Impact of pathologic re-review on grade, clinical stage, and risk stratification for patients with nonmuscle invasive bladder cancer.

OBJECTIVES: Pathologic re-review of transurethral resection of bladder tumor (TURBT) specimen is a common practice at our tertiary care center, but its impact on disease risk stratification remains unknown. We sought to determine how pathologic re-review of specimen initially read at an outside institution changed grade, clinical T (cT) stage, and AUA non-muscle-invasive bladder cancer (NMIBC) risk stratification. METHODS AND MATERIALS: The laboratory information system was searched for patients who underwent TURBT from 2021 to 2022, yielding 561 records. 173 patients met inclusion criteria: 113 with

An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer.

PURPOSE: Intravesical Bacillus Calmette-Guerin (BCG) is standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). The effect of the bladder microbiome on response to BCG is unclear. We sought to characterize the microbiome of bladder tumors in BCG-responders and non-responders and identify potential mechanisms that drive treatment response. MATERIALS AND METHODS: Patients with archival pre-treatment biopsy samples (2012-2018) were identified retrospectively. Prospectively, urine and fresh tumor samples were collected from individuals with high-risk NMIBC (2020-2023). BCG response was defined as tumor-free 2 years from induction therapy. Extracted DNA was sequenced for 16S rRNA and shotgun metagenomics. Primary outcomes were species richness (α-diversity) and microbial composition (ß-diversity). Paired t-tests were performed for α-diversity (Observed species/Margalef). Statistical analysis for ß-diversity (weighted and unweighted UniFrac distances, weighted Bray-Curtis dissimilarity) were conducted through Permanova, with 999 permutations. RESULTS: Microbial species richness (P < 0.001) and composition (P = 0.001) differed between BCG responders and non-responders. Lactobacillus spp. were significantly enriched in BCG-responders. Shotgun metagenomics identified possible mechanistic pathways such as assimilatory sulfate reduction. CONCLUSION: A compositional difference exists in the tumor microbiome of BCG responders and non-responders with Lactobacillus having increased abundance in BCG responders.

Standardization of the evaluation and surveillance of patients with BCG unresponsive high grade non-muscle invasive bladder cancer clinical trials.

There are multiple ongoing and planned clinical trials that are evaluating novel therapies to treat patients with BCG-unresponsive high grade nonmuscle invasive bladder cancer (NMIBC). Importantly, there is considerable variation in surveillance strategies between these clinical trials, specifically with regards to the use of advanced imaging, enhanced cystoscopy, and mandatory biopsies, which could impact landmark efficacy assessments of investigational agents. To present guideline recommendations for the standardization of cystoscopic evaluation, surveillance, and efficacy assessments for patients with BCG-unresponsive NMIBC participating in clinical trials. On September 29, 2023 at the annual meeting of the International Bladder Cancer Network, a breakout session was convened, during which representatives from various disciplines discussed potential guidance statements with opportunity for discussion and comment. A set of statements regarding use of white light and enhanced cystoscopy were developed to help guide a pragmatic approach to surveillance and efficacy assessments of patients in clinical trials. The use of "for cause" and "mandatory" biopsies was also addressed. A standard approach to evaluation of patients within the context of clinical trials is necessary to accurately assess the efficacy of novel agents, especially within single arm trials that lack an appropriate comparator. Additionally, the utilization and timing of mandatory biopsies is critical, as these biopsies may impact both disease evaluations and the determination of duration of response.

Acute alcohol exposure and electrocardiographic changes: Finding from the HOLIDAY trial.

BACKGROUND: Alcohol consumption is associated with a higher increased risk of atrial fibrillation (AF), but the acute effects on cardiac electrophysiology in humans remain poorly understood. The HOw ALcohol InDuces Atrial TachYarrhythmias (HOLIDAY) Trial revealed that alcohol shortened pulmonary vein atrial effective refractory periods, but more global electrophysiologic changes gleaned from the surface ECG have not yet been reported. METHODS: This was a secondary analysis of the HOLIDAY Trial. During AF ablation procedures, 100 adults were randomized to intravenous alcohol titrated to 0.08% blood alcohol concentration versus a volume and osmolarity-matched, masked, placebo. Intervals measured from 12­lead ECGs were compared between pre infusion and at infusion steady state (20 min). RESULTS: The average age was 60 years and 11% were female. No significant differences in the P-wave duration, PR, QRS or QT intervals, were present between alcohol and placebo arms. However, infusion of alcohol was associated with a statistically significant relative shortening of the JT interval (r: -14.73, p = 0.048) after multivariable adjustment. CONCLUSION: Acute exposure to alcohol was associated with a relative reduction in the JT interval, reflecting shortening of ventricular repolarization. These acute changes may reflect a more global shortening of refractoriness, suggesting immediate proarrhythmic effects pertinent to the atria and ventricles.

