Deformity, etiology, solution, sequence (DESS): Facial analysis in rhinoplasty.

PURPOSE: Rhinoplasty is amongst the most challenging surgeries to perfect and can take decades. This process begins during residency; however, residents often have limited exposure to rhinoplasty during their training and lack a standardized method for systematically analyzing and formulating a surgical plan. The DESS (Deformity, Etiology, Solution, Sequence) is a novel educational format for residents that serves to increase their pre-operative comfort with the surgical evaluation and intraoperative planning for a rhinoplasty. MATERIALS AND METHODS: A qualitative study performed at a tertiary academic institution with an otolaryngology residency program evaluating three consecutive residency classes comprised of four residents per class. A 9-item questionnaire was distributed to measure change in resident comfort after utilizing the DESS during their facial plastics rotation. Questionnaire responses highlighted resident comfort with facial nasal analysis, identifying deformities, suggesting surgical maneuvers, and synthesizing a comprehensive surgical plan. RESULTS: Ten of the twelve residents surveyed responded. Of those that responded, comfort in facial nasal analysis, identification of common nasal deformities, surgical planning, and development of an overall surgical plan were significantly improved after completion of the facial plastic rotation. These residents largely attributed their success to the systematic educational format, with an average score of 4.8/5.0 (SD 0.42). CONCLUSION: While rhinoplasty is a challenging artform to master, systematic approaches to analysis and operative planning are vital for teaching and guiding residents. Through this novel methodology, residents display significant improvement in their comfort with facial nasal analysis and overall surgical preparation.

Alcohol Prevention in Urgent and Emergency Care (APUEC): Development and Evaluation of Workforce Digital Training on Screening, Brief Intervention, and Referral for Treatment.

Excessive alcohol consumption carries a significant health, social and economic burden. Screening, brief intervention and referral to treatment (SBIRT) is one approach to identifying patients with excessive alcohol consumption and providing interventions to help them reduce their drinking. However, healthcare workers in urgent and emergency care settings do not routinely integrate SBIRT into clinical practice and raise a lack of training as a barrier to SBIRT delivery. Therefore, "Alcohol Prevention in Urgent and Emergency Care" (APUEC) training was developed, delivered, and evaluated. APUEC is a brief, stand-alone, multimedia, interactive digital training package for healthcare workers. The aim of APUEC is to increase positive attitudes, knowledge, confidence and skills related to SBIRT through the provision of (a) education on the impact of alcohol and the role of urgent and emergency care in alcohol prevention, and (b) practical guidance on patient assessment, delivery of brief advice and making referral decisions. Development involved collaborative-participatory design approaches and a rigorous six-step ASPIRE methodology (involving n = 28 contributors). APUEC was delivered to healthcare workers who completed an online survey (n = 18) and then participated in individual qualitative interviews (n = 15). Analysis of data was aligned with Levels 1-3 of the Kirkpatrick Model of Training Evaluation. Survey data showed that all participants (100%) found the training useful and would recommend it to others. Insights from the qualitative data showed that APUEC digital training increases healthcare workers' perceived knowledge, confidence and skills related to alcohol prevention in urgent and emergency care settings. Participants viewed APUEC to be engaging and relevant to urgent and emergency care workers. This digital training was perceived to be useful for workforce skills development and supporting the implementation of SBIRT in clinical practice. While the impact of APUEC on clinician behaviour and patient outcomes is yet to be tested, APUEC digital training could easily be embedded within education and continuing professional development programmes for healthcare workers and healthcare trainees of any discipline. Ultimately, this may facilitate the integration of SBIRT into routine care and contribute to population health improvement.

Attitudes and current practice in alcohol screening, brief intervention, and referral for treatment among staff working in urgent and emergency settings: An open, cross-sectional international survey.

