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Percutaneous coronary intervention in severely calcified coronaries has been associated with higher rates of procedural complications, including myocardial infarction and death in addition to increased frequency of coronary revascularization on an intermediate and long-term basis. The SYNTAX score, which is designed to assess the complexity of coronary artery disease and aids in choosing a revascularization method, allocates two points per lesion when there is heavy calcification present on fluoroscopy. With the advent of novel multimodality imaging technologies, the detection and evaluation of coronary calcifications improved significantly over the last decade. Several tools are now available for modifying calcified lesions including different types of dedicated balloons and atherectomy devices, which may create some degree of confusion regarding the suitable application of each instrument. The aim of this review is to cover this vital topic from different aspects. First, we tried to provide an overview on the pathophysiology and types of coronary calcification and its risk factors. Then, we outlined the available imaging modalities for the evaluation of calcified coronary lesions, highlighting the points of strength and weakness of each of them. A comprehensive discussion of calcium-modifying techniques was elaborated, summarizing their mechanism of action, pros and cons, and possible complications. Finally, an integrated algorithm was proposed for the best management of calcified coronary lesions.

In this paper, a numerical examination of propagating nonlinear dissipative dust-acoustic breathers and rogue waves (RWs) in electron depleted dusty plasmas having two superthermal ions of different temperature has been made. An important ingredient in this study is the inclusion of the dissipative effect due to the viscosity of the dust grains in the evolution wave equation. Accordingly, a damped/modified nonlinear Schrödinger equation (DNLSE), i.e. the standard nonlinear Schrödinger equation (NLSE) in addition to the damping term, is obtained using a reductive perturbation (the derivative expansion) method. Without taking into account the effect of dust viscosity, the standard NLSE is also examined, and the effect of relevant physical parameters on the breathers and rogue waves is examined. Moreover, the impact of dust kinetic viscosity on both breather structures and RWs is investigated by solving DNLSE numerically with the Dirichlet boundary conditions. This model may be useful to understand the excitation of dust-acoustic waves in the Earth's magnetotail. [ABSTRACT FROM AUTHOR]

Abstract Background Many previous studies reported the negative effects of right ventricular (RV) pacing on the left ventricular (LV) structure and ejection fraction. Studying pacing hemodynamics is essential to understand these detrimental effects. In this study, we tried to understand RV pacing effects on LV volumes and function using advanced tools like 3D echo and global longitudinal strain (GLS). This was a prospective study of 175 consecutive patients (LVEF>50%) presented permanent pacing. Of 175 patients, only 50 patients met study criteria, divided into two groups (single or dual pacing). LV volumes and function were assessed by full-volume 3D echocardiography and GLS before pacing, at 1-week and 6-month post-pacing. Cardiac output (COP) was calculated by pulsed wave Doppler method and 3D echo. Results Doppler method results were similar to 3D echo in calculating SV and COP. At 1-week post pacing, both groups showed a significant decrease in SV due to a drop in EDV while ESV did not change significantly. Despite the drop in SV, there was a significant increase in cardiac output (COP) due to achieving higher heart rates post-pacing. There was a significant drop in EF and GLS in both groups. At 6 months, SV continued to decrease with a corresponding decrease in COP and LVEF. This drop in SV was due to a significant increase in ESV while EDV did not show a significant change at a 6-month follow-up. Also, the drop EF and GLS became more significant. There were no significant differences between both groups regarding the changes in LV volumes (EDV, ESV, SV), LVEF or GLS throughout the study (pre-pacing, at 1-week and 6-months post pacing). However, dual-chamber pacing group provided higher heart rates and as a result higher COP than the single-chamber group. Conclusions RV pacing led to a significant drop in LV COP, ejection fraction (EF), and GLS over short- and long-term duration. Dual chamber pacing provided higher COP than a single chamber pacing. This was due to tracking the S. A node with pacing at higher heart rates not due to an increase in SV and preserving atrioventricular synchrony. Both Doppler method and 3D echo can be used to calculate SV and COP.

