Locally administered nanosuspension increases delivery of estradiol for the treatment of vaginal atrophy in mice.

Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy.

Investigating inhibitors of 1-deoxy-d-xylulose 5-phosphate synthase in a mouse model of UTI.

The rising rate of antimicrobial resistance continues to threaten global public health. Further hastening antimicrobial resistance is the lack of new antibiotics against new targets. The bacterial enzyme, 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), is thought to play important roles in central metabolism, including processes required for pathogen adaptation to fluctuating host environments. Thus, impairing DXPS function represents a possible new antibacterial strategy. We previously investigated a DXPS-dependent metabolic adaptation as a potential target in uropathogenic Escherichia coli (UPEC) associated with urinary tract infection (UTI), using the DXPS-selective inhibitor butyl acetylphosphonate (BAP). However, investigations of DXPS inhibitors in vivo have not been conducted. The goal of the present study is to advance DXPS inhibitors as in vivo probes and assess the potential of inhibiting DXPS as a strategy to prevent UTI in vivo. We show that BAP was well-tolerated at high doses in mice and displayed a favorable pharmacokinetic profile for studies in a mouse model of UTI. Further, an alkyl acetylphosphonate prodrug (homopropargyl acetylphosphonate, pro-hpAP) was significantly more potent against UPEC in urine culture and exhibited good exposure in the urinary tract after systemic dosing. Prophylactic treatment with either BAP or pro-hpAP led to a partial protective effect against UTI, with the prodrug displaying improved efficacy compared to BAP. Overall, our results highlight the potential for DXPS inhibitors as in vivo probes and establish preliminary evidence that inhibiting DXPS impairs UPEC colonization in a mouse model of UTI.IMPORTANCENew antibiotics against new targets are needed to prevent an antimicrobial resistance crisis. Unfortunately, antibiotic discovery has slowed, and many newly FDA-approved antibiotics do not inhibit new targets. Alkyl acetylphosphonates (alkyl APs), which inhibit the enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), represent a new possible class of compounds as there are no FDA-approved DXPS inhibitors. To our knowledge, this is the first study demonstrating the in vivo safety, pharmacokinetics, and efficacy of alkyl APs in a urinary tract infection mouse model.

Nanomedicine for Maternal and Fetal Health.

Conception, pregnancy, and childbirth are complex processes that affect both mother and fetus. Thus, it is perhaps not surprising that in the United States alone, roughly 11% of women struggle with infertility and 16% of pregnancies involve some sort of complication. This presents a clear need to develop safe and effective treatment options, though the development of therapeutics for use in women's health and particularly in pregnancy is relatively limited. Physiological and biological changes during the menstrual cycle and pregnancy impact biodistribution, pharmacokinetics, and efficacy, further complicating the process of administration and delivery of therapeutics. In addition to the complex pharmacodynamics, there is also the challenge of overcoming physiological barriers that impact various routes of local and systemic administration, including the blood-follicle barrier and the placenta. Nanomedicine presents a unique opportunity to target and sustain drug delivery to the reproductive tract and other relevant organs in the mother and fetus, as well as improve the safety profile and minimize side effects. Nanomedicine-based approaches have the potential to improve the management and treatment of infertility, obstetric complications, and fetal conditions.

Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo.

BACKGROUND & AIMS: Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes. METHODS: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis. RESULTS: Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation. CONCLUSIONS: The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.

In vitro and ex vivo models for evaluating vaginal drug delivery systems.

Vaginal drug delivery systems are often preferred for treating a variety of diseases and conditions of the female reproductive tract (FRT), as delivery can be more targeted with less systemic side effects. However, there are many anatomical and biological barriers to effective treatment via the vaginal route. Further, biocompatibility with the local tissue and microbial microenvironment is desired. A variety of in vitro and ex vivo models are described herein for evaluating the physicochemical properties and toxicity profile of vaginal drug delivery systems. Deciding whether to utilize organoids in vitro or fresh human cervicovaginal mucus ex vivo requires careful consideration of the intended use and the formulation characteristics. Optimally, in vitro and ex vivo experimentation will inform or predict in vivo performance, and examples are given that describe utilization of a range of methods from in vitro to in vivo. Lastly, we highlight more advanced model systems for other mucosa as inspiration for the future in model development for the FRT.

Next generation strategies for preventing preterm birth.

