A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

Syngeneic murine models with distinct immune microenvironments represent subsets of human intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a poorly immunogenic malignancy associated with limited survival. Syngeneic immunocompetent mouse models of CCA are an essential tool to elucidate the tumor immune microenvironment (TIME), understand mechanisms of tumor immune evasion, and test novel immunotherapeutic strategies. The scope of this study was to develop and characterize immunocompetent CCA models with distinct genetic drivers, and correlate tumor genomics, immunobiology, and therapeutic response. METHODS: A multifaceted approach including scRNA-seq, CITE-seq, whole exome and bulk RNA sequencing was employed. FDA-approved PD-1/PD-L1 antibodies were tested in humanized PD-1/PD-L1 mice (HuPD-H1). RESULTS: A genetic mouse model of intrahepatic CCA (iCCA) driven by intrabiliary transduction of Fbxw7ΔF/Akt that mimics human iCCA was generated. From the Fbxw7ΔF/Akt tumors, a murine cell line (FAC) and syngeneic model with genetic and phenotypic characteristics of human iCCA were developed. Established SB1 (YAPS127A/Akt) and KPPC (KrasG12Dp53L/L) models were compared to the FAC model. Although the models had transcriptomic similarities, they had substantial differences as well. Mutation patterns of FAC, SB1, and KPPC cells matched different mutational signatures in Western and Japanese CCA patient cohorts. KPPC tumors had a high tumor mutation burden. FAC tumors had a T cell-infiltrated TIME, while SB1 tumors had a preponderance of suppressive myeloid cells. FAC, SB1, and KPPC tumors matched different immune signatures in human iCCA cohorts. Moreover, FAC, SB1, and KPPC tumor-bearing HuPD-H1 mice displayed differential responses to nivolumab or durvalumab. CONCLUSIONS: Syngeneic iCCA models display a correlation between tumor genotype and TIME phenotype, with differential responses to FDA-approved immunotherapies. This study underscores the importance of leveraging multiple preclinical models to understand responses to immunotherapy in different genetic subsets of human CCA. IMPACT AND IMPLICATIONS: Understanding the relationship between tumor genotype and the phenotype of the immune microenvironment is an unmet need in cholangiocarcinoma (CCA). Herein, we use syngeneic murine models of intrahepatic CCA with different genetic drivers to demonstrate a correlation between tumor genotype and immune microenvironment phenotype in murine models, which is associated with differential responses to FDA-approved immunotherapies. This information will help guide other preclinical studies. Additionally, it emphasizes that immune checkpoint inhibition in patients with CCA is not a "one-size-fits-all" approach. Our observations suggest that, as for targeted therapies, patients should be stratified and selected for treatment according to their tumor genetics.

Baseline Characteristics and Utility of Pretherapeutic Fluorodeoxyglucose-PET for Pancreatic Cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection is the only curative modality combined with neoadjuvant chemotherapy to improve survival. Given the limitations of traditional responses like cross-sectional imaging (CT/MRI) or tumor markers, carbohydrate antigen 19-9 (CA19-9), the 2023 National Comprehensive Cancer Network (NCCN) guidelines included fluorodeoxyglucose-positron emission tomography (FDG-PET) as an adjunct to assess response to neoadjuvant chemotherapy. There are common misconceptions on the metabolic activity (tumor avidity) in PDAC, so we aimed to describe the baseline characteristics and utility of FDG-PET in a cohort of treatment naïve PDAC patients. METHODS: A single center retrospective study was conducted capturing all biopsy proven, treatment naïve PDAC patients that underwent either baseline FDG-PET/CT or FDG-PET/MRI imaging between (2008-2023). Baseline FDG-PET characteristics were collected, including primary tumors' maximum standardized uptake value (SUVmax) defined as metabolic activity (FDG uptake) of tumor compared to surrounding pancreatic parenchymal background, and the identification of extra-pancreatic metastatic disease. RESULTS: We identified 1095 treatment naïve PDAC patients that underwent baseline FDG-PET imaging at diagnosis. CA19-9 was elevated in 76% of patients. Overall, 96.3% (n=1054) of patients had FDG-avid tumors with a median SUVmax of 6.4. FDG-PET also identified suspicious extrapancreatic metastatic lesions in 50% of patients, with a higher proportion (p < 0.001) in PET/MRI (59.9%) vs. PET/CT (44.3%). After controlling for CA19-9 elevation, PET/MRI was superior in detection of extrapancreatic lesions compared to PET/CT. CONCLUSION: FDG-PET has significant utility in PDAC as a baseline imaging modality prior neoadjuvant therapy given the majority of tumors are FDG avid. Furthermore, FDG-PET can identify additional extrapancreatic suspicious lesions allowing for optimal initial staging, with PET/MRI having increased sensitivity over PET/CT.

Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Growth in Cholangiocarcinoma.

BACKGROUND & AIMS: Proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in human beings, challenging the concept of TRAIL as a potent anticancer agent. Herein, we aimed to define mechanisms by which TRAIL+ cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA). METHODS: Multiple immunocompetent syngeneic, orthotopic models of CCA were used. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of CD45+ cells in murine tumors from the different CCA models was conducted. RESULTS: In multiple immunocompetent murine models of CCA, implantation of TRAIL+ murine cancer cells into Trail-r-/- mice resulted in a significant reduction in tumor volumes compared with wild-type mice. Tumor-bearing Trail-r-/- mice had a significant decrease in the abundance of MDSCs owing to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent nuclear factor-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of immune cells from murine tumors showed enrichment of a nuclear factor-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis owing to enhanced expression of cellular FLICE inhibitory protein, an inhibitor of proapoptotic TRAIL signaling. Accordingly, cellular FLICE inhibitory protein knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell-restricted deletion of Trail significantly reduced MDSC abundance and murine tumor burden. CONCLUSIONS: Our findings highlight the therapeutic potential of targeting TRAIL+ cancer cells for treatment of a poorly immunogenic cancer.

Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Progression in Cholangiocarcinoma.

Proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in humans, challenging the concept of TRAIL as a potent anticancer agent. Herein, we demonstrate that TRAIL + cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA). In multiple immunocompetent syngeneic, orthotopic murine models of CCA, implantation of TRAIL + murine cancer cells into Trail-r -/- mice resulted in a significant reduction in tumor volumes compared to wild type mice. Tumor bearing Trail-r -/- mice had a significant decrease in the abundance of MDSCs due to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent NF-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of CD45 + cells in murine tumors from three distinct immunocompetent CCA models demonstrated a significant enrichment of an NF-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis due to enhanced expression of cellular FLICE inhibitory protein (cFLIP), an inhibitor of proapoptotic TRAIL signaling. Accordingly, cFLIP knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell-restricted deletion of Trail significantly reduced MDSC abundance and murine tumor burden. In summary, our findings define a noncanonical TRAIL signal in MDSCs and highlight the therapeutic potential of targeting TRAIL + cancer cells for the treatment of a poorly immunogenic cancer.

Immunobiology of cholangiocarcinoma.

Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of the immune landscape has defined new patient subtypes. While not utilised in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumour-associated macrophages and myeloid-derived suppressor cells, form a barrier that shields tumour cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumour cells leads to poor tumour immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumour antigens. While immunotherapeutic strategies are gaining traction for the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.

LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma.

BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.

SHP2 inhibition enhances Yes-associated protein-mediated liver regeneration in murine partial hepatectomy models.

Disrupted liver regeneration following hepatectomy represents an "undruggable" clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.

Social participation and marital satisfaction in mid to late life marriage.

Objectives: Research shows that social participation is beneficial for overall health and well-being. Yet, no research to our knowledge has examined whether social participation is associated with greater marital satisfaction in middle-aged and older couples. We hypothesized that middle-aged and older adults would have greater marital satisfaction when their spouse engaged in social groups because there would be greater opportunity for self-expansion and for social support from ties outside the marriage. Methods: We used background self-report data from a multi-method study of 98 middle-aged and older adult married couples (N = 196) with chronic conditions. As part of the study, spouses completed questionnaires that measured the frequency and intensity of involvement in social groups (e.g., church, business groups). Marital satisfaction was measured with the Locke Wallace Marital Adjustment Test. Results: Contrary to our hypotheses, results from actor-partner interdependence models provided no evidence that one's own social participation was associated with one's own marital satisfaction (actor effects). However, in line with our hypotheses regarding partner effects, one spouse's (a) report of any social participation with church organizations, business groups, or social groups, (b) greater number of affiliations with different organizations, (c) greater frequency of participation, and (d) being an active officer in a social organization were significantly associated with the other spouse's greater marital satisfaction. Discussion: Findings of this study suggest that having a spouse who participates in social groups is good for relationship satisfaction in mid to late life marriage.