Impact of Neoadjuvant Chemotherapy on Pathologic Downstaging in Patients With Variant Histology Undergoing Radical Cystectomy.

INTRODUCTION: Variant histology (VH) bladder cancer is often associated with poor outcomes and the role of neoadjuvant chemotherapy (NAC) remains incompletely defined. Our objective was to determine comparative pathologic downstaging at radical cystectomy (RC) following NAC for patients with and without VH. PATIENTS AND METHODS: Patients who underwent RC at 2 tertiary referral centers (1996-2018) were included. Patients with VH (sarcomatoid, nested, micropapillary, plasmacytoid) were matched 1:2 to patients with pure urothelial carcinoma by age, sex, clinical T (cT)stage, clinical N (cN)stage, cystectomy year and receipt of NAC. The primary outcome was pathologic downstaging (pT-stage < cT-stage). The differential impact of NAC on pathologic downstaging between VH and non-VH was assessed using multivariable logistic regression with interaction analysis. RESULTS: 225 VH and 437 non-VH patients were included. One hundred twenty-eight of six hundred sixty-two (19.3%) patients experienced downstaging, including 54/121 (44.6%) patients who received NAC and 74/542 (13.2%) patients who did not (P < .01). Rates of downstaging after NAC for subgroups were: 45/78 (57.7%) urothelial, 3/8 (37.5%) sarcomatoid, 2/12 (16.7%) nested, 3/14 (21.4%) micropapillary, and 1/8 (12.5%) plasmacytoid. Collectively, 9/42 (21.4%) of VH patients who received NAC were downstaged. On multivariable analyses, NAC was associated with increased likelihood of downstaging in the overall cohort (OR 5.25, 95% CI, 3.29-8.36, P < .0001) and this effect was not modified by VH versus non-VH histology (P = .13 for interaction). VH patients had worse survival outcomes compared to non-VH (P < 0.01 for all). CONCLUSION: When comparing patients with VH to matched pure urothelial carcinoma controls, VH did not have an adverse effect on downstaging following NAC. VH patients should not be excluded from NAC if otherwise eligible.

Oncologic outcomes of intravesical therapy in the management of nonmuscle invasive bladder cancer with variant histology.

PURPOSE: There is limited data on oncologic outcomes in nonmuscle invasive bladder cancer (NMIBC) with variant histology (VH) managed with intravesical therapy. We sought to evaluate oncologic outcomes for this cohort at a high-volume center. MATERIALS AND METHODS: A retrospective review of an IRB-approved bladder cancer database was performed. Patients with a history of NMIBC with VH present on transurethral resection of bladder tumor (TURBT) treated with intravesical therapy (BCG or chemotherapy) were identified. Outcomes of interest included recurrence within the bladder, progression to muscle-invasive bladder cancer (MIBC), metastatic progression, cancer-specific, and overall survival. Survival time was computed from the date of initiation of intravesical therapy to the date of event or censoring. For patients who underwent radical cystectomy, recurrence-free, cancer-specific, and overall survival were also computed. The Kaplan-Meier method with log rank was utilized to compare survival time between VH sub-groups. RESULTS: Ninety patients were included in the final cohort with a median follow-up of 38 months. The majority of patients had T1 disease (72%) and received intravesical BCG (83%) as their only form of intravesical therapy. The most commonly represented VH in this series were glandular and squamous differentiation (26%). Forty-eight patients (53%) experienced recurrence within the bladder with a median recurrence-free survival of 24 months (95% Confidence Interval [CI]: 2-46 months). Five-year rates of progression to MIBC and distant metastasis were both 14% respectively. Twenty-six patients (28%) eventually required cystectomy. When stratifying by VH, patients with sarcomatoid, plasmacytoid, and micropapillary had significantly worse oncologic outcomes. CONCLUSION: In this series of highly-selected patients with NMIBC and VH, bladder-sparing treatment with intravesical therapy demonstrated acceptable oncologic outcomes for most VHs. This may be an acceptable treatment option for patients without plasmacytoid, sarcomatoid, or micropapillary features who are not suitable cystectomy candidates or who prioritize bladder-sparing treatment.

