Hard flaccid syndrome symptoms, comorbidities, and self-reported efficacy and satisfaction of treatments: a cross-sectional survey.

Hard flaccid syndrome (HFS) is a poorly understood condition with no formal consensus on its definition. We aimed to advance the understanding of HFS by evaluating symptom prevalence, cause of symptom onset, comorbidities, and self-reported efficacy and satisfaction with current treatments. An online, open, 42-question survey on Qualtrics with purposive and convenience sampling methods was conducted between May 9 and June 9, 2023 on participants self-identifying as having HFS. Participants were recruited through social media platforms. Only 58.0% of participants reported their HFS symptoms began following a specific incident/injury. Changes in penis shape/size (92.3%) and rigid penis when not erect (90.9%) were the most common complaints. Activities such as laying down and stretching improved symptoms in 73.0% and 44.1% of the participants, respectively, while masturbation and standing worsened symptoms in 75.9%, and 64.5% of the participants, respectively. Pudendal neuralgia (16.9%) was the most prevalent comorbid condition. Of those who participated in therapies, phosphodiesterase-5 (PDE5) inhibitor treatment had the highest patient global impression of change (PGIC) score (2.6 ± 1.1), indicating little to moderate improvement in symptoms. All other therapies scored between 1 and 2, indicating no change to little improvement in symptoms: pelvic floor physical therapy (PFPT) (1.8 ± 0.9), shockwave therapy (1.6 ± 1.1), diet/nutrition changes (1.6 ± 0.8), nerve blocks (1.6 ± 0.8), muscle relaxants (1.5 ± 0.6), anti-inflammatory medications (1.5 ± 0.7), cognitive therapy (1.4 ± 0.7), and nerve pain medications (1.4 ± 0.5). Overall, a direct injury to the penis may not necessarily be the only cause of HFS for some patients, and current therapies generally do not benefit most patients. A better understanding of the root causes of HFS and innovative treatment strategies are greatly needed for HFS patients.

A scoping review: sexual activity and functioning before and after surgery for femoroacetabular impingement (FAI), labral tears, and hip dysplasia.

INTRODUCTION: There is limited information on sexual activity and functioning for patients with hip abnormalities, specifically femoroacetabular impingement (FAI), labral tears, and hip dysplasia, before and after surgical interventions. OBJECTIVES: The aim of this review was to synthesize the existing literature on sexual activity and functioning for patients with FAI, labral tears, and/or hip dysplasia before and after their respective surgeries. METHODS: We performed a rigorous, comprehensive search on multiple databases including PubMed, EMBASE, CINAHL, and Web of Science. Subject headings and a search string of key terms including Medical Subject Headings were used systematically to search these databases. The reference list was reviewed with an additional reviewer to reduce bias. RESULTS: A total of 726 articles were found during the search, which were narrowed down to 22 articles that included at least 1 hip abnormality in relation to sexual functioning, sexual pain, or sexual activity. FAI, labral tears, and hip dysplasia can affect sexual activity, functioning, and positioning, and corrective surgery generally improves these metrics. Surgery improved vulvodynia, clitorodynia, and scrotal pain symptoms for some patients, though arthroscopy resulted in some instances of temporary pudendal nerve dysfunction. CONCLUSION: This review may serve as an important resource for surgeons, healthcare providers, researchers, physical therapists, and patients to understand the relationship between the hips and sexual functioning, and to bridge the gaps among the disciplines of orthopedics, pelvic floor physiology, and sexual health. Hip anatomy impacts sexual activity, functioning, and positioning as well as vulvodynia and scrotal pain symptoms for some patients, and a comprehensive hip evaluation by a qualified hip specialist should be considered for patients with such complaints.

Beyond Primary Care: Renewing the Community Health Center Vision for Today's Health Crisis.

United States community health centers address socioeconomic and environmental conditions and provide comprehensive primary care despite market forces that reinforce a medical model. Collaborating with 14 health center organizations, the RCHN Community Health Foundation promoted the original and broader health center vision of health, launching its population health management initiative in 2015. Although participating organizations were recognized as patient-centered medical homes and achieved rewards for quality, most identified gaps in their capacity for population health management. These challenges, addressed through peer learning and local initiatives, included engaging target populations, care coordination, socioeconomic and clinical data collection, and working with nontraditional local organizations. With relatively small funding, the zeal and enthusiasm for population health was revitalized among health center staff. The current pandemic and growing national concern for health disparities represents an opportunity to expand this broader vision of population health and to sustain it as the COVID-19 pandemic eventually subsides.

Application of a Scavenger Receptor A1-Targeted Polymeric Prodrug Platform for Lymphatic Drug Delivery in HIV.