BACKGROUND: The aim of the study was to ascertain the views and experiences of those working in urgent and emergency care (UEC) settings towards screening, brief intervention, and referral to treatment (SBIRT) for alcohol, to inform future practice. OBJECTIVES: To explore i) views towards health promotion, ii) views towards and practice of SBIRT, iii) facilitators and barriers to delivering SBIRT, iv) training needs to support future SBIRT practice, and v) comparisons in views and attitudes between demographic characteristics, geographical regions, setting and occupational groups. METHODS: This was an open cross-sectional international survey, using an online self-administered questionnaire with closed and open-ended responses. Participants were ≥18 years of age, from any occupational group, working in urgent and emergency care (UEC) settings in any country or region. RESULTS: There were 362 respondents (aged 21-65 years, 87.8% shift workers) from 7 occupational groups including physicians (48.6%), nurses (22.4%) and advanced clinical practitioners (18.5%). Most believed that health promotion is part of their role, and that SBIRT for alcohol prevention is needed and appropriate in UEC settings. SBIRT was seen to be acceptable to patients. 66% currently provide brief alcohol advice, but fewer screen for alcohol problems or make alcohol-related referrals. The most common barriers were high workload and lack of funding for prevention, lack of knowledge and training on SBIRT, lack of access to high-quality resources, lack of timely referral pathways, and concerns about patient resistance to advice. Some views and attitudes varied according to demographic characteristics, occupation, setting or region. CONCLUSIONS: UEC workers are willing to engage in SBIRT for alcohol prevention but there are challenges to implementation in UEC environments and concerns about workload impacts on already-burdened staff, particularly in the context of global workforce shortages. UEC workers advocate for clear guidelines and policies, increased staff capacity and/or dedicated health promotion teams onsite, SBIRT education/training/resources, appropriate physical spaces for SBIRT conversations and improved alcohol referral pathways to better funded services. Implementation of SBIRT could contribute to improving population health and reducing service demand, but it requires significant and sustained commitment of time and resources for prevention across healthcare organisations.

RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic cancer subtype, which is generally untreatable once it metastasizes. We hypothesized that interfering with the Receptor for Advanced Glycation End-products (RAGE) signaling with the small molecule RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1) would impair TNBC metastasis and impair fundamental mechanisms underlying tumor progression and metastasis. Both TTP488 and FPS-ZM1 impaired spontaneous and experimental metastasis of TNBC models, with TTP488 reducing metastasis to a greater degree than FPS-ZM1. Transcriptomic analysis of primary xenograft tumor and metastatic tissue revealed high concordance in gene and protein changes with both drugs, with TTP488 showing greater potency against metastatic driver pathways. Phenotypic validation of transcriptomic analysis by functional cell assays revealed that RAGE inhibition impaired TNBC cell adhesion to multiple extracellular matrix proteins (including collagens, laminins, and fibronectin), migration, and invasion. Neither RAGE inhibitor impaired cellular viability, proliferation, or cell cycle in vitro. Proteomic analysis of serum from tumor-bearing mice revealed RAGE inhibition affected metastatic driver mechanisms, including multiple cytokines and growth factors. Further mechanistic studies by phospho-proteomic analysis of tumors revealed RAGE inhibition led to decreased signaling through critical BC metastatic driver mechanisms, including Pyk2, STAT3, and Akt. These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis. Importantly, as TTP488 displays a favorable safety profile in human studies, our study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic TNBC.

Microneedle electrochemical aptamer-based sensing: Real-time small molecule measurements using sensor-embedded, commercially-available stainless steel microneedles.

Microneedle sensors could enable minimally-invasive, continuous molecular monitoring - informing on disease status and treatment in real-time. Wearable sensors for pharmaceuticals, for example, would create opportunities for treatments personalized to individual pharmacokinetics. Here, we demonstrate a commercial-off-the-shelf (COTS) approach for microneedle sensing using an electrochemical aptamer-based sensor that detects the high-toxicity antibiotic, vancomycin. Wearable monitoring of vancomycin could improve patient care by allowing targeted drug dosing within its narrow clinical window of safety and efficacy. To produce sensors, we miniaturize the electrochemical aptamer-based sensors to a microelectrode format, and embed them within stainless steel microneedles (sourced from commercial insulin pen needles). The microneedle sensors achieve quantitative measurements in body-temperature undiluted blood. Further, the sensors effectively maintain electrochemical signal within porcine skin. This COTS approach requires no cleanroom fabrication or specialized equipment, and produces individually-addressable, sterilizable microneedle sensors capable of easily penetrating the skin. In the future, this approach could be adapted for multiplexed detection, enabling real-time monitoring of a range of biomarkers.