Comparison of non-laser and laser transvenous lead extraction: a systematic review and meta-analysis.

AIMS: Transvenous lead extraction (TLE) is performed using non-laser and laser techniques with overall high efficacy and safety. Variation in outcomes between the two approaches does exist with limited comparative evidence in the literature. We sought to compare non-laser and laser TLE in a meta-analysis. METHODS AND RESULTS: We searched Medline, Embase, Scopus, ClinicalTrials.gov, and CENTRAL databases for TLE studies published between 1991 and 2021. From the included 68 studies, safety and efficacy data were carefully evaluated and extracted. Aggregated cases of outcomes were used to calculate odds ratio (OR), and pooled rates were synthesized from eligible studies to compare non-laser and laser techniques. Subgroup comparison of rotational tool and laser extraction was also performed. Non-laser in comparison with laser had lower procedural mortality (pooled rate 0% vs. 0.1%, P < 0.01), major complications (pooled rate 0.7% vs. 1.7%, P < 0.01), and superior vena cava (SVC) injury (pooled rate 0% vs. 0.5%, P < 0.001), with higher complete success (pooled rate 96.5% vs. 93.8%, P < 0.01). Non-laser comparatively to laser was more likely to achieve clinical [OR 2.16 (1.77-2.63), P < 0.01] and complete [OR 1.87 (1.69-2.08), P < 0.01] success, with a lower procedural mortality risk [OR 1.6 (1.02-2.5), P < 0.05]. In the subgroup analysis, rotational tool compared with laser achieved greater complete success (pooled rate 97.4% vs. 95%, P < 0.01) with lower SVC injury (pooled rate 0% vs. 0.7%, P < 0.01). CONCLUSION: Non-laser TLE is associated with a better safety and efficacy profile when compared with laser methods. There is a greater risk of SVC injury associated with laser sheath extraction.

Heat shock induces alternative polyadenylation through dynamic DNA methylation-regulated chromatin looping.

Alternative cleavage and polyadenylation (APA) is a gene regulatory mechanism used by cells under stress to upregulate proteostasis-promoting transcripts, but how cells achieve this remains poorly understood. Previously, we elucidated a DNA methylation-regulated APA mechanism, in which gene body DNA methylation enhances distal poly(A) isoform expression by blocking CTCF binding and chromatin loop formation at APA control regions. We hypothesized that DNA methylation-regulated APA is one mechanism cells employ to induce proteostasis-promoting poly(A) isoforms. At the DNAJB6 co-chaperone gene locus, acute heat shock resulted in binding of stress response transcription factors HSF1, ATF6, and YY1 at the APA control region and an increase in the expression of the proximal poly(A) isoform known to prevent protein aggregation. Furthermore, TET1 was recruited to rapidly demethylate DNA, facilitating CTCF binding and chromatin loop formation, thereby reinforcing preferential proximal poly(A) isoform expression. As cells recovered, the transcription factors vacated the APA control region, and DNMT1 was recruited to remethylate the region. This process resolved chromatin looping and reset the poly(A) isoform expression pattern. Our findings unveil an epigenetic mechanism enabling cells to dynamically modulate poly(A) isoforms in response to stress while shedding light on the interplay between DNA methylation, transcription factors, and chromatin looping.

Physiologic tension of the abdominal wall.

