Ligand-Receptor Interactions and Structure-Function Relationships in Off-Target Binding of the ß3-Adrenergic Agonist Mirabegron to α1A-Adrenergic Receptors.

The ß3-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to α1-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure-function relationships in the binding of mirabegron to a cryo-electron microscopy structure of α1A. The binding was simulated by docking mirabegron to a 3D structure of a human α1A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the α1A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of α1A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of α1A, accounts for mirabegron binding to α1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α1A-blockers and no effects on voiding symptoms.

Intramedullary Fixation Versus Plate Fixation of Distal Fibular Fractures: A Systematic Review.

INTRODUCTION: The purpose of this systematic review and meta-analysis was to provide an update of the recent literature comparing clinical outcomes of surgically treated fibular fractures using intramedullary nailing (IMN) with open reduction and internal plate fixation (ORIF). METHODS: A literature search reporting clinical outcomes after IMN or ORIF of the distal fibula was conducted on PubMed. Inclusion criteria consisted of original studies; studies focusing on clinical outcomes after IMN or IMN and ORIF published before May 11, 2022; studies with at least 5 patients; and studies reporting union rates, complication rates, and patient-reported outcomes such as American Orthopaedic Foot and Ankle Society (AOFAS) and Olerud-Molander scores. RESULTS: Of 2,394 studies identified, a total of 29 studies (4 LOE-I, 2 LOE-II, 6 LOE-III, 17 LOE-IV) were included consisting of 1,850 IMN patients and 514 plate patients. The pooled mean age of IMN patients was 58 years (95% confidence interval [CI], 54 to 62, I2 = 42%) versus 57 years (95% CI, 53 to 62, I2 = 49%) in ORIF. Union rates for IMN patients revealed a 99% union rate (95% CI, 0.98 to 1.00, I2 = 20%) versus 97% union rate for ORIF patients (95% CI, 0.94 to 0.99, I2 = 0%). Studies that compared IMN with ORIF revealed no difference in union rates (risk ratio [RR] = 0.99, 95% CI, 0.96 to 1.02, I2 = 0%). IMN patients showed a 15% complication rate (95% CI, 0.09 to 0.23, I2 = 89%), whereas plate patients had a complication rate of 30% (95% CI, 0.18 to 0.46, I2 = 63%). When comparing studies with both treatments, IMN patients had a significantly lower risk of complications (RR = 0.49, 95% CI, 0.29 to 0.82, I2 = 50%). The IMN group trended toward a higher mean AOFAS and Olerud-Molander score than the plate group by 4.53 (95% CI, -14.58 to 23.65, I2 = 85%) and 3.54 (95% CI, -2.32 to 9.41, I2 = 76%) points, respectively. CONCLUSION: Current literature reveals near equivalence in union rates and a markedly lower risk of complications when comparing IMN with plate fixation. While IMN patients had higher AOFAS and Olerud-Molander scores, these differences were not statistically significant. Notably, subgroup analyses indicated that rates of symptomatic implant and removal of implant were comparable between IMN and ORIF, which may indicate that wound-related complications were reduced in the minimally invasive IMN technique. While the high cost of IMN implants remains a barrier to their widespread adoption, the long-term benefits of reducing complications, specifically associated with wound complications in high-risk populations, may greatly improve quality of care for patients with distal fibula fractures. Additional research and cost-effectiveness analyses are warranted to fully assess the long-term benefits and economic feasibility of using IMN fixation for distal fibula fractures. LEVEL OF EVIDENCE: Therapeutic Level IV.

Immunomodulatory imide drugs inhibit human detrusor smooth muscle contraction and growth of human detrusor smooth muscle cells, and exhibit vaso-regulatory functions.

BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Sustainability initiatives in inpatient psychiatry: tackling food waste.

