Interdependence and the cost of uncoordinated responses to COVID-19.

Social distancing is the core policy response to coronavirus disease 2019 (COVID-19). But, as federal, state and local governments begin opening businesses and relaxing shelter-in-place orders worldwide, we lack quantitative evidence on how policies in one region affect mobility and social distancing in other regions and the consequences of uncoordinated regional policies adopted in the presence of such spillovers. To investigate this concern, we combined daily, county-level data on shelter-in-place policies with movement data from over 27 million mobile devices, social network connections among over 220 million Facebook users, daily temperature and precipitation data from 62,000 weather stations, and county-level census data on population demographics to estimate the geographic and social network spillovers created by regional policies across the United States. Our analysis shows that the contact patterns of people in a given region are significantly influenced by the policies and behaviors of people in other, sometimes distant, regions. When just one-third of a state's social and geographic peer states adopt shelter-in-place policies, it creates a reduction in mobility equal to the state's own policy decisions. These spillovers are mediated by peer travel and distancing behaviors in those states. A simple analytical model calibrated with our empirical estimates demonstrated that the "loss from anarchy" in uncoordinated state policies is increasing in the number of noncooperating states and the size of social and geographic spillovers. These results suggest a substantial cost of uncoordinated government responses to COVID-19 when people, ideas, and media move across borders.

DNA nanotherapy for pre-neoplastic cervical lesions.

OBJECTIVE: This study aims to test the hypothesis that targeted nanoparticle delivery of DNA encoding HPV16-regulated diphtheria toxin (DT-A) will result in the death of HPV16-infected cells. MATERIALS AND METHODS: Plasmid constructs containing a HPV16 Long Control Region (LCR) DNA sequence upstream of DT-A or luciferase reporter (Luc) DNA sequences were used to formulate poly(ß-amino ester) nanoparticles. The effect on tumor growth of HPV/DT-A-nanoparticle injection directly into HPV16(+) CaSki human cervical cancer cell-derived xenografts in mice was determined. To evaluate the ability of the HPV16 LCR regulatory sequence to activate gene expression specifically in HPV16-infected cells, mice underwent bioluminescent optical imaging following intraperitoneal injection of HPV/Luc-nanoparticles. The use of Lutrol F127, a thermal-sensitive gel, to target delivery of nanoparticles and subsequent gene expression to cervical epithelial cells was evaluated in ex vivo cultures of mouse cervix and following intravaginal delivery of nanoparticle/gel in mice, as well as in ex vivo cultures of surgical LEEP samples. RESULTS: The selected HPV16 LCR regulatory sequence activates gene expression in both HPV16-infected cells and non-infected cells. However, in the cervix, it is specifically active in epithelial cells. Following exposure of cervical cells to HPV/DT-A-nanoparticles mixed with Lutrol F127 gel, DT-A is expressed and cells die. CONCLUSIONS: An HPV16 DNA sequence that targets gene expression specifically to HPV16-infected cells remains to be discovered. Topical application of a Lutrol F127 thermal gel/nanoparticle mix is illustrative of how to restrict exposure of cells to therapeutic nanoparticles, thereby allowing for targeted DNA delivery to cervical pre-cancerous lesions.

Posthysterectomy cytology screening: indications and clinical implications.

OBJECTIVE: To review the results of patients who were referred for posthysterectomy of abnormal cytology based on screening indications. MATERIALS AND METHODS: We performed a retrospective review of 64 patients who have been referred for posthysterectomy vaginal colposcopy to the gynecologic oncology service. Patients' demographics, clinical features, reason for screening, and final diagnosis were recorded. Patients were divided into 2 groups based on posthysterectomy screening guidelines. Group A was considered to have undergone unnecessary screening based on national guidelines, and group B had risk factors that appropriately called for continued surveillance. The number of colposcopic examinations and the incidence of neoplasia were recorded for each group. RESULTS: The mean age of the patients was 65 years (range = 35-95 y). Group A included 22 patients with history of abnormal cytology posthysterectomy for benign disease. Of the 22 abnormal cytology results, 21 were low-grade squamous intraepithelial lesion (n = 14) or atypical squamous cells of undetermined significance (n = 7) with 1 high-grade squamous intraepithelial lesion. After referral and colposcopy of this group, no neoplasia was found. Group B included 42 total patients. Of these 42 patients, 20 (48%) had a history of cervical intraepithelial neoplasia, 12 (28%) had a history of vaginal intraepithelial neoplasia, 6 (14%) had history of cervical cancer, 2 (5%) had history of diethylstilbestrol exposure, and 2 (5%) had a history of radiation therapy. In group B, 8 (9%) and 1 (2%) of the patients had vaginal intraepithelial neoplasia 2/3 and squamous cell carcinoma, respectively. CONCLUSIONS: Current national guidelines are appropriate. Adherence to these guidelines will decrease intervention and not affect the detection of vaginal neoplasia. Patients with risk factors for lower genital tract neoplasia warrant continued screening after hysterectomy.

