affective Go/No-go task on which healthy humans have shown an attentional bias towards positive as compared to negative words. Healthy volunteers received placebo and either low-dose (0.15mg/kg) or high-dose (0.45mg/kg) hydrocortisone intravenously during two separate visits in a double-blind, randomized design. Seventy-five minutes post-infusion, the subjects performed tests of attention (Rapid Visual Information Processing [RVIP]), spatial working memory (Spatial Span) and emotional processing (Affective Go/No-go task [AGNG]). On the attention task, performance was impaired under both hydrocortisone doses relative to placebo, though the effect on error rate was not significant after controlling for age; Spatial Span performance was unaffected by hydrocortisone administration. On the AGNG task, relative to the placebo condition the low-dose hydrocortisone infusion decreased response time to emotional words while high-dose hydrocortisone increased response time. In the females specifically, both high and low dose hydrocortisone administration attenuated the normal attentional bias toward positively valenced words. These data suggest that, in healthy women, the modulation of attention by the emotional salience of stimuli is influenced by glucocorticoid hormone concentrations.

This study investigates project initiation for telemedicine, a technology innovation in healthcare organizations that manifests both intra- and inter-organizational collaboration. Moving from a telemedicine project to a sustainable telemedicine service line can be a challenge for many organizations (LeRouge, Tulu, & Forducey, 2010). Project definition (a.k.a., initiation) sets the strategic vision for a project and has been categorized as the most important stage in a project (C. Gray & Larson, 2008) and a key element for project success (Stah-Le Cardinal & Marle, 2006). Although project management best practices have been applied in many domains, there are few studies that link published best practices to the telemedicine domain. This study first presents a model, resulting from a review of project management literature that specifies the recommended components project definition. Using this model as a foundation, the authors explore how project definition is deployed in the telemedicine domain, using the instantiation of telestroke projects for this study. The authors base their findings on a multi-case qualitative data set, with each case representing a distinct telemedicine business model. Findings from this study explicate how the telestroke project initiation process is collaboratively managed and how this process impacts the overall success of the telemedicine programs through the lens of the five distinct telemedicine business models. Specifically, this study contributes insights on key elements of project initiation in the telemedicine context as well as the effects of the varying business models (focusing on commonalities and differences).

Multiple techniques exist for the automated segmentation of magnetic resonance images (MRIs). The validity of these techniques can be assessed by evaluating test-retest reliability, interscanner reliability, and consistency with manual segmentation. We evaluate these measures for the FSL/FIRST subcortical segmentation tool. We retrospectively analyzed 190 MRI scans from 87 subjects with mood or anxiety disorders and healthy volunteers scanned multiple times on different platforms (N = 56) and/or the same platform (N = 45, groups overlap), and 146 scans from subjects who underwent both high-resolution and whole brain imaging in a single session, for comparison with manual segmentation of the hippocampus. The thalamus, caudate, putamen, hippocampus, and pallidum were reliably segmented in different sessions on the same scanner (Intraclass correlation coefficient (ICC) > 0.83 scanners and diagnostic groups pooled). In these regions, the range of between platform reliabilities were lower (0.527 0.7, groups pooled), and both methods detected significant differences between genders. In addition, FIRST segmentations were consistent with manual segmentations (in a subset of images; N = 20) in the left caudate and bilateral putamen. This retrospective analysis assesses realistic performance of the algorithm in conditions like those found in multisite trials or meta-analyses. In addition, the inclusion of psychiatric patients establishes reliability in subjects exhibiting volumetric abnormalities, validating patient studies.

As veterinary nursing makes the transition from vocation to profession, it will be important that members act according to professional, legal and ethical guidelines. This article discusses a clinical scenario in order to identify how these issues can affect daily practice.