Background: Food plays a dual role in promoting human health and environmental sustainability. Yet, current food systems jeopardize both. Food waste poses a major global challenge due to its significant economic, social, and environmental impacts. Healthcare facilities generate the largest amounts of food waste compared to other forms of catering provision. Food waste correlates with environmental unsustainability and diminished patient satisfaction, compounding the prevalent challenge of hospital malnutrition and contributing to suboptimal patient outcomes. Materials and methods: In a three-year interventional study (2020-2022) at a psychiatric tertiary care center, we assessed and mitigated food waste using evidence-based measures. We conducted systematic food wastage audits over three years (2020-2022) in May and June, each lasting four weeks. Costs were analyzed comprehensively, covering food, staff, infrastructure, and disposal. Environmental impact was assessed using Umweltbelastungspunkte (UBP) and CO2e/kg emissions, alongside water usage (H2O - l/kg). Results: Economic losses due to food wastage were substantial, primarily from untouched plates and partially consumed dinners, prompting meal planning adjustments. Despite a >3% increase in meals served, both food waste mass and costs decreased by nearly 6%. Environmental impact indicators showed a reduction >20%. Vegetables, salad, and fruits constituted a significant portion of waste. Overproduction minimally contributed to waste, validating portion control efficacy. Conclusion: Our study highlights significant economic and environmental losses due to hospital food waste, emphasizing the importance of resource efficiency. The strategies outlined offer promising avenues for enhanced efficiency. The decrease in food waste observed over the three-year period underscores the potential for improvement.

Whole-brain simulation of interictal epileptic discharges for patient-specific interpretation of interictal SEEG data.

In patients with refractory epilepsy, the clinical interpretation of stereoelectroencephalographic (SEEG) signals is crucial to delineate the epileptogenic network that should be targeted by surgery. We propose a pipeline of patient-specific computational modeling of interictal epileptic activity to improve the definition of regions of interest. Comparison between the computationally defined regions of interest and the resected region confirmed the efficiency of the pipeline. This result suggests that computational modeling can be used to reconstruct signals and aid clinical interpretation.

A complex case with generalized epilepsy, probable focal seizures, and functional seizures.

In this patient, now 42 years old, genetic generalized epilepsy (juvenile myoclonic epilepsy) manifested itself at the age of 13. At the age of 39, she experienced a status episode with prolonged ICU treatment. She was left with a left-sided hippocampal sclerosis and probably focal seizures. In addition, since the age of 24, the patient also experiences functional seizures on the background of a borderline personality disorder. While generalized epileptic seizures could be controlled with antiseizure medication (ASM), the patient was multiple times admitted to Emergency Departments for her functional seizures with subsequent intensive care treatments, including intubation. As a complication, the patient developed critical illness polyneuropathy and myopathy, resulting in wheelchair dependence. Additionally, she acquired a complex regional pain syndrome after extravasation of ASM. The report demonstrates the uncommon development of hippocampal sclerosis after a generalized tonic-clonic status epilepticus and the poor treatability of functional seizures as compared to generalized and focal seizures.

The impact of preoperative 5-alpha reductase inhibitors on functional outcomes and health-related quality of life following radical prostatectomy - A propensity score matched longitudinal study.

OBJECTIVES: While the impact of treatment with 5-alpha Reductase Inhibitors (5-ARI) on the risk of cancer-related mortality in men with prostate cancer (PC) has been extensively studied, little is known about the impact of preoperative 5-ARI use on patient-reported outcomes (PROs) following radical prostatectomy (RP). METHODS: Within our prospectively maintained institutional database of 5899 patients treated with RP for PC (2008- 2021), 99 patients with preoperative 5-ARI therapy were identified. A 1:4 propensity-score matched analysis of 442 men (n = 90 5-ARI, n = 352 no 5-ARI) was conducted. Primary endpoint was continence recovery using daily pad usage and ICIQ-SF. Health-related quality of life (HRQOL) was assessed using the validated EORTC QLQ-C30 and PR25 questionnaires. Multivariable Cox-regression-models tested the effect of preoperative 5-ARI treatment on continence-recovery (p < 0.05). RESULTS: Patients were followed up perioperatively, followed by annual assessments up to 60mo postoperatively. Preoperative mean ICIQ-SF score (2.2 vs. 0.9) was significantly higher in the 5-ARI cohort (p = 0.006). 24mo postoperatively, 68.6% (no 5-ARI) vs. 55.7% (5-ARI) had full continence recovery (p = 0.002). Multivariable Cox regression analysis, revealed preoperative 5-ARI treatment as an independent predictor for impaired continence recovery (HR 0.50, 95% CI 0.27-0.94, p = 0.03) In line, general HRQOL was significantly higher for patients without 5-ARI only up to 24mo postoperatively (70.6 vs. 61.2, p = 0.045). There was no significant impact of preoperative 5-ARI treatment on erectile function, biochemical recurrence-free survival and metastasis-free survival. CONCLUSIONS: Pre-RP 5-ARI treatment was associated with impaired continence outcomes starting 24mo postoperatively, suggesting that preoperative 5-ARI treatment can impair the long-term urinary function recovery following RP.

