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In the 20 years since its inception, robotic surgery has evolved greatly in its design and clinical use. Most recently, the approach to training and gaining proficiency in robotic surgery techniques has also matured. This article reviews the development of robotic surgery systems, the trajectory of their use for patients with benign and malignant gynecologic conditions, and the advances in novel technologies that are driving the applications of robotic surgery forward. (J GYNECOL SURG 39:204) [ABSTRACT FROM AUTHOR]

To determine whether Black race is associated with treatment and survival among women with low-risk endometrial cancer. Black and White women with Stage IA grade 1–2 endometrioid endometrial carcinoma diagnosed from 2010 to 2016 in the SEER 18 dataset were identified (n = 23,431), and clinical and socioeconomic attributes obtained. Five-year cancer-specific survival (CSS) and relative survival (RS) were calculated using SEER*Stat 8.3.9. Cox proportional hazards model was used to determine predictors of overall survival (OS) and CSS. There was a significantly higher proportion of Black women who did not have surgery compared to White women (3% vs 1%, respectively; p < 0.0001). Residing in the South, being insured with Medicaid, and residing in a county with low median income were also associated with non-receipt of surgery. Black women remained less likely to undergo hysterectomy on multivariable analysis (OR 0.44, 95% CI 0.32–0.60). Non-receipt of hysterectomy was predictive of decreased CSS (HR 0.14, 95% CI 0.09–0.21) and OS (HR 0.18, 95% 0.14–0.23) on adjusted analysis. Black race was also an independent predictor of increased cancer-specific death (HR 2.07, 95% CI 1.50–2.86) as well as death from any cause (HR 1.74, 95% CI 1.44–2.09) on adjusted analysis. Black women with low-risk endometrial cancer were less likely to undergo hysterectomy and experienced decreased survival relative to White women. Further investigation is warranted to better understand the socioeconomic, geographic, and biologic factors that influence this disparity. • Black race, low socioeconomic status, and residing in the South were associated with non-receipt of cancer-directed surgery. • Five-year cancer-specific and relative survival were lower for Black women compared to White women. • Black race and receipt of hysterectomy were independent predictors of decreased cancer-specific and overall survival. [ABSTRACT FROM AUTHOR]

This article highlights the development and outcomes of a visual art educator community of practice (CoP) cultivated in partnership with the Museum of Contemporary Art in Los Angeles, known as the MOCA PD Lab. Participating researchers were interested in examining how to bring visual art teachers together outside of schools and districts to pursue their own collaborative professional development (PD) that could accommodate time, distance, and expense needs. The study focused on increasing the capacity of group members to design and facilitate PD through examining the impact of the CoP on participants' shared knowledge and reflective practices; exploring strategies to grow and sustain the CoP; and implementing organisational strategies for cultivating connections and empowering teachers to pursue ongoing professional learning (PL). Feedback from participants indicates the positive impact of this CoP on members' self-directed PL in: building community, collaborating with colleagues, developing instructional practice, and engaging in critical reflection. Now concluding its fifth year, the MOCA PD Lab continues to meet monthly to engage in visual art PL experiences to meet participants' individual learning goals. Our hope is that the MOCA PD Lab may serve as a model for educators and museums looking to create collaborative PL opportunities. [ABSTRACT FROM AUTHOR]

As climate change continues to increase both the frequency and intensity of environmental hazards and disasters, the need for a cohesive national mitigation policy grows. As the environmental federalism scholarship indicates, the inherent tension in federal, state, and local policy implementation highlights that despite a national need, environmental quality is a local public good. To complicate matters, there is disagreement about the optimal level of decision‐making regarding the adoption and implementation of environmental policy. This study addresses this gap by considering the role of policy ambiguity and conflict in policy implementation. The analysis relies on primary qualitative data collected from open‐ended interviews with 22 local government officials in 12 municipalities following Hurricane Harvey. Through the lens of policy ambiguity and conflict, we find confirmatory support for the idea that policies with less ambiguous goals are more likely to be implemented. Furthermore, we find that policy conflict arises when local governments perceive there is little for the community to gain by implementing the federal program. Thus, the level of protection afforded to citizens varies greatly between communities and is influenced heavily by politics. This research supports the Ambiguity‐Conflict Model of policy implementation, an oft‐cited but rarely tested theoretical framework for assessing the intergovernmental politics of policy implementation. It also demonstrates the barriers to local implementation of federal environmental policy in a nested system of government. [ABSTRACT FROM AUTHOR]

Objective: This study explores why state legislators think some issues are difficult and where they turn for help with these issues. Methods: We use content analysis of legislators' interview responses to identify sources of difficulty that arose during committee deliberations. Results: Many legislators say that issues are difficult because of committee and caucus politics, technical information, interest group pressure, jurisdictional competition, and budget constraints. We find few associations between sources of difficulty and legislator characteristics or institutional context. Mundane issues are often seen as difficult, with culture war issues rarely mentioned. Using cluster analysis, we identify five major categories of issue difficulty. We find that legislators grapple with these categories of difficulty by relying on interest groups, partisan staff, and committee members rather than on caucus leaders, the governor, or their voters. Conclusion: These findings contribute to our understanding of impediments to policy making that legislators navigate in legislative committees. [ABSTRACT FROM AUTHOR]