Preterm birth (PTB) is defined as delivery before 37 weeks of gestation. Globally, 15 million infants are born prematurely, putting these children at an increased risk of mortality and lifelong health challenges. Currently in the U.S., there is only one FDA approved therapy for the prevention of preterm birth. Makena is an intramuscular progestin injection given to women who have experienced a premature delivery in the past. Recently, however, Makena failed a confirmatory trial, resulting the Center for Drug Evaluation and Research's (CDER) recommendation for the FDA to withdrawal Makena's approval. This recommendation would leave clinicians with no therapeutic options for preventing PTB. Here, we outline recent interdisciplinary efforts involving physicians, pharmacologists, biologists, chemists, and engineers to understand risk factors associated with PTB, to define mechanisms that contribute to PTB, and to develop next generation therapies for preventing PTB. These advances have the potential to better identify women at risk for PTB, prevent the onset of premature labor, and, ultimately, save infant lives.

Avoiding a Sticky Situation: Bypassing the Mucus Barrier for Improved Local Drug Delivery.

The efficacy of drugs administered by traditional routes is limited by numerous biological barriers that preclude reaching the intended site of action. Further, full body systemic exposure leads to dose-limiting, off-target side effects. Topical formulations may provide more efficacious drug and nucleic acid delivery for diseases and conditions affecting mucosal tissues, but the mucus protecting our epithelial surfaces is a formidable barrier. Here, we describe recent advances in mucus-penetrating approaches for drug and nucleic acid delivery to the ocular surface, the female reproductive tract, the gastrointestinal tract, and the airways.

A Methodologic Approach to Conducting a Statewide Community Needs Assessment of Pediatric Palliative Care and Hospice Resources.

CONTEXT: Prior studies have indicated that pediatric palliative care (PPC) resources vary across states and within regions in a state. Evaluating the current status of PPC and pediatric hospice care through a community needs assessment (CNA) can help address the gaps that exist to improve and increase access to PPC for children in need. OBJECTIVES: Using the state of Georgia as an example, the process, methods, lessons learned, and limitations in conducting a statewide PPC CNA are described. METHODS: A mixed-method descriptive design with multiple stages incorporating different methodological approaches was used. These included literature review, community profile, survey and interview questionnaire development, windshield survey, identifying and interviewing key informants, and quantitative survey of the state's hospice organizations. Key themes (providing PPC, PPC environment, collaboration, and future of PPC) and subthemes emerged, which were then triangulated across all existing data collection techniques to provide recommendations of varying feasibility and importance. RESULTS: Described in a subsequent article (Johnson K.A. et al.). CONCLUSION: This approach can be used by other state organizations, coalitions, governments, or national organizations looking to perform a CNA of palliative care, hospice resources, or could be applied to other geographical settings or types of care.

Comparison of Women from Georgia and Contiguous States Who Obtained Abortions in Georgia, 1994-2016.

OBJECTIVES: To determine trends for Georgia and contiguous state residents seeking abortions in Georgia between 1994 and 2016. METHODS: We analyzed aggregate vital statistics data, collected in Georgia, on Georgia residents (n = 675,995) and contiguous state residents (Alabama, Florida, North Carolina, South Carolina, Tennessee) (n = 76,232) obtaining abortion and delivery services in Georgia between 1994 and 2016. We examined demographic, pregnancy, and abortion characteristics using counts, ratios, and χ2 tests of proportion. RESULTS: Of the data analyzed, 10.1% of all abortions were for contiguous state residents. The number of abortions in Georgia for contiguous state residents increased 35.3% from 1994 to 2016 (from n = 3115 to n = 4216) while it decreased for Georgia residents by 11.1% (from n = 32,934 to n = 29,264). Contiguous state residents exhibited a higher abortion ratio (1115) compared to Georgia women (224). These populations exhibited statistically significant differences across all variables and time points. Both populations demonstrated similar trends in ethnicity, race, education, marital status, and age. However, contiguous state residents were more likely to obtain an abortion at ≥ 20 weeks gestational age (13.8%) and obtained a lower proportion of suction curettage abortions (60.0%) and a higher proportion of dilation and evacuation procedures (31.9%). They were also less likely to be primigravid. CONCLUSIONS FOR PRACTICE: Women from neighboring states seek abortions in Georgia later in gestation and may therefore lack affordable, safe, early abortion care in their home states. Understanding trends in travel for abortion can allow providers and policymakers to better respond to the needs of patients.

Successful programmatic approaches to facilitating IUD uptake: CARE's experience in DRC.

