Peyronie's disease response to intralesional collagenase clostridium histolyticum therapy is independent of baseline testosterone.

BACKGROUND: Testosterone plays an important role in collagen metabolism, transforming growth factor-ß1 expression, and wound healing, which are all critical factors in pathogenesis of Peyronie's disease. Some clinical studies have suggested an association between Peyronie's disease and hypogonadism. OBJECTIVE: We sought to investigate whether baseline total testosterone levels influence response to intralesional collagenase clostridium histolyticum in Peyronie's disease. METHODS: A retrospective review of patients receiving collagenase clostridium histolyticum injections with available total testosterone levels within 1 year of initial injection was conducted at a single institution. Baseline demographics, hypogonadal status, total testosterone, number of collagenase clostridium histolyticum cycles, and pre- and post-treatment degrees of curvature were collected. Hypogonadism was defined as total testosterone <300 ng/dL. RESULTS AND DISCUSSION: Thirty-six men were included with mean age of 58.2 years (SD 10.4) and mean body mass index 26.8 (SD 3.2). The mean total testosterone was 459.2 ng/dL (SD 144.0), and four (11.1%) were hypogonadal. Mean pre-treatment curvature was 47.6°, and mean post-treatment curvature was 27.8°, with mean improvement of 19.9° (40.1%). Hypogonadal status was not significantly associated with more severe curvature, 46.4° among hypogonadal men as to 57.5° among eugonadal men (p = 0.32). On linear regression analysis, total testosterone did not significantly predict improvement in degrees (ß = -0.02; R2 = 0.06; p = 0.14) or percent (ß = 0.0; R2 = 0.05; p = 0.18). Improvement in neither degrees nor percent differed significantly by hypogonadal status (p = 0.41 and 0.82, respectively). The cycle number did significantly predict greater improvement in curvature on both univariate and multivariate analyses (ß = 5.7; R2 = 0.34; p < 0.01). CONCLUSION: Neither total testosterone nor hypogonadism is associated with a degree of improvement after collagenase clostridium histolyticum treatment.

Testosterone replacement therapy is associated with high satisfaction rates: results of a survey study.

Despite a well-documented increase in both the prevalence of Testosterone Deficiency (TD) and prescription of testosterone replacement therapy (TRT), few studies have investigated the preferences of patients receiving TRT and factors associated with increased treatment satisfaction. To investigate the preferences of patients receiving TRT and factors associated with improved treatment satisfaction, an open survey was completed by 140 men receiving TRT at a single institution. Survey questions investigated demographics, symptom burden of TD, TRT regimen, treatment preferences, and treatment satisfaction. 62.7% of patients were satisfied with their current TRT regimen. Those using auto-injectors (91.7%, odds ration [OR] = 9.3), subcutaneous pellets (90.0%, OR = 15.2), and intramuscular injections (67.5%, OR = 5.7), were with significantly increased satisfaction rates (p < 0.05). The majority of patients indicated that they would prefer to receive TRT injections when self-administered or administered at home. While patients noted that treatment efficacy was a significant driving factor when evaluating a TRT regimen, few patients felt that cost was the most significant factor.

Regionalization or Access to Care? A Joint Pediatric Heart Care Program That Achieves Both: One Program-Two Sites.

Background: Regionalization of care for children with congenital heart disease has been proposed as a method to improve outcomes. This has raised concerns about limiting access to care. We present the details of a joint pediatric heart care program (JPHCP) which utilized regionalization and actually improved access to care. Methods: In 2017, Kentucky Children's Hospital (KCH) launched the JPHCP with Cincinnati Children's Hospital Medical Center (CCHMC). This unique satellite model was the product of several years of planning, leading to a comprehensive strategy with shared personnel, conferences, and a robust transfer system; "one program-two sites." Results: Between March 2017 and the end of June 2022, 355 operations were performed at KCH under the auspices of the JPHCP. As of the most recent published Society of Thoracic Surgeons (STS) outcome report (through the end of June 2021), for all STAT categories, the JPHCP at KCH outperformed the STS overall in postoperative length of stay, and the mortality rate was lower than expected for the case mix. Of the 355 operations, there were 131 STAT 1, 148 STAT 2, 40 STAT 3, and 36 STAT 4 operations, with two operative mortalities: an adult undergoing surgery for Ebstein anomaly, and a premature infant who died from severe lung disease many months after aortopexy. Conclusions: With a select case mix, and by affiliating with a large volume congenital heart center, the creation of the JPHCP at KCH was able to achieve excellent congenital heart surgery results. Importantly, access to care was improved for those children at the more remote location utilizing this one program-two sites model.

