ST-2560, a selective inhibitor of the NaV1.7 sodium channel, affects nocifensive and cardiovascular reflexes in non-human primates.

BACKGROUND AND PURPOSE: The voltage-gated sodium channel isoform NaV1.7 is a high-interest target for the development of non-opioid analgesics due to its preferential expression in pain-sensing neurons. NaV1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST-2560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of NaV1.7. EXPERIMENTAL APPROACH: Potency of ST-2560 at NaV1.7 and off-target ion channels was evaluated by whole-cell patch-clamp electrophysiology. Effects on nocifensive reflexes were assessed in non-human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely-moving, telemetered NHPs following administration of vehicle and ST-2560. KEY RESULTS: ST-2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000-fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST-2560 (0.1-0.3 mg·kg-1, s.c.) suppressed noxious mechanical- and chemical-evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST-2560 (0.1-1.0 mg·kg-1, s.c.) also produced changes in haemodynamic parameters, most notably a 10- to 20-mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures. CONCLUSIONS AND IMPLICATIONS: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function.

The extent and growth of prior authorization in Medicare Advantage.

OBJECTIVES: To assess trends in the use of prior authorization requirements among Medicare Advantage (MA) plans. STUDY DESIGN: Descriptive quantitative analysis. METHODS: Data were from the CMS MA benefit and enrollment files for 2009-2019, supplemented with area-level data on demographic and provider market characteristics. For each service category, we calculated the annual share of MA enrollees in plans requiring at least some prior authorization and plotted trends over time. We mapped the county-level share of MA enrollees exposed to prior authorization in 2009 vs 2019. We quantified the association between local share of MA enrollees exposed to prior authorization and characteristics of that county in the same year. Finally, we plotted the share of MA enrollees exposed to prior authorization requirements over time for the 6 largest MA carriers. RESULTS: From 2009 to 2019, the share of MA enrollees in plans requiring prior authorization for any service remained stable. By service category, the share of MA enrollees exposed to prior authorization ranged from 30.7% (physician specialist services) to 72.2% (durable medical equipment) in 2019, with most service categories requiring prior authorization more often over time. Several area-level demographic and provider market characteristics were associated with prior authorization requirements, but these associations weakened over time. The use of prior authorization varied widely across plans. CONCLUSIONS: In 2019, roughly 3 in 4 MA enrollees were in a plan requiring prior authorization. Service-level, area-level, and carrier-level patterns suggest a wide range of approaches to prior authorization requirements.

First safety outcomes for rigicon conticlassic® artificial urinary sphincter.

The Rigicon ContiClassic® is a new sphincteric device designed to treat male stress urinary incontinence. This study evaluates the surgical outcomes and safety profile of the first 116 patients who received the implant between September 2021 and April 2022. Data were collected from patient information forms completed at the time of the implant and submitted by implanting surgeons, nursing staff in the Operating Room or company representatives present during the surgery. The study analyzed patient demographics, surgical details, and etiology of incontinence. The mean age of patients was 68.3 years +/- 9.65 yrs. Minimum age was 23 and maximum age was 83. The most common reason for implantation was urinary incontinence (58.6%) after radical prostatectomy. The results showed a revision rate of 6.90%, with three cases of fluid loss, four cases of iatrogenic mistaken sizing, and one case of patient dissatisfaction. There were no reported infections. Kaplan-Meier calculation showed survival rate of 93.2% at 12 months. This study shows the early safety outcomes for the Rigicon ContiClassic® sphincter device to be comparable to others presently on the market.

Demographic, social, and behavioral correlates of SARS-CoV-2 seropositivity in a representative, population-based study of Minnesota residents.