How does the state of American federalism explain responses to COVID-19? State-by-state variations to the COVID-19 pandemic illustrate the political dynamics of "kaleidoscopic federalism," under which there is no single prevailing principle of federalism. In the COVID-19 pandemic, features of kaleidoscopic federalism combined with shortcomings in the public health system under the Trump administration, leading to fragmented responses to the pandemic among the states. Federalism alone does not explain the shortcomings of the United States' response to the pandemic. Rather, the fragmented response was driven by state partisanship, which shaped state public health interventions and resulted in differences in public health outcomes. This has sobering implications for American federalism because state-level partisan differences yield different and unequal responses to the pandemic. [ABSTRACT FROM AUTHOR]

Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea with the potential for significant morbidity and mortality. Colonization in a susceptible individual, with risk factors such as prior antibiotic use, advanced age, or medical comorbidities, may result in symptomatic infection. Although patients with a gynecologic malignancy may be at a higher risk of developing CDI due to an increased likelihood of having one or more risk factors, data do not consistently support the idea that chemotherapy or cancer itself are independently associated with CDI. For diagnosis of CDI, we recommended using a multi-step approach, with a highly sensitive initial rapid test such as the enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) or nucleic acid amplification testing (NAAT), followed by confirmatory testing with of the above two tests or EIA toxin A/B, which has high specificity. Treatment varies based on the severity of disease. We recommend vancomycin as first-line therapy for an initial episode of mild/moderate or severe CDI, with consideration of fidaxomicin for patients at particularly high risk for recurrence. Rectal vancomycin may play an adjunctive role for some severe cases, while surgical intervention is indicated for fulminant CDI if no improvement six or more days after initiating medical therapy. For non-severe recurrent disease, the initial treatment regimen should be repeated, while subsequent episodes are more appropriately treated with a tapered and pulsed dose of vancomycin, fidaxomicin, or fecal microbiota transplantation. [ABSTRACT FROM AUTHOR]

Training in evidence-based practices may better prepare providers to address the effect of behavioral health concerns on chronic homelessness. Through the Beck Initiative, a community-academic partnership, case managers ( n = 19) were selected to incorporate a cognitive-behavioral therapy (CBT) framework into services for chronic homelessness at seven sites in Philadelphia, PA. Details of the training components and development are presented. This training program demonstrated feasibility within these low-demand shelter settings (79% completed training, 10% left employment during training, 10% did not complete). Feedback measures indicated positive feedback regarding acceptability, usefulness, and quality of training. Planned discharges from the shelters were significantly more frequent in the 6 months posttraining compared with the 6 months before training. The CBT framework shows early promise for improving services for people experiencing chronic homelessness. This program also demonstrates the benefit of involving community stakeholders and academic partners to address one aspect of chronic homelessness. [ABSTRACT FROM AUTHOR]

To determine whether Black race is associated with treatment and outcomes among a favorable cohort with low-risk endometrial cancer. All Black and White women with Stage IA grade 1-2 endometrioid endometrial carcinoma diagnosed from 2010 to 2016 in the SEER 18 dataset were identified (n=23431), and clinical and socioeconomic attributes obtained. Five-year cancer-specific survival (CSS) and relative survival (RS) were calculated using SEER*Stat 8.3.8. Statistical analyses were performed with independent t-test, Chi-Square test, and Cox proportional hazard regression. Although the majority of patients underwent surgery, there was a significantly higher proportion of Black women who did not have surgery compared to White women (1% vs 3%, respectively; p<0.0001). Reasons for having not undergone surgery were similar between the two groups: not recommended, Blacks 74% vs Whites 75%; medically contraindicated, Blacks 16% vs Whites 9%; patient refusal, Blacks 16% vs Whites 10%; p=0.293. Black women were overrepresented in groups where more women did not undergo hysterectomy: women residing in the South (2.1% vs 1.3%, p=0.002) and those with Medicaid (3.4%) or no insurance (2.1%) compared to those with private insurance or Medicare (1.3%, p<0.0001). However, Black women remained less likely to undergo hysterectomy after adjusting for age, ethnicity, geography, grade, insurance status, and socioeconomic status (OR 0.379, p<0.0001). Five-year CSS was favorable in both groups, though significantly lower among Black women (CSS 95.0%, 95% CI 93.2-96.4%) compared to White women (CSS 97.8%, 95% CI 97.5-98.1%). A similar trend was noted for 5-year RS, with 95.4% for Black women (95% CI 92.2%-97.3%) versus 100% for White women. Black race was an independent predictor of increased cancer-specific death (HR 1.76, 95% CI 1.46-2.12) as well as all-cause mortality (HR 2.14, 95% CI 1.54-2.98) on adjusted analysis. We found that, even in a good prognostic group, Black women are less likely to undergo hysterectomy and have an increased risk of death among women with low-risk endometrial cancer. This bolsters prior work demonstrating that the association of race and poor outcomes is not only due to higher grade, more aggressive histologic type, and more advanced stage at diagnosis. [ABSTRACT FROM AUTHOR]

