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PURPOSE Evidence-based guidelines recommend cascade genetic counseling and testing for hereditary cancer syndromes, providing relatives the opportunity for early detection and prevention of cancer. The current standard is for patients to contact and encourage relatives (patient-mediated contact) to undergo counseling and testing. Direct relative contact by the medical team or testing laboratory has shown promise but is complicated by privacy laws and lack of infrastructure. We sought to compare outcomes associated with patient-mediated and direct relative contact for hereditary cancer cascade genetic counseling and testing in the first meta-analysis on this topic. MATERIALS AND METHODS We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade testing. Eligible trials were subjected to meta-analysis. RESULTS Eighty-seven studies met inclusion criteria. Among relatives included in the meta-analysis, 48% (95% CI, 38 to 58) underwent cascade genetic counseling and 41% (95% CI, 34 to 48) cascade genetic testing. Compared with the patient-mediated approach, direct relative contact resulted in significantly higher uptake of genetic counseling for all relatives (63% [95% CI, 49 to 75] v 35% [95% CI, 24 to 48]) and genetic testing for first-degree relatives (62% [95% CI, 49 to 73] v 40% [95% CI, 32 to 48]). Methods of direct contact included telephone calls, letters, and e-mails; respective rates of genetic testing completion were 61% (95% CI, 51 to 70), 48% (95% CI, 37 to 59), and 48% (95% CI, 45 to 50). CONCLUSION Most relatives at risk for hereditary cancer do not undergo cascade genetic counseling and testing, forgoing potentially life-saving medical interventions. Compared with patient-mediated contact, direct relative contact increased rates of cascade genetic counseling and testing, arguing for a shift in the care delivery paradigm, to be confirmed by randomized controlled trials.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease.Significance:These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer.

Table S1: MS/MS analyses of APE2 pull-down proteins in 293T cells

Normal morphology in other organs.

Slight increase of APE2 expression in mouse PTCs after carboplatin and oxaliplatin treatment.

This article explores anti-racist, feminist performance and video art by kate-hers RHEE and Patty Chang. Parodic performances of awkward sexual encounters in works such as RHEE’s The Chocolate Kiss (2013) and Chang’s The Product Love (2009) embody and deconstruct identity formation within transnational German and Asian American contexts. I explore how RHEE and Chang distinctly challenge sexist and racist stereotypes and the objectification of Asian women, while problematizing cultural categorization through (mis)translations and poetic relations. The article illuminates how these artists complicate Asian American identities via variegated explorations of critical race theories and connected histories of cross-cultural representation.

Humans have long interacted with animals. Recently, market-based responses to societal challenges, including loneliness and mental well-being include the use of animals. Considerable research concerning consumer–animal relationships has also examined the benefits (micro, meso, and macro) of human-animal interaction and companionship. However, much of this research is fragmented and lacks a broader organizing framework. It also suffers from an anthropomorphic bias, whereby the interests of animals are excluded. To address this, we provide a macromarketing perspective on consumer–animal relations and explore the interdependencies of consumer–animal relationships on consumer, animal, and community well-being. We introduce and apply the Interactive Well-Being framework to four contexts –ranging from private to public consumption spaces– that highlight the interdependencies and systems involved in consumer–animal relationships: (1) co-habitation with animals, (2) emotional support animals, (3) working with animals, and (4) animals in commercial service contexts. We discuss the implications of our framework for the resilience of marketing systems and how the framework aligns with alternative economy development.

Purpose Several professional organizations recommend universal genetic assessment for people with ovarian cancer as identifying pathogenic variants can affect treatment, prognosis, and all-cause mortality for patients and relatives. We sought to evaluate the literature on genetic assessment for women with ovarian cancer and determine if any interventions or patient characteristics drive utilization of services. Methods We searched key electronic databases to identify trials that evaluated genetic assessment for people with ovarian cancer. Trials with the primary aim to evaluate utilization of genetic assessment with or without interventions were included. Eligible trials were subjected to meta-analysis and the moderating influence of health interventions on rates of genetic assessment were examined. Results A total of 35 studies were included (19 report on utilization of genetic services without an intervention, 7 with an intervention, and 9 with both scenarios). Without an intervention, pooled estimates for referral to genetic counseling and completion of genetic testing were 39% [CI 27–53%] and 30% [CI 19–44%]. Clinician-facilitated interventions included: mainstreaming of genetic services (99% [CI 86–100%]), telemedicine (75% [CI 43–93%]), clinic-embedded genetic counselor (76% [CI 32–95%]), reflex tumor somatic genetic assessment (64% [CI 17–94%]), universal testing (57% [28–82%]), and referral forms (26% [CI 10–53%]). Random-effects pooled proportions demonstrated that Black vs. White race was associated with a lower rate of genetic testing (26%[CI 17–38%] vs. 40% [CI 25–57%]) as was being un-insured vs. insured (23% [CI 18–28%] vs. 38% [CI 26–53%]). Conclusions Reported rates of genetic testing for people with ovarian cancer remain well below the goal of universal testing. Interventions such as mainstreaming can improve testing uptake. Strategies aimed at improving utilization of genetic services should consider existing disparities in race and insurance status.

