Testing maternal effects of vitamin-D and omega-3 levels on offspring neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. However, observational study designs cannot distinguish causal effects from confounding. METHODS: First, we conducted Mendelian randomisation (MR) using genetic instruments for vitamin-D and DHA identified in independent genome-wide association studies (GWAS). Outcomes were (1) GWAS for traits related to autism and ADHD, generated in the Norwegian mother, father, and child cohort study (MoBa) from 3 to 8 years, (2) autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa (1) to test causal effects through maternal nutrient levels, (2) to test effects of child nutrient levels, and (3) as a paternal negative control. RESULTS: Associations between higher maternal vitamin-D levels on lower ADHD related traits at age 5 did not remain after controlling for familial genetic predisposition using trio-MR. Furthermore, we did not find evidence for causal maternal effects of vitamin-D/DHA levels on other offspring traits or diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic predisposition on lower vitamin-D levels and of ADHD genetic predisposition on lower DHA levels. CONCLUSIONS: Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence that suggests that previous observational associations are likely biased by genetic confounding. Consequently, maternal supplementation is unlikely to influence these offspring neurodevelopmental traits. Notably, genetic predisposition to ADHD and autism was associated with lower DHA and vitamin-D levels respectively, suggesting previous associations might have been due to reverse causation.

Giant Star-shaped meso-substituted Fluorescent Porphyrins with Fluorenyl-containing Arms Designed for Two-photon Oxygen Photosensitization.

In the continuation of previous studies on carbon-rich meso-tetraarylporphyrins featuring 2,7-fluorene units at their periphery, the effect of changing the peripheral dendritic arms for linear arms on their oxygen-photosensitizing ability, their fluorescence and their two-photon absorption (2PA) properties is now analyzed. Thus, starburst porphyrins possessing up to twenty conjugated fluorenyl units were isolated and studied. More precisely, a series of five new free-base porphyrins featuring fully conjugated arms incorporating an increasing number of fluorenyl groups connected via 1,2-alkenyl spacers were synthesized, along with their Zn(II) complexes. Upon excitation in the arm-centred π-π* absorption band, an efficient energy transfer takes place from the peripheral fluorenyl units to the central porphyrin core, leading to intense red-light emission and oxygen photosensitization by the latter. More interestingly, while the linear optical properties of these porphyrins were only slightly improved compared to those of their dendrimer analogues for photodynamic therapy (PDT) or fluorescence imaging, their 2PA cross-sections were much more significantly boosted, evidencing the key role played by different structures on nonlinear optical properties. Finally, by comparison with other porphyrin-based two-photon photosensitizers reported in the literature, we show that these new "semi-disconnected" starburst systems exhibit a remarkable trade-off between intrinsic 2PA, fluorescence and oxygen photosensitization.

An Unusual Case of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Introduction: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare disease entity associated with textured breast implants. Though the clinical course is typically indolent, BIA-ALCL can occasionally invade through the capsule into the breast parenchyma with spread to the regional lymph nodes and beyond including chest wall invasive disease. Case: We present the case of a 51-year-old female with a history of bilateral silicone breast implants placed approximately twenty years ago who presented with two months of progressively enlarging right breast mass. Ultrasound-guided biopsy of right breast mass and right axillary lymph node showed CD 30-positive ALK-negative anaplastic large cell lymphoma, and staging work up showed extension of the tumor to chest wall and ribs consistent with advanced disease. She received CHP-BV (cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin) for six cycles with complete metabolic response. This was followed by extensive surgical extirpation and reconstruction, radiation for residual disease and consolidation with autologous stem cell transplant. She is currently on maintenance brentuximab vedotin with no evidence of active disease post autologous stem cell transplant. Conclusion: Treatment guidelines for advanced chest wall invasive BIA-ALCL are not well defined. Lack of predictive factors warrants mutation analysis and genetic sequencing to identify those at highest risk of progression to chest wall invasive disease. This rare case highlights the need for definitive consensus on the optimal management of chest wall invasive BIA-ALCL.

