Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.

Starvation sensing by mycobacterial RelA/SpoT homologue through constitutive surveillance of translation.

The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner. This loss is also observed in nonstarved cells using mutations in Rsh that block its interaction with the ribosome, indicating that Rsh association with the ribosome is important for Rsh stability. The cryo-EM structure of the Rsh-bound 70S ribosome in a translation initiation complex reveals unknown interactions between the ACT domain of Rsh and components of the ribosomal L7/L12 stalk base, suggesting that the aminoacylation status of A-site tRNA is surveilled during the first cycle of elongation. Altogether, we propose a surveillance model of Rsh activation that originates from its constitutive interaction with the ribosomes entering the translation cycle.

Overactive bladder negatively affects erectile function and promotes premature ejaculation: findings from large representative population-level study.

PURPOSE: The effect of overactive bladder (OAB) on sexual health has been evaluated extensively for women but much less for men. Therefore, the aim of this study was to evaluate the relationship between OAB and men's sexual activity and the effect of OAB on erectile dysfunction (ED) and premature ejaculation (PE) in a large representative cohort of men at the population level. METHODS: This study was based on computer-assisted web interviews that used validated questionnaires. The most recent census and the sample size estimation calculations were employed to produce a population-representative pool. RESULTS: The study included 3001 men, representative of the population in terms of age and place of residence. The frequency of sexual intercourse was higher for respondents without OAB symptoms compared with persons who had OAB (p = 0.001), but there was no association between OAB symptoms and number of sexual partners (p = 0.754). Regression models did not confirm the effect of OAB on sexual activity (odds ratio 0.993, CI 0.974-1.013, p = 0.511). Both ED and PE were more prevalent in respondents with OAB symptoms compared with persons who lacked those symptoms (p < 0.001). Importantly, the effect of OAB on ED or PE was independent of age, comorbidities, and lifestyle habits (regression coefficients of 0.13 and 0.158 for ED and PE, respectively). CONCLUSION: Overactive bladder did not significantly affect men's sexual activity, but it significantly correlated with ED and PE. Our results suggest a need in daily clinical practice to screen for OAB symptoms for persons who report ED or PE.

Urinalysis is predictive for absence of urinary tract infection in men with and without catheters.

OBJECTIVES: To determine accuracy of negative urinalysis (UA) for predicting negative urine culture and the absence of urinary tract infection (UTI), and optimal urine culture growth cutoff for UTI diagnosis in men with and without urinary catheters. SUBJECTS AND METHODS: UAs with urine cultures within 1 week from adult men were identified and evaluated. Predictive values for the absence of UTI (absence of ≥1 of the following criteria: documentation of UTI diagnosis, antibiotic prescription, uropathogen presence on culture) were calculated. RESULTS: In total, 22 883 UAs were included. Negative UA had a high predictive value for negative urine culture (0.95, 95% confidence interval [CI]: 0.94-0.95) and absence of UTI (0.99, CI: 0.99-0.995) in the overall cohort. Negative UA also had a high predictive value for negative urine culture (0.93, CI: 0.90-0.95) and absence of UTI (0.99, CI: 0.98-0.999) in those with indwelling urinary catheters. The traditional threshold of culture growth of 100 000 colony-forming units (CFU)/mL did not capture 22% of UTIs. CONCLUSION: UA exhibits high predictive value for negative urine culture and absence of UTI in men, supporting a protocol wherein culture is only performed in the context of abnormal UA. The traditional 100 000 CFU/mL cut-off may have not captured a subset of UTI in the male population, and warrants further investigation.

Sacral neuromodulation device biofilm differs in the absence and presence of infection, harbors antibiotic resistance genes, and is reproducible in vitro.