Integrated Metabolomics and Transcriptomics Analysis of Anacardic Acid Inhibition of Breast Cancer Cell Viability.

Anacardic acid (AnAc) inhibits the growth of estrogen receptor α (ERα)-positive MCF-7 breast cancer (BC) cells and MDA-MB-231 triple-negative BC (TNBC) cells, without affecting primary breast epithelial cells. RNA sequencing (seq) and network analysis of AnAc-treated MCF-7 and MDA-MB-231 cells suggested that AnAc inhibited lipid biosynthesis and increased endoplasmic reticulum stress. To investigate the impact of AnAc on cellular metabolism, a comprehensive untargeted metabolomics analysis was performed in five independent replicates of control versus AnAc-treated MCF-7 and MDA-MB-231 cells and additional TNBC cell lines: MDA-MB-468, BT-20, and HCC1806. An analysis of the global metabolome identified key metabolic differences between control and AnAc-treated within each BC cell line and between MCF-7 and the TNBC cell lines as well as metabolic diversity among the four TNBC cell lines, reflecting TNBC heterogeneity. AnAc-regulated metabolites were involved in alanine, aspartate, glutamate, and glutathione metabolism; the pentose phosphate pathway; and the citric acid cycle. Integration of the transcriptome and metabolome data for MCF-7 and MDA-MB-231 identified Signal transduction: mTORC1 downstream signaling in both cell lines and additional cell-specific pathways. Together, these data suggest that AnAc treatment differentially alters multiple pools of cellular building blocks, nutrients, and transcripts resulting in reduced BC cell viability.

Toxicity-Induced Discontinuation of Immune Checkpoint Inhibitors in Metastatic Urothelial Cancer: 6-Year Experience from a Specialized Uro-Oncology Center.

Immune checkpoint inhibitor (ICI) therapies have been established as the standard-of-care in various uro-oncological cancers. Immune-related adverse events (irAEs) are frequent, but their degree rarely leads to the discontinuation of immunotherapies. Unplanned permanent treatment discontinuation may negatively impact the outcomes of patients, but there are emerging data about a positive correlation between emergence of severe irAEs and therapeutic cancer responses. In this study, a retrospective analysis of patients treated for urothelial carcinoma (UC) with ICI-based immunotherapy was conducted. irAEs were classified according to the Common Terminology Criteria for Adverse Events (CTCAEs) and radiological responses according to the Response Evaluation Criteria In Solid Tumors (RECISTs). Out of 108 patients with metastatic urothelial cancer that underwent immunotherapy, 11 experienced a severe irAE that required permanent discontinuation of ICI therapy. The most frequent irAEs leading to discontinuation were hepatitis (n = 4), pneumonitis (n = 2), and gastritis or colitis (n = 2). Prior to discontinuation (R1), the radiological best response was complete remission (CR) in three patients, partial response (PR) in six, and stable disease (SD) in wo patients. After the discontinuation of ICI therapy (R2), the best responses were CR in six, PR in three, and SD in two patients. Following discontinuation, the majority of these patients showed a sustained treatment response, despite not receiving any cancer-specific treatment. The median time of response after discontinuation of ICI therapy was 26.0 (5.2-55.8) months. We propose accurate counseling and close follow-ups of patients following their discontinuation of ICI therapy due to irAEs, as responses can be durable and deep, and many patients do not require immediate subsequent therapies, even in urothelial cancer. More data are required to find predictors of the length of response to appropriately counsel patients.

The Influence of Size on the Intracranial Distribution of Biomedical Nanoparticles Administered by Convection-enhanced Delivery in Minipigs.