Encapsulation of Hydrophobic Porphyrins into Biocompatible Nanoparticles: An Easy Way to Benefit of Their Two-Photon Phototherapeutic Effect without Hydrophilic Functionalization.

Star-shaped hydrophobic porphyrins, acting as powerful fluorescent two-photon photosensitizers for oxygen in organic solvents, can easily be loaded into PMLABe polymeric nanoparticles at various concentrations. In this contribution, the performance of these porphyrin-containing nanoparticles in terms of photodynamic therapy (PDT) is compared to those of the corresponding water-soluble porphyrin analogues when irradiated in MCF-7 cancer cells. While quite promising results are obtained for performing PDT with these nanoparticles, validating this approach as a mean for using more easily accessible and less expensive photosensitizers, from a synthetic perspective, we also show that their luminescence can still be used for bioimaging purposes in spite of their confinement in the nanoparticles, validating also the use of these nano-objects for theranostic purposes.

Examining the Relationship between Altmetric Score and Traditional Bibliometrics in the Pathology Literature.

BACKGROUND: Recently, research data are increasingly shared through social media and other digital platforms. Traditionally, the influence of a scientific article has been assessed by the publishing journal's impact factor (IF) and its citation count. The Altmetric scoring system, a new bibliometric that integrates research "mentions" over digital media platforms, has emerged as a metric of online research distribution. The aim of this study was to explore the relationship of the Altmetric Score with IF and citation number within the pathology literature. METHODS: Citation count and Altmetric scores were obtained from the top 10 most-cited articles from the 15 pathology journals with the highest IF for 2013 and 2016. These variables were analyzed and correlated with each other, as well as the age of the publishing journal's Twitter account. RESULTS: Three hundred articles were examined from the two cohorts. The total citation count of the articles decreased from 21,043 (2013) to 14,679 (2016), while the total Altmetric score increased from 830 (2013) to 4066 (2016). In 2013, Altmetric score weakly correlated with citation number (r = 0.284, P < 0.001) but not with journal IF (r = 0.024, P = 0.771). In 2016, there was strong correlation between citation count and Altmetric Score (r = 0.714, P < 0.0001) but not the IF (r = 0.0442, P = 0.591). Twitter was the single most important contributor to the Altmetric score; however, the age of the Twitter account was not associated with citation number nor Altmetric score. CONCLUSIONS: In the pathology literature studied, the Altmetric score correlates with article citation count, suggesting that the Altmetric score and conventional bibliometrics can be treated as complementary metrics. Given the trend towards increasing use of social media, additional investigation is warranted to evaluate the evolving role of social media metrics to assess the dissemination and impact of scientific findings in the field of pathology.

Controlled propagation and jamming of a delamination front.

We study the birth and propagation of a delamination front in the peeling of a soft, weakly adhesive layer. In a controlled-displacement setting, the layer partially detaches via a subcritical instability and the motion continues until arrested, by jamming of the two lobes. Using numerical solutions and scaling analysis, we quantitatively describe the equilibrium shapes and obtain constitutive sensitivities of jamming process to material and interface properties. We conclude with a way to delay or avoid jamming altogether by tunable interface properties.

Phthalocyanine-Cored Fluorophores with Fluorene-Containing Peripheral Two-Photon Antennae as Photosensitizers for Singlet Oxygen Generation.

: A series of free base and Zn(II) phthalocyanines featuring fluorenyl antennae linked by methoxy or oxo bridges to the phthalocyanine core (Pc) were synthesized and characterized. Selected linear and nonlinear (two-photon absorption) optical properties of these new compounds were subsequently studied. As previously observed for related porphyrin dendrimers bearing 2-fluorenyl peripheral dendrons, an efficient energy transfer occurs from the peripheral antennae to the central phthalocyanine core following excitation in the fluorenyl-based π-π* absorption band of these chromophores. Once excited, these compounds relax to the ground state, mostly by emitting intense red light or by undergoing intersystem crossing. As a result, the tetrafunctionalized Zn(II) phthalocyanines are fluorescent, but can also efficiently photosensitize molecular oxygen in tetrahydrofurane (THF), forming singlet oxygen with nearly comparable yields to bare Zn(II) phthalocyanine (ZnPc). In comparison with the latter complex, the positive role of the fluorenyl-containing antennae on one- and two-photon brightness (2PA) is presently demonstrated when appended in peripheral (ß) position to the phthalocyanine core. Furthermore, when compared to known porphyrin analogues, the interest in replacing the porphyrin by a phthalocyanine as the central core to obtain more fluorescent two-photon oxygen photosensitizers is clearly established. As such, this contribution paves the way for the future development of innovative biphotonic photosensitizers usable in theranostics.

