Pudendal nerve block decreases narcotic requirements and time spent in post-anesthesia care units in patients undergoing primary inflatable penile prosthesis implantation.

Efforts to minimize narcotic usage following inflatable penile prosthesis (IPP) implantation are vital, considering the current opioid epidemic in the United States. We aimed to determine whether pudendal nerve block (PNB) utilization in a multiethnic population undergoing primary IPP implantation can decrease rates of post-operative opiate usage. A single-institution, retrospective study was conducted on patients who underwent primary IPP implantation between December 2015 and June 2022. PNB usage and intra- and post-operative outcomes were analyzed using multivariate binary logistic regression. 449 patients were included, with 373 (83.1%) in the PNB group. Median time (minutes) spent in the post-anesthesia care unit (PACU) (1499 [119-198] vs. 235 [169-322], p < 0.001) was significantly lower in the PNB group. There were no significant differences in intra-operative and PACU morphine milligram equivalents or post-operative safety outcomes between groups. However, fewer patients in the PNB group called for pain medications post-operatively (10.2% vs 19.7%, p = 0.019). Multivariate analysis revealed a significantly decreased operative time (B -6.23; 95%CI -11.28, -1.17; p = 0.016) and decreased time in recovery (B: -81.62; 95%CI: -106.49, -56.76, p < 0.001) in the PNB group. PNB decreases post-operative opioid analgesic requirements and time spent in PACU in patients undergoing a primary IPP implantation and thus may represent an attractive, non-opioid adjunct.

Volumetric segmentation in the context of posterior fossa-related pathologies: a systematic review.

BACKGROUND: Segmentation tools continue to advance, evolving from manual contouring to deep learning. Researchers have utilized segmentation to study a myriad of posterior fossa-related conditions, such as Chiari malformation, trigeminal neuralgia, post-operative pediatric cerebellar mutism syndrome, and Crouzon syndrome. Herein, we present a summary of the current literature on segmentation of the posterior fossa. The review highlights the various segmentation techniques, and their respective strengths and weaknesses, employed along with objectives and outcomes of the various studies reported in the literature. METHODS: A literature search was conducted in PubMed, Embase, Cochrane, and Web of Science up to November 2023 for articles on segmentation techniques of posterior fossa. The two senior authors searched through databases based on the keywords of the article separately and then enrolled joint articles that met the inclusion and exclusion criteria. RESULTS: The initial search identified 2205 articles. After applying inclusion and exclusion criteria, 77 articles were selected for full-text review after screening of titles/abstracts. 52 articles were ultimately included in the review. Segmentation techniques included manual, semi-automated, and fully automated (atlas-based, convolutional neural networks). The most common pathology investigated was Chiari malformation. CONCLUSIONS: Various forms of segmentation techniques have been used to assess posterior fossa volumes/pathologies and each has its advantages and disadvantages. We discuss these nuances and summarize the current state of literature in the context of posterior fossa-associated pathologies.

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Long-Term Outcomes of Mechanical Aortic Valve Replacement in Children.

When the options of aortic valve repair or the Ross procedure are not feasible or have been exhausted, mechanical aortic valve replacement (AVR) may provide a reliable and structurally durable alternative, but with the limitations of long-term anticoagulation, thrombosis risk and lack of valve growth potential. In this article, we review the longitudinal outcomes of mechanical AVR in children in our institution and compare them to those recently reported by others. From 1978 to 2020, 62 patients underwent mechanical AVR at a median age of 12.4 years (interquartile range (IQR): 8.6-16.8 years). The most common underlying diagnoses were: conotruncal anomalies (40%, 25/62), congenital aortic stenosis (16%, 10/62), rheumatic valve disease (16%, 10/62), connective tissue disease (8.1%, 5/62) and infective endocarditis (6.5%, 4/62). Thirty-two patients (52%, 32/62) had at least 1 prior aortic valve surgery prior to mechanical AVR. Early death was 3.2% (2/62). Median follow-up was 14.4 years (IQR: 8.4-28.2 years). Kaplan-Meier survival was 96.8%, 91.9%, 86.3%, and 81.9% at 1, 5, 10, and 20 years. On competing risk analysis, the proportion of patients alive without aortic valve reoperation at 1, 5, 10, and 20 years was 95.2%, 87.0%, 75.5% and 55.4%, respectively, while the proportion of patients that had aortic valve reoperation (with death as a competing event) at 1, 5, 10, and 20 years was 1.6%, 4.9%, 12.8%, and 28.5%, respectively. In conclusion, when the options of aortic valve repair or the Ross procedure are not feasible in children, mechanical AVR is an alternative, yet the long-term rates of mortality and need for aortic valve reoperation are of concern.

