A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

Characteristics associated with blood transfusion among women undergoing laparoscopic myomectomy: a National Surgical Quality Improvement Program study.

BACKGROUND: Uterine fibroids are the most common benign tumors that affect females. A laparoscopic myomectomy is the standard surgical treatment for most women who wish to retain their uterus. The most common complication of a myomectomy is excessive bleeding. However, risk factors for hemorrhage during a laparoscopic myomectomy are not well studied and no risk stratification tool specific for identifying the need for a blood transfusion during a laparoscopic myomectomy currently exists in the literature. OBJECTIVE: This study aimed to identify risk factors for intraoperative and postoperative blood transfusion during laparoscopic myomectomies and to develop a risk stratification tool to determine the risk for requiring a blood transfusion. STUDY DESIGN: This was a retrospective cohort study of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2020. Women who underwent a laparoscopic (conventional or robotic) myomectomy were included. Women who received 1 or more blood transfusions within 72 hours after the start time of a laparoscopic myomectomy were compared with those who did not require a blood transfusion. A multivariable analysis was performed to identify risk factors independently associated with the risk for transfusion. Two risk stratification tools to determine the need for a blood transfusion were developed based on the multivariable results, namely (1) based on preoperative factors and (2) based on preoperative and intraoperative factors. RESULTS: During the study period, 11,498 women underwent a laparoscopic myomectomy. Of these, 331(2.9%) required a transfusion. In a multivariable regression analysis of the preoperative factors, Black or African American and Asian races, Hispanic ethnicity, bleeding disorders, American Society of Anesthesiologists class III or IV classification, and a preoperative hematocrit value ≤35.0% were independently associated with the risk for transfusion. Identified intraoperative factors included specimen weight >250 g or ≥5 intramural myomas and an operation time of ≥197 minutes. A risk stratification tool was developed in which points are assigned based on the identified risk factors. The mean probability of transfusion can be calculated based on the sum of the points. CONCLUSION: We identified preoperative and intraoperative independent risk factors for a blood transfusion among women who underwent a laparoscopic myomectomy. A risk stratification tool to determine the risk for requiring a blood transfusion was developed based on the identified risk factors. Further studies are needed to validate this tool.

Anatomic maps of erogenous sensation and pleasure in the penis: are there difference between circumcised and uncircumcised men?

BACKGROUND: The effects of male circumcision on sexual function remain controversial. Heterogeneity across previous studies and low-quality scientific evidence have resulted in poor understanding of the effects of circumcision on erogenous sensation of the penis and orgasm function. AIM: In this study we sought to describe and assess differences in erogenous genital sensation and reported orgasm function in circumcised compared with uncircumcised men. METHODS: Adult male subjects who were recruited on a paid anonymous online survey platform were shown illustrations of 12 anatomic regions of the penis. Subjects were prompted to designate regions as pleasurable when touched during partnered sex and to rate each on a 1-10 scale, with higher erogeneity scores correlating with greater pleasure. Subjects were also asked to characterize their orgasms across 6 experiential domains. OUTCOMES: Outcomes were differences between circumcised and uncircumcised men in the probabilities that regions would be designated as pleasurable, average pleasure scores, and self-reported orgasm parameters. RESULTS: In total, 227 circumcised (mean [SD] age 46.6 [17.7] years) and 175 uncircumcised men (47.8 [18.1] years) completed the survey. There were no significant differences in average ratings across all regions between circumcised and uncircumcised men. However, significantly more circumcised men reported preferences for the tip of the penis (38% vs 17%, P = .02) and the middle third of the ventral penile shaft (63% vs 48%, P = .04). Additionally, there were no significant differences in orgasm quality and function across all queried domains between circumcised and uncircumcised cohorts. CLINICAL IMPLICATIONS: Our findings suggest that circumcision does not change how men describe erogenous genital sensation or how they experience orgasm. STRENGTHS AND LIMITATIONS: In this study we expanded upon existing literature regarding comparison of sexual function in circumcised and uncircumcised men in its scale and investigation of diverse domains. Limitations include the survey format of data collection. CONCLUSION: We found no differences in reported erogenous ratings or orgasm function between circumcised and uncircumcised men. These findings suggest that male circumcision does not negatively impact penile erogeneity or orgasm function.

Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?

OBJECTIVE: To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. METHODS: We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. RESULTS: There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. CONCLUSIONS: Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.

Quality of Care Program Reduces Unplanned Health Care Utilization in Patients With Inflammatory Bowel Disease.

INTRODUCTION: There is significant variation in processes and outcomes of care for patients with inflammatory bowel disease (IBD), suggesting opportunities to improve quality of care. We aimed to determine whether a structured quality of care program can improve IBD outcomes, including the need for unplanned health care utilization. METHODS: We used a structured approach to improve adult IBD care in 27 community-based gastroenterology practices and academic medical centers. Patient-reported outcomes (PRO) and health care utilization were collected at clinical visits. Outcomes were monitored monthly using statistical process control charts; improvement was defined by special cause (nonrandom) variation over time. Multivariable logistic regression was applied to patient-level data. Nineteen process changes were offered to improve unplanned health care utilization. Ten outcomes were assessed, including disease activity, remission status, urgent care need, recent emergency department use, hospitalizations, computed tomography scans, health confidence, corticosteroid or opioid use, and clinic phone calls. RESULTS: We collected data prospectively from 20,382 discrete IBD visits. During the 15-month project period, improvement was noted across multiple measures, including need for urgent care, hospitalization, steroid use, and opioid utilization. Adjusted multivariable modeling showed significant improvements over time across multiple outcomes including urgent care need, health confidence, emergency department utilization, hospitalization, corticosteroid use, and opioid use. Attendance at monthly coached webinars was associated with improvement. DISCUSSION: Outcomes of IBD care were improved using a structured quality improvement program that facilitates small process changes, sharing of best practices, and ongoing feedback. Spread of these interventions may facilitate broad improvement in IBD care when applied to a large population.

Which U.S. States' Medicaid Programs Provide Coverage for Gender-Affirming Hormone Therapy and Gender-Affirming Genital Surgery for Transgender Patients?: A State-by-State Review, and a Study Detailing the Patient Experience to Confirm Coverage of Services.

BACKGROUND: To date, a comprehensive state-by-state assessment of transgender transition-related health care coverage for gender-affirming hormone therapy (GAHT) and genital gender-affirming surgery (GAS) has not been reported. AIMS: The aims of this study were 1) to verify which U.S. states' Medicaid systems do/do not cover GAHT and GAS; 2) to assess the ease/difficulty for patients to determine whether GAHT and GAS are Medicaid-covered benefits; and 3) to understand possible state-related predictors of Medicaid coverage for gender-affirming care. METHODS: We reviewed the official Medicaid Handbook and website for all 51 states (+D.C.) and 5 territories to confirm whether GAHT and GAS are covered benefits. When indeterminate, we called the Medicaid office in each state, and for many, Medicaid managed care organizations (MCOs), and individual in-state providers, to confirm coverage. We recorded our experiences, number of, and duration of phone calls to confirm coverage. OUTCOMES: The main outcome was a definitive answer from the state/territory's Medicaid program or MCOs regarding whether GAHT and GAS are/are not covered benefits. Secondary outcome measures included responses we received and the total number/duration of phone calls necessary to confirm coverage. RESULTS: Only 12 of 51 states and 0 of 5 territories featured their policy regarding coverage for GAHT in their Medicaid Handbook/webpages. We confirmed that 34 of 51 state Medicaid programs do cover GAHT, whereas 9 of 51 states' and 2 of 5 territories' do not. We could not confirm coverage of GAHT in 8 of 51 states and 3 of 5 territories. Only 26 of 51 states and 0 of 5 territories featured their policy regarding coverage for GAS in their Medicaid Handbook/webpages. We confirmed that 25 of 51 state Medicaid programs do cover GAS, whereas 22 of 51 states' and 3 of 5 territories' do not. We could not confirm coverage of GAS in 4 of 51 states and 2 of 5 territories. Up to 12 calls, lasting up to 125 minutes, were required to confirm coverage for GAHT/GAS. CLINICAL IMPLICATIONS: Our findings indicate that important health care access barriers/disparities exist today and warrant improvement. STRENGTHS & LIMITATIONS: To our knowledge, this is the most comprehensive assessment of transgender transition-related health care coverage. Limitations include possible bias, as it could be that we were more persistent than actual patients would be to determine service coverage, and a lack of specificity regarding which specific hormone formulations or procedures are/are not covered. CONCLUSION: Our findings show that only 34 of 51 (67%) states' Medicaid programs include GAHT and 25 of 51 (49%) include GAS as covered benefits. Our experience suggests that the process to confirm coverage can be especially time-consuming and frustrating for patients. Zaliznyak M, Jung EE, Bresee C, et al. Which U.S. States' Medicaid Programs Provide Coverage for Gender-Affirming Hormone Therapy and Genital Gender-Affirming Surgery for Transgender Patients?: A State-by-State Review, and a Study Detailing the Patient Experience to Confirm Coverage of Service. J Sex Med 2021;18:410-422.