BACKGROUND: Achieving the unfinished agenda towards sexual and reproductive health and rights requires overcoming remaining barriers to contraceptive uptake, which can be method-specific. Women's uptake of the IUD is poor across sub-Saharan Africa. The objective of this paper is to identify the reasons for comparatively high IUD use observed in a CARE project in DRC, together with the programmatic characteristics which facilitated uptake. METHODS: Qualitative data were collected in 2015 as part of a reproductive health project in the DRC. Using purposive sampling, 15 focus group discussions took place with IUD users, users of other methods and non-users of modern contraception as well as their male partners. Eighteen in-depth interviews were conducted with health providers, project staff, community health workers and local stakeholders to capture a range of experiences. Data were analyzed using content theory approach and contextualized through a review of routine monitoring data. RESULTS: In an area with practically no previous IUD use, 38,662 new FP clients were served during the first 5 years of the project and 82% (31,569) chose long-acting or permanent methods. Over 10,000 clients chose an IUD, representing 30% of the total FP clients. Key informants expressed mainly positive views about the IUD and quality of service. Concerns related to method insertion, which some perceived as too intimate or shameful. Findings indicate that this uptake reflects effective supply chains, good provider training and supervision and multiple communication strategies including those which target men. Community engagement was enhanced by local stakeholders' participation in sensitization and quality assurance as well in analysis of data for decision-making. CONCLUSIONS: The findings of the paper showed that by involving local stakeholders in addressing structural and socio-cultural barriers to women's free access to FP, programs can positively influence quality of service and method mix as well as knowledge and attitudes surrounding FP use and thus improve the uptake of FP in general and IUDs in particular, even in conflict-affected settings. A Theory of Change for enhancing IUD provision within family planning programs is suggested.

Prostatic Artery Embolization for Benign Prostatic Hyperplasia: Patient Evaluation, Anatomy, and Technique for Successful Treatment.

Symptomatic benign prostatic hyperplasia is a common condition in the aging population that results in bothersome lower urinary tract symptoms and decreased quality of life. Patients often are treated with medication and offered surgery for persistent symptoms. Transurethral resection of the prostate is considered the traditional standard of care, but several minimally invasive surgical treatments also are offered. Prostatic artery embolization (PAE) is emerging as an effective treatment option with few reported adverse effects, minimal blood loss, and infrequent overnight hospitalization. The procedure is offered to patients with moderate to severe lower urinary tract symptoms and depressed urinary flow due to bladder outlet obstruction. Proper patient selection and meticulous embolization are critical to optimize results. To perform PAE safely and avoid nontarget embolization, interventional radiologists must have a detailed understanding of the pelvic arterial anatomy. Although the prostatic arteries often arise from the internal pudendal arteries, several anatomic variants and pelvic anastomoses are encountered. Prospective cohort studies, small randomized controlled trials, and meta-analyses have shown improved symptoms after treatment, with serious adverse effects occurring rarely. This article reviews the basic principles of PAE that must be understood to develop a thriving PAE practice. These principles include patient evaluation, review of surgical therapies, details of pelvic arterial anatomy, basic principles of embolization, and an overview of published results. Online supplemental material is available for this article. ©RSNA, 2019.

Vessel sealing comparison: old school is still hip.

BACKGROUND: Ligation with either absorbable or non-absorbable sutures has been the traditional state of the art, but a proliferation of technology now offers a host of methods to close and divide vessels. Only limited data are available that objectively compare different vessel sealing methods. The objective of this study was to compare a broad variety of methods of surgical vessel closure in a reproducible, independent, standardized test-to-failure ex vivo pressure challenge. METHODS: Ten of the most common surgical sealing devices were represented in this study, including both mechanical and energy devices. Unfixed porcine carotid arteries were selected for testing. They were connected to a pump, and automated controlled infusion was initiated. Upon identification of a leak at the source of sealing, the maximum pressure in mmHg was logged. RESULTS: There were a total of 184 trials conducted using the 10 vessel sealing methods. The average burst pressure across all trials was 1100 mmHg with a range of 51.3-5171 mmHg. Suture-based methods displayed the highest average pressure until failure. Stapling methods showed the lowest burst pressures. All methods showed mean burst pressures above the "physiologically relevant" level of 250 mmHg. CONCLUSIONS: This study presents an independent, reproducible, ex vivo comparison of multiple methods of surgical arterial closure. In these laboratory conditions, tests to failure demonstrated widely varying sealing strength, highly dependent on method. All hemostatic modalities tested are capable of securing vessels safely and well above physiologic blood pressures, while suture-based methods were significantly stronger than other mechanical methods or modern energy devices.

Staffing patterns of primary care practices in the comprehensive primary care initiative.