Key content Gynaecological and breast cancers affect premenopausal and perimenopausal women at rates ranging 15-70% and treatment often causes the abrupt onset of menopause., Available studies do not show an increase in recurrence or decrease in survival among women with endometrial, ovarian or cervical cancer who use hormone replacement therapy (HRT)., Data regarding the risks of systemic HRT in survivors of breast cancer are varied, and an increase in breast cancer recurrence with the use of systemic HRT has been demonstrated in randomised controlled trials. Limited data exist regarding the use of vaginal estrogen, however, no effect on recurrence has been demonstrated., The decision regarding the use of HRT in women with cancer must be individualised and should take into account issues regarding quality of life., Learning objectives To review the evidence regarding the cancer-specific risks, that is, recurrence or death, of HRT in survivors of gynaecological and breast cancer., To provide recommendations for the use of HRT in survivors of gynaecological and breast cancer., Ethical issues How to balance the risks of HRT with quality of life concerns in survivors of gynaecological and breast cancer when evidence to guide our recommendations is limited? [ABSTRACT FROM AUTHOR]

Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1 to 2 years of age to a slower progressive course that causes significant morbidity and early mortality in children and adults. The aim of this study is to better understand the biochemical consequences of glycogen accumulation in the Pompe mouse. We evaluated glycogen metabolism in heart, triceps, quadriceps, and liver from wild type and several strains of GAA−/− mice. Unexpectedly, we observed that lysosomal glycogen storage correlated with a robust increase in factors that normally promote glycogen biosynthesis. The GAA−/− mouse strains were found to have elevated glycogen synthase (GS), glycogenin, hexokinase, and glucose-6-phosphate (G-6-P, the allosteric activator of GS). Treating GAA−/− mice with recombinant human GAA (rhGAA) led to a dramatic reduction in the levels of glycogen, GS, glycogenin, and G-6-P. Lysosomal glycogen storage also correlated with a dysregulation of phosphorylase, which normally breaks down cytoplasmic glycogen. Analysis of phosphorylase activity confirmed a previous report that, although phosphorylase protein levels are identical in muscle lysates from wild type and GAA−/− mice, phosphorylase activity is suppressed in the GAA−/− mice in the absence of AMP. This reduction in phosphorylase activity likely exacerbates lysosomal glycogen accumulation. If the dysregulation in glycogen metabolism observed in the mouse model of Pompe disease also occurs in Pompe patients, it may contribute to the observed broad spectrum of disease severity. [ABSTRACT FROM AUTHOR]

Background: The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes. Methods: A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years. Results: In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ⩾6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed. Conclusions: Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW. Trial Registration: ClinicalTrials.gov NCT00308139 [ABSTRACT FROM AUTHOR]

Abstract: Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1–2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle. [Copyright &y& Elsevier]

Abstract: Antiviral antibodies within the human population remain a barrier to the effective clinical use of viral gene transfer vectors. We have asked whether local, balloon catheter-mediated delivery of a viral vector to the rabbit liver using a hepatic vein might mitigate the neutralizing effects of antiviral antibodies. We have compared directly the ability of adenovirus (Ad2) encoding nuclear-localized β-galactosidase to infect the rabbit liver after local and systemic delivery in both the presence and the absence of defined anti-Ad2 antibody titers. In naive rabbits, local delivery resulted in higher β-galactosidase expression compared to systemic delivery. In the presence of passively administered anti-Ad2 antibodies, local delivery resulted in expression levels that were comparable to those obtained in naive rabbits by systemic delivery. Local delivery also resulted in the majority of expression originating from hepatocytes, even in passively immunized animals, a result that could not be duplicated using the systemic approach. Since systemic delivery of adenovirus in naive animal models results in transgene expression levels often regarded as therapeutic, these results predict that local hepatic vein delivery of a viral vector is a clinically practical approach to mitigate neutralizing antiviral antibodies and generate therapeutic levels of transgene expression. [Copyright &y& Elsevier]

Abstract: Background:: Exenatide (synthetic exendin-4;AC2993) is a 39-amino acid peptide in the new class of antidiabetic agents known as incretin mimetics. In clinical trials, exenatide exhibited glucoregulatory effects (glucose-dependent stimulation of insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying) in patients with type 2 diabetes mellitus (DM). Objective:: The goal of this study was to determine the relative bioavailability of exenatide injected subcutaneously into the abdomen, arm, or thigh. Methods:: Patients with type 2 DM were randomized in an open-label, crossover study to assess relative bioavailability of exenatide (10 μg) injected into the arm and thigh versus injection into the abdomen. Serial plasma exenatide concentrations were measured for 10 hours after injection. A sample size of >24 patients provided ∼80% power to ensure that 90% CIs were within the 80% to 125% interval for the ratios (geometric least squares [LS] means) of AUC0−∞. Results:: Twenty-eight patients were randomized intothe study (mean age, 56 [8] years; glycosylated hemoglobin, 8.0 [1.7]%; body mass index, 33 [5] kg/m2; all values given as mean [SD]). AUC0−∞ values (geometric LS mean SE for SC injections into the abdomen arm and thigh were 63,935 (6608), 59,573 (6157), and 62,148 (6424) pg·/mL, respectively. The AUC (geometric LS mean ratio for relative bioavailability) for arm versus abdomen was 0.93 (geometric 90% CI, 0.82–1.05); for thigh versus abdomen it was 0.97 (geometric 90% CI, 0.86–1.10). Consistent with the observed data, intrasubject variability of AUC0−∞ was low among the 3 treatments (coefficient of variation, 26%). Cmax values (geometric LS mean [SE]) were 220 (24) pg/mL, abdomen; 218 (23) pg/mL, arm; and 193 (21) pg/mL, thigh. The Cmax (geometric LS mean ratio) for arm versus abdomen was 0.99 (geometric 90% CI, 0.85–1.15), and for thigh versus abdomen it was 0.88 (geometric 90% CI, 0.75–1.02). The most common treatment-emergent adverse events were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Three patients received an inadvertent 10-fold overdose and were withdrawn from the study immediately. All experienced severe nausea and vomiting, and 1 patient experienced severe hypoglycemia requiring aid. All recovered without mishap and were excluded from statistical and tolerability results. There were no adverse events related to the injection or the injection site. Conclusion:: In this study of patients with type 2DM, SC administration of exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability. [Copyright &y& Elsevier]