Does Medicaid cover artificial urinary sphincter and male urethral sling surgery?-a state-by-state analysis.

Background: Information regarding the Medicaid coverage of artificial urinary sphincter (AUS) and male suburethral slings (MS) placement in the United States (US) is not readily available. In this manuscript, we seek to elucidate the state-by-state Medicaid coverage of these two procedures in the US. Methods: State Medicaid websites were utilized to access publicly available physician fee schedules for the calendar year 2020. Fee schedules were searched for current procedural terminology (CPT) codes. CPT codes representing insertion of tandem cuff, insertion of AUS, removal of AUS, removal and replacement AUS, sling operation for correction of male stress urinary incontinence (SUI), and removal or revision of sling for male SUI were utilized. Data were recorded by the procedure for each device, including the coverage status and physician fees. Results: Of the 50 US states analyzed, 49 publish publicly accessible physician fee schedules. All 49 of these states reported coverage for removal with and without revision of the AUS, and 48 states reported coverage for insertion of an AUS, and insertion of a tandem cuff. The median reimbursement for each AUS related procedure was $624.00 ($181.84-$10,960.90) for tandem cuff, $665.54 ($199.89-$11,949.86) for AUS insertion, $528.03 ($146.90-$1,893.12) for AUS removal, and $630.29 ($208.55-$11,586.74) for AUS revision. All 49 states reported coverage for placement of MS, and 48 states reported coverage for removal or revision of MS. The median reimbursement was $652.57 ($198.00-$5,237.35) for MS placement and $554.47 ($104.27-$2,288.93) for MS revision. Conclusions: AUS and MS procedures in the Medicaid population are covered by nearly all states. Therefore, surgical treatment of SUI may be offered to Medicaid patients in most states without reimbursement concerns.

Contemporary cost-analysis comparison of direct-to-consumer vs. traditional prescriptions of phosphodiesterase-5 inhibitors.

After a focused telehealth visit, patients can now access phosphodiesterase-5 inhibitor (PDE5 inhibitor) prescriptions through online direct-to-consumer (DTC) healthcare companies. This study seeks to quantify the cost of DTC PDE5 inhibitor treatment compared to a traditional physician visit and local pharmacy prescription. Two DTC companies, two compounding pharmacies with national reach, three online Canadian pharmacies, and sixteen American pharmacy chains were queried for prices of 90-day regimens of common PDE5 inhibitors. Prices for chains were determined using their publicly available price on GoodRx® with coupon. Cost of physician visit was determined using 2020 Center for Medicare and Medicaid Services reimbursement for a level 3 new patient visit. For sildenafil 20 mg, a physician visit and local prescription cost a low of $125.45 compared to $144.35 for compounding, $169.34 for Canadian, and $195.00 for DTC. For sildenafil 100 mg, a physician visit and local prescription cost a low of $137.16 compared to $289.35 for compounding, $200.36 for Canadian, and $900.00 for DTC. For tadalafil 5 mg, a physician visit and local prescription cost a low of $125.80 compared to $169.35 for compounding, $195.34 for Canadian, and $720.00 for DTC. For tadalafil 20 mg, a physician visit and local prescription cost a low of $161.00 compared to $289.35 for compounding, $229.00 for Canadian, and $2880.00 for DTC. Thus, local pharmacies, in conjunction with online coupons, consistently provide a markedly less-expensive option for fulfillment of PDE5 inhibitor prescriptions than online DTC services.

A versatile viral toolkit for functional discovery in the nervous system.