Because of the blood-brain barrier (BBB), successful drug delivery to the brain has long been a key objective for the medical community, calling for pioneering technologies to overcome this challenge. Convection-enhanced delivery (CED), a form of direct intraparenchymal microinfusion, shows promise but requires optimal infusate design and real-time distribution monitoring. The size of the infused substances appears to be especially critical, with current knowledge being limited. Herein, we examined the intracranial administration of polyethylene glycol (PEG)-coated nanoparticles (NPs) of various sizes using CED in groups of healthy minipigs (n = 3). We employed stealth liposomes (LIPs, 130 nm) and two gold nanoparticle designs (AuNPs) of different diameters (8 and 40 nm). All were labeled with copper-64 for quantitative and real-time monitoring of the infusion via positron emission tomography (PET). NPs were infused via two catheters inserted bilaterally in the putaminal regions of the animals. Our results suggest CED with NPs holds promise for precise brain drug delivery, with larger LIPs exhibiting superior distribution volumes and intracranial retention over smaller AuNPs. PET imaging alongside CED enabled dynamic visualization of the process, target coverage, timely detection of suboptimal infusion, and quantification of distribution volumes and concentration gradients. These findings may augment the therapeutic efficacy of the delivery procedure while mitigating unwarranted side effects associated with nonvisually monitored delivery approaches. This is of vital importance, especially for chronic intermittent infusions through implanted catheters, as this information enables informed decisions for modulating targeted infusion volumes on a catheter-by-catheter, patient-by-patient basis.

Calorie restriction and life-extending mutation downregulate miR-34a to facilitate lipid metabolism in the liver.

Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that enable these organisms to have extended lifespan is useful for the development of interventions to slow aging and deter age-related disease. Nonalcoholic fatty liver disease (NAFLD) is a condition that is characterized by the accumulation of excess adipose tissue in the liver. Previous studies highlight the potential of calorie restriction (CR) in promoting longevity, but little is known about its effects on the biomolecular processes that govern NAFLD. In this study, we examined the role of 6-month CR on genes regulating lipid metabolism in the livers of long-living df/df mice and their N littermates. Importantly, our findings showed significant downregulation of miR-34a-5p in N-CR mice and df/df mice regardless of dietary regimen. Alongside, our RT-PCR results indicated that downregulation of miR-34a-5p is correlated with the expression of metabolism-associated mRNAs involved in modulating the processes of de novo lipogenesis (DNL), fatty acid oxidation (FAO), very-low density lipoprotein transport (VLDL-T), and reverse cholesterol transport (RCT). To further verify the role of miR-34a-5p in regulating metabolic processes, we transfected the human liver cancer (HepG2) cell line with miR-34a mimic, and studied its effect on direct targets Sirt1, Ampk, and Ppara as well as downstream lipid transport regulating genes. Our findings suggest that CR and df/df life extending mutation are robust drivers of the miR-34a-5p signaling pathway and prevent the pathogenesis of age-related diseases by improving overall lipid homeostasis.

Age-dependent increase of perineuronal nets in the human hippocampus and precocious aging in epilepsy.

OBJECTIVE: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. METHODS: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. RESULTS: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). SIGNIFICANCE: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. PLAIN LANGUAGE SUMMARY: "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.

Outcomes After Exoscopic Versus Microscopic Type 1 Tympanoplasty.

OBJECTIVE: To analyze the outcomes of exoscopic versus microscopic type 1 tympanoplasty. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care otology-neurotology practice. PATIENTS: Adult subjects with a diagnosis of tympanic membrane perforation from 2018 to 2022. INTERVENTION: Exoscopic or microscopic tympanoplasty with cartilage + perichondrium or perichondrium/fascia graft. MAIN OUTCOME MEASURES: Primary outcomes were graft success rate (1 wk, 3 wk, 3 mo, and 6 mo postoperatively) and operative time. Secondary outcomes included audiometric outcomes of postoperative air-bone gap (ABG), change in ABG, pure tone average (PTA), speech reception threshold (SRT), and word recognition score (WRS) at 6-month follow-up and complication rates of cerebrospinal fluid leak, facial nerve injury, persistent tinnitus, and persistent vertigo. RESULTS: Seventy-one patients underwent type 1 tympanoplasty by a single surgeon. Thirty-six patients underwent exoscopic tympanoplasty, and 35 patients underwent microscopic tympanoplasty. Cartilage and perichondrium were utilized in 27 subjects (75.0%) in the exoscopic group and in 25 subjects (71.4%) in the microscopic group (p = 0.7, Cramer's V = 0.04). Graft success rate was as follows (exoscope versus microscope): 100% (36/36) versus 100% (35/35) at 1 week (p = 1.0, Cramer's V = 0.0), 97.2% (35/36) versus 100% (35/35) at 3 weeks (p = 1.0, Cramer's V = 0.1), 97.2% (35/36) versus 94.3% (33/35) at 3 months (p = 1.0, Cramer's V = 0.07), and 91.7% (33/36) versus 91.4% (32/35) at 6 months (p = 0.7, Cramer's V = 0.0). Operative time was 57.7 minutes for the exoscopic group and 65.4 minutes for the microscopic group (p = 0.08, 95% CI [-16.4, 0.9], Cohen's d = 0.4). There were no serious complications. All preoperative and postoperative audiometric outcomes were comparable. CONCLUSIONS: The outcomes after exoscopic versus microscopic type 1 tympanoplasty are comparable.