International audience; β1 integrins are important in blood vessel formation and function, finely tuning the adhesion of endothelial cells to each other and to the extracellular matrix. The role of integrins in the vascular disease, cerebral cavernous malformation (CCM) has yet to be explored in vivo. Endothelial loss of the gene KRIT1 leads to brain microvascular defects, resulting in debilitating and often fatal consequences. We tested administration of a monoclonal antibody that enforces the active β1 integrin conformation, (clone 9EG7), on a murine neonatal CCM mouse model, Krit1 flox/flox ;Pdgfb-iCreERT2 (Krit1 ECKO), and on KRIT1-silenced human umbilical vein endothelial cells (HUVECs). In addition, endothelial deletion of the master regulator of integrin activation, Talin 1 (Tln1), in Krit1 ECKO mice was performed to assess the effect of completely blocking endothelial integrin activation on CCM. Treatment with 9EG7 reduced lesion burden in the Krit1 ECKO model and was accompanied by a strong reduction in the phosphorylation of the ROCK substrate, myosin light chain (pMLC), in both retina and brain endothelial cells. Treatment of KRIT1-silenced HUVECs with 9EG7 in vitro stabilized cell-cell junctions. Overnight treatment of HUVECs with 9EG7 resulted in significantly reduced total surface expression of β1 integrin, which was associated with reduced pMLC levels, supporting our in vivo findings. Genetic blockade of integrin activation by Tln1 ECKO enhanced bleeding and did not reduce CCM lesion burden in Krit1 ECKO mice. In sum, targeting β1 integrin with an activated-specific antibody reduces acute murine CCM lesion development, which we found to be associated with suppression of endothelial ROCK activity.

Introduction In the United States, the annual incidence of breast cancer and comorbid type 2 diabetes mellitus (T2DM) in women is ∼40,000. Both conditions are associated with cognitive decline, which adversely affects self-management behaviors (SMBs) including adherence to medication, dietary and exercise recommendations. Patients with breast cancer also self-report decreased cognitive ability. Such perceptions can result from objective decline in cognitive function as well as factors such as anxiety and depression. Yet, the effect of perceived cognitive function on diabetes SMBs remains unclear. We evaluated the relationship between perceived cognitive function and adherence to SMBs in breast cancer survivors with T2DM. Hypothesis Greater adherence to diabetes SMBs will be associated with higher perceived cognitive function. Methodology We enrolled women ≥ 55 years with pre-existing T2DM who were diagnosed with Stage 0-IIIA breast cancer in the past 15 years, had completed adjuvant chemotherapy and/or prescribed hormonal therapy, and were taking ≥ 1 oral diabetes medication. We measured perceived cognitive function with the Functional Assessment of Cancer Therapy-Cognition (FACT-Cog, version 3) and diabetes SMBs adherence with the Summary of Diabetes Self Care Activities (SDSCA) questionnaire. Adherence to diabetes medications was assessed using an electronic monitoring bottlecap (eCAP). Data were dichotomized into adherent vs non-adherent. Wilcoxon rank-sum tests were used to compare cognition scores between groups. Results 239 patients (mean age: 66.5 years; 28% Black, 39% white, 6% Asian, 7% other, 20% unanswered) completed interviews. Cancer survivors who were non-adherent with their diabetes medication perceived themselves as having lower cognitive function (Total FACT-Cog median (interquartile range; IQR) 102 (36.7) vs. 115 (30), p< 0.05), with lower scores on the perceived cognitive ability and impact of cognitive impairments on quality of life (QOL) subscales (Cognitive-ability median (IQR) 20 (9) vs. 23 (7), p< 0.001; QOL median (IQR) 13 (6) vs 16 (3), p< 0.05). Similarly, those who reported healthy eating for Conclusion Among breast cancer survivors with T2DM, adherence to diet and medication was associated with greater self-perceptions of cognitive function. Future studies will test whether interventions to improve patients’ perceptions of their cognitive abilities can influence self-care. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Gene therapy, cell therapy and vaccine research have led to an increased use of qPCR/ddPCR in bioanalytical laboratories. CROs are progressively undertaking the development and validation of qPCR and ddPCR assays. Currently, however, there is limited regulatory guidance for the use of qPCR and a complete lack of any regulatory guidelines for the use of the newer ddPCR to support regulated bioanalysis. Hence, the Global CRO Council in Bioanalysis (GCC) has issued this White Paper to provide; 1) a consensus on the different validation parameters required to support qPCR/ddPCR assays; 2) a harmonized approach to their validation and 3) a consistent development of standard operating procedures (SOPs) for all the bioanalytical laboratories using these techniques.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. Significance: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer.