INTRODUCTION/PURPOSE: Sacral neuromodulation (SNM) is effective therapy for overactive bladder refractory to oral therapies, and non-obstructive urinary retention. A subset of SNM devices is associated with infection requiring surgical removal. We sought to compare microbial compositions of explanted devices in the presence and absence of infection, by testing phase, and other clinical factors, and to investigate antibiotic resistance genes present in the biofilms. We analyzed resistance genes to antibiotics used in commercially-available anti-infective device coating/pouch formulations. We further sought to assess biofilm reconstitution by material type and microbial strain in vitro using a continuous-flow stir tank bioreactor, which mimics human tissue with an indwelling device. We hypothesized that SNM device biofilms would differ in composition by infection status, and genes encoding resistance to rifampin and minocycline would be frequently detected. MATERIALS/METHODS: Patients scheduled to undergo removal or revision of SNM devices were consented per IRB-approved protocol (IRB 20-415). Devices were swabbed intraoperatively upon exposure, with controls and precautions to reduce contamination of the surrounding field. Samples and controls were analyzed with next-generation sequencing and RT-PCR, metabolomics, and culture-based approaches. Associations between microbial diversity or microbial abundance, and clinical variables were then analyzed using t-tests and ANOVA. Reconstituted biofilm deposition in vitro using the bioreactor was compared by microbial strain and material type using plate-based assays and scanning electron microscopy. RESULTS: Thirty seven devices were analyzed, all of which harbored detectable microbiota. Proteobacteria, Firmicutes and Actinobacteriota were the most common phyla present overall. Beta-diversity differed in the presence versus absence of infection (p = 0.014). Total abundance, based on normalized microbial counts, differed by testing phase (p < 0.001), indication for placement (p = 0.02), diabetes mellitus (p < 0.001), cardiac disease (p = 0.008) and history of UTI (p = 0.008). Significant microbe-metabolite interaction networks were identified overall and in the absence of infection. 24% of biofilms harbored the tetA tetracycline/minocycline resistance gene and 53% harbored the rpoB rifampin resistance gene. Biofilm was reconstituted across tested strains and material types. Ceramic and titanium did not differ in biofilm deposition for any tested strain. CONCLUSIONS: All analyzed SNM devices harbored microbiota. Device biofilm composition differed in the presence and absence of infection and by testing phase. Antibiotic resistance genes including to rifampin and tetracycline/minocycline, which are used in commercially-available anti-infective pouches, were frequently detected. Isolated organisms from SNM devices demonstrated the ability to reconstitute biofilm formation in vitro. Biofilm deposition was similar between ceramic and titanium, materials used in commercially-available SNM device casings. The findings and techniques used in this study together provide the basis for the investigation of the next generation of device materials and coatings, which may employ novel alternatives to traditional antibiotics. Such alternatives might include bacterial competition, quorum-sensing modulation, or antiseptic application, which could reduce infection risk without significantly selecting for antibiotic resistance.

Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection.

Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.

Outcomes of sequential third-line therapies in patients with refractory overactive bladder.

INTRODUCTION: Sacral neuromodulation (SNM) and onabotulinumtoxinA (BoNTA) injection are third-line therapies for overactive bladder (OAB). Although the efficacy of each third-line treatment has been well established in clinical trials, there is far less information about performing one third-line therapy after the other. Our aim is thus to investigate the outcomes of post-SNM BoNTA and post-BoNTA SNM as "second" third-line treatments. METHODS: We retrospectively reviewed all OAB patients who had both SNM and BoNTA between 2013 and 2022. The primary endpoint was the response rates (>50% improvements) of the second third-line treatments. Secondary endpoints were the proportion of the patients who achieved total dry, the duration of treatments of patients who had significant responses, and risk factors that are associated with treatment response or duration of treatments. RESULTS: A total of 172 patients had two third-line therapies. There were 104 patients who had post-SNM BoNTA and 68 patients who had post-BoNTA SNM. In the post-SNM BoNTA group, 62.5% (65/104) had significant responses after BoNTA treatment. In the post-BoNTA SNM group, 61.8% (44/68) had significant responses after SNM treatment. The proportions of patients who became dry were 21.2% and 23.5%, respectively. In the post-SNM BoNTA group, spinal pathology is associated with a lower probability of a significant response (48.9% vs. 73.7%, p-value = 0.0105). CONCLUSIONS: BoNTA or SNM remains a viable option for refractory OAB after patients fail from one another. Spinal pathology is associated with a poorer response of post-SNM BoNTA.

