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Lennon et al. recently proposed a clinical polygenic score (PGS) pipeline as part of the Electronic Medical Records and Genomics (eMERGE) network initiative. In this spotlight article we discuss the broader context for the use of PGS in preventive medicine and highlight key limitations and challenges facing their inclusion in prediction models.

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Since early detection of osteoporosis is essential, the development of an efficient and cost-effective screening model would be incredibly beneficial. The aim of this study was to evaluate the diagnostic accuracy of MCW and MCI indices from dental panoramic radiographs in combination with a new variable, age at menarche, for the detection of osteoporosis. The study enrolled 150 Caucasian women (aged 45 to 86) who met the eligibility criteria, had DXA scans of the left hip and lumbar spine (L2 to L4), and were classified as osteoporotic, osteopenic, or normal based on T-score. Two observers evaluated MCW and MCI indexes on panoramic radiographs. There was a statistically significant correlation between the T-score and MCI and MCW. In addition, age at menarche had a statistically significant correlation with T-score (p = 0.006). In conclusion, in the current study, MCW proved to be more effective in detecting osteoporosis when combined with age at menarche. Individuals with MCW less than 3.0 mm and age at menarche later than 14 years old should be referred for DXA since they present high risk of osteoporosis.

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Deep mutational scanning assays enable the functional assessment of variants in high throughput. Phenotypic measurements from these assays are broadly concordant with clinical outcomes but are prone to noise at the individual variant level. We develop a framework to exploit related measurements within and across experimental assays to jointly estimate variant impact. Drawing from a large corpus of deep mutational scanning data, we collectively estimate the mean functional effect per AA residue position within each gene, normalize observed functional effects by substitution type, and make estimates for individual allelic variants with a pipeline called FUSE (Functional Substitution Estimation). FUSE improves the correlation of functional screening datasets covering the same variants, better separates estimated functional impacts for known pathogenic and benign variants (ClinVar BRCA1, p=2.24×10-51), and increases the number of variants for which predictions can be made (2,741 to 10,347) by inferring additional variant effects for substitutions not experimentally screened. For UK Biobank patients who carry a rare variant in TP53, FUSE significantly improves the separation of patients who develop cancer syndromes from those without cancer (p=1.77×10-6). These approaches promise to improve estimates of variant impact and broaden the utility of screening data generated from functional assays.

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Chronic kidney disease (CKD) is one of the serious health concerns in the twenty-first century. CKD impacts over 37 million Americans. By applying machine learning (ML) techniques to clinical data, CKD can be diagnosed early. This early detection of CKD can prevent numerous loss of life. In this work, clinical data set of 400 patients, available on the UCI repository, are taken. Unfortunately, this data set doesn't have an equal distribution of CKD and Non-CKD samples. This imbalanced nature of data highly influences the learning capabilities of classifiers. Genetic Programming (GP) is an ML technique based on the evolution of species. GP with standard fitness function, also impacted by this imbalanced nature of data. A new Euclidean distance-based fitness function in GP is proposed to handle this imbalanced nature of the data set. To compare the robustness of the proposed work, other classification techniques, K-nearest neighborhood (KNN), KNN with particle swarm optimization (PSO), and GP with the standard fitness function, is also applied. For ten-fold cross-validation, the KNN shows an accuracy of 83.54% with an AUC value of 0.69, the PSO-KNN shows an accuracy of 96.79% with an AUC value of 0.94, and the GP, with the newly proposed fitness function, supersedes KNN and PSO-KNN and shows the accuracy of 99.33% with an AUC value of 0.99.

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Data from recent dose-response toxicological studies suggest that the no-observed-adverse-effect-level (NOAEL) may depend upon whether hormesis is present. A further examination of these data supports this hypothesis by showing that the NOAEL was greater for living units (organisms or cells) showing hormesis than for living units showing no hormesis. For example, some cancer tissue cells may exhibit hormetic responses to an anticancer drug while some other cancer tissue cells may not. These findings suggest that living units showing hormesis may also be less susceptible than living units not showing hormesis. However, these findings are preliminary and cannot be generalized or assumed to be a norm yet. New studies are needed to evaluate how NOAEL shifts depending on the occurrence of hormesis.

