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.

Effects of Medicaid managed care on early detection of cancer: Evidence from mandatory Medicaid managed care program in Pennsylvania.

OBJECTIVE: To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania. DATA SOURCES AND STUDY SETTING: We analyzed data from the Pennsylvania cancer registry (2010-2018) for adult Medicaid beneficiaries aged 21-64 newly diagnosed with a solid tumor. To ascertain Medicaid and managed care status around diagnosis, we linked the cancer registry to statewide hospital-based facility records collected by an independent state agency (Pennsylvania Health Care Cost Containment Council). STUDY DESIGN: We leveraged a natural experiment arising from county-level variation in mandatory MMC in Pennsylvania. Using a stacked difference-in-differences design, we compared changes in the probability of late-stage cancer diagnosis among those residing in counties that newly transitioned to mandatory managed care to contemporaneous changes among those in counties with mature MMC programs. DATA COLLECTION/EXTRACTION METHODS: N/A. PRINCIPAL FINDINGS: Mandatory MMC was associated with a reduced probability of late-stage cancer diagnosis (-3.9 percentage points; 95% CI: -7.2, -0.5; p = 0.02), particularly for screening-amenable cancers (-5.5 percentage points; 95% CI: -10.4, -0.6; p = 0.03). We found no significant changes in late-stage diagnosis among non-screening amenable cancers. CONCLUSIONS: In Pennsylvania, the implementation of mandatory MMC for adult Medicaid beneficiaries was associated with earlier stage of diagnosis among newly diagnosed cancer patients with Medicaid, especially those diagnosed with screening-amenable cancers. Considering that over half of the sample was diagnosed with late-stage cancer even after the transition to mandatory MMC, Medicaid programs and managed care organizations should continue to carefully monitor receipt of cancer screening and design strategies to reduce barriers to guideline-concordant screening or diagnostic procedures.

Unraveling RNA Conformation Dynamics in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episode Syndrome with Solid-State Nanopores.

This study investigates transfer ribonucleic acid (tRNA) conformational dynamics in the context of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) using solid-state silicon nitride (SiN) nanopore technology. SiN nanopores in thin membranes with specific dimensions exhibit high signal resolution, enabling real-time and single-molecule electronic detection of tRNA conformational changes. We focus on human mitochondrial tRNALeu(UAA) (mt-Leu(UAA)) that decodes Leu codons UUA/UUG (UUR) during protein synthesis on the mt-ribosome. The single A14G substitution in mt-Leu(UAA) is the major cause of MELAS disease. Measurements of current blockades and dwell times reveal distinct conformational dynamics of the wild-type (WT) and the A14G variant of mt-Leu(UAA) in response to the conserved post-transcriptional m1G9 methylation. While the m1G9-modified WT transcript adopts a more stable structure relative to the unmodified transcript, the m1G9-modified MELAS transcript adopts a less stable structure relative to the unmodified transcript. Notably, these differential features were observed at 0.4 M KCl, but not at 3 M KCl, highlighting the importance of experimental settings that are closer to physiological conditions. This work demonstrates the feasibility of the nanopore platform to discern tRNA molecules that differ by a single-nucleotide substitution or by a single methylation event, providing an important step forward to explore changes in the conformational dynamics of other RNA molecules in human diseases.

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.

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.

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.

On the question of the internal frame.

This paper attempts to expand José Bleger's classic, metapsychological descriptions of the psychoanalytic frame to formulate and emphasize the role of the analyst's internal frame in establishing a psychoanalytic observational perspective in the analytic situation. The rationale for doing so follows from clinical necessity, especially when working with patients and psychic organizations that are 'beyond neurosis' and in non-traditional settings such as distance and telemetric analyses. Clinically speaking, in its most effective state, the analyst's internal frame can inform the possibility of an observational vertex aimed at the intuitive grasp of psychic reality rather than a sense-based, empirical observation of parameters denoted by the elements of a consensually validatable social reality.

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.

Association of Medicare eligibility with access to and affordability of care among older cancer survivors.

PURPOSE: Older cancer survivors have substantial needs for ongoing care, but they may encounter difficulties accessing care due to cost concerns. We examined whether near-universal insurance coverage through Medicare-a key source of health insurance coverage in this population-is associated with improvements in care access and affordability among older cancer survivors around age 65. METHODS: In a nationally representative sample of cancer survivors (aged 50-80) from 2006-2018 National Health Interview Survey, we employed a quasi-experimental, regression discontinuity design to estimate changes in insurance coverage, delayed/skipped care due to cost, and worries about or problems paying medical bills at age 65. RESULTS: Medicare coverage sharply increased from 8.3% at age 64 to 98.2% at age 65, ensuring near-universal insurance coverage (99.5%). Medicare eligibility at age 65 was associated with reductions in delayed/skipped care due to cost (discontinuity, - 5.7 percentage points or pp; 95% CI, - 8.1, - 3.3; P < .001), worries about paying for medical bills (- 7.7 pp; 95% CI, - 12.0, - 3.2; P = .001), and problems paying medical bills (- 3.2 pp; 95% CI, - 6.1, - 0.2; P = .036). However, a sizable proportion reported any access or affordability problems (29.7%) between ages 66 and 80. CONCLUSIONS: Near-universal Medicare coverage at age 65 was associated with a reduction-but not elimination-of access and affordability problems among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: These findings reaffirm the role of Medicare in improving access and affordability for older cancer survivor and highlight opportunities for reforms to further alleviate financial burden of care in this population.