Abstract Background Long-term RV pacing leads to ventricular dyssynchrony, in the form of LBBB-like morphology, with subsequent detrimental effects on LV structure and function. Three-dimensional echocardiography allowed early detection of volumetric changes associated with PICMP and provided more accurate assessment of mechanical dyssynchrony. Speckle tracking strain is able to identify LV dysfunction even before any reduction in LVEF. Our aim was to study pacing effects on LV function and hemodynamics using 3D echo and speckle tracking strain. Results This was a prospective study of 175 consecutive patients without structural heart disease (LVEF > 50%) presented for permanent pacing. Full-volume 3D echocardiography done before implantation, 1 week, and 6 months together with GLS. Patients were followed for 6 months to detect incidence of PIVD (defined as reduction in LVEF > 10% but still above 50%) and PICMP (defined as decrease in LVEF by 10% from baseline in absence of other known causes of cardiomyopathy resulting in EF< 50%). PIVD and PICMP predictors and risk factors were analyzed. Only 50 patients met study criteria. Twenty-five (50%) patients developed LV systolic dysfunction; of these, 19 (38%) developed PIVD and 6 (12%) developed PICMP. Pre-implantation GLS was significantly lower in the 6 patients who subsequently developed PICMP, compared to those who developed PIVD and the preserved EF group (mean GLS − 15.50 vs. − 21.0, − 20.0 respectively; p = 0.005, 0.033, respectively). At 1 week, GLS was significantly lower in the 25 patients who subsequently developed PIVD, compared to those who did not (GLS − 13.0 vs. − 18.0, respectively; p = 0.002). A reduction of baseline GLS by 15% or more at 1 week was associated with the development of PIVD and PICMP (p = < 0.001). A wider native QRS complex was associated with PIVD and PICMP (p = 0.008, 0.018, respectively). The other predictors were found non-significant. Conclusion PICMP may be more common than previously reported and it may occur shortly after implantation. Pre-implantation GLS is a sensitive parameter for PICMP. One-week GLS, pre-implantation QRS complex width are early predictors for PICMP and PIVD before any reduction in EF.

Acute aortic dissection is considered a potentially fatal condition. Neurologic manifestations such as paraplegia are quite rare. We report a case of acute paraplegia in a hypertensive smoker chronic obstructive lung disease patient. Transthoracic echocardiography revealed a dissection flap starting at the aortic annulus and extending to the descending thoracic aorta. Computed tomographic aortography confirmed the diagnosis with a dissection flap extended from the aortic annulus to the entire distal aorta. The patient was referred to another specialized cardiothoracic center, but unfortunately, he died during the surgery.

We prove that if u is an $L^p$-subharmonic function defined outside a compact set in $\mathbb{R}^n$, it is bounded above near infinity, in particular, if the subharmonic function u is in $L^p(\mathbb{R}^n)$, $1\leq p

Cutaneous BAP1-inactivated melanocytomas (BIM) are melanocytic proliferations defined histopathologically by an epithelioid, predominantly dermal melanocytic proliferation with loss of BAP1, and have been largely characterized in adult patients but less well-described in pediatric cohorts. BIM share overlapping histological features with those seen in Spitz nevi; however, unlike Spitz nevi, the majority of BIM carry both BAP1 and BRAF V600E mutations. This study investigated the potential overlap of BIMs with pediatric Spitz nevi by performing immunohistochemical staining of BAP1 and BRAF V600E on pediatric melanocytic tumors with banal Spitz and dermal features. None of the stained tumors in our study exhibited the concurrent BAP1 loss and BRAF V600E positivity that are characteristic of adult BIM, suggesting that this is a low-frequency mutation among banal tumors in the pediatric population., (© 2024 Wiley Periodicals LLC.)

Background: Pediatric melanoma presents with distinct clinical features compared to adult disease., Objective: Characterize risk factors and negative outcomes in pediatric melanoma., Methods: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers., Results: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls., Limitations: Retrospective nature, cohort size, control selection, and potential referral bias., Conclusion: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma., Competing Interests: Conflicts of interest SH reports honorarium from Elsevier and past consulting for Novan Pharmaceuticals., (Copyright © 2024. Published by Elsevier Inc.)

Pediatric melanoma of the scalp has the highest mortality of any anatomic location. We describe five pediatric patients with a diagnosis of scalp melanoma receiving care at Massachusetts General Hospital and/or Boston Children's Hospital from 2018 through 2022. Melanoma presented in diverse contexts: cellular blue nevus-associated, compound nevus-associated, spitzoid, nodular, and superficial spreading subtypes. This study describes a range of melanoma presentations and emphasizes the need for additional compilation of data on pediatric scalp melanomas to promote their recognition and improve patient care., (© 2023 Wiley Periodicals LLC.)