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Genome editing has shown great promise for clinical translation but also revealed the risk of genotoxicity caused by off-target effects of programmable nucleases. Here we describe chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing (CAST-Seq), a preclinical assay to identify and quantify chromosomal aberrations derived from on-target and off-target activities of CRISPR-Cas nucleases or transcriptional activator-like effector nucleases (TALENs), respectively, in human hematopoietic stem cells (HSCs). Depending on the employed designer nuclease, CAST-Seq detected translocations in 0%-0.5% of gene-edited human CD34+ HSCs, and up to 20% of on-target loci harbored gross rearrangements. Moreover, CAST-Seq detected distinct types of chromosomal aberrations, such as homology-mediated translocations, that are mediated by homologous recombination and not off-target activity. CAST-Seq is a sensitive assay able to identify and quantify unintended chromosomal rearrangements in addition to the more typical mutations at off-target sites. CAST-Seq analyses may be particularly relevant for therapeutic genome editing to enable thorough risk assessment before clinical application of gene-edited products.

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BACKGROUND: Rabies is endemic in southern Bhutan, associated with 1-2 human deaths and high post exposure prophylaxis (PEP) costs annually. Evaluation of clinicians' management of human cases potentially exposed to rabies could contribute to improving PEP prescribing practices to both reduce unnecessary costs associated with PEP and reach the target of zero human deaths due to rabies by 2023. METHODS: A cross-sectional survey of 50 clinicians' management of human cases potentially exposed to rabies was conducted in 13 health centers in high-rabies-risk areas of Bhutan during February-March 2016. RESULTS: Data were collected on clinicians' management of 273 human cases potentially exposed to rabies. The 50 clinicians comprised health assistants or clinical officers (55%) and medical doctors (45%) with a respective median of 19, 21 and 2 years' experience. There was poor agreement between clinicians' rabies risk assessment compared with an independent assessment for each case based on criteria in the National Rabies Management Guidelines (NRMG). Of the 194 cases for which clinicians recorded a rabies risk category, only 53% were correctly classified when compared with the NRMG. Clinicians were more likely to underestimate the risk of exposure to rabies and appeared to prescribe PEP independently of their risk classification.. Male health assistants performed the most accurate risk assessments while female health assistants performed the least accurate. Clinicians in Basic Health Units performed less accurate risk assessments compared with those in hospitals. CONCLUSIONS: This study highlights important discrepancies between clinicians' management of human cases potentially exposed to rabies and recommendations in the NRMG. In particular, clinicians were not accurately assessing rabies risk in potentially exposed cases and were not basing their PEP treatment on the basis of their risk assessment. This has significant implications for achieving the national goal of eliminating dog-mediated human rabies by 2030 and may result in unnecessary costs associated with PEP. Recommendations to improve clinician's management of human cases potentially exposed to rabies include: reviewing and updating the NRMG, providing clinicians with regular and appropriately targeted training about rabies risk assessment and PEP prescription, and regularly reviewing clinicians' practices.

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Objective@#This rapid review aimed to summarize data on the accuracy, benefits, harms, and cost-effectiveness of preoperative COVID-19 clinical risk assessment for asymptomatic individuals. @*Methods@#A comprehensive search in MEDLINE, Cochrane CENTRAL, ChinaXiv, medRxiv, and bioRxiv was done until March 10, 2021, using the keywords “COVID-19”, “surgery”, “RT-PCR”, “clinical risk assessment” and “cost-effectiveness”. We searched for studies that assessed the diagnostic accuracy of preoperative clinical risk assessment in COVID-19 screening among asymptomatic individuals, its cost-effectiveness, and its impact on surgical outcomes and management decisions. Risk of bias was assessed using Evaluation of Articles on Diagnosis (Painless Evidence Based Medicine)10 for accuracy studies, Newcastle-Ottawa Scale11 for cohort studies, and Drummond’s checklist12 for economic evaluations. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to evaluate the overall evidence. Data from included studies were collated qualitatively using summary tables and analyzed in Review Manager 5.4. Pooling of sensitivity and specificity, odds ratio or adjusted odds ratio, and cost-effectiveness measures using a random-effects model was planned. Heterogeneity was determined using I2. Subgroup and sensitivity analyses were preplanned in case significant heterogeneity was found. @*Results@#Three observational studies were included. Preoperative clinical risk assessment for COVID-19 demonstrated a sensitivity of 0.42 (95% CI 0.15-0.72) and a specificity of 0.85 (95% CI 0.76-0.92), using RT-PCR as a reference standard. Indirect evidence showed that any positive clinical risk assessment, COVID-19 antigen or RT-PCR test is done within 0–7 weeks from surgery was associated with a higher 30-day postoperative mortality (RR 3.96, 95% CI 3.41, 4.59) and pulmonary complications (RR 3.41, 95% CI 3.04, 3.83). Delaying surgery at least seven weeks from COVID-19 diagnosis was associated with lower post-surgical complications. Universal pre-endoscopy virus testing using the antigen rapid diagnostic test (Ag-RDT) (ICER = -26,286 €), standard RT-PCR (ICER = -11,128€), or rapid PCR (ICER = -13,703 €) combined with high-risk personal protective equipment (PPE) use in all patients irrespective of test results were found to be more cost-effective compared to no pre-endoscopy testing and no high-risk PPE use, at an, assumed COVID-19 prevalence of 1% or higher among asymptomatic individuals. Overall certainty of evidence was very low. @*Conclusion@#Preoperative clinical risk assessment has poor sensitivity but high specificity for detecting COVID-19 among asymptomatic individuals undergoing elective surgery. Objective diagnostic tests such as RT-PCR or Ag-RDT may still be needed to inform surgery schedules. @*@#