Canaliculitis, inflammation of the lacrimal canaliculi, can be caused by numerous pathogens, most commonly bacteria from the genera Actinomyces, Streptococcus, and Staphylococcus. Primary canalicul...

A typical clinical symptom of human norovirus infection is projectile vomiting. Although norovirus RNA and viral particles have been detected in vomitus, infectivity has not yet been reported. We detected replication-competent norovirus in 25% of vomit samples with a 13-fold to 714-fold increase in genomic equivalents, confirming infectious norovirus. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [3R 2017-01479]; ALF Grants, Region Ostergotland [LIO-934451]

Sjögren's syndrome is a systemic autoimmune disease that classically presents with xerophthalmia and xerostomia. However, neurological manifestations occur in 10 to 60% of patients with Sjögren's syndrome and can often precede classic sicca symptoms in Sjögren's syndrome in some cases up to several years. Rarely, cranial neuropathy can be the initial presentation. Here, we present the first case of a 15-year-old girl with left abducens palsy in the setting of a new diagnosis of Sjögren's syndrome. Comprehensive evaluation revealed elevated Sjögren's syndrome–related antigen A-60 antibody. Cerebrospinal fluid analysis was unremarkable. Radiological studies demonstrated evidence of chronic parotitis. Acute treatment included high-dose methylprednisolone and rituximab, and symptoms resolved by follow-up at 2 weeks. The most common neurological disorder of Sjögren's syndrome is pure sensory neuropathy. In pediatric Sjögren's syndrome, neurological complications are rare but include aseptic meningoencephalitis, acute disseminated encephalomyelitis, transverse myelitis, optic neuritis, and cranial neuropathies. In the circumstance of a cranial neuropathy, the trigeminal nerve is most commonly involved but oculomotor nerves can occasionally be affected. Abducens palsies have been described in four patients with Sjögren's syndrome, typically women and all middle aged or older, with our patient being the first pediatric case. Thus, it is important to consider screening for Sjögren's syndrome in the evaluation of pediatric patients with new onset of isolated cranial neuropathy even in the absence of classic sicca symptoms.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

Ras-related protein 1 (Rap1) is a major convergence point of the platelet-signaling pathways that result in talin-1 binding to the integrin β cytoplasmic domain and consequent integrin activation, platelet aggregation, and effective hemostasis. The nature of the connection between Rap1 and talin-1 in integrin activation is an important remaining gap in our understanding of this process. Previous work identified a low-affinity Rap1-binding site in the talin-1 F0 domain that makes a small contribution to integrin activation in platelets. We recently identified an additional Rap1-binding site in the talin-1 F1 domain that makes a greater contribution than F0 in model systems. Here we generated mice bearing point mutations, which block Rap1 binding without affecting talin-1 expression, in either the talin-1 F1 domain (R118E) alone, which were viable, or in both the F0 and F1 domains (R35E,R118E), which were embryonic lethal. Loss of the Rap1–talin-1 F1 interaction in platelets markedly decreases talin-1–mediated activation of platelet β1- and β3-integrins. Integrin activation and platelet aggregation in mice whose platelets express only talin-1(R35E, R118E) are even more impaired, resembling the defect seen in platelets lacking both Rap1a and Rap1b. Although Rap1 is important in thrombopoiesis, platelet secretion, and surface exposure of phosphatidylserine, loss of the Rap1–talin-1 interaction in talin-1(R35E, R118E) platelets had little effect on these processes. These findings show that talin-1 is the principal direct effector of Rap1 GTPases that regulates platelet integrin activation in hemostasis.