Two positron emission tomography radiotracers for the glycine transporter 1 (GlyT1) are reported here. Each radiotracer is a propylsulfonamide-containing benzamide and was labeled with either carbon-11 or fluorine-18. [¹¹C]CMPyPB was synthesized by the alkylation of a 3-hydroxypyridine precursor using [¹¹C]MeI, and [¹⁸F]MK-6577 was synthesized by a nucleophilic aromatic substitution reaction using a 2-chloropyridine precursor. Each tracer shows good uptake into rhesus monkey brain with the expected distribution of highest uptake in the pons, thalamus, and cerebellum and lower uptake in the striatum and gray matter of the frontal cortex. In vivo blockade and chase studies of [¹⁸F]MK-6577 showed a large specific signal and reversible binding. In vitro autoradiographic studies with [¹⁸F]MK-6577 showed a large specific signal in both rhesus monkey and human brain slices and a distribution consistent with the in vivo results and those reported in the literature. In vivo metabolism studies in rhesus monkeys demonstrated that only more-polar metabolites are formed for each tracer. Of these two tracers, [¹⁸F]MK-6577 was more extensively characterized and is a promising clinical positron emission tomography tracer for imaging GlyT1 and for measuring GlyT1 occupancy of therapeutic compounds.

The purpose of this study is to explore the variation in emotional closeness in the adult grandchild and grandparent relationship in relation to the occur-rence of potentially stressful life events in childhood. A sample of university students ( N = 119) completed a questionnaire measuring elements of inter-generational solidarity. Comparisons were made on emotional closeness between groups that had and had not experienced a life event, revealing it was the grandparent’s enactment of normative solidarity, as perceived by the adult grandchild, that produced greater emotional closeness. Complementing the findings of Bengston and Roberts, this research supports the theoretical view that high levels of normative solidarity lead to greater affectual solidarity, which in turn produces higher associational solidarity.

Background Hippocampal volumes obtained from a group of medication-free, remitted subjects with recurrent major depressive disorder (MDD) were compared against corresponding measures from healthy controls. Methods Thirty-one subjects with recurrent MDD in full remission, and 57 healthy controls underwent high resolution magnetic resonance imaging (MRI) on a GE 3T scanner. Eight patients with MDD were medication-naive, and twenty-three MDD patients were off antidepressant medications for a mean of 30 months at the time of the MRI study. Results Patients showed smaller total and posterior hippocampal volume relative to controls. Anterior hippocampal volume did not differ between patients and controls. Conclusions Recurrent depression is associated with smaller hippocampal volume which is most prominent in the posterior hippocampus. Smaller hippocampal volume appears to be a trait characteristic for MDD.

This ethnographic study explores army wives' adjustment to separation and reunion. The women were married to soldiers who were deployed for six months to the Sinai as part of the Multinational Force & Observers. Thirty-five women completed lengthy interviews before and during the separation, just before reunion, and six to eight weeks after the reunion. The women's behaviors, attitudes and perceptions at each of the four stages were noted, and researchers evaluated subjectively the degree to which subjects had adjusted to the separation and reunion. Junior enlisted families had more difficulty than others in coping with extended deployment. While reunion could be stressful as families integrated returning soldiers into family systems, experiences were not always negative. Being employed, having a social support network of friends and family, and participating in family support group activities were important to women who successfully adjusted.

Two positron emission tomography radiotracers for the glycine transporter 1 (GlyT1) are reported here. Each radiotracer is a propylsulfonamide-containing benzamide and was labeled with either carbon-11 or fluorine-18. [¹¹C]CMPyPB was synthesized by the alkylation of a 3-hydroxypyridine precursor using [¹¹C]MeI, and [¹⁸F]MK-6577 was synthesized by a nucleophilic aromatic substitution reaction using a 2-chloropyridine precursor. Each tracer shows good uptake into rhesus monkey brain with the expected distribution of highest uptake in the pons, thalamus, and cerebellum and lower uptake in the striatum and gray matter of the frontal cortex. In vivo blockade and chase studies of [¹⁸F]MK-6577 showed a large specific signal and reversible binding. In vitro autoradiographic studies with [¹⁸F]MK-6577 showed a large specific signal in both rhesus monkey and human brain slices and a distribution consistent with the in vivo results and those reported in the literature. In vivo metabolism studies in rhesus monkeys demonstrated that only more-polar metabolites are formed for each tracer. Of these two tracers, [¹⁸F]MK-6577 was more extensively characterized and is a promising clinical positron emission tomography tracer for imaging GlyT1 and for measuring GlyT1 occupancy of therapeutic compounds.