BACKGROUND: Tension-free abdominal closure is a primary tenet of laparotomy. But this concept neglects the baseline tension of the abdominal wall. Ideally, abdominal closure should be tailored to restore native physiologic tension. We sought to quantify the tension needed to re-establish the linea alba in patients undergoing exploratory laparotomy. METHODS: Patients without ventral hernias undergoing laparotomy at a single institution were enrolled from December 2021 to September 2022. Patients who had undergone prior laparotomy were included. Exclusion criteria included prior incisional hernia repair, presence of an ostomy, large-volume ascites, and large intra-abdominal tumors. After laparotomy, a sterilizable tensiometer measured the quantitative tension needed to bring the fascial edge to the midline. Outcomes included the force needed to bring the fascial edge to the midline and the association of BMI, incision length, and prior lateral incisions on abdominal wall tension. RESULTS: This study included 86 patients, for a total of 172 measurements (right and left for each patient). Median patient BMI was 26.4 kg/m2 (IQR 22.9;31.5), and median incision length was 17.0 cm (IQR 14;20). Mean tension needed to bring the myofascial edge to the midline was 0.97 lbs. (SD 1.03). Mixed-effect multivariable regression modeling found that increasing BMI and greater incision length were associated with higher abdominal wall tension (coefficient 0.04, 95% CI [0.01,0.07]; p = 0.004, coefficient 0.04, 95% CI [0.01,0.07]; p = 0.006, respectively). CONCLUSION: In patients undergoing laparotomy, the tension needed to re-establish the linea alba is approximately 1.94 lbs. A quantitative understanding of baseline abdominal wall tension may help surgeons tailor abdominal closure in complex scenarios, including ventral hernia repairs and open or burst abdomens.

Synergistic Combination of Visual Features in Vision-Taste Crossmodal Correspondences.

There has been a rapid recent growth in academic attempts to summarise, understand, and predict the taste profile matching complex images that incorporate multiple visual design features. While there is now ample research to document the patterns of vision-taste correspondences involving individual visual features (such as colour and shape curvilinearity in isolation), little is known about the taste associations that may be primed when multiple visual features are presented simultaneously. This narrative historical review therefore presents an overview of the research that has examined, or provided insights into, the interaction of graphic elements in taste correspondences involving colour, shape attributes, texture, and other visual features. The empirical evidence is largely in line with the predictions derived from the proposed theories concerning the origins of crossmodal correspondences; the component features of a visual stimulus are observed to contribute substantially to its taste expectations. However, the taste associated with a visual stimulus may sometimes deviate from the taste correspondences primed by its constituent parts. This may occur when a new semantic meaning emerges as multiple features are displayed together. Some visual features may even provide contextual cues for observers, thus altering the gustatory information that they associate with an image. A theoretical framework is constructed to help more intuitively predict and conceptualise the overall influence on taste correspondences when visual features are processed together as a combined image.

Oncological Outcomes for Patients with European Association of Urology Very High-risk Non-muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin or Early Radical Cystectomy.

BACKGROUND: European Urology Association (EAU) guidelines recommend immediate radical cystectomy (early RC) for patients with very high-risk (VHR) non-muscle invasive bladder cancer (NMIBC), with bacillus Calmette-Guérin (BCG) recommended only for those who refuse or are unfit for RC. OBJECTIVE: To describe oncological outcomes following BCG or early RC in a contemporary cohort of patients with VHR NMIBC (EAU criteria). DESIGN, SETTING, AND PARTICIPANTS: Patients diagnosed with VHR NMIBC between 2000 and 2020 were identified from our institutional NMIBC registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were overall survival (OS) and cancer-specific mortality (CSM). Secondary outcomes were the progression rate and high-grade recurrence (HGR) rate for patients receiving BCG. RESULTS AND LIMITATIONS: We identified 235 patients with VHR NMIBC, of whom 157 (67%) received BCG and 78 (33%) underwent early RC. The median follow-up was 52.8 mo. OS and CSM rates were 80.2% and 5.3% in the BCG group, and 88.1% and 4.9% in the early RC group, respectively with no significant difference in OS (p = 0.6) or CSM (p = 0.8) between the two groups. Among the patients treated with BCG, 5-yr HGR and progression rates were 41.9% and 17.4%, respectively; 39 patients (25%) underwent delayed RC after BCG. No significant difference in CSM emerged when comparing patients treated with delayed RC (after BCG) with those undergoing early RC (p = 0.86). CONCLUSIONS: Our findings suggest that intravesical BCG can be offered to patients as a resonable alternative to early RC for selected patients with VHR NMIBC. PATIENT SUMMARY: We evaluated outcomes for patients with very high-risk non-muscle-invasive bladder cancer (NMIBC) treated with BCG (bacillus Calmette-Guérin) versus early surgical removal of the bladder and found no differences in survival. We conclude that BCG could be offered to selected patients with this type of bladder cancer as a reasonable alternative to early bladder removal.