In this article, we first compare adolescents’ responses to two formats (easily recognizable versus not easily recognizable) Internet ads. We find that Internet literacy and ad skepticism are neces...

The literature demonstrates that the quality of cancer family history (CFH) as currently collected in the outpatient setting is inadequate to assess disease risk. Prior to implementation of a web-based application for cancer family history collection, we aimed to review the quality of collected CFH in a gynecologic oncology outpatient clinic and determine contributing patient factors. Medical records were reviewed for 200 new patients presenting between 4/2019-7/2019. CFH was collected during the patient interview and evaluated for inclusion of eight elements based on standards set by the genetics community. Univariate and multivariable linear regression analyses were utilized to evaluate the effect of patient characteristics on the number of relatives included in the CFH. Among our cohort of 200 patients, CFH was documented for 185 patients (92.5%). On univariate analysis, patients with a family history of cancer and prior genetic testing had significantly greater median number of relatives included in the CFH. On multivariable analysis, patients with family members with cancer had significantly more relatives included. Our data are consistent with the literature, suggesting that the current collection methods may not adequately capture all measures of a high quality CFH. Patients reporting no family history of cancer and those without prior genetic testing were least likely to have CFH that included key quality elements and these patients might benefit from health information technology CFH collection tools.

Background Electrographic characteristics (extreme delta brush, posterior dominant rhythm and slow waves) may predict outcomes in anti-NMDA receptor encephalitis (NMDARE). However, whether changes in EEG sleep architecture predict outcomes are unknown. We examine electrophysiological characteristics including sleep architecture in a pediatric NMDARE population and correlate with outcomes at one year. Methods Retrospective chart and EEG review was performed in pediatric NMDARE patients at a single center. Patients with first EEGs available within 48 h of admission, prior to treatment, and one-year follow-up data were included. EEGs were independently reviewed by two epileptologists, and a third when disagreement occurred. Clinical outcomes included modified Rankin scale (mRS) at one year. Results Nine patients (6 females) (range 1.9–16.7 years) were included. Five of nine patients had loss of posterior dominant rhythm (PDR) and three of nine patients had absent sleep architecture. Loss of PDR correlated with a worse mRS score at one year (2.8 versus 0.5, p = 0.038). Loss of PDR and loss of sleep architecture was associated with increased inpatient rehabilitation stay and in higher number of immunotherapy treatments administered. In multivariate analysis, absence of sleep architecture (p = 0.028), absence of PDR (p = 0.041), and epileptiform discharges (p = 0.041) were predictors of mRS at one year. Conclusions Loss of normal PDR, absence of sleep architecture, and epileptiform discharges are associated with worse outcomes at one year which has not been reported before. EEG characteristics may help prognosticate in NMDARE. Larger studies are needed to confirm these findings.

Canaliculitis, inflammation of the lacrimal canaliculi, can be caused by numerous pathogens, most commonly bacteria from the genera

Stimulating angiogenesis during wound healing continues to present a significant clinical challenge, given the limitations of current strategies to maintain therapeutic doses of growth factors and endothelial cell efficacy. Incorporating a balance of specific cues to encourage endothelial cell engraftment and cytokines to facilitate angiogenesis is necessary for blood vessel growth in the proinflammatory wound environment. Here, we incorporate a previously designed peptide (LXW7) capable of binding to the αvβ3 integrin of endothelial cells with a dermatan sulfate glycosaminoglycan backbone grafted with collagen-binding peptides (SILY). By exploiting αvβ3 integrin-mediated VEGF signaling, we propose an alternative strategy to overcome shortcomings of traditional growth factor therapy while homing the peptide to the wound bed. In this study, we describe the synthesis and optimization of LXW7-DS-SILY (LDS) variants and evaluate their angiogenic potential in vitro and in vivo. LDS displayed binding to collagen and endothelial cells. In vitro, the LDS variant with six LXW7 peptides increased endothelial cell proliferation, migration, and tubule formation through increased VEGFR2 phosphorylation compared to nontreated controls. In an in vivo chick chorioallantoic membrane assay, LDS laden collagen hydrogels increased blood vessel formation by 43% in comparison to the organism matched blank hydrogels. Overall, these findings demonstrate the potential of a robust targeted glycan therapeutic for promoting angiogenesis during wound healing.