Teaching Laboratory Stewardship in the Medical Student Core Clerkships Pathology-Teaches.

CONTEXT.­: Current health care spending is unsustainable, and there is a need to teach high-value care principles to future physicians. Pathology-Teaches is an educational intervention designed to teach laboratory stewardship early in clinical training, at the level of the medical student in their core clinical clerkships. OBJECTIVE.­: To assess the pilot implementation of case-based educational modules in 5 required core clerkships at our institution. DESIGN.­: The online cases were developed by using a multidisciplinary approach. In the Pathology-Teaches educational module, students make decisions regarding the ordering or interpretation of laboratory testing within the context of a clinical scenario and receive immediate feedback during the case. The intervention was assessed by using pretest and posttest. Student feedback was also collected from end-of-rotation evaluations. RESULTS.­: A total of 203 students completed the Pathology-Teaches pilot, including 72 in Family Medicine, 72 in Emergency Medicine, 24 in Internal Medicine, 24 in Neurology, and 11 in Obstetrics-Gynecology (OB-GYN). Pathology-Teaches utility was demonstrated by significantly increased improvement between pretest and posttest scores (mean, 63.1% versus 83.5%; P < .001; Hedge g effect size = 0.93). Of the 494 students who completed the Pathology-Teaches questions on the end-of-rotation evaluation, 251 provided specific feedback, with 38.6% (97 of 251) rating the activity as "extremely valuable" or "very valuable," and 41.4% (104 of 251) as "some/moderate value." Qualitative feedback included 17 positive comments with 6 requests to scale up or include more cases, 16 constructive comments for improvement mainly regarding the technical aspects, and 5 negative comments. CONCLUSIONS.­: Pathology-Teaches effectively teaches stewardship concepts, and most students perceived value in this educational intervention.

How to Teach Laboratory Stewardship in the Undergraduate Medical Curriculum?

OBJECTIVES: Promotion of high-quality care at a lower cost requires educational initiatives across the continuum of medical education. A needs assessment was performed to inform the design of an educational tool with the goal of teaching laboratory stewardship to medical students. METHODS: The needs assessment consisted of semistructured interviews with core clerkship directors and residency program directors at our institution, a national survey to the Undergraduate Medical Educators Section (UMEDS) of the Association of Pathology Chairs, and a review of existing online resources that teach high-value care. RESULTS: Two major themes emerged regarding opportunities to enhance laboratory stewardship education: appropriate ordering (knowledge of test indications, pretest/posttest probability, appropriateness criteria, recognition of unnecessary testing) and correct interpretation (understanding test specifications, factors that affect the test result, recognizing inaccurate results). CONCLUSIONS: The online educational tool will focus on the curricular needs identified, using a multidisciplinary approach for development and implementation.

Biocompatible conjugated fluorenylporphyrins for two-photon photodynamic therapy and fluorescence imaging.

The photophysical properties of a new series of fluorenyl porphyrins bearing water-solubilising oligoethyleneglycol chains are described. These biocompatible compounds present very good two-photon absorption and singlet oxygen generation properties, while retaining some fluorescence in water. After testing in vitro on breast cancer cells, some of them were shown to be efficient non-toxic two-photon photosensitisers allowing for fluorescence imaging, thus demonstrating their theranostic potential.

Fluorenylporphyrins functionalized by electrochromic ruthenium units as redox-triggered fluorescence switches.