Physiological correlates of support for self-expansion and links to goal pursuit in retirement.

Partner support for self-expansion has been associated with long-term health and retirement satisfaction, yet the underlying physiological correlates are unknown. We predicted that partner support for self-expansion would be associated with short-term physiology and behavior as well as long-term goal pursuit. And 100 couples with at least one retiree within 2 years of retirement visited the laboratory and had a discussion of the retirees' future goals for retirement. We recorded behaviors and physiological responses during the discussion, assessed immediate feelings of capability afterwards, and then assessed goal pursuit one year later. Laboratory results indicated that partner support for self-expansion was linked to increased stroke volume reactivity in the support-recipient (suggesting a greater challenge response), which in turn predicted greater feelings of capability of accomplishing the goal, particularly for males. In addition, decreases in the support-provider's pre-ejection period reactivity (greater sympathetic arousal) during the discussion were associated with greater partner support for self-expansion in the lab, suggesting that support providers offer greater levels of support when they exhibit greater physiological signs of task engagement. Longitudinal follow-up results indicated that immediate feelings of capability of accomplishing the goal following a discussion about that goal predicted goal pursuit 1 year later. This research leverages a dyadic design and a multi-method approach (involving physiology, observed behavior, and perceptions) to show that couple members' physiology during goal discussions has long-term implications for a support-recipient's ability to accomplish goals.

Outcomes of pancreatectomy with portomesenteric venous resection and reconstruction for locally advanced pancreatic neuroendocrine neoplasms.

BACKGROUND: While pancreatectomy with portomesenteric venous resection and reconstruction is commonly performed for locally advanced pancreatic adenocarcinoma, little is known regarding outcomes for pancreatic neuroendocrine neoplasms (panNENs). METHODS: Patients who underwent non-parenchyma-sparing pancreatectomy for panNENs at Mayo Clinic from 2000 to 2020 were retrospectively reviewed. Propensity score matching was performed and patient characteristics and outcomes compared. RESULTS: Of 867 eligible patients, 41 (4.7%) required vascular resection, including 38 patients who underwent portomesenteric venous resection only. Of these, 23 underwent pancreaticoduodenectomy or total pancreatectomy and 15 distal pancreatectomy. Patients who required portomesenteric venous resection had larger tumors, higher tumor grade, and higher disease stage. After propensity score matching to patients undergoing standard resection, the portomesenteric venous resection group had longer operative times, greater blood loss, and higher transfusion rates. While portomesenteric venous thrombosis was more common after venous resection, major complication rates and perioperative mortality were similar between the two groups, as were 5-year overall and progression-free survival. CONCLUSION: For patients with locally advanced panNENs, pancreatectomy with portomesenteric venous resection and reconstruction can be performed in selected patients at high-volume centers with acceptable perioperative morbidity and short- and long-term survival.

Laughter and short-term blood pressure reactivity in middle-aged and older adult spousal support interactions.

OBJECTIVE: Theories suggest that laughter decreases negative affect and enhances social bonds; however, no studies have examined the benefits of laughter on stress biomarkers in dyads. This study examined the hypotheses that individual and shared laughter would be associated with lower blood pressure reactivity and decreased self-reported and perceived partner distress for the target and spouse in a social support interaction. METHOD: One hundred seventy-three middle-aged and older adult couples from a larger study were video-recorded, and their blood pressure was monitored continuously in the laboratory during a resting baseline, during a social support interaction in which they discussed a target's fear related to aging, and while playing a game (used as a comparison). Both partners self-reported their own and perceived partner distress after the support interaction. Laughter behavior was coded using the Facial Action Coding System criteria. RESULTS: According to Actor Partner Interdependence Models, during the support interaction, the more the target laughed, the lower the spouse's systolic blood pressure was (partner effect). Also, greater laughter was associated with less self-reported and perceived partner distress for targets and spouses (actor effects). There were no other significant associations between individual laughter, shared laughter, systolic or diastolic blood pressure, and distress. Models controlled for gender, marital satisfaction, baseline blood pressure, and the target's baseline distress rating of their fear. CONCLUSIONS: In social support interactions, targets' laughter may have short-term blood pressure benefits for caregiving spouses and distress reducing benefits for both spouses. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and syndromic treatment of men with urethral discharge in Kingston, Jamaica, 2018-19.