Breast pocket irrigation with antiseptic solutions is performed to reduce contamination with breast implants. The optimal antiseptic irrigation solution and the efficacy of individual practices are unclear. Oxychlorosene sodium is frequently used at our institution. Oxychlorosene is bactericidal with a mechanism of action of oxidation and hypochlorination. The purpose of our study was to compare the outcomes of oxychlorosene sodium irrigation with triple antibiotic solution (TAS) in implant-based breast reconstruction.All patients who underwent implant-based reconstruction after mastectomy were reviewed. The primary predictive variable was type of solution used for pocket irrigation (TAS or oxychlorosene). Outcome variables included surgical site infection, device removal, and wound complications.Between 2013 and 2018, 331 implant-based breast reconstructions were performed. Of these, 62% (n = 206) received oxychlorosene for surgical pocket irrigation (group I), and 38% (n = 125) received TAS (group II). Group I had an 11.7% (n = 24) 90-day surgical site infection rate, with 4.9% (n = 10) requiring oral antibiotics, 2.4% (n = 5) requiring intravenous antibiotics without device removal, and 4.4% (n = 9) requiring prosthetic removal. Group II had an 11.2% (n = 14) 90-day infection rate, with 5.6% (n = 7) requiring oral antibiotics, 2.4% (n = 3) requiring intravenous antibiotics without device removal, and 3.2% (n = 4) requiring removal (Oxychlorosene and TAS have similar surgical site infection rates in prosthetic breast reconstruction. Ease of preparation and cost make oxychlorosene a more favorable option for antibiotic irrigation in reconstructive breast surgery with prosthetic devices.

Industrial knitting machines create fabric by manipulating loops held on hundreds of needles. A core problem in pattern making for these machines is transfer planning – coming up with a sequence of low-level operations that move loops to the appropriate needles so that knitting through those loops produces the correct final structure. Since each loop is connected to the larger piece in progress, transfer plans must account for not only loop position, but the way strands of yarn tangle around each other.We present the first complete, discrete representation of the machine’s loop-tangling process. Our representation combines a braid from the Artin Braid Group with an array of explicit loop positions to fully capture loop crossings. By storing braids in the Symmetric Normal Form, states can be quickly compared and updated incrementally with machine operations. This representation can be used to verify the equivalence of transfer operations, providing an important tool in optimizing knit manufacturing.We improve on prior work in transfer planning algorithms, which can only solve certain subclasses of problems and are frequently suboptimal in terms of fabrication time, by introducing a novel A* search heuristic and state-collapsing mechanism, which we show finds optimal transfer plans for a large benchmark set of small transfer planning problems.

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.

10592 Background: Evidence-based guidelines recommend that patients (probands) diagnosed with a hereditary cancer syndrome share the information with blood relatives as relatives can have 50% risk for harboring the same pathogenic mutation. This information offers the opportunity for relatives to undergo genetic counseling, genetic testing, early detection, and prevention of cancer. Limited literature on this topic suggests underutilization of recommended family member disclosure. We sought to evaluate rates of familial disclosure of hereditary cancer syndrome information in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade relative disclosure. Eligible trials were subjected to meta-analysis. Results: Thirty studies met inclusion criteria. This review included 3,779 probands and 12,751 at-risk relatives. Among 12,751 included relatives, 72% (CI 64-79%) received information about the hereditary cancer syndrome identified in their family and 28% (CI 19-37%) underwent genetic testing. On meta-analysis, there was a higher rate of disclosure among female vs male relatives (79% [73% - 84%] vs 67% [57% - 75%]) and a higher rate among first-degree vs. second degree relatives (83% [77% - 88%] vs 58% [45 – 69%]). The data regarding the contribution of race/ethnicity to disclosure were limited and inconsistent, with two studies demonstrating non-White vs. White relatives being less likely to have results disclosure and two studies finding no correlation; however, both studies finding no difference were limited by small sample sizes. Finally, one study found that higher proband annual income was associated with improved familial disclosure. Conclusions: Despite a growing understanding of the importance of cascade genetic counseling and testing, probands do not disclosure information on hereditary cancer syndromes to most at-risk relatives. Very few relatives complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Future studies are needed to elucidate barriers to hereditary cancer syndrome disclosure and create innovative strategies to facilitate this essential process.

The 13th Global CRO Council (GCC) closed forum for bioanalysis was held in New Orleans, LA, USA on 5 April 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. While ICH M10 will cover requirements for reference standards, one of the biggest challenges facing the CRO community is the lack of consistency and completeness of Certificates of Analysis for reference standards used in regulated bioanalysis. Similar challenges exist with critical reagents (e.g., capture and detection antibodies) used for assays supporting biologics. The recommendations provided in this publication are the minimum requirements for the content that GCC members believe should be included in Certificates of Analysis for reference standards obtained from commercial vendors, sponsors and compendial suppliers, for use in regulated bioanalytical studies. In addition, recommendations for internal standards, metabolites and critical reagents are discussed.