Two dyads containing tris- and tetrakis-meso-fluorenyl-substituted porphyrin and ethynylruthenium units, 1 and 2, were investigated by emission spectro-electrochemical (SEC) methods for their potential use as fluorescence switches. The ruthenium group as a potential electron donor and the porphyrin as a potential electron acceptor are connected by a phenylene bridge in 1 and by a fluorenylene bridge in 2. The new fluorenyl-linked dyad 2 was probed by UV-visible, near-infrared (NIR) and infrared (IR) absorption SEC methods, and the properties interpreted with the aid of hybrid-DFT computations, for comparison with reported data for 1. The porphyrin-based fluorescence of 1 decreased in intensity upon oxidation to 1+ and decreased further on oxidising 1+ to 12+. A much weaker change in the fluorescence intensity of 2 was observed upon oxidation to 2+ but the intensity decreased upon subsequent oxidation of 2+ to 22+. These findings contrast with data reported for some other porphyrins appended with redox-active ruthenium or iron units, where fluorescence intensities increase upon oxidation of the peripheral metal centers, but they match data reported more recently for closely related arrays. A rationale for these apparently contrasting observations is proposed.

Twelve tips for the introduction of emotional intelligence in medical education.

Emotional intelligence (EI) is the ability to recognize, understand, and manage emotions in yourself and in others. EI has long been recognized as a critical component for individual and organizational success within the business realm, and there is emerging evidence that enhancing EI is equally important in the medical setting. EI can improve interpersonal communications, enable constructive conflict resolution, and promote a culture of professionalism. As healthcare becomes increasingly team-based, proficiency in EI will be required to build consensus among multidisciplinary stakeholders, and effect change in attitudes and behaviors that result in improved patient safety and clinical outcomes. Based on the existing literature and the authors' experiences, these 12 tips provide practical suggestions on how to introduce EI into a medical curriculum. These tips have broad applicability, and can be implemented in courses on topics such as professionalism, leadership development, empathy, patient safety, or wellness.

Cyclin D1-positive Mediastinal Large B-Cell Lymphoma With Copy Number Gains of CCND1 Gene: A Study of 3 Cases With Nonmediastinal Disease.

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.

Educational Case: Chronic Lymphocytic Leukemia.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Synthesis, characterization and third-order nonlinear optical properties of a dodecaruthenium organometallic dendrimer with a zinc(ii) tetraphenylporphyrin core.

A new Zn(ii) porphyrin-based dendrimer (52) containing twelve Ru(ii) alkynyl fragments, has been prepared following a convergent approach in two steps from 5,10,15,20-tetra(4-ethynylphenyl)porphyrinatozinc(ii) (6). The cubic nonlinear optical (NLO) properties of 52 and other derivatives of 6 have been measured by third-harmonic generation (THG) at 1907 nm and by Z-scan over the spectral range 500-1700 nm, revealing the remarkable NLO response of 52 in the near-IR range. These results highlight the beneficial role of the extended "cross fourchée"-like polymetallic structure of 52 on its third-order NLO properties.

CD49d shows superior performance characteristics for flow cytometric prognostic testing in chronic lymphocytic leukemia/small lymphocytic lymphoma.

BACKGROUND: CD49d is emerging as a powerful adverse prognostic marker in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, flow cytometric testing for CD49d has not yet been widely adopted in the United States, in part due to the lack of establishment of its performance characteristics in the clinical setting, especially in comparison with the more common CLL/SLL prognostic markers CD38 and ZAP-70. METHODS: CD49d expression levels in 124 CLL/SLL cases were assessed among peripheral blood (PB), bone marrow (BM), and lymph node (LN) specimens and correlated with available CD38 and ZAP-70 expression and cytogenetic findings. For 10 PB/BM specimens, the stability of CD49d, CD38, and ZAP-70 expression was assessed at <24 hours, 48 hours, 72 hours, and 96 hours. RESULTS: 39% (28 of 71) PB, 56% (18 of 32) BM, and 71% (15 of 21) LN involved by CLL/SLL were CD49d+, using a ≥30% threshold. The mean for the CD49d+ cases was 2.8 standard deviations (SD) above the cutoff for positivity, compared with 1.7 SD for CD38 and 1.1 SD for ZAP-70. CD49d demonstrated the lowest mean SD (0.91) and coefficient of variation (CV) (8.0%) compared with CD38 (SD = 2.1, CV = 10.4%) and ZAP-70 (SD = 9.8, CV = 40.5%) in stability studies over a 96-hours time period. CD49d+ CLL/SLL correlated with trisomy 12 (P = 0.025) and lack of isolated deletion (13q) (P = 0.005). CD38+ CLL/SLL correlated with deletion (11q) (P = 0.025). ZAP-70 did not correlate with any underlying cytogenetic abnormality. CONCLUSIONS: CD49d is a robust adverse prognostic marker in CLL/SLL with superior performance characteristics. © 2016 International Clinical Cytometry Society.