HeartMate 3 implantation with an emphasis on the biventricular configuration.

OBJECTIVES: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3). METHODS: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups. RESULTS: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%. CONCLUSIONS: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support.

Widespread latent hyperactivity of nociceptors outlasts enhanced avoidance behavior following incision injury.

Nociceptors with somata in dorsal root ganglia (DRGs) exhibit an unusual readiness to switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Ongoing activity (OA) during this state is present in vivo in rats months after spinal cord injury (SCI), and has been causally linked to SCI pain. OA induced by various neuropathic conditions in rats, mice, and humans is retained in nociceptor somata after dissociation and culturing, providing a powerful tool for investigating its mechanisms and functions. An important question is whether similar nociceptor OA is induced by painful conditions other than neuropathy. The present study shows that probable nociceptors dissociated from DRGs of rats subjected to postsurgical pain (induced by plantar incision) exhibit OA. The OA was most apparent when the soma was artificially depolarized to a level within the normal range of membrane potentials where large, transient depolarizing spontaneous fluctuations (DSFs) can approach AP threshold. This latent hyperactivity persisted for at least 3 weeks, whereas behavioral indicators of affective pain - hindpaw guarding and increased avoidance of a noxious substrate in an operant conflict test - persisted for 1 week or less. An unexpected discovery was latent OA in neurons from thoracic DRGs that innervate dermatomes distant from the injured tissue. The most consistent electrophysiological alteration associated with OA was enhancement of DSFs. Potential in vivo functions of widespread, low-frequency nociceptor OA consistent with these and other findings are to amplify hyperalgesic priming and to drive anxiety-related hypervigilance.

A shared mechanism for TNP-ATP recognition by members of the P2X receptor family.

P2X receptors (P2X1-7) are non-selective cation channels involved in many physiological activities such as synaptic transmission, immunological modulation, and cardiovascular function. These receptors share a conserved mechanism to sense extracellular ATP. TNP-ATP is an ATP derivative acting as a nonselective competitive P2X antagonist. Understanding how it occupies the orthosteric site in the absence of agonism may help reveal the key allostery during P2X gating. However, TNP-ATP/P2X complexes (TNP-ATP/human P2X3 (hP2X3) and TNP-ATP/chicken P2X7 (ckP2X7)) with distinct conformations and different mechanisms of action have been proposed. Whether these represent species and subtype variations or experimental differences remains unclear. Here, we show that a common mechanism of TNP-ATP recognition exists for the P2X family members by combining enhanced conformation sampling, engineered disulfide bond analysis, and covalent occupancy. In this model, the polar triphosphate moiety of TNP-ATP interacts with the orthosteric site, while its TNP-moiety is deeply embedded in the head and dorsal fin (DF) interface, creating a restrictive allostery in these two domains that results in a partly enlarged yet ion-impermeable pore. Similar results were obtained from multiple P2X subtypes of different species, including ckP2X7, hP2X3, rat P2X2 (rP2X2), and human P2X1 (hP2X1). Thus, TNP-ATP uses a common mechanism for P2X recognition and modulation by restricting the movements of the head and DF domains which are essential for P2X activation. This knowledge is applicable to the development of new P2X inhibitors.

Is povidone-iodine pleurodesis as effective, safe and well tolerated as talc pleurodesis for recurrent malignant pleural effusions?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'For patients with malignant pleural effusion is chemical pleurodesis with povidone-iodine as effective, safe and well tolerated as talc pleurodesis for prevention of recurrent malignant pleural effusions?'. A total of 124 papers were found during the search, of which 8 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. At present, medical-grade talc is the most commonly used agent for chemical pleurodesis due to its high success rate, extensive history of clinical use and well-known side-effect profile. However, studies using povidone-iodine seek to establish it as a readily available,low-cost alternative to talc that can be easily administered through an intercostal catheter at the bedside. The summation of available evidence suggests that povidone-iodine is a safe, well-tolerated and equally efficacious agent for pleurodesis in the setting of malignant pleural effusion, when compared to talc.