Objectives: Despite clear consensus guidelines recommending universal germline genetic testing in ovarian cancer patients and a growing appreciation of the significant health implications for patients and their relatives, fewer than 50% of women with ovarian cancer undergo genetic testing. We aim to use systematic review and meta-analysis to assess the status of genetic testing in ovarian cancer and identify strategies that can improve uptake of genetic assessment in this high-risk population. Methods: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for studies reporting on genetic testing in ovarian cancer without date restriction was performed. Random effects pooled proportions were calculated using the logit transformation and 95% confidence intervals for individual study proportions were calculated using the Clopper-Pearson exact method. Results: The comprehensive search produced 3026 studies, among which 38 met inclusion criteria. Among studies listing mean age of diagnosis, stage, and histology data, the median of the mean age of diagnoses across the studies was 60.5 years. The median proportion of patients with early stage (I/II) ovarian cancer was 22.8%, late stage (III/IV) 70%, and unknown stage 3.6%. The median proportion of patients with serous histology was 74.6%, endometrioid 8.6%, mucinous 6%, clear cell 7%, mixed 3.6%, carcinosarcoma 3.4%, adenocarcinoma 5.8%, and other/unknown histology 7.9%. Twenty-one papers described rates of referral to genetic counseling and found, among 9,629 women, a referral rate of 56% [CI 32-78%]. Twenty-three papers described genetic testing uptake without a specified intervention and found, among 16,412 women, 34% [CI 23-47%] underwent genetic testing (Figure 1). For patients completing genetic testing, 27% [CI 22-32%] had a pathogenic mutation and 7% [CI 3-16%] a variant of uncertain significance. The most successful strategy aimed at improving rates of genetic testing was ‘mainstreaming,’ the process of providing counseling and testing in the oncology clinic by trained non-genetics specialists. With mainstreaming, 99% [CI 86-100%] of patients completed genetic testing. Other strategies described in the literature included the use of telemedicine for genetic services (75% underwent genetic testing [CI 43-93%]), embedding a genetic counselor in the clinic (67% [CI 32-90%]), reflex somatic tumor BRCA1/2 testing to triage to germline testing (64% [17-94%]), practice recommendation for universal testing of all ovarian cancer patients (42% [CI 15-74%]), and incorporating dedicated referral forms into practice (26% [CI 10-53%]). Download : Download high-res image (203KB) Download : Download full-size image Conclusions: Identifying causative germline mutations in ovarian cancer can impact treatment decisions, inform risk of other malignancies and guide disease prevention and early detection in at-risk relatives. Rates of both referral to genetic counseling and testing remain low, 56% and 34% respectively, despite broad recommendations for universal testing. Mainstreaming, use of telemedicine, embedding genetic counselors in the clinic, and triage via reflex somatic BRCA1/2 assessment are all strategies demonstrating success in this patient population and should be considered for those providing care to women with ovarian cancer.