Projecting the impact of an ebola virus outbreak on endangered mountain gorillas.

Ebola virus is highly lethal for great apes. Estimated mortality rates up to 98% have reduced the global gorilla population by approximately one-third. As mountain gorillas (Gorilla beringei beringei) are endangered, with just over 1000 individuals remaining in the world, an outbreak could decimate the population. Simulation modeling was used to evaluate the potential impact of an Ebola virus outbreak on the mountain gorilla population of the Virunga Massif. Findings indicate that estimated contact rates among gorilla groups are high enough to allow rapid spread of Ebola, with less than 20% of the population projected to survive at 100 days post-infection of just one gorilla. Despite increasing survival with vaccination, no modeled vaccination strategy prevented widespread infection. However, the model projected that survival rates greater than 50% could be achieved by vaccinating at least half the habituated gorillas within 3 weeks of the first infectious individual.

Effectiveness and implementation of interventions for health promotion in urgent and emergency care settings: an umbrella review.

BACKGROUND: Urgent and emergency care (UEC) settings provide an opportunity to prevent ill-health and promote healthy lifestyles with potential to screen and deliver interventions to under-served, at-risk populations. The aim of this study was to synthesise and summarise the evidence on the effectiveness and implementation of interventions for health promotion in UEC settings. METHODS: PubMed and Embase (OVID) databases were used to search for studies published in English between January 2010 and January 2023. Systematic reviews and meta-analyses of studies that examined the effectiveness or implementation of face-to-face health promotion interventions for lifestyle behaviours delivered in UEC settings were eligible. Extracted data were synthesised and qualitatively summarised by lifestyle behaviour. Reviews were quality assessed using AMSTAR 2. RESULTS: Eighteen reviews met the inclusion criteria; all included studies were conducted in emergency departments or trauma units. We identified 15 reviews on alcohol interventions (13 on effectiveness; 2 on implementation) and 3 on smoking interventions (effectiveness). There were no reviews of intervention studies targeting physical activity or diet and nutrition. There was heterogeneity across studies for study design, target populations, intervention design and content, comparator/control groups and outcomes assessed. The effectiveness of alcohol and smoking interventions in UEC settings varied but some reviews provided evidence of a significant decrease in alcohol consumption, alcohol-related outcomes and smoking in intervention groups, particularly in the short-term and in specific population groups. Research has focused on 'brief' interventions as part of screening, brief intervention and referral to treatment (SBIRT) approaches. Interventions are delivered by a wide range of staff with substantial variation in design. Alcohol brief interventions appear to be acceptable to UEC patients but clinicians face barriers in delivering them. CONCLUSIONS: UEC settings have been under-researched and appear to be under-utilised for delivering health promotion activities, except for alcohol prevention. Review level evidence suggests alcohol and smoking interventions are warranted in some population groups. However, further research is needed to determine the optimal intervention design, content and delivery mode for lifestyle behaviours which are suitable for implementation in UEC settings and promote long-term intervention effectiveness. Changes in clinical practice may be needed, including increased training, integration into service delivery and supportive policy, to facilitate the implementation of SBIRT for lifestyle behaviours. Interventions may need to be delivered in the wider UEC system such as urgent care centres, minor injury units and walk-in centres, in addition to emergency departments and trauma units, to support and increase health promotion activities in UEC settings.

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability.

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C-C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent's rule rendering the Giese addition irreversible.

A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults.

INTRODUCTION: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. METHODS: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. RESULTS: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F 3, 44  = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F 1, 14  = 0.02, p = 0.88), Dimensional-change-card-sort scores F 1, 14  = 0.25, p = 0.63, and working memory scores (F 1, 14  = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14  = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F 1, 14  = 0, p = 0.98). CONCLUSION: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement.

Synthesis and anti-microbial activity of a new series of bis(diphosphine) rhenium(V) dioxo complexes.

Rhenium-based metallodrugs have recently been highlighted as promising candidates for new antibiotics to combat multi-drug resistant (MDR) pathogens. A new class of rhenium(V) dioxo complexes were prepared from readily accessible diphosphine ligands, and have been shown to possess potent activity against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) alongside low human cell toxicity.