CpG-reduced, CMV-based plasmid DNA constructs encoding human α-galactosidase A and factor IX were injected into C57Bl/6, BALB/c, and CD1 mice using hydrodynamics-based delivery of plasmid DNA (pDNA), and gene expression was monitored for 6 months. Linearized and supercoiled pDNAs were compared for their abilities to support long-term expression and to generate immune responses to the transgene product. In all mouse strains supercoiled CpG-reduced pDNA encoding α-galactosidase A and factor IX generated higher and more sustained levels of circulating gene product than their supercoiled CpG-replete analogs. Linearizing supercoiled CpG-reduced pDNA did not significantly increase levels of circulating gene product beyond levels supercoiled CpG-reduced pDNA could achieve. Linearizing supercoiled CpG-replete pDNA vectors significantly increased expression compared to their supercoiled CpG-replete analogs, but the increase was short-lived or subtherapeutic. Regardless of vector, liver depot expression did not elicit significant antibody responses to human α-galactosidase A or factor IX. Taken together, these data suggest that a clinically acceptable hydrodynamics-based approach targeting the liver combined with CpG-reduced pDNA vectors may represent a viable option for individuals with hemophilia, a lysosomal storage disease, or other disease in which prolonged depot expression of a therapeutic protein from the liver is desirable. [Copyright &y& Elsevier]

Patients may use crowdfunding to solicit donations, typically from multiple small donors using internet-based means, to offset the financial toxicity of cancer care. To describe crowdfunding campaigns by gynecologic cancer patients and to compare campaign characteristics and needs expressed between patients with cervical, uterine, and ovarian cancer. We queried the public crowdfunding forum GoFundMe.com for "cervical cancer," "uterine cancer," and "ovarian cancer." The first 200 consecutive posts for each cancer type fundraising within the United States were analyzed. Data on campaign goals and needs expressed were manually extracted. Descriptive statistics and bivariate analyses were performed. Among the 600 fundraising pages, the median campaign goal was $10,000 [IQR $5000–$23,000]. Campaigns raised a median of 28.6% of their goal with only 8.7% of campaigns reaching their goal after a median of 54 days online. On average, ovarian cancer campaigns had higher monetary goals, more donors, and larger donation amounts than cervical cancer campaigns and raised more money than both cervical and uterine cancer campaigns. Campaigns were fundraising to support medical costs (80–85%) followed by lost wages (36–56%) or living expenses (27–41%). Cervical cancer campaigns reported need for non-medical costs more frequently than uterine or ovarian cancer campaigns. States without Medicaid expansions (31% of the national population) were over-represented among cervical cancer and uterine cancer, but not ovarian cancer campaigns. Crowdfunding pages reveal patients fundraising for out-of-pocket costs in the thousands of dollars and a wide range of unmet financial needs based on cancer type. • Patients crowdfunding for gynecologic cancer care had a median campaign goal of $10,000 and raised a median of $2800. • Campaigns raised a median of 28.6% of their goal. After a median of 54 days online, only 8.7% had reached their goal. • 82% of campaigns fundraised for medical expenses, while 32% fundraised for non-medical living expenses. • 32% of campaigns fundraised to offset lost wages, which was more common among cervical cancer campaigns. • States without an implemented Medicaid expansion were over-represented among cervical and uterine cancer campaigns. [ABSTRACT FROM AUTHOR]

To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence. • Many patients are not adherent to NCCN surveillance guidelines at time of recurrence detection. • Physical exam is an important for detecting uterine cancer recurrence. • Non-NCCN directed imaging detected almost half of asymptomatic recurrences. • Asymptomatic recurrence is detected earlier in patients who adhere to NCCN posttreatment surveillance guidelines. [ABSTRACT FROM AUTHOR]

This research investigates medium‐scale disruptive events to understand how these events influence communication and coordination between two interdependent systems (i.e., the water system and the public health system). Medium‐scale events are events that are often overlooked as routine as they occur with more frequency than large‐scale events, yet they have the potential to provide important information about the state and vulnerability of systems, and, if not managed appropriately, can cascade into larger‐scale crises. A survey of US public drinking water systems (N = 471) shows that medium‐scale events promote coordination, especially when those events have a public dimension. Findings also reveal that several features of water systems including surface water sources, system size, and ownership types are associated with higher levels of interaction with the public health systems. Additionally, a network analysis identifies three distinct subnetworks that engage in emergency response activities. The strength of the working relationship was strongly associated with coordinated emergency responses, coordinated public responses, planning, and technical assistance. Findings have implications for both theory and crisis management. [ABSTRACT FROM AUTHOR]