BACKGROUND: Monitoring COVID-19 infection risk in the general population is a public health priority. Few studies have measured seropositivity using representative, probability samples. The present study measured seropositivity in a representative population of Minnesota residents prior to vaccines and assess the characteristics, behaviors, and beliefs of the population at the outset of the pandemic and their association with subsequent infection. METHODS: Participants in the Minnesota COVID-19 Antibody Study (MCAS) were recruited from residents of Minnesota who participated in the COVID-19 Household Impact Survey (CIS), a population-based survey that collected data on physical health, mental health, and economic security information between April 20 and June 8 of 2020. This was followed by collection of antibody test results between December 29, 2020 and February 26, 2021. Demographic, behavioral, and attitudinal exposures were assessed for association with the outcome of interest, SARS-CoV-2 seroprevalence, using univariate and multivariate logistic regression. RESULTS: Of the 907 potential participants from the CIS, 585 respondents then consented to participate in the antibody testing (64.4% consent rate). Of these, results from 537 test kits were included in the final analytic sample, and 51 participants (9.5%) were seropositive. The overall weighted seroprevalence was calculated to be 11.81% (95% CI, 7.30%-16.32%) at of the time of test collection. In adjusted multivariate logistic regression models, significant associations between seroprevalence and the following were observed; being from 23-64 and 65+ age groups were both associated with higher odds of COVID-19 seropositivity compared to the 18-22 age group (17.8 [1.2-260.1] and 24.7 [1.5-404.4] respectively). When compared to a less than $30k annual income reference group, all higher income groups had significantly lower odds of seropositivity. Reporting practicing a number of 10 (median reported value in sample) or more of 19 potential COVID-19 mitigation factors (e.g. handwashing and mask wearing) was associated with lower odds of seropositivity (0.4 [0.1-0.99]) Finally, the presence of at least one household member in the age range of 6 to 17 years old was associated with higher odds of seropositivity (8.3 [1.2-57.0]). CONCLUSIONS: The adjusted odds ratio of SARS-CoV-2 seroprevalence was significantly positively associated with increasing age and having household member(s) in the 6-17 year age group, while increasing income levels and a mitigation score at or above the median were shown to be significantly protective factors.

COVID-19 Vaccine Hesitancy in a Population-Based Study of Minnesota Residents.

COVID-19 continues to be a public health concern in the United States. Although safe and effective vaccines have been developed, a significant proportion of the US population has not received a COVID-19 vaccine. This cross-sectional study aimed to describe the demographics and behaviors of Minnesota adults who have not received the primary series of the COVID-19 vaccine, or the booster shot using data from the Minnesota COVID-19 Antibody Study (MCAS) collected through a population-based sample between September and December 2021. Data were collected using a web-based survey sent to individuals that responded to a similar survey in 2020 and their adult household members. The sample was 51% female and 86% White/Non-Hispanic. A total of 9% of vaccine-eligible participants had not received the primary series and 23% of those eligible to receive a booster had not received it. Older age, higher education, better self-reported health, $75,000 to $100,000 annual household income, mask-wearing, and social distancing were associated with lower odds of hesitancy. Gender, race, and previous COVID-19 infection were not associated with hesitancy. The most frequently reported reason for not receiving a COVID-19 vaccination was safety concerns. Mask-wearing and being age 65 or older were the only strong predictors of lower odds of vaccine hesitancy for both the primary series and booster analyses.

Comparing Dementia Classification by Self-Report and Administrative Records in the National Core Indicators-Aging and Disability Survey: A Predictive Modeling Approach.

Policymakers are interested in the long-term services and supports (LTSS) needs of people living with dementia. The National Core Indicators-Aging and Disability (NCI-AD) survey is conducted to evaluate LTSS care needs. However, dementia reporting in NCI-AD varies across states, and is either obtained from state administrative records or self-reported during the survey. We explored the implications of identifying dementia from administrative records versus self-report. We analyzed 24,569 NCI-AD respondents age 65+, of which 22.4% had dementia. To assess dementia accuracy by data source, we fit separate logistic regression models using the administrative and self-reported subsamples. We applied model coefficients to the population whose dementia status came from the opposite source. Using the administrative model to predict self-reported dementia resulted in higher sensitivity than using the self-report model to predict administrative dementia (43.8% vs. 37.9%). The self-report model's diminished sensitivity suggests administrative records may capture cases of dementia missed by self-report.

Patient-facing job role is associated with SARS-CoV-2 positivity among healthcare workers in long term care facilities in Minnesota, August-December, 2020.