The ability to precisely control transgene expression is essential for basic research and clinical applications. Adeno-associated viruses (AAVs) are non-pathogenic and can be used to drive stable expression in virtually any tissue, cell type, or species, but their limited genomic payload results in a trade-off between the transgenes that can be incorporated and the complexity of the regulatory elements controlling their expression. Resolving these competing imperatives in complex experiments inevitably results in compromises. Here, we assemble an optimized viral toolkit (VTK) that addresses these limitations and allows for efficient combinatorial targeting of cell types. Moreover, their modular design explicitly enables further refinements. We achieve this in compact vectors by integrating structural improvements of AAV vectors with innovative molecular tools. We illustrate the potential of this approach through a systematic demonstration of their utility for targeting cell types and querying their biology using a wide array of genetically encoded tools.

Multiple-Organ Deceased Donation Is Associated With Superior Outcomes for Grafts and Transplant Recipients Compared With Kidney-Only Donation.

OBJECTIVES: Since the development of Kidney Donor Profile Index, outcome differences based on number of donated organs per donor have not been evaluated. MATERIALS AND METHODS: We retrospectively analyzed data from the United Network for Organ Sharing national database, which identified 176 311 adult renal transplant recipients from 2000 to 2019 with a deceased donor kidney from a kidney-only donor, from a donor of kidney and liver but no other organs, or from a multiorgan donor. Graft failure and transplant recipient survival were primary outcomes. A multivariate Cox proportional hazards model controlled for Kidney Donor Profile Index differences. RESULTS: Overall, multiorgan donors had a lower Kidney Donor Profile Index versus other donor types (odds ratio, 0.042; P < .001). Kidneys from donors with a higher Kidney Donor Profile Index were 95% less likely to be procured with other organs (P < .001). The recipient and graft survival rates for kidney transplants from kidney-only donors and from donors of kidney and liver but no other organs were 76% and 70%, respectively, whereas recipient and graft survival rates for kidney transplants from multiorgan donors were approximately 82% and 77%, respectively, at 5 years. CONCLUSIONS: After adjustment for the Kidney Donor Profile Index, the recipients of multiorgan donor grafts demonstrated superior outcomes for graft survival and mortality compared with kidney-only donors or kidney and liver only donors. The multiorgan donor status may be an additional consideration in future renal allocation calculators.

In Vitro Evaluation of Stone Fragment Evacuation by Suction.

Introduction: Contemporary, flexible stone baskets are unable to extract submillimeter stone fragments at the time of ureteroscopic laser lithotripsy. In this in vitro study, the feasibility of suctioning submillimeter fragments with a standard Luer Lock syringe through the working channel of a flexible ureteroscope was assessed. Materials and Methods: Phantom stones made from industrial plaster were mechanically fragmented into ≤1 and ≤0.5-mm groups. Both stone groups were divided into five preweighed trial samples. Each stone group was then mixed in a beaker filled with normal saline. A standard 10-mL Luer Lock syringe was connected to a fiber-optic ureteroscope with a 1.2-mm working channel. The syringe was then used to suction stone fragments from the beaker. The suctioned stone fragments and the stone fragments remaining in the beaker after removing the overlying solution were separated, centrifuged with supernatant removed, and dried in an incubator set at 33°C for 1 week. Dried weights were recorded. Results: Mean total weights for ≤0.5 and ≤1.0-mm stone groups at baseline were 0.807 and 0.806 g, respectively. The mean percentages of stone fragments suctioned through the ureteroscope for ≤0.5 and ≤1.0-mm groups were 86% and 86%, respectively (p = 0.973). During suctioning, 64% of stones in the ≤0.5-mm group were trapped in either the working channel of the ureteroscope or within the Luer Lock syringe compared with 78% of stones in the ≤1-mm group (p = 0.001) requiring cessation of the procedure to clear the channel. Conclusions: It is feasible to suction submillimeter stone fragments by connecting a Luer Lock syringe to the working channel of a flexible ureteroscope. The limiting factor for removing stone fragments appears to be the small working channel of flexible ureteroscopes as trapping of fragments during suctioning is common and requires time-consuming removal of the endoscope and clearing of the channel.