N-Centered Tripodal Phosphine Re(V) and Tc(V) Oxo Complexes: Revisiting a [3 + 2] Mixed-Ligand Approach.

N-Triphos derivatives (NP3R, R = alkyl, aryl) and asymmetric variants (NP2RXR', R' = alkyl, aryl, X = OH, NR2, NRR') are an underexplored class of tuneable, tripodal ligands in relation to the coordination chemistry of Re and Tc for biomedical applications. Mixed-ligand approaches are a flexible synthetic route to obtain Tc complexes of differing core structures and physicochemical properties. Reaction of the NP3Ph ligand with the Re(V) oxo precursor [ReOCl3(PPh3)2] generated the bidentate complex [ReOCl3(κ2-NP2PhOHAr)], which possesses an unusual AA'BB'XX' spin system with a characteristic second-order NMR lineshape that is sensitive to the bi- or tridentate nature of the coordinating diphosphine unit. The use of the asymmetric NP2PhOHAr ligand resulted in the formation of both bidentate and tridentate products depending on the presence of base. The tridentate Re(V) complex [ReOCl2(κ3-NP2PhOAr)] has provided the basis of a new reactive "metal-fragment" for further functionalization in [3 + 2] mixed-ligand complexes. The synthesis of [3 + 2] complexes with catechol-based π-donors could also be achieved under one-pot, single-step conditions from Re(V) oxo precursors. Analogous complexes can also be synthesized from suitable 99Tc(V) precursors, and these complexes have been shown to exhibit highly similar structural properties through spectroscopic and chromatographic analysis. However, a tendency for the {MVO}3+ core to undergo hydrolysis to the {MVO2}+ core has been observed both in the case of M = Re and markedly for M = 99Tc complexes. It is likely that controlling this pathway will be critical to the generation of further stable Tc(V) derivatives.

Synthesis of carbon-11 radiolabelled transition metal complexes using 11C-dithiocarbamates.

A novel radiolabelling method exploiting 11C-dithiocarbamate ligands has been used to generate 11C-labelled Au(I), Au(III), Pd(II) and Pt(II) complexes in high radiochemical yields (71-99%). Labelled complexes were prepared in a rapid one-pot procedure via the substitution reaction of 11C-dithiocarbamate ligands with appropriate transition metal chloride precursors.

Guidance for management of free-roaming community cats: a bioeconomic analysis.

OBJECTIVES: This study used computer simulation modeling to estimate and compare costs of different free-roaming cat (FRC) management options (lethal and non-lethal removal, trap-neuter-return, combinations of these options and no action) and their ability to reduce FRC population abundance in open demographic settings. The findings provide a resource for selecting management approaches that are well matched for specific communities, goals and timelines, and they represent use of best available science to address FRC issues. METHODS: Multiple FRC management approaches were simulated at varying intensities using a stochastic individual-based model in the software package Vortex. Itemized costs were obtained from published literature and expert feedback. Metrics generated to evaluate and compare management scenarios included final population size, total cost and a cost efficiency index, which was the ratio between total cost and population size reduction. RESULTS: Simulations suggested that cost-effective reduction of FRC numbers required sufficient management intensity, regardless of management approach, and greatly improved when cat abandonment was minimized. Removal yielded the fastest initial reduction in cat abundance, but trap-neuter-return was a viable and potentially more cost-effective approach if performed at higher intensities over a sufficient duration. Of five management scenarios that reduced the final population size by approximately 45%, the three scenarios that relied exclusively on removal were considerably more expensive than the two scenarios that relied exclusively or primarily on sterilization. CONCLUSIONS AND RELEVANCE: FRCs present a challenge in many municipalities, and stakeholders representing different perspectives may promote varying and sometimes incompatible population management policies and strategies. Although scientific research is often used to identify FRC impacts, its use to identify viable, cost-effective management solutions has been inadequate. The data provided by simulating different interventions, combined with community-specific goals, priorities and ethics, provide a framework for better-informed FRC policy and management outcomes.

Correction of the Nasal Ala.