Effects of carvedilol on human prostate tissue contractility and stromal cell growth pointing to potential clinical implications.

BACKGROUND: Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α1-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth. METHODS: Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth-related functions were examined in cultured stromal cells. RESULTS: Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC50 values for agonists, with unchanged Emax values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM. CONCLUSIONS: Carvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α1-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".

Perioperative Outcomes and Trends in Transurethral Resection of Bladder Tumors with Photodynamic Diagnosis: Results from the GeRmAn Nationwide Inpatient Data Study.

Background: Photodynamic diagnosis (PDD) during transurethral resection of bladder tumor (TURBT) is guideline recommended, as it improves bladder cancer detection rates. However, the extent to which PDD is implemented in everyday clinical practice has not been thoroughly assessed. We aimed to evaluate the current trends and major perioperative outcomes of TURBT with PDD. Methods: The present study evaluated the GeRmAn Nationwide inpatient Data (GRAND) from 2010 (the year when PDD started to be coded separately in Germany) to 2021, which were made available from the Research Data Center of the German Bureau of Statistics. We undertook numerous patient-level and multivariable logistic regression analyses. Results: Overall, 972,208 TURBTs [228,207 (23%) with PDD and 744,001 (77%) with white light] were performed. Patients offered PDD during TURBT were younger (p < 0.001), presented fewer comorbidities (p < 0.001) and were discharged earlier from hospital (p < 0.001). PDD was associated with additional costs of about EUR 500 compared to white-light TURBT (p < 0.001). The yearly TURBT cases remained relatively stable from 2010 to 2021, whereas utilization of PDD underwent a 2-fold increase. After adjusting for major risk factors in the multivariate regression analysis, PDD was related to lower rates of transfusion (1.4% vs. 5.6%, OR: 0.29, 95% CI: 0.28 to 0.31, p < 0.001), intensive care unit admission (0.7% vs. 1.4%, OR: 0.56, 95% CI: 0.53 to 0.59, p < 0.001) and 30-day in-hospital mortality (0.1% vs. 0.7%, OR: 0.24, 95% CI: 0.22 to 0.27, p < 0.001) compared to white-light TURBT. On the contrary, PDD was related to clinically insignificant higher rates of bladder perforation (0.6% versus 0.5%, OR: 1.3, 95% CI: 1.2 to 1.4, p < 0.001), and reoperation (2.6% versus 2.3%, OR: 1.2, 95% CI: 1.1 to 1.2, p < 0.001). Conclusions: The utilization of PDD with TURBT is steadily increasing. Nevertheless, the road toward the establishment of PDD as the standard of care for TURBT is still long, despite of the advantages of PDD.

Self-reported exhaustion and a 4-item physical frailty index to predict the incidence of major complications after onco-geriatric surgery.

