CEDNIK: Phenotypic and molecular characterization of an additional patient and review of the literature

Synaptosomal-associated protein 29 (SNAP29) is a t-SNARE protein that is implicated in intracellular vesicle fusion. Mutations in the SNAP29 gene have been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK). In patients with 22q11.2 deletion syndrome, mutations in SNAP29 on the nondeleted chromosome are linked to similar ichthyotic and neurological phenotypes. Here, the authors report a patient with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome who presented with global developmental delay, polymicrogyria, dysgenesis of the corpus callosum, optic nerve dysplasia, gaze apraxia, and dysmorphic features. He has developed ichthyosis and palmoplantar keratoderma as he has grown. Exome sequencing identified a homozygous nonsense mutation in SNAP29 gene designated as c.85C>T (p.Arg29X). The authors compare the findings in the proband with previously reported cases. The previously unreported mutation in this patient and his phenotype add to the characterization of cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome and the accumulating scientific evidence that implicates synaptic protein dysfunction in various neuroectodermal conditions

Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study

<p>Abstract</p> <p>Background</p> <p>Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect uterus; however, their biological behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate 3 different scoring mechanisms of p16^INK4aimmunohistochemical (IHC) staining in distinguishing between primary ECAs and EMAs.</p> <p>Methods</p> <p>A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue array sections were immunostained with a commercially available antibody of p16^INK4a. Avidin-biotin complex (ABC) method was used for antigens visualization. The staining intensity and area extent of the IHC reactions was evaluated using the semi-quantitative scoring system. The 3 scoring methods were defined on the bases of the following: (1) independent cytoplasmic staining alone (Method C), (2) independent nucleic staining alone (Method N), and (3) mean of the sum of cytoplasmic score plus nucleic score (Method Mean of C plus N).</p> <p>Results</p> <p>Of the 3 scoring mechanisms for p16^INK4aexpression, Method N and Method Mean of C plus N showed significant (<it>p-values </it>< 0.05), but Method C showed non-significant (p = 0.245) frequency differences between ECAs and EMAs. In addition, Method Mean of C plus N had the highest overall accuracy rate (81.6%) for diagnostic distinction among these 3 scoring methods.</p> <p>Conclusion</p> <p>According to the data characteristics and test effectiveness in this study, Method N and Method Mean of C plus N can significantly signal to distinguish between ECAs and EMAs; while Method C cannot do. Method Mean of C plus N is the most promising and favorable means among the three scoring mechanisms.</p

Dix conseils pour réussir la conception et la mise en œuvre d'un programme d’éducation médicale axée sur les compétences