Hypothyroidism after Percutaneous Patent Ductus Arteriosus Device Closure in an Extremely Preterm Infant: Possible Role of Iodinated IV Contrast.

We report a case of contrast-induced hypothyroidism in an extremely preterm infant after percutaneous patent ductus arteriosus (PDA) device closure. Iodine-induced hypothyroidism after exposure to iodine-containing antiseptics and contrast media has been previously reported in extremely preterm infants. However, this is the first report of contrast-induced hypothyroidism in an extremely preterm infant undergoing percutaneous PDA device closure. This is timely, given percutaneous PDA device closure is more frequently utilized. Guidelines for screening thyroid function pre and post contrast-requiring procedures may be warranted. Hypothyroidism if left untreated can have detrimental effects on developing brain, especially in the preterm population. Therefore, the earlier detection and treatment of iodine-induced hypothyroidism is imperative.

Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans.

Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

CIC-rearranged round cell (Ewing-like) sarcoma of the uterus: Review of the literature.

CIC-rearranged round cell sarcoma (CRS) is a rare entity that presents in various anatomical locations and involves deep soft-tissue structures and skin. Although commonly confused with and clinically similar to Ewing sarcoma (ES), investigators have recently shown that this unique condition maintains morphologic and pathologic features that are distinct from ES. In this report, we present and discuss a case of CRS of the uterus, the first of its kind to be reported in the English-language literature. We urge the scientific community to continue its investigations in elucidating the features of this entity, as young women who suffer from this condition have dismal prognoses and currently do not have access to therapeutic options for cure.

Role of NT-proBNP in the prediction of moderate to severe Bronchopulmonary Dysplasia in preterm infants.

OBJECTIVE: The objective of the study was to determine the clinical utility of brain natriuretic peptide (NT-proBNP) for prediction of moderate to severe bronchopulmonary dysplasia (BPD). We hypothesized that elevated NT-proBNP levels at 4 weeks of postnatal age may predict the severity of BPD in preterm infants. STUDY DESIGN: The study design was a prospective observational study. The research team enrolled and followed a cohort of 70 infants with gestational age less than or equal to 30 weeks. The plasma NT-proBNP levels were measured at the postnatal day 28th. We further followed and categorized infants into two groups. Infants with no or mild BPD (Group 1) and infants with moderate or severe BPD (Group 2). We compared plasma NT-proBNP levels at 28th day of postnatal life between Groups 1 and 2. The difference in NT-proBNP levels on day 28th between groups was used to predict the severity of BPD. RESULTS: Plasma NT-proBNP was significantly elevated in Group 2 compared with Group 1, median (IQR) of 845 pg/mL (553, 1632) compared with 726 pg/mL (391, 923), P = 0.02. NT-proBNP had a fair predictive accuracy (C statistics of 0.68) to determine moderate to severe BPD. CONCLUSION: NT-proBNP may be a useful biomarker in conjunction with clinical factors as a predictor of severe BPD. For future directions, the trend of NT-proBNP in infants with BPD may have clinical significance in monitoring of the disease.

Registration Accuracy of Patient-Specific, Three-Dimensional-Printed Prostate Molds for Correlating Pathology With Magnetic Resonance Imaging.