Objectives: Despite the recommendation for genetic assessment for all women with ovarian cancer, the limited available data suggest significant disparities in referral and uptake of genetic services in minority populations. Additionally, the COVID-19 pandemic has exacerbated many existing health care disparities, making it even more critical that inequalities be identified and addressed. We sought to evaluate differences in genetic counseling and genetic testing among women with ovarian cancer based on race and insurance status. Methods: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for studies reporting on genetic testing in ovarian cancer without date restriction was performed. Random effects pooled proportions were calculated using the logit transformation and 95% confidence intervals for individual study proportions were calculated using the Clopper-Pearson exact method. Results: The comprehensive search produced 3026 studies, among which 38 met inclusion criteria. Eight studies included analysis by self-reported race/ethnicity and 6 included analysis by insurance status. Among studies listing mean age of diagnosis, stage, and histology data, the median of the mean age of diagnoses across the studies was 63.3 years. The median proportion of patients with early stage (I/II) ovarian cancer was 14.7%, late stage (III/IV) 68.6%, and unknown stage 9.3%. The median proportion of patients with serous histology was 81.8%, endometrioid 12.6%, mucinous 5%, clear cell 5.8%, mixed 3.7%, carcinosarcoma 3%, and other/unknown histology 81.8%. Among 7,862 patients, 6,469 reported being White, 599 Black, and 794 Asian. Random-effects pooled proportions by race/ethnicity to follow: Among White patients, 43% [CI 26-62%] were referred for genetic counseling and 40% [CI 25-57%] completed testing, and for Black patients, 24% [CI 13-42%] were referred for counseling and 26% [CI 17-38%] completed testing. For Asian patients, 23% [CI 2-83%] were referred for counseling and 14% [CI 2-51%] completed testing, although only two studies included referral and testing proportions in Asian patients, with the majority of patient data coming from one study with referral proportion of 39% and another study with testing proportion of 31%. Among 7,681 patients, 5,320 (69%) had private insurance, 2,078 (27%) had Medicare/Medicaid, and 283 (4%) were uninsured. Random-effects pooled proportions by insurance status to follow: Among patients with private insurance, 39% [CI 26-54%] were referred for genetic counseling and 47% [CI 30-64%] completed testing. Among patients with Medicare/Medicaid, 27% [CI 18-38%] were referred for counseling and 26% [CI 16-40%] completed testing, and among uninsured patients, 24% [CI 13-41%] were referred for counseling and 23% [CI 18-28%] completed testing. Small sample and high study heterogeneity observed in the race and insurance data resulted in large confidence intervals in the pooled proportions of interest. Conclusions: Rates of genetic counseling and genetic testing are below national guidelines for all women with ovarian cancer. Our systematic review of the existing literature on this topic suggests that minority women and patients without private insurance may be disproportionally affected by lower referral rates and more limited access to genetic testing. This disparity is concerning as it can have significant impact on the health of the affected patient and her at-risk relatives. Download : Download high-res image (212KB) Download : Download full-size image

Objectives: Despite a growing understanding of familial cancer, multiple studies demonstrate that the quality of family health history (FHH) as currently collected in a clinic setting is inadequate to assess disease risk. Proposed challenges in FHH collection include lack of patient preparation, lack of FHH standardization, and time requirement (especially during the COVID-19 pandemic with intentional minimization of office time). Prior to implementation of a web-based application for FHH collection, we aimed to review the quality of collected FHH in a gynecologic oncology clinic and to determine if any patient factors affect FHH collection. Methods: This was a single institution retrospective study of FHH collection for new patient appointments at a gynecologic oncology outpatient practice between 4/2019-7/2019. FHH was collected verbally during the patient face-to-face interview. FHH was evaluated for the following, previously published, quality measures on a point system: 1) Three generations, 2) Relative gender, 3) Relative lineage (maternal vs paternal), 4) Pertinent negatives (absence of hereditary cancers), 5) Age of relatives’ cancer diagnosis, and for deceased relatives, 6) Age of death and 7) Cause of death. Results: Among the 200 evaluable patients, 185 (92.5%) had FHH documented in the medical record. The median age was 52 years (range 23-93). Eighty-nine (44.5%) included three generations, 154 (77%) relatives’ gender, 109 (54.5%) relatives’ lineage, and 77 (38.5%) pertinent negatives (Figure 1). Among 147 patients reporting a history of cancer in their family, 23 (15.6%) included age of relatives’ cancer diagnosis. Among 75 patients listing deceased relatives, 13 (17.3%) included age of death and 48 (64%) cause of death. Age and personal cancer diagnosis were not associated with quality of FHH. Patients with family history of cancer scored higher in quality of FHH than those without family history (median=3.0 [IQR 3.0; 4.0] vs. 1.0 [0.0; 2.0], P Download : Download high-res image (82KB) Download : Download full-size image Conclusions: Our data are consistent with the literature suggesting that standard collection of family history may not adequately capture all measures of a high quality oncologic FHH. Patients without prior genetic testing and no family history of cancer had the lowest scores for FHH quality and might benefit from a web-based FHH collection tool, allowing them to contact relatives for more information prior to an office visit and permitting better patient preparation and efficiency. In light of the COVID-19 pandemic, tools that minimize inoffice time are increasingly important. A prospective evaluation of a web-based FHH collection tool to address these issues is ongoing.