OBJECTIVE: Healthcare workers (HCWs) in long-term care facilities (LTCFs) are disproportionately affected by severe acute respiratory coronavirus virus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). To characterize factors associated with SARS-CoV-2 positivity among LTCF HCWs, we performed a retrospective cohort study among HCWs in 32 LTCFs in the Minneapolis-St Paul region. METHODS: We analyzed the outcome of SARS-CoV-2 polymerase chain reaction (PCR) positivity among LTCF HCWs during weeks 34-52 of 2020. LTCF and HCW-level characteristics, including facility size, facility risk score for resident-HCW contact, and resident-facing job role, were modeled in univariable and multivariable generalized linear regressions to determine their association with SARS-CoV-2 positivity. RESULTS: Between weeks 34 and 52, 440 (20.7%) of 2,130 unique HCWs tested positive for SARS-CoV-2 at least once. In the univariable model, non-resident-facing HCWs had lower odds of infection (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.36-0.70). In the multivariable model, the odds remained lower for non-resident-facing HCW (OR, 0.50; 95% CI, 0.36-0.71), and those in medium- versus low-risk facilities experienced higher odds of testing positive for SARS-CoV-2 (OR, 1.47; 95% CI, 1.08-2.02). CONCLUSIONS: Our findings suggest that COVID-19 cases are related to contact between HCW and residents in LTCFs. This association should be considered when formulating infection prevention and control policies to mitigate the spread of SARS-CoV-2 in LTCFs.

Technological advances in penile implants: past, present, future.

Attempts to "cure" erectile dysfunction (ED) are as old as recorded history. The history of penile prosthetic devices dates back over 500 years, when a French military surgeon designed the first known wooden prosthesis to support micturition. There have since been a great many technological advancements in penile prosthetics. Penile implants for the improvement of sexual function date to the twentieth century. Like all human endeavors, penile prosthesis innovations have progressed via trial and error. This review aims to provide an overview of penile prostheses for the treatment of ED since their introduction in 1936. More specifically, we aim to highlight important advances in penile prosthesis development and discuss dead ends that were abandoned. Highlights include two-piece inflatables, three-piece inflatables, and malleable/semirigid, along with modifications and updates to each basic design that improved both insertion and usability. Dead ends include innovative ideas that were lost to history due to a variety of factors. We also look to the future and discuss expected advances, including remotely activated devices and prostheses designed for special populations, including transgender men.

Association of Primary Care Visit Length With Potentially Inappropriate Prescribing.

Importance: Time is a valuable resource in primary care, and physicians and patients consistently raise concerns about inadequate time during visits. However, there is little evidence on whether shorter visits translate into lower-quality care. Objective: To investigate variations in primary care visit length and quantify the association between visit length and potentially inappropriate prescribing decisions by primary care physicians. Design, Setting, and Participants: This cross-sectional study used data from electronic health record systems in primary care offices across the US to analyze adult primary care visits occurring in calendar year 2017. Analysis was conducted from March 2022 through January 2023. Main Outcomes and Measures: Regression analyses quantified the association between patient visit characteristics and visit length (measured using time stamp data) and the association between visit length and potentially inappropriate prescribing decisions, including inappropriate antibiotic prescriptions for upper respiratory tract infections, coprescribing of opioids and benzodiazepines for painful conditions, and prescriptions that were potentially inappropriate for older adults (based on the Beers criteria). All rates were estimated using physician fixed effects and were adjusted for patient and visit characteristics. Results: This study included 8 119 161 primary care visits by 4 360 445 patients (56.6% women) with 8091 primary care physicians; 7.7% of patients were Hispanic, 10.4% were non-Hispanic Black, 68.2% were non-Hispanic White, 5.5% were other race and ethnicity, and 8.3% had missing race and ethnicity. Longer visits were more complex (ie, more diagnoses recorded and/or more chronic conditions coded). After controlling for scheduled visit duration and measures of visit complexity, younger, publicly insured, Hispanic, and non-Hispanic Black patients had shorter visits. For each additional minute of visit length, the likelihood that a visit resulted in an inappropriate antibiotic prescription changed by -0.11 percentage points (95% CI, -0.14 to -0.09 percentage points) and the likelihood of opioid and benzodiazepine coprescribing changed by -0.01 percentage points (95% CI, -0.01 to -0.009 percentage points). Visit length had a positive association with potentially inappropriate prescribing among older adults (0.004 percentage points; 95% CI, 0.003-0.006 percentage points). Conclusions and Relevance: In this cross-sectional study, shorter visit length was associated with a higher likelihood of inappropriate antibiotic prescribing for patients with upper respiratory tract infections and coprescribing of opioids and benzodiazepines for patients with painful conditions. These findings suggest opportunities for additional research and operational improvements to visit scheduling and quality of prescribing decisions in primary care.