An Icon of Painless Parker.

The discovery of two unaccredited photographs purported to be of Painless Parker occasions a discussion of the notorious "outlaw" dentist's historical significance. It is argued that social media threaten to have performance eclipse clinical skills in dentistry - a process that can be sourced to Parker's vaudevillian antics.

Clinical and experimental treatment of allergic asthma with an emphasis on allergen immunotherapy and its mechanisms.

Allergen immunotherapy (AIT) is currently the only form of treatment that modifies allergic asthma. Pharmacotherapy alone seeks to control the symptoms of allergic asthma, allergic rhinitis, and other atopic conditions. In contrast, AIT can induce long-term physiological modifications through the immune system. AIT enables individuals to live improved lives many years after treatment ends, where they are desensitized to the allergen(s) used or no longer have significant allergic reactions upon allergen provocation. The leading forms of treatment with AIT involve injections of allergen extracts with increasing doses via the subcutaneous route or drops/tablets via the sublingual route for several years. Since the initial attempts at this treatment as early as 1911 by Leonard Noon, the mechanisms by which AIT operates remain unclear. This literature-based review provides the primary care practitioner with a current understanding of the mechanisms of AIT, including its treatment safety, protocols, and long-term efficacy. The primary mechanisms underlying AIT include changes in immunoglobulin classes (IgA, IgE, and IgG), immunosuppressive regulatory T-cell induction, helper T cell type 2 to helper T cell type 1 cell/cytokine profile shifts, decreased early-phase reaction activity and mediators, and increased production of IL-10, IL-35, TGF-ß, and IFN-γ. Using the databases PubMed and Embase, a selective literature search was conducted searching for English, full-text, reviews published between 2015 and 2022 using the keywords (with wildcards) "allerg*," "immunotherap*," "mechanis*," and "asthma." Among the cited references, additional references were identified using a manual search.

First in Human Subjects Testing of the UroMonitor: A Catheter-free Wireless Ambulatory Bladder Pressure Monitor.

PURPOSE: Urodynamics is the standard method of diagnosing bladder dysfunction, but involves catheters and retrograde bladder filling. With these artificial conditions, urodynamics cannot always reproduce patient complaints. We have developed a wireless, catheter-free intravesical pressure sensor, the UroMonitor, which enables catheter-free telemetric ambulatory bladder monitoring. The purpose of this study was twofold: to evaluate accuracy of UroMonitor pressure data, and assess safety and feasibility of use in humans. MATERIALS AND METHODS: Eleven adult female patients undergoing urodynamics for overactive bladder symptoms were enrolled. After baseline urodynamics, the UroMonitor was transurethrally inserted into the bladder and position was confirmed cystoscopically. A second urodynamics was then performed with the UroMonitor simultaneously transmitting bladder pressure. Following removal of urodynamics catheters, the UroMonitor transmitted bladder pressure during ambulation and voiding in private. Visual analogue pain scales (0-5) were used to assess patient discomfort. RESULTS: The UroMonitor did not significantly alter capacity, sensation, or flow during urodynamics. The UroMonitor was also easily inserted and removed in all subjects. The UroMonitor reproduced bladder pressure, capturing 98% (85/87) of voiding and nonvoiding urodynamic events. All subjects voided with only the UroMonitor in place with low post-void residual volume. Median ambulatory pain score with the UroMonitor was rated 0 (0-2). There were no post-procedural infections or changes to voiding behavior. CONCLUSIONS: The UroMonitor is the first device to enable catheter-free telemetric ambulatory bladder pressure monitoring in humans. The UroMonitor appears safe and well tolerated, does not impede lower urinary tract function, and can reliably identify bladder events compared to urodynamics.