The effects of remote work on collaboration among information workers.

The coronavirus disease 2019 (COVID-19) pandemic caused a rapid shift to full-time remote work for many information workers. Viewing this shift as a natural experiment in which some workers were already working remotely before the pandemic enables us to separate the effects of firm-wide remote work from other pandemic-related confounding factors. Here, we use rich data on the emails, calendars, instant messages, video/audio calls and workweek hours of 61,182 US Microsoft employees over the first six months of 2020 to estimate the causal effects of firm-wide remote work on collaboration and communication. Our results show that firm-wide remote work caused the collaboration network of workers to become more static and siloed, with fewer bridges between disparate parts. Furthermore, there was a decrease in synchronous communication and an increase in asynchronous communication. Together, these effects may make it harder for employees to acquire and share new information across the network.

Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A.

The involvement of immune mechanisms in tumor angiogenesis is unclear. Here we describe a new mechanism of tumor vasculogenesis mediated by dendritic cell (DC) precursors through the cooperation of beta-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse beta-defensin-29 recruited DC precursors to tumors and enhanced tumor vascularization and growth in the presence of increased Vegf-A expression. A new leukocyte population expressing DC and endothelial markers was uncovered in mouse and human ovarian carcinomas coexpressing Vegf-A and beta-defensins. Tumor-infiltrating DCs migrated to tumor vessels and independently assembled neovasculature in vivo. Bone marrow-derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A. We show that beta-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: beta-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.

Reducing excessive toxicity in ovarian cancer treatment: a personalized approach.

The management of ovarian cancer is not only multifactorial, but also patient-specific. Different treatment modalities lead to varying levels of toxicity and individual patient responses, necessitating a personalized approach to each treatment plan. Surgical treatment along with first-line and salvage chemotherapies, are standard modalities but recent innovations in chemotherapy delivery and innovative therapy with mechanism of action are reviewed in this article. Extensive experience with standard chemotherapy has outlined algorithms for managing various toxicities. The focus of treatment may ultimately point towards palliative care and clinicians must be comfortable and well versed in addressing this important option. Overall, management of ovarian cancer requires a multi-faceted approach, keeping the patients' overall health, curative goals and well-being at the forefront. It is nearly impossible to detail exact management plans for every possible toxicity for every patient; formulating personalized treatment plans should be based on evidence and clinician experience, all part of the art of medicine. The objective of this article is to highlight the most frequently encountered and most limiting toxicities of current standard therapies for epithelial ovarian cancer.

Interdependent program evaluation: Geographic and social spillovers in COVID-19 closures and reopenings in the United States.

In an interconnected world, understanding policy spillovers is essential. We propose a program evaluation framework to measure policy spillover effects and apply that framework to study the governmental responses to COVID-19 in the United States. Our analysis suggests the presence of social spillovers. We estimate that while state closures directly reduced mobility by 3 to 4%, all other states locking down further decreased mobility in the focal state by 8 to 14%. Similarly, while reopening directly increased mobility by 2 to 3%, all other states' reopening increased mobility in the focal state by 12 to 21%. Our analysis also suggests geographic spillovers: Travel from locked down origins to open destinations increased by 12 to 29%. In contrast, travel from reopened origins to locked down destinations decreased by 6 to 7% for nearby counties and by 14 to 18% for distant counties. Despite its limitations, we believe that our approach takes the first steps toward creating a framework for interdependent program evaluation across policy domains.

Interpretability of excisional biopsies of the cervix: cone biopsy and loop excision.