BACKGROUND: The aim of this study was to analyze four pre-operative physical frailty indicators from a geriatric assessment (GA) independently and combined in a physical frailty index, in their ability to predict postoperative 30 d-complications. MATERIALS AND METHODS: In this secondary analysis of data from the published PERATECS study (ClinicalTrials.gov: NCT01278537), the predictive value of four physical frailty indicators from a defined GA battery was examined with univariable and multivariate logistic regression models in a sample of 493 onco-geriatric surgical patients. The primary endpoint was incidence of major (Clavien-Dindo ≥ grade 2 [CD ≥ 2]) complications within 30 postoperative days. Predictors of the first model included self-reported exhaustion (SRE), body mass index (BMI), Timed Up-and-Go (TUG) and handgrip strength (HGS) independently, and a second model combined these four items as a Physical Frailty Index (4i-PFI). Both regression models were adjusted for age, gender, American Society of Anesthesiologists (ASA) status, tumor sites, duration of surgery time and Mini Nutritional Assessment (MNA) score. RESULTS: A total of 233 patients (47 %) developed CD ≥ 2 complications. In addition to ASA score, length of surgery, and gynecological and upper gastrointestinal tumor sites, the first model showed that SRE (OR 1.866) predicted CD ≥ 2 complications, but not TUG, BMI and HGS. In the second model, the 4i-PFI predicted CD ≥ 2 complications (OR pre-frail = 1.808, frail = 3.787). CONCLUSIONS: Physical frailty indicators as SRE revealed a better ability to predict CD ≥ 2 complications than BMI, TUG and HGS. However, prediction of CD ≥ 2 complications was enhanced when these parameters were combined in a novel 4i-PFI.

Beta Oscillations in the Sensory Thalamus During Severe Facial Neuropathic Pain Using Novel Sensing Deep Brain Stimulation.

OBJECTIVE: Advancements in deep brain stimulation (DBS) devices provide a unique opportunity to record local field potentials longitudinally to improve the efficacy of treatment for intractable facial pain. We aimed to identify potential electrophysiological biomarkers of pain in the ventral posteromedial nucleus (VPM) of the thalamus and periaqueductal gray (PAG) using a long-term sensing DBS system. MATERIALS AND METHODS: We analyzed power spectra of ambulatory pain-related events from one patient implanted with a long-term sensing generator, representing different pain intensities (pain >7, pain >9) and pain qualities (no pain, burning, stabbing, and shocking pain). Power spectra were parametrized to separate oscillatory and aperiodic features and compared across the different pain states. RESULTS: Overall, 96 events were marked during a 16-month follow-up. Parameterization of spectra revealed a total of 62 oscillatory peaks with most in the VPM (77.4%). The pain-free condition did not show any oscillations. In contrast, ß peaks were observed in the VPM during all episodes (100%) associated with pain >9, 56% of episodes with pain >7, and 50% of burning pain events (center frequencies: 28.4 Hz, 17.8 Hz, and 20.7 Hz, respectively). Episodes of pain >9 indicated the highest relative ß band power in the VPM and decreased aperiodic exponents (denoting the slope of the power spectra) in both the VPM and PAG. CONCLUSIONS: For this patient, an increase in ß band activity in the sensory thalamus was associated with severe facial pain, opening the possibility for closed-loop DBS in facial pain.

Insertion sites of iliosacral screws on the posterior ilium: Implications for posterior pelvic fixation.

OBJECTIVES: Lateral compression type II pelvic ring injuries can be treated with fixation through open or percutaneous approaches depending on the injury pattern and available osseous fixation pathways. The start site of iliosacral screws to stabilize these injuries should be on the unstable posterior iliac fragment; however, our understanding of start sites for iliosacral screws has not been developed. The purpose of this study is to provide an analysis of iliosacral screw start sites on the posterior ilium to help guide treatment of pelvic ring injuries. METHODS: One-hundred and seventeen consecutive patients at an academic level I trauma center with pelvic ring injuries who underwent surgical treatment with iliosacral screws were included in the final analysis. The start sites of iliosacral screws with confirmed intraosseous placement on a postoperative computed tomography were mapped on the posterior ilium and analyzed according to the sacral segment and type of iliosacral screw. RESULTS: One-hundred and seventeen patients were included in the final analysis. Of the total of 272 iliosacral screw insertion sites analyzed, 145 (53%) were sacroiliac-style screws and 127 (47%) were transsacral screws. The insertion sites for sacroiliac-style screws and transsacral screws at different sacral segment levels can vary but have predictable regions on the posterior ilium relative to reliable osseous landmarks. CONCLUSIONS: Iliosacral screws start sites on the posterior ilium have reliable regions that can be used to plan posterior fixation of pelvic ring injuries.

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.