Amalgamation of the structure−activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

Objectives: Neuropsychological studies in subjects with bipolar disorder (BD) have reported deficits on a variety of cognitive measures. However, because the majority of subjects were medicated at the time of testing in previous studies, it is currently unclear whether the pattern of deficits reported is related to BD itself or to psychotropic medication. We addressed this issue by examining cognitive performance in a group of unmedicated, currently depressed subjects with BD. Methods: Forty-nine unmedicated subjects who met DSM-IV criteria for BD, depressed phase, and 55 control subjects participated in this study. Most patients were diagnosed with bipolar II disorder. Performance on emotion-dependent, or ‘hot’, and emotion-independent, or ‘cold’, cognitive tasks was assessed using tests from the Cambridge Neuropsychological Test Automated Battery. Results: The groups were well matched with respect to general intelligence and demographic variables. Deficits in the unmedicated depressed BD group were apparent on tests tapping ‘hot’ cognitive processing, for example the Cambridge Gamble task and the Probabilistic Reversal Learning task. However, other than a deficit on the Spatial Span test in the depressed BD subjects, the groups performed equivalently on most measures of ‘cold’ cognitive processing, for example visual memory, attention, and working memory. Conclusions: These data suggest that deficits on tests involving reward processing, short-term spatial memory storage, and sensitivity to negative feedback in depressed BD subjects represent an effect of the illness itself and not mood-stabilizing medication.

Hippocampal volume is reduced in posttraumatic stress disorder (PTSD). In the present study, we sought to determine whether volume loss is homogenously distributed or confined to a certain part of the structure.Twenty-two adult outpatients with PTSD (11 after prolonged prepubertal trauma and 11 after single adult trauma) and 22 matched healthy subjects were scanned at the National Institute of Mental Health using high-resolution 3T magnetic resonance imaging between September 2003 and August 2004. PTSD diagnosis was conferred using the Structured Clinical Interview for DSM-IV. Volumes of whole, anterior, and posterior hippocampus and subiculum were compared between groups.Total hippocampal volume was lower in patients with PTSD (p = .02), with a significant diagnosis by hippocampal-subregion interaction (p = .02). Post hoc analysis revealed significantly smaller posterior hippocampi in PTSD (p = .006), with no difference in the volumes of anterior hippocampus or subiculum. No volume differences were found between PTSD participants with prolonged childhood abuse compared to single adult trauma exposure.The posterior hippocampus has been associated with storage, processing, and retrieval of spatiotemporal memories, central to the protective function of fear conditioning. Volume deficit in the posterior hippocampus may indicate malfunction in this faculty, leading to the exaggerated conditioned fear response observed in PTSD.

The purpose of this section is to report our review of all of the different policy documents related to supervisor and coworker reporting and to compare and contrast the requirements of various entities with regard to this subject. PERSEREC researchers reviewed the policies, Directives, and Executive Orders that concern the reporting of CI- and security-related behaviors. The review explored areas of overlap, specificity, and authoritative procedures, i.e., whether one policy superseded another. The Clinton administration's Presidential Decision Directive PDD/NSC-12, Security Awareness and Reporting of Foreign Contacts (August 5, 1993) requires that government employees report all contacts with individuals of any nationality, either within or outside the scope of the employee s official activities, in which illegal or unauthorized access is sought to classified or otherwise sensitive information, or the employee is concerned that he or she may be the target of actual or attempted exploitation by a foreign entity.