Examining Satisfaction and Quality in Home- and Community-Based Service Programs in the United States: A Scoping Review.

BACKGROUND AND OBJECTIVES: Long-term services and supports in the United States are increasingly reliant on home- and community-based services (HCBS). Yet, little is known about the quality of HCBS. We conducted a scoping review of the peer-reviewed literature to summarize HCBS consumer, provider, and stakeholder satisfaction with services as a means of assessing quality. RESEARCH DESIGN AND METHODS: We searched PubMed, OVID-MEDLINE, and SCOPUS to identify articles published from 2000 to 2021 that reported on studies describing a U.S.-based study population. Articles were grouped into 3 categories: drivers of positive consumer satisfaction, drivers of negative consumer satisfaction, and provider and stakeholder perspectives on satisfaction. RESULTS: Our final sample included 27 articles. Positive perceptions of quality and reported satisfaction with services were driven by consistent, reliable, and respectful care providers, and adoption of person-centered models of service delivery. Mistreatment of consumers, staff turnover, training, service interruptions, and unmet functional needs were drivers of negative consumer perceptions of quality. Support for caregivers and emphasis on training were identified by providers and stakeholders as important for providing satisfactory services. DISCUSSION AND IMPLICATIONS: Multiple data challenges limit the ability to systematically evaluate HCBS program quality; however, studies examining single programs found that HCBS consumers are more satisfied and associate higher quality with easy-to-navigate programs and professional staff. Efforts to expand HCBS should also include requirements to systematically evaluate quality outcomes.

Unmet Needs for Help With Mobility Limitations Among Older Adults Aging in Place: The Role of Rurality.

OBJECTIVES: This study identifies differences in unmet mobility needs among older adults living in rural versus urban areas. METHODS: We used data from Round 9 of the National Health and Aging Trends Study (NHATS), limiting our analyses to respondents who had not moved since baseline (average housing tenure of 27 years; n = 3343). We conducted bivariate and multivariate analyses to detect rural/urban differences in unmet mobility needs, adjusting for socio-demographics, health status, and housing characteristics. RESULTS: Rural residence was associated with higher odds of any unmet mobility needs for older adults aging in place (adjusted odds ratio: 1.64, 95% confidence interval: 1.10-2.44, p < .05). The relationship between rurality and unmet needs for help with mobility limitations remained significant in fully adjusted models. DISCUSSION: Rural older adults aging in place have greater unmet needs for help with mobility limitations. This study highlights several important gaps in supporting rural older adults aging in place.

Is there still a place for malleable penile implants in the United States? Wilson's Workshop #18.

The use of semirigid rod penile prosthesis for the management of erectile dysfunction was first described over 85 years ago. Since then, there have been numerous design advancements leading to improved overall durability, concealability, rigidity, and natural feel. However, the inflatable penile prosthesis (IPP) still has a higher patient satisfaction rate and is currently the most commonly inserted prostheses in the United States. There are still certain situations and conditions where the simplicity of a rod may be preferred over an IPP. A pair of semirigid rods has been shown to have less risk of malfunction and need for revision surgery. In addition, patients with poor manual dexterity, those undergoing a salvage for infection prosthesis and those with a prolonged (> 48 h) priapic episode may be better served with a rod than an IPP. Finally, in patients compromised by infection or priapism, the rods can later successfully be exchanged for an IPP with potentially longer, wider cylinders with resultant greater patient satisfaction.

Penile prosthesis salvage: a historical look at the Mulcahy technique and a review of the latest literature.

Historically, management of inflatable penile prosthesis infection was explantation of the device with delayed reimplantation at a later date. In 1991, this paradigm was challenged when early attempts at washout and immediate salvage proved successful. The clinical experiences and data generated over the past 30 years have allowed implanters to refine their salvage procedures to improve patient outcomes. In this article, we review the original Mulcahy technique for salvage and discuss updates to this protocol based on recent data.

