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There is emerging but limited data assessing single-port (SP) robot-assisted surgery as an alternative to multi-port (MP) platforms. We compared perioperative outcomes between SP and MP robot-assisted approaches for excision of high and low complexity renal masses. Retrospective chart review was performed for patients undergoing robot-assisted partial or radical nephrectomy using the SP surgical system (n = 23) at our institution between November 2019 and November 2021. Renal masses were categorized as high complexity (7+) or low complexity (4–6) using the R.E.N.A.L. nephrometry scoring system. Adjusting for baseline characteristics, patients were matched using a prospectively maintained MP database in a 2:1 (MP:SP) ratio. For high complexity tumors (n = 12), SP surgery was associated with a significantly longer operative time compared to MP (248.4 vs 188.1 min, p = 0.02) but a significantly shorter length of stay (1.9 vs 2.8 days, p = 0.02). For low complexity tumors (n = 11), operative time (177.7 vs 161.4 min, p = 0.53), estimated blood loss (69.6.0 vs 142.0 mL, p = 0.62), and length of stay (1.6 vs 1.8 days, p = 0.528) were comparable between SP and MP approaches. Increasing nephrometry score was associated with a greater relative increase in operative time for SP compared to MP renal surgery (p = 0.07) using best of fit linear modeling. SP robot-assisted partial and radical nephrectomy is safe and feasible for low complexity renal masses. For high complexity renal masses, the SP system is associated with a significantly longer operative time compared to the MP technique. Careful consideration should be given when selecting patients for SP robot-assisted kidney surgery.

CO2 reduction (CO2RR) can convert CO2 into feedstock for the chemical industry. In aqueous CO2electrolysis a key challenge is how to combine the CO2 educt with a neutral or alkaline electrolyte andachieve a stable cell operation. We propose a novel cell design and operation mode based on a catalystcoated cation exchange membrane: a cationic acid (NH4+), with a volatile conjugate base (NH3), replacesthe protons usually present for ion transport. The approach avoids a high proton concentration at thecathode catalyst while still removing all products within the gas phase. In this paper different cell conceptsare investigated to identify a pathway to a stable, efficient and scalable operation mode. In a completelynovel cell design a FECO > 50% was already maintained for over 35 h at 50 mA cm−2, and at 200 mA cm−2a cell voltage of 3.6 V (FECO > 60%) was achieved. Surprisingly, ammonium oxidation at the anode was fullysupressed under the reaction conditions.

Usher syndrome (USH) is the most common form of hereditary deaf-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinae uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones and outer segments (OS) of rods as well as at adhesive junctions between MGCs and photoreceptor cells (PRCs) in the outer limiting membrane (OLM). Our data provide evidence for the interaction of harmonin with OLM molecules in PRCs and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. We also demonstrate that primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our studies thus provide novel insights into PRC cell biology, USH1C pathophysiology and development of gene therapy treatment(s).

The standard discharge pathway following robotic-assisted laparoscopic prostatectomy (RALP) involves overnight hospital admission. Models for same-day discharge (SDD) have been explored for multiport RALP, however, less is known regarding SDD for single-port RALP, especially in terms of patient experience.Patient enrollment, based on preoperative determination of potential SDD eligibility, commenced March 2020 and ended March 2021. Day-of-surgery criteria were utilized to determine which enrolled patients underwent SDD. Differences in preoperative characteristics and perioperative outcomes between patients undergoing SDD and patients undergoing standard discharge were evaluated. A prospectively administered questionnaire was designed to characterize patient-centered factors informing SDD perception.Fifteen patients underwent SDD and 36 underwent standard discharge. Overall mean ± SD age and BMI were 63.6 ± 7.0 years and 29.7 ± 4.4 kg/mWith comparable outcomes to the standard discharge pathway, SDD is safe and effective in single-port RALP. Post-operative pain and perceptions of distance are implicated as patient-centered barriers to SDD; proactive pain management and patient education strategies may facilitate SDD.

Osteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells—termed derived circulating tumor cells (dCTCs)—that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.

Introduction The purpose of our study was to evaluate the benefit of bilateral inferior alveolar nerve block (BIANB) in managing postoperative pain, nausea and vomiting and opioid and antiemetic consumption in mandibular osteotomy. Material and methods 51 patients operated for bilateral sagittal split osteotomy (BSSO) were included in this prospective randomized controlled, double-blind, superiority trial. In the first group (n = 25), standard protocol was applied (general anesthesia and postoperative multimodal analgesia). The second group (n = 26) received bilateral inferior alveolar nerve block anesthesia at the start of surgery in addition to routine protocol. Postoperative monitoring was conducted every 4 h over the first 24 h and targeted the following criteria: postoperative nausea and vomiting (PONV), the visual analog scale (VAS) for pain, consumption of morphine (cumulative dose) and antiemetic agents, need for removal of guiding elastics. Results PONV was significantly lower in the BIANB group (15.4 % VS 40 %, p = 0.049), as were mean VAS scores for pain (1 VS 1.57, p = 0.045) and medians of morphine bolus (8 [6–16] VS 5.5 [1–8], p = 0.033). We found no significant difference in incidence of guiding elastic removal, and antiemetic consumption. Discussion The use of BIANB in BSSO improved postoperative patient comfort in terms of PONV and pain. Furthermore, it led to a decrease in opioid consumption. In conclusion, it is an additional therapeutic means of improving patients' postoperative comfort.