Objectives: In the US there are approximately 4 million individuals with a genetic cancer predisposition syndrome, however, the majority are not aware and cannot benefit from genetically-targeted cancer prevention. Family cancer history (FCH) can identify high risk patients and triage them to genetic assessment, however there is wide variability in accuracy, breadth and strategies for FCH collection. We aim to evaluate whether a web-based tool (WBT) can result in improved quality of FCH versus standard FCH collection via face-to-face interview. Methods: All patients scheduled for a gynecologic oncology new patient visit between 9/2019-9/2020 were offered enrollment in an institutional review board-approved prospective trial. Patients were randomized to one of three arms: 1) standard of care FCH collection during the interview, 2) WBT administered at home prior to the visit, 3) WBT administered in the office prior to the visit. The primary endpoint was evaluation of FCH quality based on established quality measures. Chi-square test was used to compare FCH quality between intervention arms and ANOVA test for the number of relatives/generations in the pedigree. A Bonferroni correction was used to account for multiple comparison testing. Results: A total of 100 patients were enrolled. The mean age was 56.2 years (SD 15.2). The WBT was completed successfully by 67% (22) of patients randomized to home administration vs 94% (31) randomized to office administration (P=0.01). Patients cited the following reasons for failure to complete the WBT at home: difficulty with technology, concern about privacy and forgetting about the WBT invitation. In the intention-to-treat analysis, office WBT collection resulted in significantly higher quality FCH vs the control and home arms (Table 1). The WBT resulted in significantly greater mean number of relatives included in the pedigree (Arm 1 - 3.9 [SD 3.0], Arm 2 - 32.4 [SD 16.8], Arm 3 - 29.0 [SD 18.3], P Download : Download high-res image (102KB) Download : Download full-size image Conclusions: FCH collection is an exciting application of information technology in the current healthcare setting with a growing emphasis on cancer genetics, disease prevention and thoughtful use of WBTs. In our cohort of gynecologic-oncology patients, a WBT resulted in significantly higher quality and more comprehensive family cancer pedigrees. With the COVID-19 pandemic inspired drive to minimize in-office time, future studies must assess strategies to improve patient engagement with WBT at home prior to the visit.

This chapter examines the visual culture of Silicon Valley. I look to Silicon Valley’s “golden years,” exemplified by the establishment of Xerox PARC in the 1970s, and analyse how PARC’s researchers’ embrace of open exchange and experimentation manifested in university campus-like office design. I subsequently consider the morphing of PARC’s design into the monumental corporate architecture of Apple Park, and the work/ play environments of Google and Airbnb. I argue that these late capitalist corporations aestheticize Silicon Valley’s foundational values, transforming the promotion of cross-cultural sharing into empty visual signs that mask economic inequality and displacement. Finally, the chapter discusses collaborations between artists and community groups, facilitated by the San José Museum of Art, which aim to reclaim multiculturalism and resist the area’s unsustainable gentrification.

Gentrification is reshaping cities worldwide, resulting in seductive spaces and exclusive communities that aspire to innovation, creativity, sustainability, and technological sophistication. Gentrification is also contributing to growing social-spatial division and urban inequality and precarity. In a time of escalating housing crisis, unaffordable cities, and racial tension, scholars speak of eco-gentrification, techno-gentrification, super-gentrification, and planetary gentrification to describe the different forms and scales of involuntary displacement occurring in vulnerable communities in response to current patterns of development and the hype-driven discourses of the creative city, smart city, millennial city, and sustainable city. In this context, how do contemporary creative practices in art, architecture, and related fields help to produce or resist gentrification? What does gentrification look and feel like in specific sites and communities around the globe, and how is that appearance or feeling implicated in promoting stylized renewal to a privileged public? In what ways do the aesthetics of gentrification express contested conditions of migration and mobility? Addressing these questions, this book examines the relationship between aesthetics and gentrification in contemporary cities from multiple, comparative, global, and transnational perspectives.

Crochet is a fabrication technique in which a 3D surface is created from yarn by interlacing loops formed with a special hook. Crochet patterns are typically represented using a standardized set of abstract pictorial symbols. Unfortunately, while this notation is enough for someone well-versed in the individual stitches, it does not directly show the yarn layout of stitches. This lack of specification makes it difficult for both novice users and computer programs to parse, visualize, and design crochet patterns. We demonstrate how to represent crochet patterns within the “stitch mesh” paradigm. That is, the pattern is represented using a library of tiles, where each tile contains yarn geometry, and tiles connect along their edges. In order to adapt stitch meshes to crochet, we introduce a special edge type which captures the idea of the current loop – the loop of yarn held on the crochet hook during fabrication. We also create a library of mesh face types which model commonly-used crochet stitches. We illustrate the richness of the crochet stitch faces by showing a number of examples including patterns generated from 3D models.