Introduction: Electronic cigarettes (e-cigarettes) rapidly evolved from large modifiable (MOD) devices, to small and affordable 'POD' devices. Detailed information on user demographics and preferences according to device type, which can inform potential chemical exposure and policy recommendations, is currently limited. The goal of this study is to describe user demographics, use behaviors and preferences, as well as self-reported health outcomes according to the e-cigarette device type used., Methods: From April 2019 to March 2020, 91 participants from Maryland (18 MOD users, 26 POD users, 16 dual users (use of both combustible and e-cigarettes), and 31 non-users (never e-cigarette users and never smokers or >6 months former use) were recruited. A comprehensive questionnaire collected sociodemographic characteristics, e-cigarette/tobacco use behaviors, self-reported health outcomes, device characteristics and preferences. Chi-squared tests for categorical variables, ANOVA for continuous variables, qualitative thematic analysis, linear and logistic regressions were used to assess relationships between variables and groups., Results: POD users were younger (average 22.5 years) than MOD users (30.8 years) or dual users (34.3 years) (p<0.001). MOD users reported more puffs per day (mean ± SD: 373 ± 125 puffs) compared to POD users (123.0 ± 172.5). E-cigarette users who were former smokers used 1.16 mg/mL lower nicotine concentrations compared to lifetime exclusive e-cigarette users (p=0.03) in linear models. Exclusive POD users self-reported more coughing than exclusive MOD or dual users (p=0.02). E-cigarette users reported more shortness of breath, headaches, and fatigue from their e-cigarette use compared to non-users., Conclusions: We found significant differences between user demographics, e-cigarette preferences, device characteristics, and use behaviors by user group. This information can help explain exposure to chemicals from e-cigarettes, including compounds with known toxic effects (e.g. metals, formaldehyde), and help inform the design of prevention and intervention strategies and policy decisions., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. A. Tillery, A. Aherrera, R. Chen, M. Tehrani, J. Mihalic and A.M. Rule report that since the initial planning of the work they received support from the Food and Drug Administration Center for Tobacco Products (R01ES030025) and Maryland Cigarette Restitution Fund (PHPA-G2034). A. Tillery and A.M. Rule also report that in the past 36 months they received a grant by the National Institute for Occupational Safety and Health (T42 OH0008428). A. Aherrera reports that in the past 36 months she received grants by the National Heart, Lung, and Blood Institute (T32HL072748) and K99/R00 Pathway to Independence in Tobacco Regulatory Research (1K99ES034507) by the National Institute for Environmental Health Sciences and the U.S. Food and Drug Administration, Center for Tobacco Products. D. Moustafa reports that she has been employed by the Federal Government’s Environmental Protection Agency (EPA) since October 2022 and that she did not have a prior affiliation with EPA., (© 2023 Tillery A. et al.)

Dysregulated epigenetic modifications are common in lung cancer but have been reversed using demethylating agent like 5-Aza-CdR. 5-Aza-CdR induces/upregulates the NY-ESO-1 antigen in lung cancer. Therefore, we investigated the molecular mechanisms accompanied with the epigenetic regulation of NY-ESO-1 in 5-Aza-CdR-treated NCI-H1975 cell line. We showed significant induction of the NY-ESO-1 protein (**p < 0.0097) using Cellular ELISA. Bisulfite-sequencing demonstrated 45.6% demethylation efficiency at the NY-ESO-1 gene promoter region and RT-qPCR analysis confirmed the significant induction of NY-ESO-1 at mRNA level (128-fold increase, *p < 0.050). We then investigated the mechanism by which 5-Aza-CdR inhibits cell proliferation in the NCI-H1975 cell line. Upregulation of the death receptors TRAIL (2.04-fold *p < 0.011) and FAS (2.1-fold *p < 0.011) indicate activation of the extrinsic apoptotic pathway. The upregulation of Voltage-dependent anion-selective channel protein 1 (1.9-fold), Major vault protein (1.8-fold), Bax (1.16-fold), and Cytochrome C (1.39-fold) indicate the activation of the intrinsic pathway. We also observed the differential expression of protein Complement C3 (3.3-fold), Destrin (-5.1-fold), Vimentin (-1.7-fold), Peroxiredoxin 4 (-1.6-fold), Fascin (-1.8-fold), Heme oxygenase-2 (-0.67-fold**p < 0.0055), Hsp27 (-0.57-fold**p < 0.004), and Hsp70 (-0.39-fold **p < 0.001), indicating reduced cell growth, cell migration, and metastasis. The upregulation of 40S ribosomal protein S9 (3-fold), 40S ribosomal protein S15 (4.2-fold), 40S ribosomal protein S18 (2.5-fold), and 60S ribosomal protein L22 (4.4-fold) implied the induction of translation machinery. These results reiterate the decisive role of 5-Aza-CdR in lung cancer treatment since it induces the epigenetic regulation of NY-ESO-1 antigen, inhibits cell proliferation, increases apoptosis, and decreases invasiveness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Systematic data regarding long-term neurobehavioral effects of maternal antidepressant use during pregnancy are sparse. The aim of this study was to evaluate the impact of gestational exposure to antidepressants on later neurodevelopmental function., Methods: This study describes a cohort of mother-child dyads (44 mothers, 54 children) in which maternal depressive symptoms and medication exposures were prospectively collected across pregnancy and the postpartum period. Children age 6 to 17 were assessed using validated instruments across domains of childhood behavior and executive memory and functioning., Results: No associations were found between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and atypical neurodevelopment of children. Borderline clinical or clinical ranges of internalizing symptoms were associated with exposure to a higher maternal depressive symptom burden during pregnancy compared with those in the normal range. Compared with age- and sex-matched controls, the SSRI-exposed group showed superior performance on executive function tasks; findings did not demonstrate elevated risk for abnormal neurodevelopment in children age 6 to 17 exposed to SSRIs in utero. Deviations from the norm were instead associated with higher in utero exposure to maternal depression burden., Conclusions: This study highlights the need for rigorous studies of long-term outcomes after fetal antidepressant exposure.