Die Darmvorbereitung vor elektiven Kolonresektionen wird unterschiedlich durchgefuhrt. Ziel dieser Studie war es, den Einfluss verschiedener Darmvorbereitungen auf Wundinfektionen, Anastomoseninsuffizienzen und die postoperative Darmatonie in der elektiven Kolonchirurgie zu untersuchen. Wir fuhrten eine retrospektive Untersuchung von Patienten der eigenen Klinik mit elektiver Kolonresektion im Zeitraum 2013 bis 2019 durch. Die Patienten erhielten unterschiedliche Darmvorbereitungen und wurden in drei Gruppen eingeteilt: keine Darmspulung („MBP−“), orthograde Darmspulung ohne orale Antibiotikaprophylaxe („MBP+/OABP−“) und mit oraler Antibiotikaprophylaxe („MBP+/OABP+“). Die Gruppen wurden hinsichtlich folgender Parameter verglichen: Wundinfektionen, Anastomoseninsuffizienzen und Dauer bis zum ersten postoperativen Stuhlgang. Insgesamt 260 konsekutive Patienten („MBP−“: n = 48; „MBP+/OABP−“: n = 145; „MBP+/OABP+“: n = 67) gingen in die Analyse ein. Durch die kombinierte Darmvorbereitung konnte die Rate an SSI erheblich reduziert werden („MBP−“ vs. „MBP+/OABP+“: 16,7 % vs. 4,5 %, p = 0,05). In der multivariaten Analyse war die Darmvorbereitung der einzige Einflussfaktor auf Wundinfektionen. Dagegen hatte diese weder uni- noch multivariat Auswirkung auf die Rate an Anastomoseninsuffizienzen und die Dauer der postoperativen Darmatonie. Vor elektiven Kolonresektionen erweist sich das Vorbereitungsschema „MBP+/OABP+“ als vorteilhaft aufgrund deutlich geringerer Raten an Wundinfektionen.

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.ONE SENTENCE SUMMARYWe demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.

DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by 5 different DNAm age measures. Two-wave longitudinal data were available for 1 083 participants of the Berlin Aging Study II who were reexamined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried’s frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), finger-floor distance, Mini-Mental State Examination, Center for Epidemiologic Studies—Depression scale, activities of daily living, instrumented ADL, and mini nutritional assessment. Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL, and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analysis of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath’s clock, Hannum’s clock PhenoAge, and GrimAge) with functional assessments. In conclusion, neither rLTL nor 7-CpG DNAmAA was able to predict impairment in the analyzed assessments over a ~7-year time course. Similarly, DNAmAA estimated from 5 epigenetic clocks was not a good cross-sectional marker of health deterioration either.

The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.

Usher syndrome (USH) is the most common form of hereditary deafness-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course, and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinas uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones, and outer segments of rods as well as at adhesive junctions of MGCs and photoreceptors in the outer limiting membrane (OLM). Our data provide evidence for the interactions of harmonin with OLM molecules in photoreceptors (PRCs) and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. In addition, primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our data provide novel insights into PRC cell biology, USH1C pathophysiology, and for developing gene therapy treatment.