Inherited ichthyosis as a paradigm of rare skin disorders: Genomic medicine, pathogenesis, and management.

Great advances have been made in the field of heritable skin disorders using next-generation sequencing (NGS) technologies (ie, whole-genome sequencing, whole-exome sequencing, whole-transcriptome sequencing, and disease-targeted multigene panels). When NGS first became available, the cost and lack of access to these technologies were limiting factors; however, with decreasing sequencing costs and the expanding knowledge base of genetic skin diseases, fundamental awareness of NGS has become prudent. The heritable ichthyoses comprise a genotypically and phenotypically heterogeneous group of monogenic keratinization disorders characterized by persistent scaling, with at least 55 distinct genes currently implicated in causing nonsyndromic and syndromic forms of the disease. By providing a simplified overview of available NGS techniques and applying them in the context of ichthyosis, one of the most common genodermatoses, we hope to encourage dermatologists to offer, when appropriate, genetic testing earlier in patients with unsolved presentations. With the aid of NGS, dermatologists can provide diagnostic certainty in cases of suspected genodermatoses and offer potentially life-changing genome-guided and targeted therapies as they become available.

Cognitive impairment does not impact sacral neuromodulation implant rates for overactive bladder.

OBJECTIVE: To evaluate the impact of cognitive impairment (CI) diagnoses on sacral neuromodulation (SNM) outcomes in older patients. MATERIALS AND METHODS: We completed a retrospective review of all patients aged ≥55 years who underwent test-phase SNM (peripheral nerve evaluation (PNE) or stage 1) for overactive bladder (OAB) between 2014 and 2021 within a large multi-regional health system. Patient demographics, relevant comorbidities, CI diagnoses (dementia or mild CI), and SNM procedures were recorded. Logistic regression modeling was performed to evaluate the impact of CI on SNM implantation rates. RESULTS: Five-hundred and ten patients underwent SNM test phase (161 PNE, 349 Stage 1) during the study period. The mean age was 71.0(8.5) years, and most (80.6%) were female. Overall, 52(10.1%) patients had a CI diagnosis at the time of SNM, and 30 (5.8%) were diagnosed at a median of 18.5 [9.25, 39.5] months after SNM. Patients with CI diagnoses were older, with more comorbidities, and were more likely to undergo PNE. Univariable comparison found no difference in implantation rate based on pre-SNM CI (85.4% vs. 76.9%, p = 0.16). Multivariable analysis identified PNE (OR 0.43, 95% CI 0.26-0.71), age (OR 0.96, 95%CI 0.93-0.98), and prior beta-3 agonist use (OR 0.60, 95% CI 0.37-0.99) but not CI or dementia as independent negative predictors of implantation. Implanted patients had a median follow-up of 25 [12.0, 55.0] months. Explant and revision rates did not differ according to CI. CONCLUSION: Patients with OAB and CI diagnoses proceed to SNM implant at rates similar to patients without CI diagnoses. A diagnosis of CI should not necessarily exclude patients from SNM therapy for refractory OAB.

Effect of pulse width variations on sacral neuromodulation for overactive bladder symptoms: A prospective randomized crossover feasibility study.

