Gas Tunnel Engineering of Prolyl Hydroxylase Reprograms Hypoxia Signaling in Cells.

Cells have evolved intricate mechanisms for recognizing and responding to changes in oxygen (O2) concentrations. Here, we have reprogrammed cellular hypoxia (low O2) signaling via gas tunnel engineering of prolyl hydroxylase 2 (PHD2), a non-heme iron dependent O2 sensor. Using computational modeling and protein engineering techniques, we identify a gas tunnel and critical residues therein that limit the flow of O2 to PHD2's catalytic core. We show that systematic modification of these residues can open the constriction topology of PHD2's gas tunnel. Using kinetic stopped-flow measurements with NO as a surrogate diatomic gas, we demonstrate up to 3.5-fold enhancement in its association rate to the iron center of tunnel-engineered mutants. Our most effectively designed mutant displays 9-fold enhanced catalytic efficiency (kcat/KM=830±40 M-1 s-1) in hydroxylating a peptide mimic of hypoxia inducible transcription factor HIF-1α, as compared to WT PHD2 (kcat/KM=90±9 M-1 s-1). Furthermore, transfection of plasmids that express designed PHD2 mutants in HEK-293T mammalian cells reveal significant reduction of HIF-1α and downstream hypoxia response transcripts under hypoxic conditions of 1 % O2. Overall, these studies highlight activation of PHD2 as a new pathway to reprogram hypoxia responses and HIF signaling in cells.

Combination therapy in metastatic castration sensitive prostate cancer: A Systematic review and network meta-analysis.

Introduction: Studies directly comparing the different combination therapies offered to men with metastatic castration sensitive prostate cancer (mCSPC), are not available yet. This study was designed using the network meta-analysis (NMA) framework to provide a comparison of the different available options for the treatment of men with mCSPC. Methods: A systematic search was performed and the prospective randomized controlled trials reporting the overall survival (OS) or failure-free survival (FFS) were selected for review. A total of 14 studies were included in the NMA. Results: The addition of abiraterone, apalutamide, docetaxel, and docetaxel with zoledronic acid to the androgen deprivation therapy (ADT) demonstrated a significant improvement in the OS. In indirect comparison, abiraterone had a higher impact on the OS as compared to docetaxel (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 1.0-1.46) and docetaxel with zoledronic acid (HR: 1.31, 95% CI: 1.05-1.63) but not apalutamide. Furthermore, apalutamide was not different than docetaxel or docetaxel with zoledronic acid. There was a significant improvement in the FFS with the combination of abiraterone, apalutamide, docetaxel (HR: 0.61, 95% CI: 0.46-0.81), docetaxel with zoledronic acid (HR: 0.62, 95% CI: 0.43-0.9), and enzalutamide (HR: 0.39, 95% CI: 0.25-0.61) as compared to the ADT alone. Similar to the indirect comparison of OS, abiraterone outperformed docetaxel (HR: 1.66, 95% CI: 1.12-2.47), docetaxel with zoledronic acid (HR: 1.69, 95% CI: 1.06-2.68), and enzalutamide (HR: 1.06, 95% CI: 0.63-1.80), but not apalutamide in terms of impact on the FFS. Conclusion: Overall, abiraterone demonstrated better OS and FFS outcomes as compared to all the other combination strategies in this NMA.

Donor surfactant protein A2 polymorphism and lung transplant survival.

PURPOSE: Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the potential association between variations within the surfactant protein (SP)-A gene of the donor lung allograft and recipient post-transplant outcome. METHODS: Lung-transplant patients (n=192) were prospectively followed-up with pulmonary function tests, bronchoscopies with bronchoalveolar lavage and biopsies. Donor lungs were assayed for SP-A1 (6An) and SP-A2 (1An) gene polymorphism using the pyrosequencing method. Unadjusted and adjusted stratified Cox survival models are reported. RESULTS: SP-A1 and SP-A2 genotype frequency and lung transplant recipient and donor characteristics as well as cause of death are noted. Recipients were grouped per donor SP-A2 variants. Individuals that received lungs from donors with the SP-A2 1A0 (n=102) versus 1A1 variant (n=68) or SP-A2 genotype 1A01A0 (n=54) versus 1A0A1 (n=38) had greater survival at 1 year (log-rank p<0.025). No significant association was noted for SP-A1 variants. Stratified adjusted survival models for 1-year survival and diagnosis showed a reduced survival for 1A1 variant and the 1A01A1 genotype. Furthermore, when survival was conditional on 1-year survival no significance was observed, indicating that the survival difference was due to the first year's outcome associated with the 1A1 variant. CONCLUSION: Donor lung SP-A gene polymorphisms are associated with post-transplant clinical outcome. Lungs from donors with the SP-A2 variant 1A1 had a reduced survival at 1 year. The observed donor genetic differences, via innate immunity relate to the post-transplant clinical outcome.