Background Preclinical data from a murine model of acute colitis suggest that dual blockade of interleukin(IL)-23 and TNFα more effectively prevented the development of colonic inflammation than each monotherapy. Guselkumab(GUS), an IL-23p19 subunit antagonist, is being studied in inflammatory bowel disease. Golimumab(GOL), a TNFα antagonist, is approved for ulcerative colitis(UC). The objective of this study was to evaluate the efficacy and safety of combination induction therapy with GUS+GOL vs GUS or GOL alone in adults with moderately-to-severely active UC. Methods 214 patients(pts) naïve to TNFα antagonists and refractory or intolerant to conventional therapy(ie, immunomodulators and/or corticosteroids) were randomly assigned to receive GUS 200mg intravenous(IV) at weeks(wks) 0, 4, and 8(n=71); GOL 200mg subcutaneous(SC) at wk0 then 100mg SC at wks2, 6, and 10(n=72); or combination with GUS 200mg IV+GOL 200mg SC at wk0, GOL 100mg SC at wks2, 6, and 10, and GUS 200mg IV at wks4 and 8(n=71). The primary endpoint was clinical response at wk12; the major secondary endpoint was clinical remission at wk12. Other key endpoints were clinical remission based on the modified Mayo score (mMayo), symptomatic remission, endoscopic improvement, endoscopic normalization, histologic remission, composite histologic-endoscopic endpoints, and biomarker outcomes. Results Baseline disease characteristics were similar among groups(Table 1), however a greater proportion of pts in both monotherapy groups had pancolitis vs the combination group. A greater proportion of pts who received combination therapy achieved clinical response at wk12(83.1%) vs GUS(74.6%) or GOL(61.1%)(Table 2). Similarly, the proportion of pts who achieved clinical remission in the combination group(36.6%) was greater than that of monotherapy groups(21.1% and 22.2%, respectively). Clinical remission by mMayo score, endoscopic improvement, histologic remission, both histologic remission and endoscopic improvement, and biomarker normalization (calprotectin, CRP) rates at wk12 were also greater in the combination group vs GUS or GOL. Percentages of pts with endoscopic normalization and both histologic remission and endoscopic normalization were nearly double with combination therapy vs either monotherapy. Adverse event(AE), serious AE, and infection rates were comparable among treatment groups. One pt receiving combination therapy experienced a serious infection of influenza and sepsis. No deaths, malignancies, or TB cases were reported through wk12. Conclusion Combination induction treatment with GUS+GOL more effectively induced clinical response, clinical remission, and endoscopic improvement at wk12 than either monotherapy alone. AE rates were comparable among the treatment groups.

Most diagnostic testing for West Nile virus (WNV) disease is accomplished using serologic testing, which is subject to cross-reactivity, may require cumbersome confirmatory testing, and may fail to detect infection in specimens collected early in the course of illness. The objective of this project was to determine whether a combination of molecular and serologic testing would increase detection of WNV disease cases in acute serum samples. A total of 380 serum specimens collected ≤7 days after onset of symptoms and submitted to four state public health laboratories for WNV diagnostic testing in 2014 and 2015 were tested. WNV immunoglobulin M (IgM) antibody and RT-PCR tests were performed on specimens collected ≤3 days after symptom onset. WNV IgM antibody testing was performed on specimens collected 4–7 days after onset and RT-PCR was performed on IgM-positive specimens. A patient was considered to have laboratory evidence of WNV infection if they had detectable WNV IgM antibodies or WNV RNA in the submitted serum specimen. Of specimens collected ≤3 days after symptom onset, 19/158 (12%) had laboratory evidence of WNV infection, including 16 positive for only WNV IgM antibodies, 1 positive for only WNV RNA, and 2 positive for both. Of specimens collected 4–7 days after onset, 21/222 (9%) were positive for WNV IgM antibodies; none had detectable WNV RNA. These findings suggest that routinely performing WNV RT-PCR on acute serum specimens submitted for WNV diagnostic testing is unlikely to identify a substantial number of additional cases beyond IgM antibody testing alone.

Purpose The purpose of this paper is to explore how Monte Carlo Simulation (MCS) could have enhanced understanding of the risks involved in the financial strategy for revitalization of Rio de Janeiro’s central city based on the capture of value generated by government interventions. Design/methodology/approach The study first describes the process involved in developing the financial strategy and model without MCS. Then, it shows how the MCS could have been integrated into this process and evaluates its potential impacts on the quality of risk analysis. Findings If MCS is fully integrated into the decision-making process, it can serve as a heuristic tool that helps team members to better understand risks by generating forecasts of land value and other variables as a probability distributions. By showing the variance of the forecasted variable, MCS integrates elements of modern risk analysis into financial model development in a cost-effective manner. Research limitations/implications MCS covers only the risks associated with the variables in the financial model. Events that seem extremely unlikely (i.e. “black swans”) can occur and must be assessed separately. Practical implications MCS can help analysts to understand the financial risks of large-scale development projects involving value capture, even in the prefeasibility stage. Social implications By facilitating value capture, MCS could help close the financing gap for sustainable urban development and subsidies for lower income families. Originality/value The study “retrofits” MCS on a successfully completed financial prefeasibility study to assess its usefulness as a heuristic tool.