Background: Globally there is a move to adopt competency-based medical education (CBME) at all levels of the medical training system. Implementation of a complex intervention such as CBME represents a marked paradigm shift involving multiple stakeholders. Methods: This article aims to share tips, based on review of the available literature and the authors’ experiences, that may help educators implementing CBME to more easily navigate this major undertaking and avoid “black ice” pitfalls that educators may encounter. Results: Careful planning prior to, during and post implementation will help programs transition successfully to CBME. Involvement of key stakeholders, such as trainees, teaching faculty, residency training committee members, and the program administrator, prior to and throughout implementation of CBME is critical. Careful and selective choice of key design elements including Entrustable Professional Activities, assessments and appropriate use of direct observation will enhance successful uptake of CBME. Pilot testing may help engage faculty and learners and identify logistical issues that may hinder implementation. Academic advisors, use of curriculum maps, and identifying and leveraging local resources may help facilitate implementation. Planned evaluation of CBME is important to ensure choices made during the design and implementation of CBME result in the desired outcomes. Conclusion: Although the transition to CBME is challenging, successful implementation can be facilitated by careful design and strategic planning.Contexte&nbsp;: Partout dans le monde, on observe une tendance en faveur de l’éducation médicale axée sur les compétences (EMAC) à tous les niveaux du système d’éducation médicale. Une intervention complexe comme l’élaboration d’un programme d’EMAC représente un important changement de paradigme qui nécessite l’implication de plusieurs parties prenantes. Méthode&nbsp;: L’objectif de cet article est de partager des conseils dégagés par les auteurs d’une revue de la littérature et de leur propre expérience afin d’aider les éducateurs à mieux s’orienter dans cette entreprise de taille qu’est la mise en œuvre de l’EMAC et à éviter les écueils. Résultats&nbsp;: Une planification minutieuse avant, pendant et après la transition des programmes vers l’EMAC contribue à garantir son succès. L'implication des principales parties prenantes, telles que les stagiaires, le corps enseignant, les membres du comité du programme de résidence et l'administrateur du programme, avant et pendant la mise en œuvre est essentielle. La sélection attentive des éléments clés, comme les activités professionnelles confiables, les évaluations et l'utilisation appropriée de l'observation directe, favorisera l'adoption de l’EMAC. Des tests pilotes peuvent permettre la participation du corps professoral et des apprenants, et à déceler les problèmes logistiques qui peuvent entraver la mise en œuvre. Les conseillers pédagogiques, le recours à la cartographie des programmes d'études et le repérage et la mobilisation de ressources locales peuvent faciliter la mise en œuvre des programmes d’EMAC. L’évaluation planifiée de ces programmes est importante pour garantir que les choix faits lors de leur conception et mise en œuvre aboutissent aux résultats souhaités. Conclusion&nbsp;: Puisque la transition vers l’EMAC peut comporter de nombreux défis, elle peut néanmoins être opérée avec succès grâce à une conception et une planification stratégique minutieuses

Understanding cognition in older patients with cancer

Cancer and neurocognitive disorders, such as dementia and delirium, are common and serious diseases in the elderly that are accompanied by high degree of morbidity and mortality. Furthermore, evidence supports the under-diagnosis of both dementia and delirium in older adults. Complex questions exist regarding the interaction of dementia and delirium with cancer, beginning with guidelines on how best measure disease severity, the optimal screening test for either disorder, the appropriate level of intervention in the setting of abnormal findings, and strategies aimed at preventing the development or progression of either process. Ethical concerns emerge in the research setting, pertaining to the detection of cognitive dysfunction in participants, validity of consent, disclosure of abnormal results if screening is pursued, and recommended level of intervention by investigators. Furthermore, understanding the ways in which comorbid cognitive dysfunction and cancer impact both cancer and non-cancer-related outcomes is essential in guiding treatment decisions. In the following article, we will discuss what is presently known of the interactions of pre-existing cognitive impairment and delirium with cancer. We will also discuss identified deficits in our knowledge base, and propose ways in which innovative research may address these gaps

White paper: Research Challenges at the Intersection of Energy and Equity in the Energy Transition

Summary report from NSF2026: Conference Workshops to Identify Research Challenges at the Intersection of Energy and Equity in the Energy Transitio

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

The Cd isotope composition of atmospheric aerosols from the Tropical Atlantic Ocean

Stable isotope compositions can potentially be used to trace atmospheric Cd inputs to the surface ocean and anthropogenic Cd emissions to the atmosphere. Both of these applications may provide valuable insights into the effects of anthropogenic activities on the cycling of Cd in the environment. However, a lack of constraints for the Cd isotope compositions of atmospheric aerosols is currently hindering such studies. Here we present stable Cd isotope data for aerosols collected over the Tropical Atlantic Ocean. The samples feature variable proportions of mineral dust-derived and anthropogenic Cd, yet exhibit similar isotope compositions, thus negating the distinction of these Cd sources by using isotopic signatures in this region. Isotopic variability between these two atmospheric Cd sources may be identified in other areas, and thus warrants further investigation. Regardless, these data provide important initial constraints on the isotope composition of atmospheric Cd inputs to the ocean

Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma

"Purpose: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors. Experimental Design: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings. Results: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis. Conclusions: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.