Factor XIII Subunit A Immunohistochemical Expression is Associated With Inferior Outcomes in Acute Promyelocytic Leukemia.

Coagulation factor XIII subunit A (FXIIIa) intracellular expression has been described in platelets, megakaryocytes, monocytic cells, and leukemic blasts. Flow cytometric-based studies have suggested prognostic implications of FXIIIa expression, especially within the acute promyelocytic leukemia (APL) subgroup of acute myeloid leukemia (AML); however, its prognostic correlate by immunohistochemistry (IHC) is unknown. The aims of this study were to (1) define the clinicopathologic features of FXIIIa IHC-positive AML and (2) compare APL with other AML subtypes. Eighty-seven bone marrow biopsies or clot/particle preparations from our institution were evaluated with FXIIIa IHC. The study cohort consisted of bone marrow evaluations of 36 consecutive pretherapy APL, 42 selected pretherapy non-APL AML, and 9 negative staging cases. FXIIIa IHC expression was correlated with clinical and pathologic features and overall survival (OS). Leukemic blast FXIIIa cytoplasmic positivity was noted in 56% (20/36) APL and 74% (31/42) non-APL AML (P=0.10). FXIIIa IHC expression was associated with inferior OS within the APL cohort (P=0.04). No OS differences were noted in comparing FXIIIa IHC expression in all AML (P=0.17), or FXIIIa IHC expression within favorable, intermediate or adverse cytogenetic groups (P=0.14, 0.22 and 0.87, respectively). FXIIIa IHC expression is observed among a broad spectrum of AML subtypes and is not characterized by specific pathologic features. However, within the APL subgroup, FXIIIa IHC expression is associated with an inferior outcome and may be useful for additional prognostic risk stratification.

Microstructural white matter changes and their relation to neuropsychological deficits in patients with juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy syndrome. Neuropsychological, electrophysiological, and neuroimaging studies have led to the hypothesis that JME is related to dysfunction of frontal brain regions and mainly frontal thalamocortical networks. METHODS: We investigated possible microstructural white matter abnormalities of 20 patients with JME as compared with 20 healthy control subjects using diffusion tensor imaging (DTI). We analyzed whole-head DTI scans without an a-priori hypothesis using Tract-Based Spatial Statistics (TBSS). To analyze associated gray matter changes, we applied voxel-based morphometry (VBM) to a 3D T1 magnetization prepared rapid gradient echo (MPRAGE) sequence. Neuropsychological testing and personality trait tests were performed to bridge the gap between structure and function. RESULTS: In patients, DTI revealed microstructural white matter changes in anterior parts of the Corpus callosum, anterior parts of the cingulate gyrus, and widespread frontal white matter bilaterally as well as in anterior parts of the right thalamus, which were not accompanied by gray matter changes in VBM. Microstructural changes in the cingulum correlated with personality traits. Neuropsychological test results showed impaired attention and executive functions and reduced short-term memory in the patient group. Also, there was a tendency toward alexithymia and significantly higher scores on depression. SIGNIFICANCE: The present study results showed neuropsychological deficits including frontal lobe cognitive performance and a tendency toward alexithymia as well as accompanying microstructural neuroimaging changes in patients with JME, which all point to alterations in frontal brain regions and frontal thalamocortical networks in these patients.

Correction for Mahic et al., "Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring".

[This corrects the article DOI: 10.1128/mSphere.00016-17.].