Serum Testosterone 60 Months after Passive-Scatter Proton Therapy for Localized Prostate Cancer.

Studies demonstrate a decline of ∼10% in serum testosterone (ST) level after X-ray radiotherapy for prostate cancer. We evaluated changes in ST for patients with low- and intermediate-risk prostate cancer receiving 70-82Gy(RBE) using passive-scatter proton therapy (PT). ST was checked at baseline (n = 358) and at 60+ months after PT (n = 166). The median baseline ST was 363.3 ng/dl (range, 82.0-974.0). The median ST 5 years after PT was 391.5 ng/dl (range, 108.0-1061.0). The difference was not statistically significant (p = 0.9341). Passive-scatter PT was not associated with testosterone suppression at 5 years, suggesting that protons may cause less out-of-field scatter radiation than X-rays.

Evaluating a Situational Judgment Test for Use in Medical School Admissions: Two Years of AAMC PREview Exam Administration Data.

PURPOSE: To examine the relationship between the Association of American Medical Colleges (AAMC) Professional Readiness Exam (PREview) scores and other admissions data, group differences in mean PREview scores, and whether adding a new assessment tool affected the volume and composition of applicant pools. METHOD: Data from the 2020 and 2021 PREview exam administrations were analyzed. Two U.S. schools participated in the PREview pilot in 2020 and 6 U.S. schools participated in 2021. PREview scores were paired with data from the American Medical College Application Service (undergraduate grade point averages [GPAs], Medical College Admission Test [MCAT] scores, race, and ethnicity) and participating schools (interview ratings). RESULTS: Data included 19,525 PREview scores from 18,549 unique PREview examinees. Correlations between PREview scores and undergraduate GPAs ( r = .16) and MCAT scores ( r = .29) were small and positive. Correlations between PREview scores and interview ratings were also small and positive, ranging between .09 and .14 after correcting for range restriction. Small group differences in mean PREview scores were observed between White and Black or African American and White and Hispanic, Latino, or of Spanish origin examinees. The addition of the PREview exam did not substantially change the volume or composition of participating schools' applicant pools. CONCLUSIONS: Results suggest the PREview exam measures knowledge of competencies that are distinct from those measured by other measures used in medical school admissions. Observed group differences were smaller than group differences observed with traditional academic assessments and evaluations. The addition of the PREview exam did not substantially change the overall volume of applications or the proportions of out-of-state, underrepresented in medicine, or lower socioeconomic status applicants. While more research is needed, these results suggest the PREview exam may provide unique information to the admissions process without adversely affecting applicant pools.

Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials.

BACKGROUND: To assess genitourinary (GU) function and toxicity in patients treated with image-guided proton therapy (PT) for early- and intermediate-risk prostate cancer and to analyze the impact of pretreatment urinary obstructive symptoms on urinary function after PT. MATERIAL AND METHODS: Two prospective trials accrued 171 prostate cancer patients from August 2006 to September 2007. Low-risk patients received 78 cobalt gray equivalent (CGE) in 39 fractions and intermediate-risk patients received 78-82 CGE. Median follow-up was five years. The International Prostate Symptom Score (IPSS) and GU toxicities (per CTCAE v3.0 and v4.0) were documented prospectively. RESULTS: Five transient GU events were scored Gr 3 per CTCAE v4.0, for a cumulative late GU toxicity rate of 2.9% at five years. There were no Gr 4 or 5 events. On multivariate analysis (MVA), the only factor predictive of Gr 2 + GU toxicity was pretreatment GU symptom management (p = 0.0058). Patients with pretreatment IPSS of 15-25 had a decline (clinical improvement) in median IPSS from 18 before treatment to 10 at their 60-month follow-up. At last follow-up, 18 (54.5%) patients had a > 5-point decline, 14 (42.5%) remained stable, and two patients (3%) had a > 5-point rise (deterioration) in IPSS. Patients with IPSS < 15 had a stable median IPSS of 6 before treatment and at 60 months. CONCLUSION: Urologic toxicity at five years with image-guided PT has been uncommon and transient. Patients with pretreatment IPSS of < 15 had stable urinary function five years after PT, but patients with 15-25 showed substantial improvement (decline) in median IPSS, a finding not explained by initiation or dose adjustment of alpha blockers. This suggests that PT provides a minimally toxic and effective treatment for low and intermediate prostate cancer patients, including those with significant pretreatment GU dysfunction (IPSS 15-25).

Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression.

BACKGROUND: To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. MATERIAL AND METHODS: Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. RESULTS: The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. CONCLUSION: Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy.

Predictors of readmission and impact of same-day discharge in holmium laser enucleation of the prostate.

Background: Holmium enucleation of the prostate (HoLEP) is becoming the gold standard for the treatment of benign prostatic hyperplasia (BPH). Our objective was to identify predictors of 30-day readmission and the impact of same-day discharge after HoLEP. Methods: Using NSQIP data from 2011 to 2019, we identified men who underwent HoLEP for the treatment of BPH. We compared patients based on time of discharge and readmission status. We used multivariable logistic regression analysis (MLRA) to identify independent factors associated with 30-day readmission. Results: A total of 3,489 patients met inclusion criteria with 833 (23.88%) being discharged within 24 hours and 2,656 (76.12%) discharged after 24 hours. There were 158 (4.53%) 30-day readmissions, mostly due to hematuria and urinary tract infection. Patients being readmitted were older (72 vs. 70 years old, P = 0.001), were more likely to have preoperative anemia (36.7% vs. 23.1%; P < 0.001), chronic kidney disease (29.7% vs. 19.7%; P < 0.001), bleeding disorder (10.8% vs. 2.8%; P < 0.001), higher American Society of Anesthesiologists (ASA) scores (≥3: 70.3% vs. 46.7%; P < 0.001) and a higher frailty burden (5-item modified frailty index [5i-mFI] ≥ 2: 36.1% vs. 19.1%; P < 0.001) compared to their counterparts. Factors independently associated with 30-day readmission were bleeding disorder (OR 2.89; 95% CI 1.63-5.11; P < 0.001), 5i-mFI ≥ 2 (OR 1.67; 95% CI 1.03-2.71; P = 0.038) and an ASA score ≥3 (OR 1.80; 95% CI 1.21-2.70; P = 0.004); however, same-day discharge was not found to be a significant predictor of 30-day readmissions. Conclusion: The overall readmission rate after HoLEP is low. Patients discharged within 24 hours have similar rates of readmission compared to patients discharged after 24 hours. We found bleeding disorder, frailty burden, and ASA score to be independent predictors of 30-day readmission.

Interview Invitations for Otolaryngology Residency Positions Across Demographic Groups Following Implementation of Preference Signaling.

Importance: Preference signaling is a new initiative in the residency application process that has been adopted by 17 specialties that include more than 80% of applicants in the 2023 National Resident Matching cycle. The association of signals with interview selection rate across applicant demographics has not been fully examined. Objective: To assess the validity of survey-based data on the association of preference signals with interview offers and describe the variation across demographic groups. Design, Setting, and Participants: This cross-sectional study examined the interview selection outcomes across demographic groups for applications with and without signals in the 2021 Otolaryngology National Resident Matching cycle. Data were obtained from a post-hoc collaboration between the Association of American Medical Colleges and the Otolaryngology Program Directors Organization evaluating the first preference signaling program used in residency application. Participants included otolaryngology residency applicants in the 2021 application cycle. Data were analyzed from June to July 2022. Exposures: Applicants were provided the option of submitting 5 signals to otolaryngology residency programs to indicate specific interest. Signals were used by programs when selecting candidates to interview. Main Outcomes and Measures: The main outcome of interest was the association of signaling with interview selection. A series of logistic regression analyses were conducted at the individual program level. Each program within the 3 program cohorts (overall, gender, and URM status) was evaluated with 2 models. Results: Of 636 otolaryngology applicants, 548 (86%) participated in preference signaling, including 337 men (61%) and 85 applicants (16%) who identified as underrepresented in medicine, including American Indian or Alaska Native; Black or African American; Hispanic, Latino, or of Spanish origin; or Native Hawaiian or other Pacific Islander. The median interview selection rate for applications with a signal (48% [95% CI, 27%-68%]) was significantly higher than for applications without a signal (10% [95% CI, 7%-13%]). No difference was observed in median interview selection rates with or without signals when comparing male (46% [95% CI, 24%-71%] vs 7% [95% CI, 5%-12%]) and female (50% [95% CI, 20%-80%] vs 12% [95% CI, 8%-18%]) applicants or when comparing applicants who identified as URM (53% [95% CI, 16%-88%] vs 15% [95% CI, 8%-26%]) with those who did not identify as URM (49% [95% CI, 32%-68%] vs 8% [95% CI, 5%-12%]). Conclusions and Relevance: In this cross-sectional study of otolaryngology residency applicants, preference signaling was associated with an increased likelihood of applicants being selected for interview by signaled programs. This correlation was robust and present across the demographic categories of gender and self-identification as URM. Future research should explore the associations of signaling across a broad range of specialties and the associations of signals with inclusion and position on rank order lists and match outcomes.