OBJECTIVE: This investigation was performed to evaluate the registration accuracy between magnetic resonance imaging (MRI) and pathology using three-dimensional (3-D) printed molds. METHODS: Tissue-mimicking prostate phantoms were manufactured with embedded fiducials. The fiducials were used to measure and compare target registration error (TRE) between phantoms that were sliced by hand versus phantoms that were sliced within 3-D-printed molds. Subsequently, ten radical prostatectomy specimens were placed inside molds, scanned with MRI, and then sliced. The ex vivo scan was used to assess the true location of whole mount (WM) slides relative to in vivo MRI. The TRE between WM and in vivo MRI was measured using anatomic landmarks. RESULTS: Manually sliced phantoms had a 4.1-mm mean TRE, whereas mold-sliced phantoms had a 1.9-mm mean TRE. Similarly, mold-assisted slicing reduced mean angular misalignment around the left-right (LR) anatomic axis from 10.7° to 4.5°. However, ex vivo MRI revealed that excised prostates were misaligned within molds, including a mean 14° rotation about the LR axis. The mean in-plane TRE was 3.3 mm using molds alone and 2.2 mm after registration was corrected with ex vivo MRI. CONCLUSION: Patient-specific molds improved accuracy relative to manual slicing techniques in a phantom model. However, the registration accuracy of surgically resected specimens was limited by their imperfect fit within molds. This limitation can be overcome with the addition of ex vivo imaging. SIGNIFICANCE: The accuracy of 3-D-printed molds was characterized, quantifying their utility for facilitating MRI-pathology registration.

Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.

The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Analysis of 9763 HIV-infected individuals from 21 cohorts shows that higher HLA-A levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A natural killer (NK) cell receptor. HLA-B haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Therapeutic blockade of HLA-E:NKG2A interaction may yield benefit in HIV disease.

HIV-1 Vpu Mediates HLA-C Downregulation.

Many pathogens evade cytotoxic T lymphocytes (CTLs) by downregulating HLA molecules on infected cells, but the loss of HLA can trigger NK cell-mediated lysis. HIV-1 is thought to subvert CTLs while preserving NK cell inhibition by Nef-mediated downregulation of HLA-A and -B but not HLA-C molecules. We find that HLA-C is downregulated by most primary HIV-1 clones, including transmitted founder viruses, in contrast to the laboratory-adapted NL4-3 virus. HLA-C reduction is mediated by viral Vpu and reduces the ability of HLA-C restricted CTLs to suppress viral replication in CD4+ cells in vitro. HLA-A/B are unaffected by Vpu, and primary HIV-1 clones vary in their ability to downregulate HLA-C, possibly in response to whether CTLs or NK cells dominate immune pressure through HLA-C. HIV-2 also suppresses HLA-C expression through distinct mechanisms, underscoring the immune pressure HLA-C exerts on HIV. This viral immune evasion casts new light on the roles of CTLs and NK cells in immune responses against HIV.

Effect of suberoylanilide hydroxamic acid (SAHA) administration on the residual virus pool in a model of combination antiretroviral therapy-mediated suppression in SIVmac239-infected indian rhesus macaques.

Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4(+) T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches.

Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants.

Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.

Chronic low dose-rate radiation down-regulates transcription related to mitosis and chromosomal movement similar to acute high dose in prostate cells.

PURPOSE: Despite concerns over risks from exposure to low-dose ionizing radiations encountered in the environment and workplace, the molecular consequences of these exposures, particularly at representative doses and dose-rates, remains poorly understood. MATERIALS AND METHODS: Using a novel flood source construct, we performed a direct comparison of genome-wide gene expression regulations resulting from exposure of primary human prostate fibroblast cultures to acute (10 cGy and 200 cGy) and longer-term chronic (1.0-2.45 cGy cumulative over 24 h) exposures. RESULTS: Expression profiling showed significant differential regulation of 396 genes with no measureable changes in the acute 10 cGy dose. However, there were 106 genes in common between samples given an acute 200 cGy dose compared to those given chronic doses, most of which were decreased and related to cell cycle or chromosomal movement in M-phase. Biological pathway analysis showed decreases in cell cycle, chromosomal movement, cell survival and DNA replication, recombination and repair as well as a predicted activation of transcriptional regulators TP53, RB1 and CDKN2A. In agreement with these results, prostate epithelial cells given 200 cGy or chronic doses displayed functional decreases in proliferation and mitotic cells. CONCLUSIONS: In summary, we showed a contrast to the common observation of constant or reduced effect per unit dose as the dose (acute) was diminished, that even very low total doses delivered chronically could rival the perturbing effect of acute doses 100 times as intense. Underscored is the importance of the means of dose delivery, shown to be as important as dose size when considering biologic effect.