OBJECTIVES: To quantitatively determine the antimicrobial susceptibility of clinical Neisseria gonorrhoeae isolates from men with urethral discharge in Jamaica and to describe the syndromic treatment therapies administered. METHODS: Urethral eSwabs (Copan) were collected from 175 men presenting with urethral discharge to the Comprehensive Health Centre STI Clinic, Kingston, Jamaica. Clinical information was collected and MICs of eight antimicrobials were determined for N. gonorrhoeae isolates (n = 96) using Etest and interpreted using CLSI criteria. RESULTS: The median age of the subjects was 28 years (range: 18-73 years) with a median of 2 sexual partners (range: 1-25) per male in the previous 3 months. All examined N. gonorrhoeae isolates were susceptible to ceftriaxone (96/96), azithromycin (91/91), cefixime (91/91) and spectinomycin (91/91). For ciprofloxacin and gentamicin, respectively, 98.9% (91/92) and 91.3% (84/92) of the isolates were susceptible and 1.1% (1/92) and 8.7% (8/92) showed intermediate susceptibility/resistance. For tetracycline and benzylpenicillin, respectively, 38.0% (35/92) and 22.0% (20/91) of the isolates were susceptible, 52.2% (48/92) and 74.7% (68/91) showed intermediate susceptibility/resistance and 9.8% (9/92) and 3.3% (3/91) were resistant. Syndromic treatment was administered as follows: 93.1% received 250 mg of ceftriaxone intramuscularly plus 100 mg of doxycycline orally q12h for 1-2 weeks and 6.9% received 500 mg of ciprofloxacin orally plus 100 mg of doxycycline orally q12h for 1 week. CONCLUSIONS: Ceftriaxone (250 mg) remains appropriate for gonorrhoea treatment in the examined population of men in Kingston, Jamaica. Surveillance of N. gonorrhoeae AMR should be expanded in Jamaica and other Caribbean countries to guide evidence-based treatment guidelines.

Fusidic acid resistance through changes in the dynamics of the drug target.

Antibiotic resistance in clinically important bacteria can be mediated by target protection mechanisms, whereby a protein binds to the drug target and protects it from the inhibitory effects of the antibiotic. The most prevalent source of clinical resistance to the antibiotic fusidic acid (FA) is expression of the FusB family of proteins that bind to the drug target (Elongation factor G [EF-G]) and promote dissociation of EF-G from FA-stalled ribosome complexes. FusB binding causes changes in both the structure and conformational flexibility of EF-G, but which of these changes drives FA resistance was not understood. We present here detailed characterization of changes in the conformational flexibility of EF-G in response to FusB binding and show that these changes are responsible for conferring FA resistance. Binding of FusB to EF-G causes a significant change in the dynamics of domain III of EF-GC3 that leads to an increase in a minor, more disordered state of EF-G domain III. This is sufficient to overcome the steric block of transmission of conformational changes within EF-G by which FA prevents release of EF-G from the ribosome. This study has identified an antibiotic resistance mechanism mediated by allosteric effects on the dynamics of the drug target.

Growing into retirement: Longitudinal evidence for the importance of partner support for self-expansion.