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O seguinte relatório visa documentar a minha experiência e evolução profissional no desenvolvimento das Competências do Enfermeiro Especialista em Saúde Mental e Psiquiatria, no âmbito do Curso de Mestrado na Área de Especialidade em Enfermagem de Saúde Mental e Psiquiatria. Paralelamente, apresento como missão, explorar a intervenção do Enfermeiro Especialista em Saúde Mental e Psiquiatria, na gestão de comportamentos agressivos num internamento em Psiquiatria, no âmbito da Avaliação de Risco Clínico. Englobado em dois módulos, enquadramento concetual e metodológico, ao longo da sua leitura, exponho as principais atividades realizadas no meu percurso, fundamentadas no conhecimento científico e experiencial, que me conduziram à concretização dos meus objetivos. No que confere aos campos de estágio, estes prenderam-se num Serviço de Psiquiatria com crianças e adolescentes, o principal palco de intervenção, e no Hospital de Dia de Psiquiatria com adolescentes e adultos. À medida que se avança na leitura deste trabalho, são descortinadas as questões ao nível dos comportamentos agressivos, como parte integrante do Ser Humano, e as principais intervenções do enfermeiro na sua gestão. Como a base para a construção de todas as intervenções em enfermagem é a relação terapêutica, apresento a discussão e reflexão de alguns casos clínicos, aquando das minhas intervenções, com o Cliente. A população-alvo incidiu no adolescente e no adulto, no entanto, com contacto mais prolongado com o adolescente, pelo que a metodologia selecionada foi assente na Teoria das Transições de Afaf Meleis, que enquadram este estadío da adolescência, em processos de transição, que podem ser geradores de sofrimento/conflito. A Avaliação de Risco Clínico surgiu como um instrumento fundamental no planeamento de intervenções de enfermagem e como promotor de sucesso no restabelecimento da Saúde Mental para o Cliente.

The following report aims to document my experience and professional evolution in the development of the Skills of the Specialist Nurse in Mental Health and Psychiatry, within the scope of the Master's Course in the Area of Specialty in Mental Health Nursing and Psychiatry. At the same time, I present as a mission, to explore the intervention of the Specialist Nurse in Mental Health and Psychiatry, in the management of aggressive behaviors in a psychiatric hospital, within the scope of the Clinical Risk Assessment. Included in two modules, conceptual and methodological framework, throughout its reading, I expose the main activities carried out on my path, based on scientific and experiential knowledge, which leads me to the achievement of my goals. As far as the internship fields are concerned, they were held in a Psychiatry Service with children and adolescentes, the main intervention stage, and in the Psychiatry Day Hospital with adolescents and adults. As the reading of this work progresses, questions of aggressive behavior are revealed, as an integral part of the Human Being, and the main interventions of nurses in their management. As the basis for the construction of all nursing interventions is the therapeutic relationship, I present the discussion and reflection of some clinical cases, during my interventions, with the Client. The target population focused on the teenager and the adult, however, with more prolonged contact with the teenager, so the selected methodology was based on the Theory of Transitions by Afaf Meleis, which frame this stage of adolescence, in transition processes, which they can generate suffering / conflict. The Clinical Risk Assessment emerged as a fundamental instrument in the planning of more individualized nursing interventions and as a promoter of success in the restoration of Mental Health for the Client.