Policy entrepreneurs are thought to be instrumental in agenda change, yet we lack knowledge of how legislators perceive their role in the agenda formation process. Using data from a national survey of state legislators, we examine whether entrepreneurs shape the legislative agenda on disaster preparedness and relief, which types of entrepreneurs are most influential, and what strategies they use in their interactions with legislators. The results indicate that legislators who report contact with policy entrepreneurs are more likely to have introduced related legislation, evidence of the important link between entrepreneurs and policy change. While entrepreneurs utilize a variety of different strategies, the analysis reveals policymakers are particularly receptive to entrepreneurs who provide new and reliable information. This finding suggests the influence of entrepreneurs lies not only in their ability to define problems and build coalitions, but also in their distinctive ability to provide information to elected officials, an important role that has largely been overlooked by existing literature. [ABSTRACT FROM AUTHOR]

The article discusses the author's sentiments over the suicide act committed by one of her high school students. When the author heard about the news, she barely felt anything for she thought she barely know the student. But after sometime, she remembered the letter writing project she asked her student to do. Through that project she came to realize the suicidal intention of her student.

An abstract of the article "Balloon Catheter-Mediated Hepatic Vein Delivery of a Viral Vector Mitigates Neutralization by Anti-Viral Antibodies and Results in Efficient Transduction of Rabbit Liver," by Bradley L. Hodgesand colleagues is presented.

Objectives: Endometrial cancer due to loss of mismatch repair proteins may be caused by epigenetic or genetic factors. Complete profiling is not routinely performed in clinical practice. We sought to explore outcomes of women with mismatch repair deficiency (MMRd) due to epigenetic MLH-1 promoter hypermethylation (MMRd-MLH). We hypothesize that MMRd-MLH correlates with worse clinical outcomes in endometrial cancer. Methods: Under an IRB protocol, we retrospectively identified patients with endometrioid endometrial adenocarcinoma undergoing hysterectomy at our institution from 2016-2020. These patients underwent routine immunohistochemical testing for MMRd, with subsequent genetic testing or methylation studies for loss of MMR proteins. We examined patient data in three cohorts: MMR proficient (MMRp), MMRd-MLH, and MMRd deficiency due to germline mutation (MMRd-G). We excluded patients who did not undergo MMR testing and those who were MMR deficient due to other causes. We examined clinical data via univariate and multivariate tests and Kaplan-Meier survival analyses. Results: We identified 327 patients who met the criteria for review. The majority (243, 74%) were MMRp, 74 (23%) were MMRd-MLH, and ten (3%) were MMRd-G. On univariate analysis, we observed no differences in the history of post-menopausal hormone replacement therapy, family history of cancer, personal history of hypertension or diabetes mellitus, or body mass index. We found that when compared to the other two groups, MMRd-MLH patients were more like to have grade 2-3 tumors (p < 0.01) and LVSI (p < 0.001). We identified statistically significant associations between age at surgery (60, 67, and 60 years, respectively) and depth of invasion (0.41cm, 0.67cm, and 0.18cm). We did not observe significant differences in the stage. We identified that MMRd-MLH was associated with pathologic high-intermediate risk factors leading to increased adjuvant therapy in stage I disease (p=0.04). We observed a 4.1% recurrence rate in MMRp compared to 8.1% in the MMRd-MLH group compared to no recurrences in MMRd-G (p = NS). When comparing MMRp and MMRd-MLH in Kaplan-Meier analyses, we observed a statistical difference in disease-free survival favoring those who were MMRp (p = 0.02). Median survival was not reached. There were no significant differences in overall survival between MMRp and MMRd-MLH. We did not identify independent prognostic factors for recurrence when controlling for age, stage, grade, or MMR status. [Display omitted] Conclusions: MMRd-MLH is associated with LVSI, higher grade, deeper tumor invasion, and a significantly higher rate of adjuvant therapy. We observed patients with MMRd-MLH were more likely to recur despite adjuvant therapy. MMRd-MLH may represent a poor prognostic factor and a target for further adjuvant therapy. [ABSTRACT FROM AUTHOR]

Whereas policy change is often characterized as a gradual and incremental process, effective crisis response necessitates that organizations adapt to evolving problems in near real time. Nowhere is this dynamic more evident than in the case of COVID‐19, which forced subnational governments to constantly adjust and recalibrate public health and disease mitigation measures in the face of changing patterns of viral transmission and the emergence of new information. This study assesses (a) the extent to which subnational policies changed over the course of the pandemic; (b) whether these changes are emblematic of policy learning; and (c) the drivers of these changes, namely changing political and public health conditions. Using a novel dataset analyzing each policy's content, including its timing of enactment, substantive focus, stringency, and similar variables, results indicate the pandemic response varied significantly across states. The states examined were responsive to both changing public health and political conditions. This study identifies patterns of preemptive policy learning, which denotes learning in anticipation of an emerging hazard. In doing so, the study provides important insights into the dynamics of policy learning and change during disaster. [ABSTRACT FROM AUTHOR]

OBJECTIVE- In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-I) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 rag) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks. RESEARCH DESIGN AND METHODS-- In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. RESULTS -- Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean -2.0% [95% CI -2.1 to - 1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≥6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. CONCLUSION -- Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. [ABSTRACT FROM AUTHOR]