Background: Antimicrobial stewardship programs (ASPs) play a big role in minimizing antimicrobial resistance. Pharmacists are essential members of the health care team and in order for them to fulfill roles on ASP teams and become antimicrobial stewards, they must be prepared adequately by pharmacy schools prior to entry into actual practice. Although programming has been implemented into entry-to-practice programs worldwide, little is known about how students interpret antimicrobial stewardship (AMS) data and arrive at clinical decisions. We aimed to explore students' cognitive processes and determine how they formulate therapeutic decisions when presented with AMS cases., Methods: This was a qualitative study conducted using a case study approach, in which a sample (n=20) of pharmacy students was recruited to interpret AMS cases. Semi-structured 1-on-1 interviews were arranged with each participant. A think-aloud procedure with verbal protocol analysis was adopted to determine students' decision-making processes. Thematic analysis was used to interpret themes from the interview data., Results: Two themes were interpreted from the data: students' focus and students' approach to case interpretation. Students' focus relates to external factors students consider when interpreting AMS case data and use to make and justify therapeutic decisions including patient-centered factors, drug-related factors, AMS interventions, and pharmacist's role. Students' clinical reasoning describes the approach that students use to interpret the data and the decision-making processes they employ to arrive at a clinical decision including a systematic approach versus non-systematic approach., Conclusions: Students vary in their focus and the cognitive strategies used to interpret AMS cases. Findings support the notion that clinical reasoning and decision-making should be explicitly taught in pharmacy curricula, in order to help students become aware of their own cognitive processes and decision-making abilities., (© 2022. The Author(s).)

Background/objectives: The diagnostic distinction between atypical Spitz tumor (AST) and malignant melanoma (MM) in pediatric tumors is challenging. Molecular tests are increasingly used to characterize these neoplasms; however, limited studies are available in pediatric patients. This study aimed to provide a genomic comparison of pediatric MM and AST in the context of comprehensive clinical annotation., Methods: Pediatric patients diagnosed with MM (n=11) and AST (n=12) were compared to a cohort of 693 adult melanoma patients. DNA next-generation sequencing assessed kinase gene fusions, tumor mutational burden, sequence variants, copy number alterations, structural variants, microsatellite instability, and mutational signatures., Results: Seven AST cases and eight MM cases were successfully sequenced. Kinase gene fusions were identified in both the MM and AST cohorts (NTRK1, ROS1, and MET). MM cases had TERT, BRAF, and CDKN2A alterations, which were not identified in the AST cohort. Tumor mutational burden (TMB) analysis showed pediatric ASTs had an average of 2.82 mutations/Mb, pediatric MM had an average of 5.7 mutations/Mb, and adult MM cases averaged 18.8 mut/Mb. One pediatric MM case had an elevated TMB of 15 mutations/Mb and a UV mutational signature., Conclusions: These data expand our understanding of pediatric malignant melanoma. The differences between the molecular signatures for AST and MM are not statistically significant, and histopathology remains the gold standard for the diagnosis of pediatric AST and MM at this time. With more data, molecular studies may provide additional support for diagnosis and targeted therapeutics., (© 2022 Wiley Periodicals LLC.)