Real-world four-year functional and surgical outcomes of Rezum therapy in younger versus elderly men.

BACKGROUND: Management of urinary symptoms in elderly patients with benign prostatic hyperplasia (BPH) is complex given challenges with medications and invasive surgeries. Rezum, a minimally invasive water vapor therapy, is an emerging alternative. We compare real-world Rezum outcomes between young and elderly patients over 4 years. METHODS: We retrospectively analyzed a multiethnic population treated with Rezum at a single center between 2017-2019. Patients were stratified into young (<65 years) or elderly (≥65 years) cohorts. International Prostate Symptom Score (IPSS), Quality of Life (QoL), maximum urinary flow rate (Qmax), decisional regret scores, and adverse events (AEs) were assessed at baseline, 1-, 3-, 6-, 12-, and/or 48-months. Descriptive statistics were compared using t-tests, Chi-squared, or Mann-Whitney U tests. Changes in outcomes were assessed using Wilcoxon signed-rank tests, stratified by age. RESULTS: 256 patients - 146 (57%) young and 110 (43%) elderly - were included. The majority were Asian (33.2%) or non-Hispanic Black (28.9%). Significant improvements were observed in the combined cohort at 4-years in IPSS, QoL, and Qmax when compared to baseline (all p < 0.05). Between the age cohorts, there were no significant differences in IPSS, QoL, or Qmax at any follow-up. Within both cohorts, significant improvements in IPSS and QoL were found from baseline to all follow-ups. In the young cohort, Qmax was significantly improved from baseline to all follow-ups while in the elderly cohort, this was observed only at the 3-month follow-up. No significant differences in AEs or regret was found between cohorts. There was no significant difference in 4-year surgical retreatment rates between cohorts (elderly 4.0% vs young 4.4%, p = 0.86). CONCLUSIONS: There were no significant differences in IPSS, QoL, or AEs between elderly and younger men over 4 years following Rezum, suggesting comparable benefits and risks. Future research is warranted to clarify the impact of Rezum on Qmax in elderly men.

Outcomes of neo-aortic valve and root surgery late after arterial switch operation.

BACKGROUND: Neo-aortic root dilatation and valve regurgitation are emerging problems late after arterial switch operation (ASO). We sought to evaluate the prevalence and outcomes of neo-aortic root or valve reoperation after ASO. METHODS: All patients with biventricular circulation who underwent an ASO between 1983 and 2015 were included at a single institution. RESULTS: In our cohort of 782 late ASO survivors, the median duration of follow-up was 18.1 years (interquartile range [IQR], 11.3-25.6 years). During follow-up, 47 patients (6.0%) underwent 60 reoperations on the neo-aortic valve/root. The first neo-aortic valve/root reoperation occurred at a median of 15.2 years (IQR, 7.8-18.4 years) after ASO. Operations included mechanical Bentall (31.9%; n = 15), aortic valve repair (25.5%; n = 12), mechanical aortic valve replacement (AVR) (21.3%; n = 10), valve-sparing root replacement (19.1%; n = 9), and the Ross procedure (2.1%; n = 1). There was 1 late death (2.1%). Multivariable predictors of neo-aortic valve/root reoperation were bicuspid valve (hazard ratio [HR], 4.8; 95% confidence interval [CI], 2.1-10.7; P < .001), Taussig-Bing anomaly (HR, 3.0; 95% CI, 1.2-7.4; P < .02), previous pulmonary artery band (HR, 2.8; 95% CI, 1.2-6.3; P < .01) and left ventricular outflow tract obstruction before ASO (HR, 2.4; 95% CI, 1.0-5.8; P < .04). Freedom from neo-aortic valve or root reoperation was 98.0% (95% CI, 96.7%-98.8%) at 10 years, 93.3% (95% CI, 90.8%-95.2%) at 20 years, and 88.5% (95% CI, 84.1%-91.8%) at 30 years after ASO. Among the 47 patients who underwent neo-aortic reoperation, freedom from AVR was 82.3% (95% CI, 67.7%-90.7%) at 10 years, 58.0% (95% CI, 41.8%-71.2%) at 20 years, and 43.2% (95% CI, 27.0%-58.3%) at 25 years after ASO. CONCLUSIONS: The need for neo-aortic valve or root reoperation surpasses 10% by 30 years post-ASO. Evolving understanding of the mechanisms of neo-aortic valve insufficiency and techniques of neo-aortic valve repair may decrease the need for AVR.

Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance.

ABSTRACT: Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions.

Druggable site near the upper vestibule determines the high affinity and P2X3 homotrimer selectivity of sivopixant/S-600918 and its analogue DDTPA.

BACKGROUND AND PURPOSE: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-([3-chloro-4-isopropoxyphenyl]amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear. EXPERIMENTAL APPROACH: To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole-cell recording. KEY RESULTS: The high affinity and selectivity of sivopixant/DDTPA for hP2X3 receptors was determined by the tri-symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant/DDTPA as the hP2X3 homotrimer. CONCLUSION AND IMPLICATIONS: From the receptor-ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough-suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors.

hnRNPA1 SUMOylation promotes cold hypersensitivity in chronic inflammatory pain by stabilizing TRPA1 mRNA.

TRPA1 is pivotal in cold hypersensitivity, but its regulatory mechanisms in inflammatory cold hyperalgesia remain poorly understood. We show here that the upregulation of SUMO1-conjugated protein levels in a complete Freund's adjuvant (CFA)-induced inflammatory pain model enhances TRPA1 mRNA stability, ultimately leading to increased expression levels. We further demonstrate that hnRNPA1 binds to TRPA1 mRNA, and its SUMOylation, upregulated in CFA-induced inflammatory pain, contributes to stabilizing TRPA1 mRNA by accumulating hnRNPA1 in the cytoplasm. Moreover, we find that wild-type hnRNPA1 viral infection in dorsal root ganglia neurons, and not infection with the SUMOylation-deficient hnRNPA1 mutant, can rescue the reduced ability of hnRNPA1-knockdown mice to develop inflammatory cold pain hypersensitivity. These results suggest that hnRNPA1 is a regulator of TRPA1 mRNA stability, the capability of which is enhanced upon SUMO1 conjugation at lysine 3 in response to peripheral inflammation, and the increased expression of TRPA1 in turn underlies the development of chronic inflammatory cold pain hypersensitivity.

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

N-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization.

Small ubiquitin-like modifier (SUMO) typically conjugates to target proteins through isopeptide linkage to the ε-amino group of lysine residues. This posttranslational modification (PTM) plays pivotal roles in modulating protein function. Cofilins are key regulators of actin cytoskeleton dynamics and are well-known to undergo several different PTMs. Here, we show that cofilin-1 is conjugated by SUMO1 both in vitro and in vivo. Using mass spectrometry and biochemical and genetic approaches, we identify the N-terminal α-amino group as the SUMO-conjugation site of cofilin-1. Common to conventional SUMOylation is that the N-α-SUMOylation of cofilin-1 is also mediated by SUMO activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by the SUMO deconjugating enzyme, SENP1. Specific to the N-α-SUMOylation is the physical association of the E1 enzyme to the substrate, cofilin-1. Using F-actin co-sedimentation and actin depolymerization assays in vitro and fluorescence staining of actin filaments in cells, we show that the N-α-SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization. This covalent conjugation by SUMO at the N-α amino group of cofilin-1, rather than at an internal lysine(s), serves as an essential PTM to tune cofilin-1 function during regulation of actin dynamics.

Intraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.

Targeting greater pump flow and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) could potentially alleviate renal hypoxia and reduce the risk of postoperative acute kidney injury (AKI). Therefore, in an observational study of 93 patients undergoing on-pump cardiac surgery, we tested whether intraoperative hemodynamic management differed between patients who did and did not develop AKI. Then, in 20 patients, we assessed the feasibility of a larger-scale trial in which patients would be randomized to greater than normal target pump flow and MAP, or usual care, during CPB. In the observational cohort, MAP during hypothermic CPB averaged 68.8 ± 8.0 mmHg (mean ± SD) in the 36 patients who developed AKI and 68.9 ± 6.3 mmHg in the 57 patients who did not (p = 0.98). Pump flow averaged 2.4 ± 0.2 L/min/m2 in both groups. In the feasibility clinical trial, compared with usual care, those randomized to increased target pump flow and MAP had greater mean pump flow (2.70 ± 0.23 vs. 2.42 ± 0.09 L/min/m2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m2 ). Target MAP ≥80 mmHg was achieved in 66.6% of patients in the intervention group but in only 27.3% of patients in the usual care group. Nevertheless, MAP during CPB did not differ significantly between the two groups. We conclude that little insight was gained from our observational study regarding the impact of variations in pump flow and MAP on the risk of AKI. However, a clinical trial to assess the effects of greater target pump flow and MAP on the risk of AKI appears feasible.