Abstract: Background: Myocardial acidosis during cardiac surgery and postoperative troponin I are markers of myocardial damage that have been shown to predict adverse outcomes. We investigated the relationship between troponin I and myocardial tissue pH, patient outcomes, and cost. Methods: Data were prospectively collected on 205 cardiac surgery patients. Troponin I was sampled upon arrival to the intensive care unit (ICU) and every 6 hours thereafter for 24 hours. The lowest pH encountered during aortic cross clamp (LpH) was related to postoperative troponin I on the multivariate level. Multivariate models were constructed to predict adverse events (AE) and cost. Results: LpH was an independent inverse determinant of postoperative troponin I (P = .0067). Troponin I and its interaction with LpH were multivariate predictors of AE (P = .0012; .0001;odds ratio = 6.9, 10.2, respectively). Troponin I independently predicts surgical ICU (SICU) cost (P = .0256). Conclusion: Postoperative troponin I elevation reflects intraoperative myocardial acidosis and damage. The strong relationship between troponin I, AE, and cost indicates the damage incurred is clinically and economically relevant. Strategies to ameliorate intraoperative myocardial tissue acidosis will decrease troponin I release, subsequent AE, and associated costs. [Copyright &y& Elsevier]

The article presents the background, data and results of a study which examined the use of Exenatide once weekly versus twice daily for the treatment of type 2 diabetes. Exenatide falls into a class of antidiabetic agents which are based on potentiation of incretin action called incretin mimetics. The primary endpoint was the change in haemoglobin A1c (HbA1c) at 30 weeks. Charts presenting changes in cardiovascular parameters, incidence of adverse events and plasma glucose levels for Exenatide once a week versus twice a day are presented. A statistical analysis of the data is included. It is reported that Exenatide once weekly produced greater improvements in glycaemic control than Exenatide given twice a day.

Aims: Methionine aminopeptidase 2 (MetAP2) inhibition has been shown to result in significant weight loss and improved glucose control. This Phase 1 clinical trial assessed the safety and tolerability, pharmacokinetics and preliminary efficacy of a novel MetAP2 inhibitor, ZGN‐1061. Methods: This clinical trial included a single ascending dose (SAD) phase in healthy subjects (BMI, 23 to <30 kg/m2) and a multiple ascending dose (MAD) phase in otherwise healthy subjects (BMI, 27 to 40 kg/m2). SAD phase doses, administered subcutaneously (SC), were 0.2, 0.6, 1.2, 2.4, 3.6 and 4.8 mg and the MAD phase evaluated doses of 0.2, 0.6 and 1.8 mg twice weekly SC for 4 weeks. Results: The SAD phase included 39 subjects (ZGN‐1061, N = 28; placebo, N = 11); 90% were male and BMI was 26.4 kg/m2. ZGN‐1061 was well tolerated across all doses, with the most frequent adverse events being mild headache and procedural‐related irritation. There were no severe or serious adverse events. All doses of ZGN‐1061 were rapidly absorbed and cleared, resulting in short duration of exposure that is anticipated to minimize potential off‐drug target risks. The MAD phase included 29 subjects (ZGN‐1061, N = 22; placebo, N = 7); 76% were male and BMI was 33.5 kg/m2. Safety observations were consistent with SAD findings. Efficacy measures in the MAD phase indicated trends for weight change (−1.5 kg total ZGN‐1061 vs −0.2 kg placebo) and other biomarker changes. Conclusions: ZGN‐1061 was well tolerated with no safety signals in all doses tested. In addition, the desired pharmacokinetic profile and preliminary efficacy observations with ZGN‐1061 support evaluation in larger and longer clinical trials. [ABSTRACT FROM AUTHOR]

Progress bringing evidence-based practice (EBP) to community behavioral health (CBH) has been slow. This study investigated feasibility, acceptability, and fidelity outcomes of a program to implement transdiagnostic cognitive therapy (CT) across diverse CBH settings, in response to a policy shift toward EBP. Method: Clinicians (n = 348) from 30 CBH programs participated in workshops and 6 months of consultation. Clinician retention was examined to assess feasibility, and clinician feedback and attitudes were evaluated to assess implementation acceptability. Experts rated clinicians' work samples at baseline, mid-, and end-of-consultation with the Cognitive Therapy Rating Scale (CTRS) to assess fidelity. Results: Feasibility was demonstrated through high program retention (i.e., only 4.9% of clinicians withdrew). Turnover of clinicians who participated was low (13.5%) compared to typical CBH turnover rates, even during the high-demand training period. Clinicians reported high acceptability of EBP and CT, and self-reported comfort using CT improved significantly over time. Most clinicians (79.6%) reached established benchmarks of CT competency by the final assessment point. Mixed-effects hierarchical linear models indicated that CTRS scores increased significantly from baseline to the competency assessment (p < .001), on average by 18.65 points. Outcomes did not vary significantly between settings (i.e., outpatient vs. other). Conclusions: Even clinicians motivated by policy-change rather than self-nomination may feasibly be trained to deliver a case-conceptualization driven EBP with high levels of competency and acceptability. [ABSTRACT FROM AUTHOR]