Purpose: The physician voice is crucial to shaping health policy and public health guidelines, particularly during COVID-19. However, there are gaps in health policy and advocacy education within graduate medical education. This study sought to characterise the impact of a virtual COVID-19 focused advocacy day among medical trainees in Massachusetts., Study Design: The half-day event featured speakers drawn from government relations experts, physician advocates, and state and federal legislators as well as breakout discussions among attendees. A 25-question Redcap survey and list of resources/opportunities for continued advocacy was administered to all participants at event's conclusion on 19 May 2020., Results: There were 60 responses from 141 participants (43% response rate). One-third reported no prior formal health policy instruction, and over half reported getting information from news publications, social media and peers. 58% believed physician involvement in advocacy to be 'extremely important' prior to COVID-19; 83% believed the same after onset of COVID-19 (p<0.0001). The most common barriers to advocacy engagement were lack of time and knowledge. Most attendees felt participation increased their knowledge and likelihood to engage in the COVID-19 response, imparted useful skills/knowledge for continued advocacy, increased their interest in future similar events, and that such events should be available to all trainees., Conclusions: Trainees recognise the importance of health policy and advocacy and value opportunities to gain the necessary skills/knowledge to effect tangible change. Virtual advocacy days can be replicated nationwide to help trainees learn about advocacy efforts and find their legislative voices during COVID-19 and beyond., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Pyogenic granulomas are benign vascular proliferations of the skin and mucous membranes that tend to bleed easily. They typically require procedural treatments that can be difficult for patients with intellectual disabilities or behavioral concerns to tolerate. In our practice, we have found the use of topical clobetasol to be effective to induce regression of cutaneous pyogenic granulomas. We present here a case of an adolescent patient with autism and two bleeding pyogenic granulomas who poorly tolerated a biopsy of the first lesion and could not tolerate subsequent procedures. Topical therapy with clobetasol effectively managed the second pyogenic granuloma, an approach representative of a noninvasive practice utilized in our clinic., (© 2021 Wiley Periodicals LLC.)

Language-congruent care can improve clinical outcomes. As a quality improvement initiative supported by the Department of Dermatology at Massachusetts General Hospital, the American Academy of Dermatology, and the Society for Pediatric Dermatology, our group established monthly pediatric dermatology "Spanish clinics" that scheduled Spanish-speaking patients on the same day and utilized a dedicated, live interpreter who stayed with the clinical team throughout the clinic. Patients reported high satisfaction scores, averaging 9.8 out of 10, and 90.5% of patients preferred this model to traditional appointments. Our participating physician found "Spanish clinics" allowed for more efficient care not only in the monthly pilot clinics, but in all clinics occurring during the time period., (© 2021 Wiley Periodicals LLC.)

Background: Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized., Objective: To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines., Methods: A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination., Results: From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions., Limitations: Registry analysis does not measure incidence. Morphologic misclassification is possible., Conclusions: We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination., Competing Interests: Conflicts of interest Drs Freeman, Hruza, Rosenbach, Lipoff, and Fox are members of the American Academy of Dermatology (AAD) COVID-19 Ad Hoc Task Force. Dr French is the President and Dr Lim is a board member of the International League of Dermatological Societies. Dr Thiers is the President of the American Academy of Dermatology. Dr Freeman is an author of COVID-19 dermatology for UpToDate. Drs Amerson, Desai, and Blumenthal and authors McMahon, Moustafa, and Tyagi have no conflicts of interest to declare., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Nevus of Ota is an uncommon benign mesodermal melanosis that involves the first and second divisions of the trigeminal nerve. Primary non-cutaneous melanoma often involves distinct genetic mutations compared to cutaneous melanoma. In primary central nervous system (CNS) melanomas associated with nevus of Ota, somatic mutations most commonly occur at the Q209 and R183 residues of GNAQ and likely induce tumorigenesis through upregulation of the MAP kinase pathway. This case underscores the importance of elucidating neurologic symptoms early in patients with nevus of Ota, as a delayed presentation of CNS melanoma could portend a devastating outcome., (© 2021 Wiley Periodicals LLC.)

Triple negative breast cancer (TNBC) represents approximately 10-15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells., Competing Interests: The authors have declared that no competing interests exist.

Background: Pediatric melanoma is rare and diagnostically challenging., Objective: To characterize clinical and histopathologic features of fatal pediatric melanomas., Methods: Multicenter retrospective study of fatal melanoma cases in patients younger than 20 years diagnosed between 1994 and 2017., Results: Of 38 cases of fatal pediatric melanoma identified, 57% presented in white patients and 19% in Hispanic patients. The average age at diagnosis was 12.7 years (range, 0.0-19.9 y), and the average age at death was 15.6 years (range, 1.2-26.2 y). Among cases with known identifiable subtypes, 50% were nodular (8/16), 31% were superficial spreading (5/16), and 19% were spitzoid melanoma (3/16). One fourth (10/38) of melanomas arose in association with congenital melanocytic nevi., Limitations: Retrospective nature, cohort size, and potential referral bias., Conclusions: Pediatric melanoma can be fatal in diverse clinical presentations, including a striking prevalence of Hispanic patients compared to adult disease, and with a range of clinical subtypes, although no fatal cases of spitzoid melanoma were diagnosed during childhood., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To update pediatric providers on new developments in our understanding of the clinical presentation, genetics, and systemic risks associated with congenital melanocytic nevi (CMN)., Recent Findings: CMN are primarily caused by sporadic postzygotic somatic mutations, most frequently in NRAS, and studies of the genetic underpinnings of CMN have demonstrated a diverse array of genetic drivers. The primary complications of large and giant CMN include neurocutaneous melanocytosis and malignant melanoma. Abnormalities in CNS MRI may predict a worse clinical course for patients and increased risk of melanoma. Targeted therapies of the MEK pathway have begun to be studied for the treatment of CMN and prevention of associated complications., Summary: Patients with large and giant CMN should be managed by an interdisciplinary care team for the monitoring of dermatologic, neurologic, and psychosocial concerns. Ongoing research is underway to better characterize the genetic drivers of CMN and to better guide development of targeted therapeutics.