Temporal trends in the incidence of severe pelvic fracture urethral injuries in the United States from 1998 to 2014.

OBJECT: To use a contemporary population-based cohort to investigate temporal trends in the national incidence of pelvic fracture urethral injuries (PFUIs) in the United States. METHODS: Using the NIS (National Inpatient Sample), we identified patients with a severe PFUI by a combination of an ICD-9 diagnosis code for pelvic fracture (808.xx) and ICD-9 procedure code for suprapubic tube (57.17 or 57.18) from 1998 to 2014. We compared the annual rates of PFUIs and the annual rates of pelvic fractures alone. RESULTS: An estimated total of 6052 ± 347 males with PFUIs were identified. The average age was 38.4 ± 0.5 years. 9.1% ± 0.8% of patients died while hospitalized. In the time frame studied, the rate of PFUI significantly decreased during from 532 patients in 1998 to 255 patients in 2014. Sensitivity analysis excluding patients with bladder repairs identified a similar trend. The annual rate of PFUI per 1000 pelvic fractures has also decreased from 14.6 ± 1.6 in 1998 to 6.5 ± 0.9 in 2014 (p = 0.001). CONCLUSIONS: In this population level study, the number of severe PFUIs has decreased in the United States from 1998 to 2014, which coincides with the implementation and enforcement of seat belt and air bag regulations. Given the rarity of these cases, there is a strong need for collaborative efforts in research and teaching at tertiary care centers for reconstructive urology.

Pain in Inflammatory Bowel Disease Is Not Improved During Hospitalization: The Impact of Opioids on Pain and Healthcare Utilization.

BACKGROUND: Most patients with IBD experience pain, especially during acute disease exacerbations. Opioid use continues to be more prevalent in IBD than any other chronic gastrointestinal condition, and the majority of IBD patients consume narcotics during hospitalization despite the risks of infection and death. METHODS: We performed a retrospective review of 57 subjects aimed at quantifying pain and opiate consumption for IBD-related admissions over a 3-month period. For each patient, the average and maximum of each day's pain scores were used to measure changes in pain from admission to discharge using mixed model regression, with opiate use as a time-dependent covariate. RESULTS: The daily average pain score over the entire hospitalization was 4.23 ± 2.09, and the maximum pain score was 8.28 ± 1.75. Among opioid users (n = 51), the daily average pain score was 4.65 ± 2.16 and the maximum pain score was 7.53 ± 2.56. Across all cases from admission to discharge, there was less than a 1-point change in daily average pain (- 0.96 ± 2.03, p = 0.0009), and no change in maximum pain (- 0.89 ± 3.59, p = 0.0671). Opioid users, a subset of the overall cohort, had a similar less than one-point drop in daily average pain (- 0.94 ± - 0.29, p = 0.0024) and no change in daily maximum pain scores (- 0.81 ± - 0.47, p = 0.0914). Patients on average used 20 ± 25 mg morphine equivalents per day. Opioid-naïve patients used similar doses to those who used opioids prior to admission (PTA). Almost half of all cases (47%) were discharged with an opioid prescription, the majority (71%) of whom were not on opioids PTA. CONCLUSIONS: Pain in IBD is not well controlled through hospitalization, with less than a 1-point change from admission to discharge, despite significant opioid consumption. Alternative analgesic methods should be explored, given the significant impact of narcotics on long-term outcomes including mortality and quality of life.