Gas tunnel engineering of prolyl hydroxylase reprograms hypoxia signaling in cells.

Molecular engineering of biocatalysts has revolutionized complex synthetic chemistry and sustainable catalysis. Here, we show that it is also possible to use engineered biocatalysts to reprogram signal transduction in human cells. More specifically, we manipulate cellular hypoxia (low O2) signaling by engineering the gas-delivery tunnel of prolyl hydroxylase 2 (PHD2), an iron-dependent enzymatic O2 sensor. Using computational modeling and rational protein design techniques, we resolve PHD2's gas tunnel and critical residues therein that limit the flow of O2 to PHD2's catalytic core. Systematic modification of these residues open the constriction topology of PHD2's gas tunnel with the most effectively designed mutant displaying 11-fold enhanced hydroxylation efficiency. Furthermore, transfection of plasmids that express these engineered PHD2 mutants in HEK-293T cells reveal significant reduction in the levels of hypoxia inducible factor (HIF-1α) even under hypoxic conditions. Our studies reveal that activated PHD2 mutants can reprogram downstream HIF pathways in cells to simulate physiological O2-like conditions despite extreme hypoxia and underscores the potential of engineered biocatalysts in controlling cellular function.

Lung transplant waitlist outcomes among ABO blood groups vary based on disease severity.

BACKGROUND: Blood group O candidates have lower lung transplantation rates despite having the most common blood group. We postulated that waitlist outcomes among these candidates and those with other blood types vary with disease severity and lung allocation score (LAS). METHODS: We performed a retrospective cohort study of 32,772 waitlist candidates using the United Network of Organ Sharing registry from May 2005 to 2020. After identifying an interaction between blood group and LAS, we evaluated the association between blood group and waitlist outcomes within LAS quartiles using unadjusted and adjusted competing risk models. RESULTS: In the lowest LAS quartile, blood group O had a 20% reduced transplantation rate (SHR: 0.80, 95%CI: 0.75-0.85) and higher waitlist death/removal (1.33, 95%CI: 1.15-1.55) compared with group A. Blood group AB had a 52% higher transplantation rate (SHR: 1.52, 95%CI: 1.34-1.73) in the lowest LAS quartile compared with group A. In the highest LAS quartile, there was no difference in transplantation rates between groups O and A. In contrast, group B had a 19% reduced transplantation rate (SHR, 0.81 95%CI: 0.73-0.89) and AB had a 28% reduced transplantation rate (SHR: 0.72, 95%CI: 0.61-0.86) in the highest LAS quartile. Additionally, groups B and AB had increased risk of waitlist death/removal in the highest LAS quartile compared with A (SHR: 1.27, 95%CI: 1.08-1.48; SHR: 1.31, 95%CI: 1.00-1.72). CONCLUSIONS: Waitlist outcomes among ABO blood groups vary depending on illness severity, which is represented by LAS. Blood group O has lower transplantation rates at low LAS while groups B and AB have lower transplantation rates at high LAS.

Natural history, and impact of surgery and radiation on survival outcomes of men diagnosed with low-grade prostate cancer at ≤ 55 years of age: a 25-year follow-up of > 60,000 men.