We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine.

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented.

Choosing between medical management and liver transplant in urea cycle disorders: A conceptual framework for parental treatment decision-making in rare disease.

Urea cycle disorders (UCD) are rare inherited metabolic disorders caused by deficiencies of enzymes and transporters required to convert neurotoxic ammonia into urea. These deficiencies cause elevated blood ammonia, which if untreated may result in death, but even with optimal medical management, often results in recurrent brain damage. There are two major treatments for UCD: medical management or liver transplantation. Both are associated with mortality and morbidity but the evidence comparing outcomes is sparse. Thus, families face a dilemma: should their child be managed medically, or should they undergo a liver transplant? To (a) describe the factors that contribute to treatment choice among parents of children diagnosed with UCD and to (b) organise these factors into a conceptual framework that reflects how these issues interrelate to shape the decision-making experience of this population. Utilising grounded theory, qualitative data were collected through semi-structured interviews with parents (N = 35) and providers (N = 26) of children diagnosed with UCD and parent focus groups (N = 19). Thematic content analysis and selective and axial coding were applied. The framework highlights the life-cycle catalysts that frame families' personal perceptions of risks and benefits and describes the clinical, personal, social, and system factors that drive treatment choice including disease severity, stability, and burden, independence, peer experiences, and cost, coverage and access to quality care. Findings equip providers with evidence upon which to prepare for productive patient interactions about treatment options. They also provide a foundation for the development of patient-centred outcome measures to better evaluate effectiveness of treatments in this population.

Total drug quantification in prodrugs using an automated elemental analyzer.

Polymeric prodrugs have become an increasingly popular strategy for improving the pharmacokinetic properties of active pharmaceutical ingredients (API). Therefore, identifying a robust method for quantification of the API in these prodrug products is a key part of the drug development process. Current drug quantification methods include hydrolysis followed by reversed phase high-performance liquid chromatography (RP-HPLC), size exclusion chromatography (SEC)-based molecular weight determination, and mass spectrometry. These methods tend to be time-consuming and often require challenging method development. Here, we present a comparative study highlighting the automated elemental analyzer as a facile approach to drug quantification in this up-and-coming class of therapeutics. A polymeric prodrug using poly(L-lysine succinylated) (PLS) and the drug lamivudine (LAM) was prepared and analyzed using the elemental analyzer in comparison to the traditional approaches of hydrolysis followed by RP-HPLC and SEC using multi-angle light scattering (MALS) detection. The elemental analysis approach showed excellent agreement with the conventional methods but proved much less laborious, highlighting this as a rapid and sensitive analytical method for the quantitative determination of drug loading in polymeric prodrug products.

Effectiveness of Evidence-Based Asthma Interventions.

BACKGROUND AND OBJECTIVES: Researchers often struggle with the gap between efficacy and effectiveness in clinical research. To bridge this gap, the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) study adapted an efficacious, randomized controlled trial that resulted in evidence-based asthma interventions in community health centers. METHODS: Children (aged 5-12 years; N = 590) with moderate to severe asthma were enrolled from 3 intervention and 3 geographically/capacity-matched control sites in high-risk, low-income communities located in Arizona, Michigan, and Puerto Rico. The asthma intervention was tailored to the participant's allergen sensitivity and exposure, and it comprised 4 visits over the course of 1 year. Study visits were documented and monitored prospectively via electronic data capture. Asthma symptoms and health care utilization were evaluated at baseline, and at 6 and 12 months. RESULTS: A total of 314 intervention children and 276 control children were enrolled in the study. Allergen sensitivity testing (96%) and home environmental assessments (89%) were performed on the majority of intervention children. Overall study activity completion (eg, intervention visits, clinical assessments) was 70%. Overall and individual site participant symptom days in the previous 4 weeks were significantly reduced compared with control findings (control, change of -2.28; intervention, change of -3.27; difference, -0.99; P < .001), and this result was consistent with changes found in the rigorous evidence-based interventions. CONCLUSIONS: Evidence-based interventions can be successfully adapted into primary care settings that serve impoverished, high-risk populations, reducing the morbidity of asthma in these high-need populations.

Health Centers after Fifty Years: Lessons from the Health Disparities Collaboratives.

The fertile social movements of the 1960s in the United States gave birth to the community health center model. During the past 50 years, health centers have emerged as a national primary care institution serving over 20 million of the nation's most vulnerable people. Founded on the shared health center mission and commitment to collective action, the Health Disparities Collaboratives (HDC) provided a cultural and social milieu for accelerated learning as well as a homegrown system and infrastructure for collaborative learning and improvement. Although the HDC only existed during the years from 1999-2006, they generated positive health outcomes and strengthened the capacity of health centers for quality improvement. After a description of the history and the characteristics of the HDC, six recommendations are presented for the re-design and implementation of a second-generation health center learning and improvement system.