Purpose of Review: To inform pediatric providers of the clinical characteristics, underlying genetic drivers, and therapeutic options for skin cancer arising in childhood and adolescence., Recent Findings: The incidence of melanoma in pediatric patients has been declining in the past decades. Pediatric-specific diagnostic criteria should be utilized when assessing lesions concerning for melanoma to better account for the different presentations seen in pediatric disease compared with adults, such as an increased prevalence of amelanotic melanoma or frequent mimic of benign pediatric lesions. Pediatric melanoma often presents with a higher histopathologic stage and a higher Breslow depth as compared with adult melanoma. Pediatric nonmelanoma skin cancer including basal cell carcinoma and squamous cell carcinoma are associated with genetic conditions and immunosuppression, both iatrogenic and inherited., Summary: Melanoma in pediatric patients often presents differently from conventional adult melanoma, including Spitz melanoma and melanoma associated with congenital melanocytic nevi. Pediatric patients with nonmelanoma skin cancers should be evaluated for predisposing risk factors. More research on therapeutic options for pediatric skin cancer is vital to understanding the tolerance and response of our pediatric patients to therapies that are more frequently utilized in adult disease.

Background: Maternal major depressive disorder (MDD) has an adverse effect on child development and increases risk for child psychopathology. It is paramount to understand the course of maternal depression during the childhood years particularly before, during, and after pregnancy., Objective: To follow the course of MDD in women with prior histories of depression followed during an index pregnancy., Methods: Subjects were women with histories of MDD who had participated in prior prospective, observational studies during pregnancy. In the follow-up, participants completed a structured interview that addressed (1) the course of MDD since their index pregnancy, (2) new psychiatric diagnoses, and (3) the course of MDD and treatment across subsequent pregnancies., Results: Out of 129 eligible women, 48.8% participated (N = 63) with an average/mean time of 12.9 years (SD = 1.9, 8.8-16.7) elapsed since participation in the prior pregnancy studies. Although approximately one third reported sustained remission from MDD since the pregnancy during which they had been originally followed, of the remaining two thirds of women who reported subsequent depressive episodes, almost one fifth (∼12% of the total sample) endorsed depression more than 50% of the time following their index pregnancy. A total of 6.3% of the women with previous validated diagnoses of MDD reported new diagnoses of bipolar disorder. Women reported similar treatment choices regarding the use of antidepressants during pregnancies subsequent to the one followed in the previous study., Conclusion: Women with MDD experienced high rates of recurrent depression across the childbearing years. This represents a critical variable for clinical care and research., (© 2018 Wiley Periodicals, Inc.)

Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Obesity during pregnancy is the most common high-risk obstetric condition, resulting in increased rates of adverse maternal and neonatal outcomes. Individuals with psychiatric disorders have a higher risk of obesity than the general population, but data regarding implications of obesity in women with psychiatric disorders are sparse., Objective: The objective of this study was to assess pre-pregnancy weights and gestational weight gain in women who were exposed to second-generation antipsychotics (SGAs) during pregnancy compared to controls., Methods: We assessed pre-pregnancy weights and gestational weight gain from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics for patients exposed to SGAs and controls unexposed to these medicines during pregnancy. Both groups experienced similar psychiatric morbidity., Results: A total of 403 participants had evaluable data for these analyses (N = 279 exposed to SGAs; N = 124 controls). The mean pre-pregnancy weight, body mass index (BMI), and likelihood to begin pregnancy with an obese BMI were significantly higher in the exposed group compared to controls (p = 0.0003, p < 0.0001, and p < 0.0001 respectively), as were the mean weight and BMI at delivery (p < 0.0001). The mean weight gain did not differ significantly between groups. Across pre-pregnancy BMI categories, both groups gained more than the recommended amount of weight during pregnancy., Conclusion: We found that women exposed to SGAs began pregnancy with higher BMIs than controls. Both exposed and unexposed groups experienced similar weight gain during pregnancy. Strategies are needed to prevent excessive gestational weight gain and to reduce pre-pregnancy obesity in women with psychiatric disorders, especially those treated with SGAs., (Copyright © 2018 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: In a preliminary trial, we assessed the efficacy of vortioxetine for major depressive disorder (MDD) during the menopausal transition. Secondary outcomes included hot flashes (HFs), anxiety, and cognitive complaints., Methods: Perimenopausal and early postmenopausal women with MDD (N = 27) received 8 weeks of open-label, flexible-dose treatment with vortioxetine. The Montgomery-Åsberg Depression Rating Scale (MADRS) was the primary outcome measure. Secondary measures included: HF frequency, the Greene Climacteric Scale (GCS), Menopause-Specific Quality of Life Questionnaire (MEN-QOL), Beck Anxiety Inventory (BAI), Cognitive and Physical Functioning Questionnaire (CPFQ), Digit Symbol Substitution Test (DSST), and Cogstate testing., Results: Of the 27 women, 24 (88.8%) were evaluated (≥1 follow-up), and 21 (77.8%) completed the study; 1 discontinued because of adverse effects. The mean MADRS score decreased significantly (P = .0001) from 31.3 (standard deviation [SD] = 5.5) at pretreatment to 8.1 (SD = 7.8) at posttreatment. The depression response rate (≥50% reduction in MADRS) and remission rate (final MADRS ≤10) were 75% and 70.8%, respectively. GCS, MEN-QOL, BAI, CPFQ, and DSST scores improved significantly (P = .0030, P = .0001, P = .0001, P = .0001, and P = .0133, respectively); Cogstate test scores did not. Frequency and severity of HFs improved significantly (P = .0291 and P = .0299, respectively)., Conclusions: These data support further study of vortioxetine for treating menopausal depression and associated symptoms.