OBJECTIVE To evaluate long-term outcomes and identify factors associated with death or the need for revision surgery in dogs with permanent tracheostomies (PTs). DESIGN Retrospective cohort study. ANIMALS 69 client-owned dogs that received a PT between January 2002 and June 2016 at 1 of 4 veterinary teaching hospitals. PROCEDURES Medical records were reviewed, and data extracted included signalment, history, clinical signs, radiographic and laryngeal examination findings, presence of esophageal abnormalities, date and reason for receiving a PT, postoperative complications, cause of death, and survival time. Dogs surviving < 2 weeks after receiving a PT were excluded. RESULTS Major complications occurred in 42 of 69 (61%) dogs, with aspiration pneumonia (13 [19%]), skinfold occlusion (13 [19%]), and stoma stenosis (12 [17%]) being most common. Revision surgery was performed in 24 of 69 (35%) dogs, most commonly because of stoma stenosis or skinfold occlusion (9/24 [38%] each). Brachycephalic dogs were more likely (OR, 3.5; 95% confidence interval, 1.2 to 10.2) to require revision surgery than were nonbrachycephalic dogs. The overall median survival time was 1,825 days, and dogs that received corticosteroids before receiving a PT, had tracheal collapse, or were older had shorter survival times. CONCLUSIONS AND CLINICAL RELEVANCE Results of the present study indicated that creation of a PT was a viable treatment option for obstructive upper airway diseases in dogs and that long-term survival after receiving a PT was possible; however, a PT may not reduce the risk of aspiration pneumonia in dogs.

The gold standard for the evaluation of liver fibrosis is histology. However, the heterogenous distribution of fibrosis limits the sensitivity of histology. The collection of two samples with a 16G needle is therefore recommended to reduce the risk of sampling error. The aim of this study was to investigate whether this standard is also applicable to patients with autoimmune hepatitis (AIH). This retrospective study included patients with AIH, who underwent mini-laparoscopic biopsy at our center between 2011 and 2020 (n = 32). Diagnosis was verified by usage of the simplified AIH score (≥ 6). Patients were categorized into three groups, based on the number of portal fields (PF) in the collected liver tissue (10 PF, 10 - 19 PF, ≥ 20 PF). We correlated the histological staging for these groups with the mini-laparoscopic fibrosis score (MLFS). Furthermore, non-invasive methods for the assessment of fibrosis were correlated with the histological staging (acoustic radiation force impulse (ARFI) and FIB-4 score). MLFS correlated well with histological staging (r = 0.649, p = 0.0001). The correlation between MLFS and histology improved with higher numbers of histologically analyzed portal fields (10 PF: r = 0.400, p = 0.378; 10 - 19 PF: r = 0.5467, p = 0.023; ≥ 20 PF: r = 0.956, p = 0.0002). The probability of collecting at least 10 or 20 portal fields was dependent on the number and diameter of the samples. For all patients with at least two 16G biopsies, 10 or more PF were available. With three 16G biopsies, at least 20 PF were obtained for all patients. ARFI correlated with MLFS and histological staging only in patients with low/moderate-grade inflammation as defined by ALT10xULN (upper limit of normal) (MLFS: r = 0.723; p = 0.004; histology: r = 0.619, p = 0.018). FIB-4 did not correlate with histological staging. The amount of liver tissue obtained by liver biopsy is crucial to minimalize the risk of sampling error and thus underestimation of fibrosis. This study was the first to investigate the amount of liver tissue required for histological staging in AIH. Our data suggest that diagnostic accuracy is likely to be higher with 20 PF compared to the generally recommended 10 PF. We therefore recommend to perform three biopsies with a 16G needle in (suspected) AIH patients. ARFI correlated well with histological staging unless inflammatory activity is high.

To determine whether androgen, estrogen, and/or progesterone signaling play a role in the pathophysiology of adherent perinephric fat (APF). We prospectively recruited patients undergoing robotic assisted partial nephrectomy during 2015-2017. The operating surgeon documented the presence or absence of APF. For those with clear cell renal cell carcinoma (ccRCC), representative sections of tumor and perinephric fat were immunohistochemically stained with monoclonal antibody to estrogen α, progesterone, and androgen receptors. Patient characteristics, operative data, and hormone receptor presence were compared between those with and without APF. Of 51 patients total, 18 (35.3%) and 33 (64.7%) patients did and did not have APF, respectively. APF was associated with history of diabetes mellitus (61.1% vs 24.2%, p = 0.009) and larger tumors (4.0 cm vs 3.0 cm, p = 0.017) but not with age, gender, BMI, Charleston comorbidity index, smoking, or preoperative estimated glomerular filtration rate. APF was not significantly associated with length of operation, positive margins, or 30-day postoperative complications but incurred higher estimated blood loss (236.5 mL vs 209.2 mL, p = 0.049). Thirty-two had ccRCC and completed hormone receptor staining. The majority of tumors and perinephric fat were negative for estrogen and progesterone while positive for androgen receptor expression. There was no difference in hormone receptor expression in either tumor or perinephric fat when classified by presence or absence of APF (p 0.05). APF is more commonly present in patients with diabetes or larger tumors but was not associated with differential sex hormone receptor expression in ccRCC.