OBJECTIVE: To compare the results of cold knife conization (CKC) and loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia to determine if excisional method has effects on pathologic interpretation. METHODS: Retrospective review of the perioperative medical records of patients who had a CKC and electrosurgical loop excision of cervix. Patients selected had either primary treatment for cervical intraepithelial neoplasia, suspected invasion, glandular abnormalities or discordant cytology. RESULTS: Among the eligible patients, 61 had CKC and 96 had LEEP. Overall, CKC specimens had interpretable surgical margins more frequently than LEEP (95% vs 85%); however, it was not statistically significant (p=.1). Margins were less likely to be involved with neoplasia in CKC specimens (16% vs 38%; p=.005). Loop electrosurgical excision procedure specimens were less likely to yield a single intact specimen (1.1 vs 1.9; p=.000). Logistic regression showed a significant effect of specimen number (p=.04) on interpretability. CONCLUSION: Current American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for diagnostic excisional procedure used for glandular lesions suggest that the procedure provides "an intact specimen with interpretable margins." Loop electrosurgical excision procedure in the current study was associated with an increased number of specimens that limited interpretability and an increased number of positive margins. Cold knife conization is preferred in cases where margin status is critical, such as glandular lesions and suspected microinvasion. If LEEP is performed, clinicians should attempt to obtain a single surgical specimen maximizing the pathologic interpretation and disease-free margins.

Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer.

Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials.

Varying coefficient model with unknown within-subject covariance for analysis of tumor growth curves.

SUMMARY: In this article we develop a nonparametric estimation procedure for the varying coefficient model when the within-subject covariance is unknown. Extending the idea of iterative reweighted least squares to the functional setting, we iterate between estimating the coefficients conditional on the covariance and estimating the functional covariance conditional on the coefficients. Smoothing splines for correlated errors are used to estimate the functional coefficients with smoothing parameters selected via the generalized maximum likelihood. The covariance is nonparametrically estimated using a penalized estimator with smoothing parameters chosen via a Kullback-Leibler criterion. Empirical properties of the proposed method are demonstrated in simulations and the method is applied to the data collected from an ovarian tumor study in mice to analyze the effects of different chemotherapy treatments on the volumes of two classes of tumors.

Has the use of routine episiotomy decreased? Examination of episiotomy rates from 1983 to 2000.

OBJECTIVE: To determine if practice patterns have been altered by the large body of literature strongly advocating the selective use of episiotomy. METHODS: An electronic audit of the medical procedures database at Thomas Jefferson University Hospital from 1983 to 2000 was completed. Univariate and multivariable models were computed using logistic regression models. RESULTS: Overall episiotomy rates in 34,048 vaginal births showed a significant reduction from 69.6% in 1983 to 19.4% in 2000. Significantly decreased risk of episiotomy was seen based upon year of childbirth (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.86, 0.87), black race (OR 0.29, 95% CI 0.28, 0.31), and spontaneous vaginal delivery (OR 0.40, 95% CI 0.36, 0.45). Increased association with episiotomy was seen in forceps deliveries (OR 4.04, 95% CI 3.46, 4.72), and with third- or fourth-degree lacerations (OR 4.87, 95% CI 4.38, 5.41). In deliveries with known insurance status, having Medicaid insurance was also associated with a decreased episiotomy risk (OR 0.59, 95% CI 0.54, 0.64). CONCLUSION: There was a statistically significant reduction in the overall episiotomy rate between 1983 and 2000. White women consistently underwent episiotomy more frequently than black women even when controlling for age, parity, insurance status, and operative vaginal delivery.

PTEN expression in tamoxifen-associated endometrial cancers.

UNLABELLED: Tamoxifen is associated with increased rates of endometrial hyperplasia and adenocarcinoma. Our previous work suggested tamoxifen-associated endometrial cancers might be associated with p53 mutations. PTEN, a tumor suppressor gene, is altered in low-grade endometrial carcinoma. This study evaluates PTEN immunohistochemical (IHC) expression in tamoxifen-associated endometrial cancers. MATERIALS AND METHODS: Twenty-eight endometrial carcinoma specimens were examined from patients with a history of breast cancer. Patients who had taken Tamoxifen (15) were compared to non-users (13). IHC staining was performed for PTEN; overexpression was defined as greater than 70% positivity. RESULTS: The mean duration of tamoxifen use was 3.3 years (3-171 months). Four out of 15 (27%) tamoxifen users expressed PTEN compared with 2 out of 13 (15%) of non-users. CONCLUSION: In this study, it appears that tamoxifen-associated endometrial cancers are not significantly different from sporadic endometrial cancer with regards to PTEN IHC expression, although there is a trend towards retained PTEN expression.

Traditional management of invasive cervical cancer.