Prepulse inhibition (PPI) is a suppression of the startle reflex that occurs when an intense startling stimulus is preceded by a weaker 'prepulse' stimulus. PPI deficits have been implicated in the biological bases of schizophrenia and some other neuropsychiatric disorders and proposed as a possible biological marker (endophenotype) for genetic studies. However, little is known about the genetic determination of PPI in humans. We examined acoustic eye-blink startle reflex and PPI in 142 young female twins (40 monozygotic and 31 dizygotic pairs) and conducted a biometrical genetic analysis using structural equation modeling. PPI showed significant heritability suggesting that over 50% of PPI variance in this sample can be attributed to genetic factors. Baseline startle magnitude showed higher heritability (about 70%).

PERSEREC examined government requirements that cleared supervisors and employees report to security managers behavior they observe among subordinates and coworkers that they believe to be security-relevant. Despite formal policies, very few reports are made. Authors reviewed research literature and discussed the topic with personnel security and management personnel in 20 government agencies and with supervisors and coworkers in focus groups. While supervisors and employees are not averse to reporting genuine security infractions, they rarely report other behaviors. They are confused about precisely what to report and anguish over reporting gray-area behaviors they do not consider to be necessarily connected to security. The study recommends that DoD Directive 5200.2-R be modified to include supervisor and coworker reporting as a priority and to protect the confidentiality of people who report, if requested. It recommends that PERSEREC, with the help of counterintelligence and security personnel, develop a list of behaviors that pose a palpable threat to national security and must be reported, if observed. The list will contain behavioral examples to clarify what is considered egregious and critical to national security. It is also recommended that the Assistant Secretary of Defense (Command, Control, Communications and Intelligence) (ASD C3I) issue a memorandum advising certain changes be made in the government's philosophy, i.e., that the personnel security community be more proactive in ensuring that personal problems get addressed before they become security problems. The memorandum should also emphasize enhanced training, including developing clear guidance as to what must be reported and making the personnel security system more accessible and transparent to employees.

PERSEREC examined the relationship between DoD security policy and federally mandated employee assistance programs (EAPs) for civilians and counseling/referral services for military personnel to identify any barriers for cleared DoD employees to using these programs. The study, based largely on interviews, but also on focus-group information and on a review of policy documents and other literature, found that policy is in place to help cleared individuals with personal problems get access to the counseling and treatment they need. However, research showed that cleared employees, civilian or military, often remain suspicious that their attendance at such programs will result in clearance revocation. Thus, some consult counseling programs outside the federal system, eschewing the very programs that the government has set up to help them. Report 1, designed for the policymaker, makes various recommendations for augmenting policy guidance, and for enhancing security education programs to underscore the fact that people can get help without putting their security status in danger. Report 2 documents the research and presents findings and conclusions; it also contains a series of appendices that provides background information for the interested reader on such topics as the EAP movement, military counseling/referral programs, and DoD personnel security policies and programs.

The Defense Industrial Security Program (DISP) was established to ensure that classified information released to industry is properly safeguarded. It encompasses approximately 12,000 contractor organizations and 900,000 cleared employees. With regard to the protection of classified government information, the heart of the DISP is the security program in place at each of the contractor sites. Facility security officers (FSOs) play a key role in translating Department of Defense (DoD) security requirements into organization specific Standard Practice Procedures that serve as the security manuals for defense contractor sites. FSOs are tasked with implementing and maintaining security programs that meet DoD security requirements as presented in the DOD 5220.22-M, Industrial Security Manual for Safeguarding Classified information (ISM). However, rules and procedures alone do not guarantee acceptance and compliance by cleared employees. FSOs must ensure commitment to security requirements through support from management and other key groups, and through security education and training programs. FSOs must be effective managers if their programs are going to be successful. Keywords: Military publications; Periodicals; Reports.