PURPOSE: Low-grade prostate cancer has low mortality rates at 10 years; however, it is unclear if the response is sustained for up to 25 years of follow-up. METHODS: Using Surveillance, Epidemiology, and End Results database, the overall and cancer-specific mortality rates were compared among men ≤ 55 years of age diagnosed with low-grade prostate cancer that either had radical prostatectomy, radiotherapy, or no known treatment. RESULTS: Of the 62,772 men diagnosed with low-grade prostate cancer between 1975 and 2016, about 60%, 20% and 20% of men underwent radical prostatectomy, radiotherapy, and no known treatment, respectively. At a median follow-up of 10 years, almost 2% and 7% of men died of prostate cancer and other causes, respectively. The overall mortality was significantly better in radical prostatectomy group compared to no known treatment group (HR 1.99, CI 1.84-2.15, P value < 0.001), but not between the radiotherapy and no known treatment groups. Moreover, the overall and cancer-specific mortality rates in the radiotherapy group were almost two and three times compared to the radical prostatectomy group, respectively (HR 2.15, CI 2.01-2.29, P value < 0.001 for overall mortality and HR 2.87, CI 2.5-3.29, P value < 0.001 for cancer-specific mortality). CONCLUSIONS: The study confirms low mortality rates in men diagnosed with low-grade prostate cancer for over 25 years' follow-up. While radical prostatectomy improves survival significantly compared to no known treatment, radiotherapy is associated with an increase in overall and cancer-specific mortality, which may be related to long-term toxicities.

Extramural venous invasion: a novel magnetic resonance imaging biomarker for adverse pathology in bladder cancer.

Extramural venous invasion (EMVI) recognized on magnetic resonance imaging (MRI) is an unequivocal biomarker for detecting adverse outcomes in rectal cancer: however it has not yet been explored in the area of bladder cancer. In this study, we assessed the feasibility of identifying EMVI findings on MRI in patients with bladder cancer and its avail in identifying adverse pathology. In this single-institution retrospective study, the MRI findings inclusive of EMVI was described in patients with bladder cancer that had available imaging between January 2018 and June 2020. Patient demographic and clinical information were retrieved from our electronic medical records system. Histopathologic features frequently associated with poor outcomes including lymphovascular invasion (LVI), variant histology, muscle invasive bladder cancer (MIBC), and extravesical disease (EV) were compared to MRI-EMVI. A total of 38 patients were enrolled in the study, with a median age of 73 years (range 50-101), 76% were male and 23% were females. EMVI was identified in 23 (62%) patients. There was a significant association between EMVI and MIBC (OR = 5.30, CI = 1.11-25.36; P = 0.036), and extravesical disease (OR = 17.77, CI = 2.37-133; P = 0.005). We found a higher probability of presence of LVI and histologic variant in patients with EMVI. EMVI had a sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of 90%, 73%, 94% and 63% respectively in detecting extravesical disease. Our study suggests, EMVI may be a useful biomarker in bladder cancer imaging, is associated with adverse pathology, and could be potentially integrated in the standard of care with regards to MRI reporting systems. A larger study sample size is further warranted to assess feasibility and applicability.

Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger.

BACKGROUND: This study sought to evaluate patient-reported health-related quality of life following proton therapy for prostate cancer in men ≤ 60 years old. METHODS: Between August 2006 and January 2010, 262 hormone-naive men ≤ 60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score ≥ 60. RESULTS: Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was ≤5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose ≥40 cobalt Gy equivalents (P = .012) and radiation dose ≥ 80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015). CONCLUSIONS: Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings.

Contribution of flexor pollicis longus to pinch strength: an in vivo study.

PURPOSE: To estimate the contribution of the flexor pollicis longus (FPL) to key pinch strength. Secondary outcomes include tip pinch, 3-point chuck pinch, and grip strength. METHODS: Eleven healthy volunteers consented to participate in the study. We recorded baseline measures for key, 3-point chuck, and tip pinch and for grip strength. In order to control for instability of the interphalangeal (IP) joint after FPL paralysis, pinch measurements were repeated after immobilizing the thumb IP joint. Measures were repeated after subjects underwent electromyography-guided lidocaine blockade of the FPL muscle. Nerve conduction studies and clinical examinations were used to confirm FPL blockade and to rule out median nerve blockade. Paired t-tests were used to compare pre- and postblock means for both unsplinted and splinted measures. The difference in means was used to estimate the contribution of FPL to pinch strength. RESULTS: All 3 types of pinch strength showed a significant decrease between pre- and postblock measurements. The relative contribution of FPL for each pinch type was 56%, 44%, and 43% for key, chuck, and tip pinch, respectively. Mean grip strength did not decrease significantly. Splinting of the IP joint had no significant effect on pinch measurements. CONCLUSIONS: FPL paralysis resulted in a statistically significant decrease in pinch strength. IP joint immobilization to simulate IP joint fusion did not affect results. CLINICAL RELEVANCE: Reconstruction after acute or chronic loss of FPL function should be considered when restoration of pinch strength is important.