Cervical carcinoma is staged clinically by examination and simple radiological procedures. CT and MRI can, however, be used to guide management. Prognosis is best made by tumor size. depth of invasion, parametrial involvement, nodal status, LVSI, and histology. CIN III and CIS can be treated by ablative or excisional procedures. Hysterectomy should not be the primary treatment. Microinvasive (<3 mm) Stage IA cervical carcinoma can be treated conservatively with conization in patients who desire fertility, but the standard of care remains simple hysterectomy. Stages IB and IIA can be treated with either radical hysterectomy or radiation therapy dependent upon the patient's health and preference. Risk factors after radical hysterectomy (eg, bulky tumors, deep invasion, involved nodes or margins. LVSI) might warrant adjuvant radiation therapy. Chemoirradiation is the current standard of care for treatment for Stages IIB, III, and [VA. Some clinicians also use this modality in patients with Stage IB disease who are undergoing radiation as the primary treatment. Locally recurrent disease can be treated with either radiation (after radical hysterectomy) or pelvic exeteration (after primary radiation therapy). Exenteration in appropriately selected patients yields 5-year survival rates up to 82% with low complication rates. Many exenterations are aborted intraoperatively because of distant or unresectable disease, however. The incidence of glandular carcinoma of the cervix is rising, particularly in younger women. Cervical carcinoma detected during pregnancy requires the combined efforts of the gynecologic oncologist and the maternal-fetal medical specialist to determine the timing and method of treatment.

Endometrial cancer surgery costs: robot vs laparoscopy.

STUDY OBJECTIVE: To compare surgical costs for endometrial cancer staging between robotic-assisted and traditional laparoscopic methods. DESIGN: Retrospective chart review from November 2005 to July 2006 (Canadian Task Force classification II-3). SETTING: Non-university-affiliated teaching hospital. PATIENTS: Thirty-three women with diagnosed endometrial cancer undergoing hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymph node resection. INTERVENTIONS: Patients underwent either robotic or traditional laparoscopic surgery without randomization. MEASUREMENTS AND MAIN RESULTS: Hospital cost data were obtained for operating room time, instrument use, and disposable items from hospital billing records and provided by the finance department. Separate overall hospital stay costs were also obtained. Mean operative costs were higher for robotic procedures ($3323 vs $2029; p<.001), due in part to longer operating room time ($1549 vs $1335; p=.03). The more significant cost difference was due to disposable instrumentation ($1755 vs $672; p<.001). Total hospital costs were also higher for robotic-assisted procedures ($5084 vs $ 3615; p=.002). CONCLUSION: Robotic surgery costs were significantly higher than traditional laparoscopy costs for staging of endometrial cancer in this small cohort of patients.

Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice.

There is currently no effective therapy for patients with advanced ovarian cancer. To address the need for a more effective treatment for this deadly disease, we conducted preclinical tests in ovarian tumor-bearing mice to evaluate the therapeutic efficacy of using a cationic biodegradable poly(beta-amino ester) polymer as a vector for nanoparticulate delivery of DNA encoding a diphtheria toxin suicide protein (DT-A). The promoter sequences of two genes that are highly active in ovarian tumor cells, MSLN and HE4, were used to target DT-A expression to tumor cells. Administration of DT-A nanoparticles directly to s.c. xenograft tumors and to the peritoneal cavity of mice bearing primary and metastatic ovarian tumors resulted in a significant reduction in tumor mass and a prolonged life span compared to control mice. Minimal nonspecific tissue and blood chemistry toxicity was observed following extended treatment with nanoparticles. DT-A nanoparticle therapy suppressed tumor growth more effectively than treatment with clinically relevant doses of cisplatin and paclitaxel. Our findings suggest that i.p. administration of polymeric nanoparticles to deliver DT-A encoding DNA, combined with transcriptional regulation to target gene expression to ovarian tumor cells, holds promise as an effective therapy for advanced-stage ovarian cancer.

A review of topotecan in combination chemotherapy for advanced cervical cancer.

Treatment of advanced, recurrent or persistent cervical cancer includes radiotherapy and chemotherapy. Radiation has been the primary treatment modality for locoregionally advanced cervical cancer. Concomitant systemic cisplatin chemotherapy and radiation have shown high response rates with improvements in durable remissions and overall survival. Cisplatin has been the standard medication for the treatment of advanced cervical cancer. Combinations with other chemotherapeutic agents have been the subject of clinical trials with varying results. The toxicity of combination chemotherapy and tolerability of patients are other factors that should be considered in the management of patients with advanced disease. Recently topotecan, in combination with cisplatin, achieved increased response and overall survival rates without further compromising the patients' quality of life. This review focuses on the mechanism of action and toxicities of topotecan, as well as its role as a radio-sensitizer and chemotherapeutic agent in the management of advanced, recurrent, or persistent cervical cancer. Other combination modalities and dosages are also discussed.

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation.

Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r = 0.8962, P < 0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P < 0.0001) and nodal metastasis (P = 0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P = 0.0009) and overall (P = 0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.