Discovery of Selective Inhibitors of NaV1.7 Templated on Saxitoxin as Therapeutics for Pain.

The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of NaV1.7. Most inhibitors of NaV1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate NaV1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.

Associations Between Use of Paid Help and Care Experiences Among Medicare-Medicaid Enrolled Older Adults With and Without Dementia.

OBJECTIVES: Community-living older Medicare and Medicaid enrollees ("dual-enrollees") have high care needs and commonly receive paid and unpaid long-term services and supports (LTSS) to help with routine activities. Little is known about whether receiving paid help or individuals' state and neighborhood environmental context ("LTSS environment") relates to dual-enrollees' care experiences. METHODS: We examine a sample of n = 979 community-dwelling dual-enrollees with disabilities from 2011 to 2015 National Health and Aging Trends Study, linked to measures of neighborhood disadvantage and state Medicaid home and community-based services (HCBS) generosity. Logistic regression models stratified by dementia status assess associations between paid help and: (a) adverse consequences due to unmet care needs, and (b) participation restrictions in valued activities, among dual-enrollees with and without dementia, adjusting for individual and LTSS environmental characteristics. RESULTS: Use of paid help was greater for those with (versus without) dementia (46.9% vs. 37.8%). Neighborhood disadvantage was associated with greater use of paid help among dual-enrollees living with dementia. High state Medicaid HCBS generosity was associated with the use of paid help, regardless of dementia status. Dual-enrollees with dementia receiving paid help had higher odds of experiencing adverse consequences due to unmet need (adjusted odds ratio = 2.05; 95% confidence interval 1.16-3.61; p = .02)-no significant associations were observed for participation restrictions. Use of paid help and LTSS environment were not significantly associated with care experiences for dual-enrollees without dementia. DISCUSSION: Findings highlight the complexities of caring for dual-enrollees, particularly those with dementia, and emphasize the need to strengthen the delivery of paid care with considerations for the LTSS environment.

Nuances of subcoronal inflatable penile prosthesis for physicians accustomed to penoscrotal approach.

In a special miniseries highlighting the different surgical techniques to the inflatable penile prosthesis (IPP), Wilson's Workshop seeks to bring forth skill considerations for the modern implanter. Each work is authored by a highly regarded surgeon who has truly honed the art of their respective approach. Today, most implanters are comfortable with either the penoscrotal or suprapubic incision. The following work directs the spotlight onto a much newer and less known technique, IPP implant via the subcoronal incision. SHP leads the Urology Center of Excellence in Seoul, South Korea, and has implanted more than 700 IPPs using the subcoronal approach since 2015. Here, he will share the clinical pearls of this novel incision gathered through trial and error over many repetitions. We are hopeful that this work will peak the interest of inquisitive minds and help disseminate improved implant techniques.

Role of NaV 1.7 in action potential conduction along human bronchial vagal afferent C-fibres.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the role of NaV 1.7 in action potential conduction in C-fibres in the bronchial branches of the human vagus nerve. EXPERIMENTAL APPROACH: Bronchial branches of the vagus nerve were dissected from human donor tissue. The C-wave of the electrically evoked compound action potential was quantified in the absence and presence of increasing concentrations of the selective NaV 1.7 blocking drugs, PF-05089771 and ST-2262, as well as the NaV 1.1, 1.2, and 1.3 blocking drug ICA121-431. The efficacy and potency of these inhibitors were compared to the standard NaV 1 blocker, tetrodotoxin. We then compared the relative potencies of the NaV 1 blockers in inhibiting the C-wave of the compound action potential, with their ability to inhibit parasympathetic cholinergic contraction of human isolated bronchi, a response previously shown to be strictly dependent on NaV 1.7 channels. KEY RESULTS: The selective NaV 1.7 blockers inhibited the C-wave of the compound action potential with potencies similar to that observed in the NaV 1.7 bronchial contractions assay. Using rt-PCR, we noted that NaV 1.7 mRNA was strongly expressed and transported down the vagus nerve bundles. CONCLUSIONS AND IMPLICATIONS: NaV 1.7 blockers can prevent action potential conduction in the majority of vagal C-fibres arising from human bronchi. Blockers of NaV 1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fibre activation in inflammatory airway disease, responses that include coughing as well as reflex bronchoconstriction and secretions.