Chromogranin B (CHGB) is dimorphic and responsible for dominant anion channels delivered to cell surface via regulated secretion.

Regulated secretion is conserved in all eukaryotes. In vertebrates granin family proteins function in all key steps of regulated secretion. Phase separation and amyloid-based storage of proteins and small molecules in secretory granules require ion homeostasis to maintain their steady states, and thus need ion conductances in granule membranes. But granular ion channels are still elusive. Here we show that granule exocytosis in neuroendocrine cells delivers to cell surface dominant anion channels, to which chromogranin B (CHGB) is critical. Biochemical fractionation shows that native CHGB distributes nearly equally in soluble and membrane-bound forms, and both reconstitute highly selective anion channels in membrane. Confocal imaging resolves granular membrane components including proton pumps and CHGB in puncta on the cell surface after stimulated exocytosis. High pressure freezing immuno-EM reveals a major fraction of CHGB at granule membranes in rat pancreatic ß-cells. A cryo-EM structure of bCHGB dimer of a nominal 3.5 Å resolution delineates a central pore with end openings, physically sufficient for membrane-spanning and large single channel conductance. Together our data support that CHGB-containing (CHGB+) channels are characteristic of regulated secretion, and function in granule ion homeostasis near the plasma membrane or possibly in other intracellular processes.

High resolution cryo-EM structures of TRPC5-Gαi3 complexes reveal direct activation of an ion channel by Gαi-GTP.

Transient receptor potential canonical 4 and 5 (TRPC4 and TRPC5) are Ca2+-permeable nonselective cation channels known to be activated by Gi/o proteins. Recently, Won et al. (Nat Commun. 2023, 14:2550) reported the cryo-EM structures of TRPC5 in complex with Gαi3. The G protein alpha subunit was found to directly bind to an ankyrin-like repeat domain in the periphery of the cytosolic portion of TRPC5 some 50 Å away from the membrane. This establishes the TRPC4/C5 ion channels as true effectors of Gα subunits, although the channel gating still depends on the coexistence of Ca2+ and phosphatidylinositol 4,5-bisphosphate.

Development and validation of nomogram to improve the specificity of multiparametric MRI for clinically significant prostate cancer.

OBJECTIVE: To develop and validate a nomogram to improve the specificity of prostate imaging reporting and data system (PI-RADS) on multiparametric magnetic resonance imaging (MRI) for clinically significant prostate cancer on targeted fusion biopsy. METHODS: A retrospective review of patients who underwent fusion biopsy for PI-RADS 3-5 lesions using UroNav and Artemis systems between 2016 and 2022 was performed. Patients were divided into those with CS disease on fusion biopsy (Gleason grade group ≥2) versus those without. Multivariable analysis was used to identify variables associated with CS disease. A 100-point nomogram was constructed, and ROC curve was generated. RESULTS: 1485 lesions (1032 patients) were identified, 510 (34%) were PI-RADS 3, 586 (40%) were PI-RADS 4, and 389 (26%) were PI-RADS 5. Of these, 11% of PI-RADS 3, 39% of PI-RADS 4, and 61% of PI-RADS 5 showed CS disease. CS disease was associated with older age (OR 1.04, 95% CI 1.02-1.06, p < 0.01), previous negative biopsy (OR 0.52, 95% CI 0.36-0.74, p < 0.01), presence of multiple PI-RADS 3-5 lesions (OR 0.61, 95% CI 0.45-0.83, p < 0.01), peripheral zone location (OR 1.88, 95% CI 1.30-2.70, p < 0.01), PSA density (OR 1.48 per 0.1 unit, 95% CI 1.33-1.64, p < 0.01), PI-RADS score 4 (OR 3.28, 95% CI 2.21-4.87, p < 0.01), and PI-RADS score 5 (OR 7.65, 95% CI 4.93-11.85, p < 0.01). Area under ROC curve was 82% for nomogram compared to 75% for PI-RADS score alone. CONCLUSION: We report a nomogram that combines PI-RADS score with other clinical parameters. The nomogram outperforms PI-RADS score for the detection of CS prostate cancer.