Retirement can be a turbulent time of life in which people must navigate changes in their identity from ending a career and beginning a new phase of life. However, retirement can also provide opportunities for growth or self-expansion. We examined the benefits of partner support for self-expansion by using longitudinal evidence (at 3 time points) in a sample of 73 couples. We tested a theoretical model proposing that partner support for self-expansion at Time 1 would predict retirement satisfaction and overall health 1 year later and that these effects would be mediated by self-expansion at 6 months. Using structural equation modeling, we found significant indirect effects for both retirement satisfaction and health, supporting all hypotheses. These results suggest that during retirement, partners play an important role in encouraging opportunities for growth as an investment toward future retirement satisfaction and health. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Congenital Cytomegalovirus and Hearing Loss: A Pilot Cross-Sectional Survey of Otologists' and Pediatric Otolaryngologists' Knowledge.

OBJECTIVE: To evaluate pediatric otolaryngologists, neurotologists, and otologists on awareness and knowledge of congenital cytomegalovirus (cCMV). STUDY DESIGN: Pilot cross-sectional online survey. SETTING: Otolaryngology practices. SUBJECTS AND METHODS: An electronic multiple-choice questionnaire was sent email listserv to physician members of the American Society of Pediatric Otolaryngology and American Otological Society. The survey assessed demographics, physician awareness, and practice patterns. Data were collected and analyzed. RESULTS: Seventy (14.5%) pediatric otolaryngologists and otologists responded. All responded that they are familiar with cCMV. Most were familiar with symptoms associated with cCMV with the exception of petechia/purpura. Less than 50% knew the incidence/natural history of cCMV-induced hearing loss. Only 63% knew that saliva or urine polymerase chain reaction/culture should be performed prior to 3 weeks of age. Less than half knew the indications for dry blood spot testing, and many incorrectly recommended serologic saliva or urine testing in a child >3 weeks old. Most respondents do not offer any diagnostic testing for cCMV or referral for antiviral therapy for those who may benefit from this treatment. Most either did not know the cCMV screening policy or did not have one at their institution. CONCLUSION: Despite a relatively low overall response rate, this study suggests several knowledge gaps and underutilization of cCMV testing by physicians who frequently encounter pediatric hearing loss. The findings from this pilot study demonstrate the need for further educational directives focused on cCMV to improve knowledge and incorporation of cCMV best practices.

Privileges and penalties in the legal profession: an intersectional analysis of career progression.

Intersectionality theory is concerned with integrating social characteristics to better understanding complex human relations and inequalities in organizations and societies (McCall 2005). Recently, intersectionality research has taken a categorical and quantitative turn as scholars critically adopt but retain existing social categories to explain differences in labour market outcomes. A key contention is that social categories carry penalties or privileges and their intersection promotes or hinders the life chances of particular groups and individuals. An emergent debate is whether the intersection of disadvantaged characteristics (such as female gender or minority ethnic status) produce penalties that are additive, multiplicative or ameliorative. Research is inconclusive and as yet pays little attention to moderating factors such as employer type, size, geographic location or work profile. Drawing on administrative records for individuals qualified as solicitors in England and Wales, collected by the Solicitors Regulation Authority (SRA), combined with aggregated workforce data and firm characteristics of their law firms, we undertake a statistical analysis of the intersection of gender and ethnicity in the profession with a degree of precision and nuance not previously possible. In response to calls to broaden studies of inequalities and intersectionality beyond their effect on pay or income (Castilla 2008) we focus on career progression to partnership as our key measure of success. The original contribution of our study is twofold. First, we establish statistically different profiles of law firms, showing how the solicitors' profession is stratified by gender, ethnicity and socio-economic background, as well as the type of legal work undertaken by developing a model of socio-economic stratification in the profession. Second, we demonstrate that while penalties tend to be additive (i.e. the sum of the individual ethnic and gender penalties) this varies significantly by law firm profile and in some situations the effect is ameliorative.

Dispersal of harmful fruit fly pests by international trade and a loop-mediated isothermal amplification assay to prevent their introduction.

Global trade of plant products represents one of the major driving forces for the spread of invasive insect pests. This visualization illustrates the problem of unintended dispersal of economically harmful fruit fly pests using geospatial maps based on interception data from the Swiss import control process. Furthermore, it reports the development of a molecular diagnostic assay for rapid identification of these pests at points of entry such as sea- and airports as a prevention measure. The assay reliably differentiates between target and non-target species within one hour and has been successfully evaluated for on-site use at a Swiss point of entry.