Objectives: Surveillance follow-up for women with vaginal and vulvar cancer, extrapolated by National Comprehensive Cancer Network (NCCN), includes a physical exam every 3-6 months during the first two years, followed by every 6-12 months for three to five years after treatment. For VAIN, general recommendations for follow-up suggest a physical exam every six months for the first two years and yearly after. For VIN, physical exams every six months for the first five years are recommended. Little is known regarding rates of retention for follow-up in these rare cancers and dysplasia. We sought to explore post-treatment retention for patients with vaginal and vulvar cancer and dysplasia at our institution. Methods: After IRB approval, we retrospectively identified patients treated for vaginal and/or vulvar intraepithelial neoplasia or carcinoma between 2011-2016. Baseline demographic, pathologic, treatment, surveillance, and recurrence data were collected. We examined the continuous and total retention of post-treatment surveillance visits for patients diagnosed with cancer VIN, VAIN, or concomitant VIN and VAIN. Continuous retention was defined as sequential visits no longer than one year apart. Descriptive statistics were used to analyze the data. Results: We identified 40 patients who met the criteria for review. The median age of treatment was 60 years old. Most patients were White (75%), followed by Asian (10%), Black (5%), other (8%), and American Indian (3%). The most common diagnoses were VIN III (25%), VAIN III (22%), and squamous cell carcinoma (22%). Most were treated with wide local excision (42.5%), followed by radical surgery (30%), and laser surgery (15%). The median times for total and continuous post-treatment retention were 27.5 and 21 months, respectively. The median number of visits and pap smears in the first post-treatment year were 2 and 1, respectively. The median number of visits and pap smears in the second post-treatment year were 1 and 1, respectively. Only 29% of patients continued with surveillance in the third post-treatment year. Recurrence was noted in ten patients (25%) with a median time of recurrence of 29 months with a range of 1-69 months. The most common primary diagnoses associated with recurrence were VIN III (40%), VAIN III (20%), VIN II (20%), and squamous cell carcinoma (20%). Conclusions: This is the first baseline assessment of post-treatment surveillance retention for VAIN, VIN, or vulvovaginal carcinoma. We observed that our population generally adheres to NCCN surveillance guidelines during the first year; however, the adherence drops in the following years with a median continuous retention rate of less than two years. Further work is needed to enhance post-treatment surveillance and identify barriers to follow-up for patients. [ABSTRACT FROM AUTHOR]

The efficacy of recombinant enzyme therapy for genetic diseases is limited in some patients by the generation of a humoral immune response to the therapeutic protein. Inducing immune tolerance to the protein prior to treatment has the potential to increase therapeutic efficacy. Using an AAV8 vector encoding human acid α-glucosidase (hGAA), we have evaluated direct intrathymic injection for inducing tolerance. We have also compared the final tolerogenic states achieved by intrathymic and intravenous injection. Intrathymic vector delivery induced tolerance equivalent to that generated by intravenous delivery, but at a 25-fold lower dose, the thymic hGAA expression level was 10,000-fold lower than the liver expression necessary for systemic tolerance induction. Splenic regulatory T cells (Tregs) were apparent after delivery by both routes, but with different phenotypes. Intrathymic delivery resulted in Tregs with higher FoxP3, TGFβ, and IL-10 mRNA levels. These differences may account for the differences noted in splenic T cells, where only intravenous delivery appeared to inhibit their activation. Our results imply that different mechanisms may be operating to generate immune tolerance by intrathymic and intravenous delivery of an AAV vector, and suggest that the intrathymic route may hold promise for decreasing the humoral immune response to therapeutic proteins in genetic disease indications. [ABSTRACT FROM AUTHOR]

The article offers information on an open-label randomized study which compared the efficacy of exenatide with insulin glargine titrated to glucose targets in lowering hemoglobin A1c. The study subjects, which involved adults with type 2 diabetes who had suboptimum glycaemic control, were randomly assigned to add exenatide or insulin glargine to their blood-glucose lowering regimens. Presented in details are the findings of the study. It concludes that exenatide is ideal for patients whose risk for hypoglycemia, weight loss and convenience are particular concerns.

Objective: In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID-->QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.Results: Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean -2.0% [95% CI -2.1 to -1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and 40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. [ABSTRACT FROM AUTHOR]

Many experimental studies have been performed to evaluate mild diabetes effects. However, results are divergent regarding glycemia and insulin measurement, fetal macrossomia, and placental weights. The aim was to investigate repercussions of neonatally-induced mild diabetes on the maternal organism and presence of congenital defects in their offspring in other mild diabetes model. On the day of birth, female offspring were distributed into two groups: Group streptozotocin (STZ): received 100 mg STZ/kg body weight, and Control Group: received vehicle in a similar time period. Maternal weights and glycemias were determined at days 0, 7, 14 and 21 of pregnancy. At day 21 of pregnancy, the rats were anesthetized and a laparotomy was performed to weigh and analyze living fetuses and placentas. The fetuses were classified as small (SPA), appropriate (APA) and large (LPA) for pregnancy age. Fetuses were also analyzed for the presence of external anomalies and processed for skeletal anomaly and ossification sites analysis. Statistical significance was considered as p < 0.05. In STZ group, there was increased glycemia at 0 and 14 days of pregnancy, lower weights throughout pregnancy, higher placental weight and index, an increased proportion of fetuses classified as SPA and LPA, and their fetuses presented with an increased frequency of abnormal sternebra, and absent cervical nuclei, which were not enough to cause the emergence of skeletal anomalies. Thus, this study shows that mild diabetes altered fetal development, characterized by intrauterine growth restriction. Further, the reached glycemia does not lead to any major congenital defects in the fetuses of streptozotocin-induced mild diabetic rats. [ABSTRACT FROM AUTHOR]