An evolutionarily nascent architecture underlying the formation and emergence of biomolecular condensates.

Biomolecular condensates are implicated in core cellular processes such as gene regulation and ribosome biogenesis. Although the architecture of biomolecular condensates is thought to rely on collective interactions between many components, it is unclear how the collective interactions required for their formation emerge during evolution. Here, we show that the structure and evolution of a recently emerged biomolecular condensate, the nucleolar fibrillar center (FC), is explained by a single self-assembling scaffold, TCOF1. TCOF1 is necessary to form the FC, and it structurally defines the FC through self-assembly mediated by homotypic interactions of serine/glutamate-rich low-complexity regions (LCRs). Finally, introduction of TCOF1 into a species lacking the FC is sufficient to form an FC-like biomolecular condensate. By demonstrating that a recently emerged biomolecular condensate is built on a simple architecture determined by a single self-assembling protein, our work provides a compelling mechanism by which biomolecular condensates can emerge in the tree of life.

A Randomized Trial of High vs Standard Power Radiofrequency Ablation for Pulmonary Vein Isolation: SHORT-AF.

BACKGROUND: High-power, short duration (HPSD) radiofrequency ablation (RFA) is a commonly used strategy for pulmonary vein isolation (PVI). OBJECTIVES: This study sought to compare HPSD with standard power, standard duration (SPSD) RFA in patients undergoing PVI. METHODS: Patients with paroxysmal or persistent (<1 year) atrial fibrillation (AF) were randomized to HPSD (50 W) or SPSD (25-30 W) RFA to achieve PVI. Outcomes assessed included time to achieve PVI (primary), left atrial dwell time, total procedure time, first-pass isolation, PV reconnection with adenosine, procedure complications including asymptomatic cerebral emboli (ACE), and freedom from atrial arrhythmias. RESULTS: Sixty patients (median age 66 years; 75% male) with paroxysmal (57%) or persistent (43%) AF were randomized to HPSD (n = 29) or SPSD (n = 31). Median time to achieve PVI was shorter with HPSD vs SPSD (87 minutes vs 126 minutes; P = 0.003), as was left atrial dwell time (157 minutes vs 180 minutes; P = 0.04). There were no differences in first-pass isolation (79% vs 76%; P = 0.65) or PV reconnection with adenosine (12% vs 20%; P = 0.26) between groups. At 12 months, recurrent atrial arrhythmias occurred less in the HPSD group compared with the SPSD group (n = 3 of 29 [10%] vs n = 11 of 31 [35%]; HR: 0.26; P = 0.027). There was a trend toward more ACE with HPSD RFA (40% HPSD vs 17% SPSD; P = 0.053). CONCLUSIONS: In patients undergoing AF ablation, HPSD compared with SPSD RFA results in shorter time to achieve PVI, greater freedom from AF at 12 months, and a trend toward increased ACE.

The Value of Programmed Ventricular Extrastimuli From the Right Ventricular Basal Septum During Supraventricular Tachycardia.