INTRODUCTION/BACKGROUND: The pulse width (PW) parameter in sacral neuromodulation (SNM) is understudied, with no evidence-based guidance available on optimal PW for urinary indications. The aim of this prospective, randomized, single-blinded, 3 × 3 cross over design study was to estimate the effect of two PW settings (60 µs, 420 µs) compared to the industry standard (210 µs) on SNM efficacy, quality of life, and device parameters in patients who were stable and satisfied with their SNM treatment. METHODS/MATERIALS: Eligible patients were previously implanted and had urge incontinence or urgency-frequency with satisfaction on SNM at time of enrollment. Patients completed a 3-day voiding diary, validated questionnaires, and device interrogations with sensory threshold assessment at baseline and after a 4-week period on each of the three PW settings, to which they were randomized. Eighteen participants completed the study, as called for by power analysis. RESULTS: Eighteen patients were enrolled in the study. Mean age was 68 years and implant duration at the time of participation was 4.4 years. While PW variations did not produce significant differences in overall objective outcomes, device parameters, including sensory threshold amplitude and battery life differed significantly. Shortened PW necessitated higher amplitude while conserving battery life. Stimulus sensation location, quality, and intensity did not differ between PW. Standard PW was chosen by 11 patients after the study, 5 chose extended, and 2 chose shortened. Those who chose alternative PW achieved significant reductions in urinary frequency from enrollment -2.23 voids/day (p = 0.015). Upon sub-analysis, patients reporting "much better" or "very much better" on extended PW achieved significant reductions in urinary frequency and nocturia at 5.6 and 0.4, compared to 8.5 and 2.16 at baseline (p = 0.005, p = <0.001). Whereas those reporting "much better" or "very much better" on shortened PW achieved significant reductions in urinary frequency at 5.15 compared to 7.35 (p = 0.026). There were no adverse events or complications. CONCLUSIONS: Overall SNM effectiveness was unchanged with alternative PW; however, 39% of patients preferred alternative to standard PW and achieved significant improvements in urinary symptoms with such. Shorter PW can also provide savings in estimated battery life without sacrificing therapeutic efficacy.

Microreticular perineurioma: A new morphological subtype of a rare entity.

Perineurioma is a benign peripheral nerve sheath tumor. Several subtypes have been described, including plexiform, reticular, and sclerosing. The reticular variant has been previously described as having a net or lace-like growth pattern consisting of large anastomosing cords of spindle-shaped cells. We report a case of an 11-year-old male who presented with a 2-year history of a slowly enlarging, tan-white lesion on the finger. Microscopically, the lesion consisted of cells with ovoid nuclei and delicate, elongate cytoplasmic processes, arranged in a microreticular pattern. The lesional cells were markedly positive for epithelial membrane antigen and claudin-1. Based on these features and the unusual morphology, the case was called a microreticular perineuroma. The patient underwent complete excision of the lesion with no recurrence 9 months after follow-up. To our knowledge, this is the first reported case of this morphologic variant. Awareness of this entity is important to avoid inappropriate management.

Update on Management and Outcomes of Congenital Diaphragmatic Hernia.

Infants with congenital diaphragmatic hernia (CDH) benefit from comprehensive multidisciplinary teams that have experience in caring for the unique and complex issues associated with CDH. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies and pulmonary hypertension management, and extracorporeal membrane oxygenation, mortality and morbidity remain high. These infants have unique and complex issues that begin in fetal and infant life, but persist through adulthood. Here we will review the literature and share our clinical care pathway for neonatal care and follow up. While many advances have occurred in the past few decades, our work is just beginning to continue to improve the mortality, but also importantly the morbidity of CDH.