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation.

One-pot polyglycidol nanogels via liposome master templates for dual drug delivery.

Polyglycidol-based nanohydrogels (nHGs) have been prepared by optimizing the use of liposome master templates resulting in a high-yielding and more practical one-pot process to provide materials capable of carrying drugs of adverse chemical nature. The nanogels prepared with the one-pot method showed favorable kinetics for the release of either Nile Red (NR) or lysozyme (LYS), loaded with gel precursors such as semi-branched poly(glycidol allylglycidyl ether), PEG dithiol (1KDa), a free radical initiator and liposomal lipids at the liposome formation step. This process is superior to a comparable step-wise traditional approach and circumvents loading of the gel precursors with the hydrophilic drug into preformed liposome templates. A thiol-ene crosslinking reaction accomplishes the formation of the nanonetwork resulting in nHGs prepared in the traditional step-wise (nHG-SW) approach and the one-pot (nHG-OP) process. Both nanogel networks were characterized in terms of particle size and zeta (ζ) potential with average values of 148nm±39nm and -25.9mV±9.2 for the nHG-SW and 132nm±32 and -23.1mV±9.7 for the nHG-OPs. Loading efficiency for both of the nanogels with NR was determined by spectrophotometry to be 28% (nHP-SW) and 31% (nHP-OP). The LYS loading was based on the target loading of 10µg/mg for both nanogels found to be 84% and 86% for the nHG-SW and nHP-OP, respectively. As proof of concept for combination drug delivery, the in vitro release of both drug mimics, NR and LYS, were monitored under physiologically relevant conditions by an optimized dialysis method. The implementation of the multi-functional and semi-branched polyglycidol is recognized as the main contributor for the observed highly controlled release of proteins that are otherwise rapidly released from common PEG-based nanogel networks. Furthermore, the one-pot process led to be the most favorable drug delivery system based on the release kinetics pointing to a denser polymer network.

Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.

We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.

Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.

Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFß. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1(flox/flox) bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx (-/-) mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.

Nanosponge formation from organocatalytically-synthesized poly(carbonate) copoplymers.

Advanced organocatalytic synthesis methods were employed to prepare linear poly(carbonate)s with control over functional group incorporation and molecular weight. Pendant allyl or epoxide groups served as reaction partners in thiol-ene click or epoxide-amine reactions with ethylene oxide-containing crosslinking groups to form a panel of six novel poly(carbonate) nanosponges with crosslinking densities ranging from 5%, 10% and 20% via an intermolecular chain-crosslinking approach.

The diabetes primary prevention initiative interventions focus area: a case study and recommendations.

BACKGROUND: In 2005, CDC began the Diabetes Primary Prevention Initiative Interventions Focus Area (DPPI-IFA), which funded five state Diabetes Prevention and Control Programs (DPCPs) to translate diabetes primary prevention trials into real-world settings by developing and implementing a framework for state-level diabetes primary prevention. PURPOSE: The purpose of this case study, conducted in 2007, was to describe DPPI-IFA implementation, including facilitators and challenges to the initiative. METHODS: Case studies of the five DPCPs in the DPPI-IFA involving site visits with key informant interviews of state staff and partners and archival record collection. RESULTS: Partners recruited for DPPI-IFA activities included local or state public health agencies (three of five DPCPs); regional or state nonprofit organizations (five DPCPs); businesses or employers (three DPCPs); and healthcare organizations (four DPCPs). The DPCPs implemented a variety of interventions in three main domains: diabetes primary prevention and prediabetes awareness, screening activities and lifestyle interventions, and prediabetes-related health policy efforts. Preliminary outcomes are described at the individual and organization/partnership levels. Results suggest the importance of utilizing preexisting partnerships to extend work into diabetes prevention, providing even small amounts of funding to partners, and prior program planning for diabetes prevention. Challenges for the DPPI-IFA included recruiting participants, establishing links with providers to obtain diagnostic testing for people screened for prediabetes, and offering a lifestyle intervention. CONCLUSIONS: The DPPI-IFA represents a unique effort by state public health programs in the translation of diabetes primary prevention trials into real-world settings. The experiences of the DPPI-IFA programs offer valuable lessons for future community-based diabetes prevention initiatives, especially regarding the need to strengthen clinical-community partnerships for referral of people with prediabetes to evidence-based lifestyle programs.