Estimated Glomerular Filtration Rate Predicts Complications Following Artificial Urinary Sphincter Surgery.

OBJECTIVE: To assess whether estimated glomerular filtration rate (eGFR) independently predicts adverse outcomes after AUS surgery. METHODS: Using a large national database, we identified adult males who underwent AUS surgery between 2005-2019. To calculate eGFR (ml/min/1.73 m2), the Cockroft-Gault equation was utilized. Patients were classified into five different groups: 0-29 (advanced chronic kidney disease [CKD]), 30-59 (Stage III CKD), 60-89 (Stage II CKD), 90-119 (normal), and >120 (hyperfiltration). We investigated 30-day outcomes including any complication, readmission, reoperation, major and minor complications, extended length of stay, and non-home discharge. Multivariable logistic regression analysis (MLRA) was performed to assess eGFR categories as independent predictors for each outcome. RESULTS: A total of 1,910 cases met inclusion criteria. Patients with advanced CKD had a higher frailty burden (5-item modified frailty index ≥2: 39.1% vs. 22.2%), higher American Society of Anesthesiologists score (ASA III or IV: 95.7% vs. 53.5%), and lower BMI (median kg/m²: 29.3 vs. 30.9) compared to patients with normal eGFR. Likewise, patients with advanced CKD had higher rates of any complication, readmission, reoperation, extended length of stay, non-home discharge, as well as major and minor complications, compared to patients with normal eGFR. On MLRA, advanced CKD (0-29) was independently associated with reoperation (OR 5.14; 95% CI 1.06 - 20.84; p = 0.043). CONCLUSIONS: Patients with advanced CKD had a higher likelihood of reoperation when compared to patients with normal eGFR. Patients with advanced CKD should be counseled prior to AUS surgery due to a potential higher risk of 30-day reoperation.

Geographic disparities in lung transplantation in the United States before and after the November 2017 allocation change.

BACKGROUND: The primary lung allocation unit was expanded from the donation service area to a 250-mile radius in 2017. Prior to the change, geographic disparities in donor lung availability impacted waitlist outcomes. We sought to determine if the new allocation system improved these disparities. METHODS: We conducted a retrospective cohort study comparing the 2-year period before and after the change. Donor lung availability was defined as the ratio of donor lungs to waitlist candidates in the primary allocation unit. Transplant centers were divided into quartiles by donor lung availability. Multivariable competing risk models were used to determine the association between lung availability and waitlist outcomes. Multivariable Cox proportional hazards models compared post-transplant survival. RESULTS: Prior to the allocation change, the unadjusted transplant rate at centers in the lowest and highest quartiles was 132 and 607 transplants per 100 waitlist years. Candidates in the lowest quartile of donor lung availability had a 61% adjusted lower transplantation rate compared to candidates in highest quartile (sub-hazard ratio [sHR]: 0.39, 95% confidence interval [CI]: 0.34-0.44). After the allocation change, the disparity decreased resulting in an unadjusted transplant rate of 141 and 309 among centers in the lowest and highest quartiles. Candidates in the lowest quartile had a 38% adjusted lower transplantation rate compared to those in the highest (sHR: 0.62, 95% CI: 0.57-0.68). There was no significant difference in 1-year post-transplant survival. CONCLUSIONS: Although the expansion of the primary allocation unit improved disparities in waitlist outcomes without any change in post-transplant survival, there still remain significant differences due to geography.

Identification of Lung Transplant Recipients With a Survival Benefit After Fundoplication.