Patient perceived improvement and medication resumption rates after intradetrusor onabotulinumtoxina for idiopathic urgency urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Intradetrusor onabotulinumtoxinA (BTX-A) is a third-line therapy for overactive bladder (OAB), however several gaps exist in periprocedural care. Prior studies have demonstrated BTX-A efficacy at 2-3 weeks, but there are limited data documenting when patients should begin to note symptom improvement. The primary aim of this study was to evaluate patient-reported temporal improvement in symptoms, with secondary aim to evaluate medication resumption rates, following initial BTX-A injection. METHODS: A prospective, single-arm cohort study of patients with non-neurogenic urgency incontinence undergoing initial BTX-A injection was performed. Intradetrusor 100 units BTX-A was administered in standard 20-site template. Patients discontinued OAB medication(s) at BTX-A injection and completed a daily Patient Global Impression of Improvement (PGI-I) diary for 3 weeks. Data were collected at 1 month, including final satisfaction score, medication resumption rates, and adverse outcomes. RESULTS: Fifty-one patients were included, with 25 patients (49%) actively taking an OAB medication. Median time to first improvement was 3 days, at least "much better" (PGI-I <2) was 5 days, and maximal improvement was 7 days. Twenty of 25 patients (80%) opted to remain off OAB medications at 1 month based on symptomatic improvement following injection. Adverse outcomes included urinary tract infection in three patients (6%) and symptomatic incomplete emptying requiring temporary intermittent catheterization in two patients (4%). CONCLUSIONS: Median time to first and maximal improvement was 3 and 7 days, respectively, following initial 100 units BTX-A. Eighty percent of patients on medications opted to remain off at 1 month. These data may help further counsel patient expectations following initial BTX-A therapy.

Neural networks outperform expert humans in predicting patient impressions of symptomatic improvement following overactive bladder treatment.

INTRODUCTION AND HYPOTHESIS: The objective was to accurately predict patient-centered subjective outcomes following the overactive bladder (OAB) treatments OnabotulinumtoxinA (OBTX-A) injection and sacral neuromodulation (SNM) using a neural network-based machine-learning approach. In the context of treatments designed to improve quality of life, a patient's perception of improvement should be the gold standard outcome measure. METHODS: Cutting-edge neural network-based algorithms using reproducing kernel techniques were trained to predict patient-reported improvements in urinary leakage and bladder function as assessed by Patient Global Impression of Improvement score using the ROSETTA trial datasets. Blinded expert urologists provided with the same variables also predicted outcomes. Receiver operating characteristic curves and areas under the curve were generated for algorithm and human expert predictions in an out-of-sample holdout dataset. RESULTS: Algorithms demonstrated excellent accuracy in predicting patient subjective improvement in urinary leakage (OBTX-A: AUC 0.75; SNM: 0.80). Similarly, algorithms accurately predicted patient subjective improvement in bladder function (OBTX-A: AUC 0.86; SNM: 0.96). The top-performing algorithms outcompeted human experts across outcome measures. CONCLUSIONS: Novel neural network-based machine-learning algorithms accurately predicted OBTX-A and SNM patient subjective outcomes, and generally outcompeted expert humans. Subtle aspects of the physician-patient interaction remain uncomputable, and thus the machine-learning approach may serve as an aid, rather than as an alternative, to human interaction and clinical judgment.

Risk of hospitalization associated with different constellations of home & community based services.

BACKGROUND: Identify the association between specific combinations of home and community-based services (HCBS) and risk of acute hospitalization. METHODS: Data for this study came from Pennsylvania Medicaid claims and Medicare records. This was a retrospective, observational cohort study that examined hospitalization, HCBS service use and patient characteristics between July, 2014 and December, 2016. This analysis compared risk of inpatient hospitalization risk for community dwelling disabled older adults using a range of Medicaid financed HCBS. Twelve constellations of HCBS were identified representing different combinations of common services (personal assistive services [PAS], delivered meals, and adult day care). Since HCBS users are not randomly assigned to different combinations of services, we used logistic regression to estimate the predicted probability of experiencing hospitalization conditional on the constellation of services, and adjusting for demographics, health and level of disability. RESULTS: The most common constellation was people who used under four hours of PAS per person per day. This group experienced a hospitalization rate of 13.7%. however, those individuals receiving more than 4 h per person per day experienced only a 10.2% hospitalization rate. Similar trends were seen for people who used PAS in combination with home delivered meals. However, those who used adult day care experienced higher hospitalization rates as the number of hours of personal assistive service increased: increasing from 6.8% among those with under 4 h, to 8.6% among those with 8 or more hours per person per day. CONCLUSION: Using medium and high levels of PAS was associated with lower hospitalization risk for people who PAS alone or in combination with delivered meals. By contrast, higher levels of PAS was associated with increased hospitalization for adult day users (both alone or in combination). Policy makers should consider offering higher levels of PAS to offset potential risk of hospitalization. Future research is needed to explain the association between adult day care and risk.