BACKGROUND: The difference between the right ventricular (RV) apical stimulus-atrial electrogram (SA) interval during resetting of supraventricular tachycardia (SVT) versus the ventriculoatrial (VA) interval during SVT (ΔSA-VAapex) is an established technique for discerning SVT mechanisms but is limited by a significant diagnostic overlap. OBJECTIVES: This study hypothesized that the difference between the RV SA interval during resetting of SVTs versus the VA interval during SVTs (ΔSA-VA) would yield a more robust differentiation of atrioventricular nodal re-entrant tachycardia (AVNRT) from atrioventricular reciprocating tachycardia (AVRT) when using the RV basal septal stimulation (ΔSA-VAbase) as compared to the RV apical stimulation (ΔSA-VAapex). Moreover, it was predicted that the ΔSA-VAbase might distinguish septal from free wall accessory pathways (APs) effectively. METHODS: In this prospective study, 105 patients with AVNRTs (age 48 ± 20 years, 44% male) and 130 with AVRTs (age 26 ± 18 years, 54% male) underwent programmed ventricular extrastimuli delivered from both the RV basal septum and RV apex. The ΔSA-VA values were compared between the 2 sites. RESULTS: The ΔSA-VAbase was shorter than the ΔSA-VAapex during AVRT (44 ± 30 ms vs 58 ± 29 ms; P < 0.001), and the opposite occurred during AVNRT (133 ± 31 ms vs 125 ± 25 ms; P = 0.03). A ΔSA-VAbase of ≧85 milliseconds had a sensitivity of 97% and specificity of 96% for identifying AVNRT. Furthermore, a ΔSA-VAbase of 45-85 milliseconds identified AVRT with left free wall APs (sensitivity 86%, specificity 95%), 20-45 milliseconds for posterior septal APs (sensitivity 72%, specificity 96%), and <20 milliseconds for right free wall or anterior/mid septal APs (sensitivity 86%, specificity 98%). CONCLUSIONS: The ΔSA-VAbase during programmed ventricular extrastimuli produced a robust differentiation between AVNRT and AVRT regardless of the AP location with ≧85 milliseconds as an excellent cutoff point. This straightforward technique further allowed localizing 4 general AP sites.

COVID-19 and employee job performance trajectories: The moderating effect of different sources of status.

This study investigates the impact of the COVID-19 pandemic on employee job performance trajectories, and further examines the moderating effects of different sources of status. Drawing from event system theory (EST), we propose that employee job performance decreases upon COVID-19 onset, but gradually increases during the postonset period. Furthermore, we argue that status from society, occupation, and workplace functions to moderate such performance trajectories. We test our hypotheses with a unique dataset of 708 employees that combines survey responses and job performance archival data over 21 consecutive months (10,808 observations) spanning the preonset, onset, and postonset periods of the initial encounter with COVID-19 in China. Utilizing discontinuous growth modeling (DGM), our findings indicate that the onset of COVID-19 created an immediate decrease in job performance, but such decrease was weakened by higher occupation and/or workplace status. However, the postonset period resulted in a positive employee job performance trajectory, which was strengthened for employees with lower occupational status. These findings enrich our understanding of COVID-19's impact on employee job performance trajectories, highlight the role of status in moderating such changes over time, and also provide practical implications to understand employee performance when facing such a crisis.

Randomized Comparison of a Radiofrequency Wire Versus a Radiofrequency Needle System for Transseptal Puncture.

BACKGROUND: Transseptal puncture is a necessary component of many electrophysiology and structural heart procedures. Improving this technique has broad ramifications for the overall efficiency and safety of these interventions. A new technology uses a specialized introducer wire to cross the septum with radiofrequency (RF) energy, eliminating the need for a transseptal needle and wire/needle exchanges. OBJECTIVES: This study sought to compare the efficacy and safety of an RF needle versus RF wire approach for transseptal puncture. METHODS: Individuals ≥18 years of age undergoing double transseptal puncture for atrial fibrillation or left atrial flutter ablation were randomized to a transseptal approach with either an RF needle or RF wire. The primary outcome was time to achieve first transseptal puncture. Secondary outcomes included second and combined transseptal puncture time, fluoroscopy time, number of equipment exchanges, and complications. RESULTS: A total of 75 participants were enrolled (36 RF needle, 39 RF wire). No crossovers occurred. Randomization to the RF wire resulted in a significant reduction in first transseptal time compared with the RF needle (median 9.2 [IQR: 5.7-11.2] minutes vs 6.9 [IQR: 5.2-8.4] minutes, P = 0.03). Second and combined transseptal times, and number of equipment exchanges, were also reduced with the RF wire. One participant in the RF needle group experienced transient atrioventricular block due to mechanical trauma from the sheath/dilator assembly. There were no complications in the RF wire group. CONCLUSIONS: The RF wire technique resulted in faster time to transseptal puncture and fewer equipment exchanges compared with an RF needle with no difference in complications.