Priapism from Recreational Intracavernosal Injections in a High-Risk Metropolitan Community.

INTRODUCTION: Recreational use of intracavernosal injections (ICIs) is a high-risk behavior that involves sharing of these agents by men without physician regulation. AIM: To characterize the etiologies and outcomes of priapism at a Los Angeles metropolitan medical center to better understand patterns of usage of recreational ICIs and the public health implications of such practices. METHODS: With institutional review board approval, we retrospectively reviewed all cases of priapism presenting to the emergency room of a Los Angeles tertiary medical center from 2010 to 2018. We compared outcomes between patients who presented with priapism after recreational ICI and patients who presented with other etiologies. MAIN OUTCOME MEASURE: We describe patient characteristics, etiologies, and treatments of priapism at our institution. RESULTS: We identified 169 priapism encounters by 143 unique patients. Recreational ICIs accounted for 82 of the 169 priapism encounters (49%). Patients who used recreational injections were younger than those who presented with other etiologies (43.5 years vs 47.5 years; P = .048) and had delayed presentations (median, 12 hours vs 8 hours; P < .0001). There was no statistical difference across groups in the proportion of patients requiring operative intervention (14.6% of recreational ICI users vs 16.1% of all other patients; P = .23). A total of 36 out of 72 patients who used recreational ICIs (50%) were HIV+. CLINICAL IMPLICATIONS: Our study adds to the relatively sparse literature on priapism outcomes. We identify and describe a high-risk population that uses recreational intracavernosal injections. STRENGTHS & LIMITATIONS: To our knowledge, this is the largest series of priapism encounters. However, the data are retrospective from a single institution, and there is a lack of long-term follow up. CONCLUSION: A large proportion of priapism visits at our institution were attributed to recreational use of ICIs. This is a high-risk patient population that may not be aware of the risks of recreational ICIs and the consequences of priapism. Further effort should be made to increase public and physician awareness of this harmful practice. Zhao H, Berdahl C, Bresee C, et al. Priapism from Recreational Intracavernosal Injections in a High-Risk Metropolitan Community. J Sex Med 2019;16:1650-1654.

The misdiagnosis of interstitial cystitis/bladder pain syndrome in a VA population.

AIMS: The complexity of Interstitial Cystitis/bladder Pain Syndrome (IC/BPS) has led to a great deal of uncertainty around the diagnosis and prevalence of the condition. Under the hypothesis that IC/BPS is frequently misdiagnosed, we sought to assess the accuracy of the ICD-9/ICD-10 code for IC/BPS using a national data set. METHODS: Using the Veterans Affairs Informatics and Computing Infrastructure, we identified a random sample of 100 patients with an ICD-9/ICD-10 diagnosis of IC/BPS (595.1/N30.10) by querying all living patients in the Veterans Affairs (VA) system. We purposely sampled men and women equally to better understand gender-specific practice patterns. Patients were considered a correct IC/BPS diagnosis if they had two visits complaining of bladder-centric pain in the absence of positive urine culture at least 6 weeks apart. Patients were considered not to have IC/BPS if they had a history of pelvic radiation, systemic chemotherapy, metastatic cancer, or bladder cancer. RESULTS: Of the 100 patients, 48 were female and 52 were male. Five had prior radiation, one had active cancer, and 10 had bladder cancer (all male), and an additional fifteen had insufficient records. Of the remaining 69 patients, 43% did not have IC/BPS. Of these patients who did not have IC/BPS, 43% complained only of overactive bladder (OAB) symptoms, which was more common in women (63%) than men (21%), P = .003. CONCLUSIONS: In our small sample from a nationwide VA system, results indicate that IC/BPS has a high misdiagnosis rate. These findings shed light on the gender-specific diagnostic complexity of IC/BPS.