The alar-columellar relationship is an important concept for the rhinoplasty surgeon to master. The alar rim in particular is a critical component of the nasal tip, contributing to both overall symmetry and proportion of the nasal base. The retracted ala creates a displeasing aesthetic to the tip complex, distorts the nostril openings, and may have functional implications of the external nasal valve. While alar retraction can occur naturally or as the result of trauma, the majority of cases are post-surgical in nature. Many techniques have been described for correction of alar retraction, most of which require open rhinoplasty and many fail to add the soft tissue within the vestibule necessary to properly lower the alar margin. Herein, we present our experience with the auricular chondrocutaneous composite graft-a simple, reliable, and effective technique to correct moderate to severe alar retraction via either open or endonasal rhinoplasty.

Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are recruited to the tumor microenvironment (TME) and are critical drivers of breast cancer (BC) malignancy. Circulating tumor cells (CTCs) travel through hematogenous routes to establish metastases. CTCs circulate both individually and, more rarely, in clusters with other cell types. Clusters of CTCs have higher metastatic potential than single CTCs. Previously, we identified circulating CAFs (cCAFs) in patients with BC and found that while healthy donors had no CTCs or cCAFs, both were present in most Stage IV patients. cCAFs circulate individually, as cCAF-cCAF homotypic clusters, and in heterotypic clusters with CTCs. METHODS: In this study, we evaluate CTCs, cCAFs, and heterotypic cCAF-CTC clusters in patients with stage I-IV BC. We evaluate the association of heterotypic clusters with BC disease progression and metastasis in a spontaneous mouse model. Using previously established primary BC and CAF cell lines, we examine the metastatic propensity of heterotypic cCAF-CTC clusters in orthotopic and tail vein xenograft mouse models of BC. Using an in vitro clustering assay, we determine factors that may be involved in clustering between CAF and BC cells. RESULTS: We report that the dissemination of CTCs, cCAFs, and clusters is an early event in BC progression, and we find these clusters in all clinical stages of BC. Furthermore, cCAFs-CTC heterotypic clusters have a higher metastatic potential than homotypic CTC clusters in vivo. We also demonstrate that the adhesion and stemness marker CD44, found on a subset of CTCs and CAF cells, is  involved in heterotypic clustering of these cells. CONCLUSION: We identify a novel subset of circulating tumor cell clusters that are enriched with stromal CAF cells in BC patient blood and preclinical mouse models of BC metastasis. Our data suggest that clustering of CTCs with cCAFs augments their metastatic potential and that CD44 might be an important mediator of heterotypic clustering of cCAFs and BC cells.

On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes.

Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined formats for reporting data, the current reporting of DSC results for thermal hazard assessment has shown concerning trends. Around half of all results in 2019 did not include experimental details required to replicate the procedure. Furthermore, analysis for thermal hazard assessment is often only conducted in unsealed crucibles, which could lead to misleading results and dangerously incorrect conclusions. We highlight the specific issues with DSC analysis of hazardous compounds currently in the organic chemistry literature and provide simple "best practice" guidelines which will give chemists confidence in reported DSC results and the conclusions drawn from them.

Thermal Stability and Explosive Hazard Assessment of Diazo Compounds and Diazo Transfer Reagents.