Quorum sensing (QS) is a bacterial cell-to-cell communication process that relies on the production, release, and response to extracellular signaling molecules called autoinducers. QS controls virulence and biofilm formation in the human pathogen Pseudomonas aeruginosa. P. aeruginosa possesses two canonical LuxI/R-type QS systems, LasI/R and RhlI/R, which produce and detect 3OC12-homoserine lactone and C4-homoserine lactone, respectively. Here, we use biofilm analyses, reporter assays, RNA-seq studies, and animal infection assays to show that RhlR directs both RhlI-dependent and RhlI-independent regulons. In the absence of RhlI, RhlR controls the expression of genes required for biofilm formation as well as genes encoding virulence factors. Consistent with these findings, ΔrhlR and ΔrhlI mutants have radically different biofilm phenotypes and the ΔrhlI mutant displays full virulence in animals whereas the ΔrhlR mutant is attenuated. The ΔrhlI mutant cell-free culture fluids contain an activity that stimulates RhlR-dependent gene expression. We propose a model in which RhlR responds to an alternative ligand, in addition to its canonical C4-homoserine lactone autoinducer. This alternate ligand promotes a RhlR-dependent transcriptional program in the absence of RhlI.

The complete mitochondrial genome of the western honey bee subspecies Apis mellifera lamarckii was sequenced. This mitochondrial genome is 16,589 bp in length with 37 classical eukaryotic mitochondrial genes and an A + T-rich region. Gene directions and arrangements are similar to those of other Apis mitogenomes. Seven genes begin with ATT, four with ATG, and two with ATA (none with ATC) and all genes terminate with TAA. Four genes are encoded on the heavy strand and nine are encoded on light strand. All of the 22 tRNA genes, ranging from 66 to 80 bp, have a typical cloverleaf structure. A phylogenetic tree showed that A.m. lamarckii clusters with other A. mellifera subspecies, as expected., Competing Interests: No potential conflict of interest was reported by the authors., (© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: In our previous work, we have extensively evaluated the physiochemical characteristics of Gum Arabic-encapsulated gold nanoparticles (GA-AuNPs; 15-18nm) and reported their effectiveness in stopping the tumor initiation via inhibiting the pre-neoplastic lesions in liver., Objective: The rationale of this study is to detect the efficiency of using GA-AuNPs in photothermal application as a non-invasive technique against lung tumor. We investigated the cytotoxicity of GA-AuNPs on A549 cells, and then studied their apoptotic, anti-inflammatory, lipid peroxidation and anti-neovascular effect in in vivo model using a chemically-induced lung cancer in mice. The histopathological changes due to GA-AuNPs were investigated., Results: In the presence of laser irradiation, GA-AuNPs had a considerable cytotoxicity against A549 cells. The treatment of lung tumor-bearing mice with GA-AuNPs followed by laser exposure enhanced the apoptotic pathway and this was obvious from the histopathological investigations and the elevations in cytochrome-c, death receptor 5 and the subsequent upregulation of caspase-3, we also reported a significant reduction in the levels of the inflammatory mediator TNF-α and the angiogenesis inducer VEGF. An induction of lipid peroxidation was also reported upon treatment with either GA or GA-AuNPs., Conclusion: GA-AuNPs showed no cytotoxicity in the absence of light, however the combination of GA-AuNPs with laser induced cell death in lung tumor tissues with a reduction in the inflammation and angiogenesis together with an elevation in lipid peroxidation, suggesting the potential use of these functionalized nanoparticles as a promising photothermal non-invasive treatment modality., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