BACKGROUND: Gastroesophageal reflux disease (GERD) and aspiration of enteric contents are associated with worse outcomes after lung transplantation. The purpose of this study was to elucidate populations of patients who benefit the most from fundoplication after lung transplantation. METHODS: Lung transplantations from 2001 to 2019 (n = 971) were retrospectively reviewed and stratified by fundoplication before (n = 128) or after (n = 24) chronic lung allograft dysfunction (CLAD) development vs patients who did not undergo fundoplication. Patients with a fundoplication before CLAD were propensity matched to patients without a fundoplication. The primary outcome of interest was posttransplant survival. Time-to-event rates were calculated using a multivariable Cox proportional hazards model and Kaplan-Meier functions. RESULTS: Fundoplication before CLAD improved posttransplant survival before and after propensity matching, and it remained a significant predictor after adjusting for baseline characteristics (hazard ratio [HR],0.57; 95 % confidence interval [CI], 0.4 to 0.8; P = .001). Transplant recipients with a restrictive disorder (HR, 0.46; 95 % CI, 0.3 to 0.73; P = .001), age younger than 65 years (HR, 0.48; 95 % CI, 0.32 to 0.71; P < ;0.001), and with both single (HR, 0.47; 95 % CI, 0.28 to 0.79; P = .005) and double (HR, 0.55; 95 % CI, 0.32 to 0.93; P = .027) lung transplants had a significant decrease in mortality after fundoplication. The effect was present after excluding early deaths and CLAD diagnoses. Gastroesophageal reflux disease diagnosed by pH, impedance, or esophagogastroduodenoscopy was not associated with worse outcomes. Among patients with CLAD, a fundoplication was an independent predictor of post-CLAD survival (HR, 0.27; 95 % CI; 0.12 to 0.61; P = .002). CONCLUSIONS: Fundoplication before or after CLAD development is an independent predictor of survival. Younger patients with restrictive disease, independent of the type of transplant, have a survival benefit. Gastroesophageal reflux disease diagnosed by conventional methods was not associated with worse survival.

Percutaneous intervention of large bladder calculi in neuropathic voiding dysfunction.

PURPOSE: To report our results and rationale for treating large bladder calculi in patients with neuropathic voiding dysfunction (NVD) using percutaneous cystolithalopaxy. MATERIALS AND METHODS: Ten patients with a previously diagnosed NVD presenting with a large stone burden were identified from our department database and a retrospective review of case notes and imaging was performed. RESULTS: Percutaneous access to remove bladder stones (range 8x7 to 3x2 cm) had a mean surgery length of 150 min and blood loss of 23 mL. Six of the seven patients treated percutaneously were discharged on the day of surgery and suffered no complications, while one patient experienced poor suprapubic tube drainage and required overnight admission with discharge the following day. Transurethral removal of stone burden (range 4x4 to 4x3 cm) had a mean surgery length of 111 min and blood loss of 8 mL. Each of these three patients were under our care for less than 23 hours, and one patient required a second attempt to remove 1x0.5 cm of stone fragments. There was no statistical difference between mean operative times and estimated blood loss, p = 0.5064 and p = 0.0944 respectively, for the two treatment methods. CONCLUSION: In this small series, percutaneous cystolithalopaxy was a safe, effective, and often preferred minimally invasive option for removal of large calculi in patients with NVD. We suggest possible guidelines for best endoscopic approach in this population, although a larger and prospectively randomized series will be ideal for definitive conclusions.

Water quality measurements in Buzzards Bay by the Buzzards Bay Coalition Baywatchers Program from 1992 to 2018.

The Buzzards Bay Coalition's Baywatchers Monitoring Program (Baywatchers) collected summertime water quality information at more than 150 stations around Buzzards Bay, Massachusetts from 1992 to 2018. Baywatchers documents nutrient-related water quality and the effects of nitrogen pollution. The large majority of stations are located in sub-estuaries of the main Bay, although stations in central Buzzards Bay and Vineyard Sound were added beginning in 2007. Measurements include temperature, salinity, Secchi depth and concentrations of dissolved oxygen, ammonium, nitrate + nitrite, total dissolved nitrogen, particulate organic nitrogen, particulate organic carbon, ortho-phosphate, chlorophyll a, pheophytin a, and in lower salinity waters, total phosphorus and dissolved organic carbon. The Baywatchers dataset provides a long-term record of the water quality of Buzzards Bay and its sub-estuaries. The data have been used to identify impaired waters, evaluate discharge permits, support the development of nitrogen total maximum daily loads, develop strategies for reducing nitrogen inputs, and increase public awareness and generate support for management actions to control nutrient pollution and improve water quality.