PURPOSE: Despite growing calls for team-based care, the current staff composition of primary care practices is unknown. We describe staffing patterns for primary care practices in the Centers for Medicare and Medicaid Services (CMS) Comprehensive Primary Care (CPC) initiative. METHODS: We undertook a descriptive analysis of CPC initiative practices' baseline staffing using data from initial applications and a practice survey. CMS selected 502 primary care practices (from 987 applicants) in 7 regions based on their health information technology, number of patients covered by participating payers, and other factors; 496 practices were included in this analysis. RESULTS: Consistent with the national distribution, most of the CPC initiative practices included in this study were small: 44% reported 2 or fewer full-time equivalent (FTE) physicians; 27% reported more than 4. Nearly all reported administrative staff (98%) and medical assistants (89%). Fifty-three percent reported having nurse practitioners or physician assistants; 47%, licensed practical or vocational nurses; 36%, registered nurses; and 24%, care managers/coordinators-all of these positions are more common in larger practices. Other clinical staff were reported infrequently regardless of practice size. Compared with other CPC initiative practices, designated patient-centered medical homes were more likely to have care managers/coordinators but otherwise had similar staff types. Larger practices had fewer FTE staff per physician. CONCLUSIONS: At baseline, most CPC initiative practices used traditional staffing models and did not report having dedicated staff who may be integral to new primary care models, such as care coordinators, health educators, behavioral health specialists, and pharmacists. Without such staff and payment for their services, practices are unlikely to deliver comprehensive, coordinated, and accessible care to patients at a sustainable cost.

Toward understanding EHR use in small physician practices.

This article presents insights into the use of electronic health records (EHRs) by small physician practices participating in a CMS pay-for-performance demonstration. Site visits to four States reveal slow movement toward improved EHR use. Factors facilitating use of EHRs include customization of EHR products and being owned by a larger organization. Factors limiting use of EHRs include system limitations, cost, and lack of strong incentives to improve. Practices in one State were moving more vigorously toward improved EHR use than those in the other States. Many practices also increased use of medical assistants after implementing EHRs.

Adaptation of the preventive intervention program for depression for use with predominantly low-income Latino families.

This paper describes the process for and safety/feasibility of adapting the Beardslee Preventive Intervention Program for Depression for use with predominantly low income, Latino families. Utilizing a Stage I model for protocol development, the adaptation involved literature review, focus groups, pilot testing of the adapted manual, and open trial of the adapted intervention with 9 families experiencing maternal depression. Adaptations included conducting the intervention in either Spanish or English, expanding the intervention to include the contextual experience of Latino families in the United States with special attention to cultural metaphors, and using a strength-based, family-centered approach. The families completed preintervention measures for maternal depression, child behavioral difficulties, global functioning, life stresses, and an interview that included questions about acculturative stressors, resiliency, and family awareness of parental depression. The postintervention interview focused on satisfaction, distress, benefits of the adapted intervention, and therapeutic alliance. The results revealed that the adaptation was nonstressful, perceived as helpful by family members, had effects that seem to be similar to the original intervention, and the preventionists could maintain fidelity to the revised manual. The therapeutic alliance with the preventionists was experienced as quite positive by the mothers. A case example illustrates how the intervention was adapted.

Impacts of a disease management program for dually eligible beneficiaries.

The LifeMasters Supported SelfCare demonstration program provides disease management (DM) services to Florida Medicare beneficiaries who are also enrolled in Medicaid and have congestive heart failure (CHF), diabetes, or coronary artery disease (CAD). The population-based program provides primarily telephonic patient education and monitoring services. Findings from the randomized, intent-to-treat design over the first 18 months of operations show virtually no overall impacts on hospital or emergency room (ER) use, Medicare expenditures, quality of care, or prescription drug use for the 33,000 enrollees. However, for beneficiaries with CHF who resided in high-cost South Florida counties, the program reduced Medicare expenditures by 9.6 percent.

Practical approach for using Medicare data to estimate costs for cost-effectiveness analysis.

Many methods have been used to measure costs for cost-effectiveness analysis in healthcare. A central challenge in cost estimation is determining the direct cost of medical goods and services from a societal perspective. This review applies the methodology for calculating Medicare reimbursements for physician services, hospital services and medications as a means of estimating healthcare costs from a US societal perspective. This review provides the tools and information needed to calculate direct medical costs related to in- and outpatient services provided by physicians and hospitals, as well as drug costs using Medicare reimbursement data. The data used in calculating Medicare reimbursements was obtained from the Centers for Medicare and Medicaid Services website. Methods for estimating costs for a particular service in a specific location using Medicare and Medicaid Services are described and demonstrated. A method based on Medicare data that uses the unadjusted geographic practice cost index and standard hospital base rate to estimate healthcare costs that can be generalized to the US population is described and demonstrated. This review provides cost-effectiveness analysts with the tools needed to calculate healthcare service costs for economic research. It contains links to all websites needed for obtaining Medicare and Medicaid Services data and provides a step-by-step analysis of the methodology involved in calculating costs. A practical guide for applying the methodology used by Medicare and Medicaid Services to calculate direct medical costs in order to estimate US societal costs in cost-effectiveness analysis is provided.