This study validates the utility of Gum Arabic-conjugated gold nanoparticles (GA-AuNPs) and laser to induce photothermal inhibition of hepatocarcinogenesis, via employing a diethylnitrosamine (DEN)-mediated hepatocellular carcinoma model. This work included both of in vitro and in vivo studies; to investigate the GA-AuNPs cytotoxicity and phototoxicity in hepatic cell line; to delineate the GA-AuNPs therapeutic efficiency in DEN-induced preneoplastic lesions (PNLs) in the liver of Balb-C mice. The therapeutic effects of GA-AuNPs on the mediators of apoptosis, inflammation, and tumor initiation, as well as the histopathological changes in preneoplastic liver have been investigated. Our results infer that GA-AuNPs in combination with laser irradiation led to a significant reduction in the cell viability and in histone deacetylase activity in hepatocarcinoma HepG2 cells. In chemically-induced PNLs mice model our results have demonstrated that GA-AuNPs, with or without laser irradiation, induced cancer cell apoptosis through the activation of death receptors DR5 and caspase-3 and inhibited both of the PNLs incidence and the initiation marker (placental glutathione S-transferase; GST-P). The laser-stimulated GA-AuNPs significantly reduced the tumor necrosis factor-α levels. In summary, GA-AuNPs with laser treatment inhibited liver PNLs via the induction of the extrinsic apoptosis pathway and the inhibition of inflammation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Women of reproductive age commonly use integrative treatments. However, the reproductive safety for most complementary products lacks systematic study. We aimed to study the use of supplements by women in a prospective pregnancy registry. The Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics was established to evaluate the reproductive safety of atypical antipsychotics. Exposed and control participants were systematically queried about the use of vitamins and supplements. Slightly greater than half (53.2 %) of the participants eligible for analysis (N = 534) were using at least one vitamin or supplement at the time of enrollment, not including prenatal vitamins or folic acid. The most common supplements used were omega-3 fatty acids (38.0 %), vitamin D (11.0 %), calcium (8.2 %), and iron (4.7 %). Probiotics and melatonin were used by 2.6 and 0.9 %, respectively. In this prospective pregnancy registry, we found that over half of the participants were taking supplements or vitamins other than prenatal vitamins and folic acid. These findings underscore the need for active query on the part of health care providers about the use of supplements during pregnancy, and the need to obtain rigorous reproductive safety and efficacy data for supplements used by pregnant women and reproductive aged women.

Objective: Second-generation antipsychotics are used to treat a spectrum of psychiatric illnesses in reproductive-age women. The National Pregnancy Registry for Atypical Antipsychotics was established to determine the risk of major malformations among infants exposed to second-generation antipsychotics during pregnancy relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity., Method: Women were prospectively followed during pregnancy and the postpartum period; obstetric, labor, delivery, and pediatric medical records were obtained. Eligible enrollees were pregnant women ages 18-45. The Registry is based at the Center for Women's Mental Health at Massachusetts General Hospital. Women were recruited through provider referral, self-referral, and the Center's web site., Results: As of December 2014, 487 women were enrolled: 353 who used second-generation antipsychotics and 134 comparison women. Medical records were obtained for 82% of participants. A total of 303 women had completed the study and were eligible for inclusion in the analysis. Of 214 live births with first-trimester exposure to second-generation antipsychotics, three major malformations were confirmed. In the control group (N=89), one major malformation was confirmed. The absolute risk of major malformations was 1.4% for exposed infants and 1.1% for unexposed infants. The odds ratio for major malformations comparing exposed infants with unexposed infants was 1.25 (95% CI=0.13-12.19)., Conclusions: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety.

Human brucellosis, a zoonotic disease of major public health concern in several developing countries, is primarily caused by Brucella abortus, Brucella melitensis, and Brucella suis. No brucellosis vaccine is available for human use. The aim of this study was to determine if Brucella neotomae, a bacterium not known to cause disease in any host, can be used for developing brucellosis vaccines. B. neotomae and its recombinant strains overexpressing superoxide dismutase and a 26 kDa periplasmic protein were rendered non-replicative through exposure to gamma-radiation and used as vaccines in a murine brucellosis model. All three vaccines induced antigen-specific antibody and T cell responses. The vaccinated mice showed significant resistance against challenge with virulent B. abortus 2308, B. melitensis 16 M, and B. suis 1330. These results demonstrate that the avirulent B. neotomae is a promising platform for developing a safe and effective vaccine for human brucellosis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)