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Genetic testing for BRCA1, a DNA repair protein, can identify carriers of pathogenic variants associated with a substantially increased risk for breast and ovarian cancers. However, an association with increased risk is unclear for a large fraction of BRCA1 variants present in the human population. Most of these variants of uncertain clinical significance lead to amino acid changes in the BRCA1 protein. Functional assays are valuable tools to assess the potential pathogenicity of these variants. Here, we systematically probed the effects of substitutions in the C terminus of BRCA1: the N- and C-terminal borders of its tandem BRCT domain, the BRCT-[N-C] linker region, and the α1 and α'1 helices in BRCT-[N] and -[C]. Using a validated transcriptional assay based on a fusion of the GAL4 DNA-binding domain to the BRCA1 C terminus (amino acids 1396-1863), we assessed the functional impact of 99 missense variants of BRCA1. We include the data obtained for these 99 missense variants in a joint analysis to generate the likelihood of pathogenicity for 347 missense variants in BRCA1 using VarCall, a Bayesian integrative statistical model. The results from this analysis increase our understanding of BRCA1 regions less tolerant to changes, identify functional borders of structural domains, and predict the likelihood of pathogenicity for 98% of all BRCA1 missense variants in this region recorded in the population. This knowledge will be critical for improving risk assessment and clinical treatment of carriers of BRCA1 variants.

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Visible particulate matter in injectables presents one important question for consideration: "What are the potential implications to the patient?" The risks of visible particulate matter to patient safety have been comprehensively reviewed elsewhere. However, the methods used to assess and characterize the risks have been explained with various degrees of specificity and supporting rationale. To date, the assessment process lacks the necessary consensus to permit a more standardized and consistent approach to evaluate the potential patient risks.The purpose of this commentary is to provide one model that might be used to evaluate the three most relevant factors impacting the risk of injections containing particulate matter: the source of the particle, particle-specific attributes, and characteristics of the intended patient population. Each of these factors is considered with a focus on the more important aspects that might be relevant to imposing untoward risk. The discussion also includes the importance of differentiating the concepts of risk assessment from risk acceptance when establishing criticality levels for product attributes.LAY ABSTRACT: Pharmaceutical products intended for injection or infusion may contain particles that can emanate from different sources. Some particles, such as suspensions, are intended. Others are not, and those particles are the subject of rigorous manufacturing process controls to limit their presence and reject units that might contain visible defects. However, no technology exists that can prevent or eliminate all particles from these products. As a result, comprehensive risk assessments must be conducted to identify the capability of manufacturing systems to limit particles and detect and reject atypical units. An essential component of this strategy includes understanding the potential impact that injected or infused particles might have to a patient receiving these medications. The purpose of this paper is to provide one approach that clinicians might use to conduct that risk assessment by discussing the important aspects of the source of the particle, its characteristics (such as size or composition), and the relevant patient factors such as the illness being treated or other medical conditions that might impact the risk to these patients if particles are injected or infused.

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OBJECTIVES: Biocompatibility of dental materials has gained increasing interest during recent decades. Meanwhile, legal regulations and standard test procedures are available to evaluate biocompatibility. Herein, these developments will be exemplarily outlined and some considerations for the development of novel materials will be provided. METHODS: Different aspects including test selection, release of substances, barriers, tissue healing, antibacterial substances, nanoparticles and environmental aspects will be covered. The provided information is mainly based on a review of the relevant literature in international peer reviewed journals, on regulatory documents and on ISO standards. RESULTS: Today, a structured and systematic approach for demonstrating biocompatibility from both a scientific and regulatory point of view is based on a clinical risk assessment in an early stage of material development. This includes the analysis of eluted substances and relevant barriers like dentin or epithelium. ISO standards 14971, 10993, and 7405 specify the modes for clinical risk assessment, test selection and test performance. In contact with breached tissues, materials must not impair the healing process. Antibacterial effects should be based on timely controllable substances or on repellant surfaces. Nanoparticles are produced by intraoral grinding irrespective of the content of nanoparticles in the material, but apparently at low concentrations. Concerns regarding environmental aspects of mercury from amalgam can be met by amalgam separating devices. The status for other materials (e.g. bisphenol-A in resin composites) needs to be evaluated. Finally, the public interest for biocompatibility issues calls for a suitable strategy of risk communication. SIGNIFICANCE: A wise use of the new tools, especially the clinical risk assessment should aim at preventing the patients, professionals and the environment from harm but should not block the development of novel materials. However, biocompatibility must always be weighed against the beneficial effects of materials in curing/preventing oral diseases.

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The purpose of this article is to review legislation on 'dangerous sex offenders' critically. Most modern legislation determines an individual to be 'dangerous' if he or she is at unacceptably high risk of committing further sexual violence. While the decision is judicial in practice, clinical testimony is utilised to inform courts' decision-making. Dangerousness may be a normative (legal) construct, but it is reliant on clinical assessment. Offenders are not at risk only due to historical factors; the possibility of committing sexual violence in the future is likely affected by temporal factors such as response to therapy, substance misuse, and proximity to victims. It is not clear that mental illness would place an offender at risk, although certain personality disorders are considered to be risk factors. In reporting actual risk, clinicians need to consider a range of variables, and not exclusively use actuarial measures or unstructured clinical interviews.

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