Subanalgesic morphine doses augment fentanyl analgesia by interacting with delta opioid receptors in male rats.

Opioids are commonly used for the treatment of postoperative and post-traumatic pain; however, their therapeutic effectiveness is limited by undesirable and life-threatening side effects. Researchers have long attempted to develop opioid co-administration therapies that enhance analgesia, but the complexity of opioid analgesia and our incomplete mechanistic understanding has made this a daunting task. We discovered that subanalgesic morphine doses (100 ng/kg-10 µg/kg) augmented the acute analgesic effect of fentanyl (20 µg/kg) following subcutaneous drug co-administration to male rats. In addition, administration of equivalent drug ratios to naïve rat spinal cord membranes induced a twofold increase in G protein activation. The rate of GTP hydrolysis remained unchanged. We demonstrated that these behavioral and biochemical effects were mediated by the delta opioid receptor (DOP). Subanalgesic doses of the DOP-selective agonist SNC80 also augmented the acute analgesic effect of fentanyl. Furthermore, co-administration of the DOP antagonist naltrindole with both fentanyl-morphine and fentanyl-SNC80 combinations prevented augmentation of both analgesia and G protein activation. The mu opioid receptor (MOP) antagonist cyprodime did not block augmentation. Confocal microscopy of the substantia gelatinosa of rats treated with fentanyl, subanalgesic morphine, or this combination showed that changes in MOP internalization did not account for augmentation effects. Together, these findings suggest that augmentation of fentanyl analgesia by subanalgesic morphine is mediated by increased G protein activation resulting from a synergistic interaction between or heterodimerization of MOPs and DOPs. This finding is of great therapeutic significance because it suggests a strategy for the development of DOP-selective ligands that can enhance the therapeutic index of clinically used MOP drugs.

Is sacral neuromodulation effective in patients with Parkinson's disease? A retrospective review.

INTRODUCTION AND OBJECTIVE: Parkinson's disease (PD) is the second-most common degenerative neurologic disease worldwide. Overactive bladder (OAB) is prevalent in this population but can be challenging to treat. Sacral neuromodulation (SNM) is an attractive option but remains understudied. We have utilized SNM in PD patients and herein describe our outcomes. METHODS: We performed a retrospective chart review of PD patients who underwent peripheral nerve evaluation (PNE) or Stage 1 SNM from 2000 to 2020. The primary outcome was progression to a permanent implant. The impact of PD stage and preprocedural urodynamic (UDS) parameters on test-phase outcome were investigated. Long-term efficacy was assessed using Wilcoxon matched-pairs test looking at a change in urinary symptoms (frequency, nocturia, incontinence episodes, and pad use) documented at follow-up visits and further need for treatment. RESULTS: Thirty-four patients underwent test phase SNM (7 PNE and 27 Stage 1). Median follow-up was 11 (interquartile range 5.8-29.8) months. Indications included refractory OAB (30/34) and nonobstructive urinary retention (4/34). Overall, 82% (28/34) of patients proceeded to a permanent implant. 71% (5/7) of PNEs were successful. Test-phase success did not differ based on PD disease severity or UDS parameters. In patients with OAB/urgency incontinence who progressed to the permanent implant, there was a statistically significant improvement in their urinary symptoms from baseline. Most (68%) patients were able to discontinue OAB medications post-implant. The overall lead revision rate was 14% (4/28) and 3 devices required removal. CONCLUSIONS: SNM is an efficacious treatment option for PD patients with a high percentage of patients having improvement in their urinary symptoms.