Despite their wide use in academia as metal-carbene precursors, diazo compounds are often avoided in industry owing to concerns over their instability, exothermic decomposition, and potential explosive behavior. The stability of sulfonyl azides and other diazo transfer reagents is relatively well understood, but there is little reliable data available for diazo compounds. This work first collates available sensitivity and thermal analysis data for diazo transfer reagents and diazo compounds to act as an accessible reference resource. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and accelerating rate calorimetry (ARC) data for the model donor/acceptor diazo compound ethyl (phenyl)diazoacetate are presented. We also present a rigorous DSC dataset with 43 other diazo compounds, enabling direct comparison to other energetic materials to provide a clear reference work to the academic and industrial chemistry communities. Interestingly, there is a wide range of onset temperatures (T onset) for this series of compounds, which varied between 75 and 160 °C. The thermal stability variation depends on the electronic effect of substituents and the amount of charge delocalization. A statistical model is demonstrated to predict the thermal stability of differently substituted phenyl diazoacetates. A maximum recommended process temperature (T D24) to avoid decomposition is estimated for selected diazo compounds. The average enthalpy of decomposition (ΔH D) for diazo compounds without other energetic functional groups is -102 kJ mol-1. Several diazo transfer reagents are analyzed using the same DSC protocol and found to have higher thermal stability, which is in general agreement with the reported values. For sulfonyl azide reagents, an average ΔH D of -201 kJ mol-1 is observed. High-quality thermal data from ARC experiments shows the initiation of decomposition for ethyl (phenyl)diazoacetate to be 60 °C, compared to that of 100 °C for the common diazo transfer reagent p-acetamidobenzenesulfonyl azide (p-ABSA). The Yoshida correlation is applied to DSC data for each diazo compound to provide an indication of both their impact sensitivity (IS) and explosivity. As a neat substance, none of the diazo compounds tested are predicted to be explosive, but many (particularly donor/acceptor diazo compounds) are predicted to be impact-sensitive. It is therefore recommended that manipulation, agitation, and other processing of neat diazo compounds are conducted with due care to avoid impacts, particularly in large quantities. The full dataset is presented to inform chemists of the nature and magnitude of hazards when using diazo compounds and diazo transfer reagents. Given the demonstrated potential for rapid heat generation and gas evolution, adequate temperature control and cautious addition of reagents that begin a reaction are strongly recommended when conducting reactions with diazo compounds.

Paget's disease of the nipple in a Her2-positive breast cancer xenograft model.

PURPOSE: Paget's disease (PD) of the breast is an uncommon disease of the nipple usually accompanied by an underlying carcinoma, often HER2 + , and accounting for 0.5-5% of all breast cancer. To date, histogenesis of PD of the breast remains controversial, as two theories-transformation and epidermotropic-have been proposed to explain this disease. Currently, animal models recapitulating PD of the nipple have not been described. METHODS: HER2-enriched DT13 breast cancer cells were injected into the mammary fat pad of NOD scid gamma null (NSG) female mice. Immunohistochemical staining and pathological studies were performed on tumor samples, and diagnosis of PD of the nipple was confirmed by expression of proteins characteristic of Paget cells (epidermal growth factor 2 (HER2), androgen receptor (AR), cytokeratin 7 (CK7), cytokeratin 8/18 (CK8/18), and mucin 1 (MUC1)). In addition, DT13 cells grown in 2D culture and in soft agar assays were sensitive to in vitro treatment with pharmacological inhibitors targeting Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. RESULTS: Mice developed tumors and nipple lesions that were detected exclusively on the tumor-bearing mammary fat pad. Tumor cells were positive for proteins characteristic of Paget cells. In vitro, DT13 cells were sensitive to inhibition of Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. CONCLUSIONS: Our results suggest that injection of HER2 + DT13 cells into the mammary fat pad of NSG mice recapitulates critical aspects of the pathophysiology of PD of the nipple, supporting the epidermotropic theory as the more likely to explain the histogenesis of this disease.

Breeding Centers, Private Ranches, and Genomics for Creating Sustainable Wildlife Populations.

Human-induced changes to environments are causing species declines. Beyond preserving habitat (in situ), insurance (ex situ) populations are essential to prevent species extinctions. The Conservation Centers for Species Survival (C2S2) is leveraging space of breeding centers and private ranches to produce "source populations"-genetically diverse reservoirs that also support research and reintroductions. The initial focus is on four African antelopes. C2S2 has developed a program, the Source Population Alliance, that emphasizes animals living in spacious, naturalistic conditions in greater numbers than can be accommodated by urban zoos. Simulation modeling demonstrates how herds can rapidly increase population abundance and retain genetic diversity. Advances in genomics and resulting DNA data allow monitoring of genetic diversity and parentage as well as refined decision-making. This approach, neither pure in situ nor ex situ, but rather "sorta situ", is an innovative way of linking public and private sector resources to ensure that endangered species survive.

Management of Lip Complications.

This article discusses complications that may occur after procedures on the lips, specifically focusing on injectable fillers. Evidence-based guidelines and suggested methods to manage these complications are presented in a systematic format.