Approach to the Patient With Type 2 Diabetes Requiring Add-On Medication.

In the last 20 years, the number of approved agents and agent classes for management of type 2 diabetes has expanded significantly. This more robust armamentarium affords us the opportunity to utilize drugs with complementary modes of action to address progressive hyperglycemia as insulin secretion declines over time. Furthermore, some of these agents provide additional benefits, such as weight loss, prevention of major adverse cardiac events (MACE), and protection against declining renal function. This dramatic increase of treatment options has led to complex published treatment advice which may be challenging for the busy clinician. A critical element in medication selection is awareness of the hemoglobin A1c (HbA1c)-lowering potency of the agent being considered, and the distance of the patient's HbA1c level from the individualized goal. Other important factors in choosing medication as diabetes progresses include the recognition that there is a diminishing return of glucose-lowering efficacy as add-on agents are introduced, and that the extent of benefit for cardiac and renal protection is not fully understood. In addition, the availability of newer non-insulin agents may distract the clinician from utilizing insulin, the most potent agent available. The goal of this article is to provide a straightforward approach to add-on medication in the treatment of type 2 diabetes, recognizing the limits of polypharmacy and the importance of employing agents best suited to achieving treatment targets. Proposed is a practical tool which provides stepwise guidance, utilizing available data on medication efficacy, while allowing flexibility based on clinician and patient preference.

Co-Delivery of a Novel Lipidated TLR7/8 Agonist and Hemagglutinin-Based Influenza Antigen Using Silica Nanoparticles Promotes Enhanced Immune Responses.

Co-delivery of antigens and adjuvants to the same antigen-presenting cells (APCs) can significantly improve the efficacy and safety profiles of vaccines. Here, we report amine-grafted silica nanoparticles (A-SNP) as a tunable vaccine co-delivery platform for TLR7/8 agonists along with the recombinant influenza antigen hemagglutinin H7 (H7) to APCs. A-SNP of two different sizes (50 and 200 nm) were prepared and coated with INI-4001 at different coating densities, followed by co-adsorption of H7. Both INI-4001 and H7 showed >90% adsorption to the tested A-SNP formulations. TNF-α and IFN-α cytokine release by human peripheral blood mononuclear cells as well as TNF-α, IL-6, and IL-12 release by mouse bone marrow-derived dendritic cells revealed that the potency of the INI-4001-adsorbed A-SNP (INI-4001/A-SNP) formulations was improved relative to aqueous formulation control. This improved potency was dependent on particle size and ligand coating density. In addition, slow-release profiles of INI-4001 were measured from INI-4001/A-SNP formulations in plasma with 30-50% INI-4001 released after 7 days. In vivo murine immunization studies demonstrated significantly improved H7-specific humoral and Th1/Th17-polarized T cell immune responses with no observed adverse reactions. Low-density 50 nm INI-4001/A-SNP elicited significantly higher IFN-γ and IL-17 induction over that of the H7 antigen-only group and INI-4001 aqueous formulation controls. In summary, this work introduces an effective and biocompatible SNP-based co-delivery platform that enhances the immunogenicity of TLR7/8 agonist-adjuvanted subunit influenza vaccines.

To Feel in My Flesh: Receptivity, Resonance, Representation, and The Beta Screen.

When we are confronted with the challenge of trying to fully convey or describe something about human life and emotional experience, we find ourselves up against the very limitations of language. This problem becomes especially relevant as we attempt to expand psychoanalytic theory so as to enable us to "approach a mental life unmapped by the theories elaborated for the understanding of neurosis" (Bion1962, p. 37). This paper seeks to aid in that expansion by revisiting Bion's early writings about the beta screen, extending his conclusions about communication from the psychotic part of the mind to the broad area of the unrepresented (the unstructured unconscious), suggesting that there is often a potentially communicative meaning, a mute plea for intersubjective regulatory assistance (alpha function), embedded in the unconscious evocation of emotions in the object and that this cry for help may be encrypted in even the most seemingly destructive, resistant and oppositional patients.

On looking into The Ego and the Id 100 years after its publication.

Freud's publication of The Ego and the Id sparked a diverging set of psychoanalytic models - ego psychology, structural conflict theory, Kleinianism, object relations theories, Lacanianism, etc. - each of which attempted to deal with the clinical limitations of his first topography in regard to unconscious guilt, negative therapeutic reactions and primitive character organizations. This paper attempts to look back on these developments from the perspective of contemporary, post-Freudian psychoanalytic theories.

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.