Background: Experimental models are necessary to elucidate diabetes pathophysiological mechanisms not yet understood in humans. Objective: To evaluate the repercussions of the mild diabetes, considering two methodologies, on the pregnancy of Wistar rats and on the development of their offspring. Methods: In the 1st induction, female offspring were distributed into two experimental groups: Group streptozotocin (STZ, n = 67): received the β-cytotoxic agent (100 mg STZ/kg body weight - sc) on the 1st day of the life; and Nondiabetic Group (ND, n = 14): received the vehicle in a similar time period. In the adult life, the animals were mated. After a positive diagnosis of pregnancy (0), female rats from group STZ presenting with lower glycemia than 120 mg/dL received more 20 mg STZ/kg (ip) at day 7 of pregnancy (2nd induction). The female rats with glycemia higher than 120 mg/dL were discarded because they reproduced results already found in the literature. In the mornings of days 0, 7, 14 and 21 of the pregnancy glycemia was determined. At day 21 of pregnancy (at term), the female rats were anesthetized and killed for maternal reproductive performance and fetal development analysis. The data were analyzed using Student-Newman-Keuls, Chi-square and Zero-inflated Poisson (ZIP) Tests (p < 0.05). Results: STZ rats presented increased rates of pre (STZ = 22.0%; ND = 5.1%) and post-implantation losses (STZ = 26.1%; ND = 5.7%), reduced rates of fetuses with appropriate weight for gestational age (STZ = 66%; ND = 93%) and reduced degree of development (ossification sites). Conclusion: Mild diabetes led a negative impact on maternal reproductive performance and caused intrauterine growth restriction and impaired fetal development. [ABSTRACT FROM AUTHOR]

Mutations in BRCA1 and BRCA2 increase the risk of epithelial ovarian cancer (EOC). Emerging evidence suggests obesity may influence BRCA tumor biology; body mass index (BMI) appears to correlate with DNA damage in breast epithelium in BRCA women. We hypothesized that obesity negatively influences tumor biology in BRCA women with EOC, and sought to identify correlations with BMI and clinical outcomes in this population. We performed an IRB approved retrospective study. We identified patients with BRCA -associated EOC diagnosed between 1990-2015. All women underwent surgical resection with platinum-based chemotherapy. We abstracted clinical and pathologic data, and calculated BMI at the time of diagnosis. Obesity was examined per WHO criteria of normal weight, overweight, class I obesity, and class II obesity. We performed descriptive statistics with Kaplan-Meier, Cox Proportional Hazards Regression, and univariate analyses. We identified 179 women meeting criteria. Most were BRCA1 (125, or 70%); 53 (30%) were BRCA2 ; and 1 had both a BRCA1 and BRCA2 mutation. The majority had stage III/IV disease (137, 77%) and grade 3 serous histology (168, 94%); 150 patients underwent optimal cytoreduction (87%). BMI was distributed throughout the WHO strata: 101 women had normal weight; 46 were overweight; 20 had class I obesity; 12 had class II obesity. Age, medical comorbidities, and rates of optimal surgical cytoreduction were similar among these groups. In a subcohort of patients with stage III/IV disease, we identified a significant trend between increased BMI strata and poor disease-free survival (35, 32, 25, and 13.5 months, p =0.003). This was also observed for overall disease-specific survival (132, 144, 112, and 72.5 months, p =0.0306). Multivariable analyses of the entire cohort confirmed that age (p =0.035), stage (p <0.001), and BMI (p =0.017) remained significant independent prognosticators after controlling for grade and optimal cytoreduction. [Display omitted] We identified a significant and independent association between BMI and clinical outcome in BRCA positive women with EOC. Factors associated with obesity may negatively influence BRCA associated ovarian cancer biology, and suggest this may be a modifiable risk factor to target for therapy. [ABSTRACT FROM AUTHOR]

Summary: Background: Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer''s disease, with carriers of the ɛ4 allele being at increased risk and carriers of the ɛ2 allele possibly at decreased risk compared with non-carriers. Our aim was to determine whether possession of an ɛ4 allele would confer children with a neural substrate that might render them at risk for Alzheimer''s disease, and whether carriers of the ɛ2 allele might have a so-called protective cortical morphology. Methods: 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. Findings: Cortical thickness of the left entorhinal region was significantly thinner in ɛ4 carriers than it was in non-ɛ4 carriers (3·79 [SE 0·06] mm, range 1·54–5·24 vs 3·94 [0·03] mm, 2·37–6·11; p=0·03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with ɛ4 carriers having the thinnest cortex and ɛ2 carriers the thickest, with ɛ3 homozygotes occupying an intermediate position (left β 0·11 [SE 0·05], p=0·02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy ɛ4 carriers. Interpretation: Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the ɛ4 allele might contribute to risk of Alzheimer''s disease. [Copyright &y& Elsevier]