Flow disruptions in robotic-assisted abdominal sacrocolpopexy: does robotic surgery introduce unforeseen challenges for gynecologic surgeons?

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to apply a human factors research approach to identify flow disruptions, deviations in the optimal course of care, in robotic abdominal sacrocolpopexy procedures with the ultimate goal of developing system interventions to improve the safety and efficiency of robotic surgery. METHODS: Twenty-four robotic abdominal sacrocolpopexy procedures were observed for flow disruptions. Surgeries were divided into four phases: (1) patient arrival and induction of anesthesia; (2) port placement and robot docking; (3) console time; (4) undocking of robot, incision closure, and patient exiting the OR. RESULTS: Flow disruptions were observed at a rate of 10.9 ± 5.1 per hour. The most frequently observed flow disruptions involved training issues (2.8 ± 2.4 flow disruptions per hour), equipment (2.2 ± 1.6 flow disruptions per hour), and poor coordination (2.0 ± 1.3 flow disruptions per hour). The rate of flow disruptions was highest in phase 2 (19.2 ± 14.4 flow disruptions per hour). Cases with more experienced surgeons involved shorter console times by 1.5 h (95% CI: 0.1, 3.0, p = 0.033) and 1.8 fewer (95% CI: 1.2, 2.6, p = 0.001) flow disruptions per hour. Surgeries were 1 h shorter on average (95% CI: 0.1, 1.9, p = 0.034) in cases in which the patient was > 65 years old. Da Vinci S console times were 0.8 h longer (95% CI: 0.01, 1.5, p = 0.047) than Si. CONCLUSIONS: Flow disruptions in robotic abdominal sacrocolpopexy surgery occur about every 6 min. Flow disruption rates are highest during the most complex portions of the surgery. More experienced surgeons have lower flow disruption rates and operate more quickly.

Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. RESULTS: After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. CONCLUSIONS: Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.

NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances.

OBJECTIVES: Chronic infection with hepatitis C virus (HCV) was previously the leading indication for liver transplant (LT) in the United States. However, since 2014 the use of direct-acting antivirals (DAAs) has decreased the chronic HCV burden, while the prevalence of nonalcoholic steatohepatitis (NASH) has risen substantially through the last decade. Both gender and ethnic disparities in indications for LT have been shown in the past but no data on this have been reported since the implementation of DAAs. METHODS: We assessed changes in etiologies for LT listing and in gender and ethnic differences in those listed for LT. Adult patients registered for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between January 1, 2004 and December 31, 2016 were included. Multinomial logistic regression modeling was used to test for changes in waitlist or liver transplant rates. RESULTS: The study included 127,164 adult patients registered for LT. By 2016, alcoholic liver disease (ALD) was the leading etiology for waitlisting and LT; NASH was second; hepatocellular carcinoma (HCC) due to chronic HCV and chronic HCV alone were 3rd and 4th. NASH was the leading cause for LT for women and the 2nd leading cause for men (following ALD). NASH increased as the cause in all ethnic subgroups and was the leading cause in 2016 among Asian, Hispanic, and non-Hispanic white females. We also found that although the indication for liver transplant for hepatocellular carcinoma (HCC) due to HCV has increased over the years, this indication decreased for the first time between 2015 and 2016 in both males and females. CONCLUSIONS: NASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.

Inflammation-induced Gro1 triggers senescence in neuronal progenitors: effects of estradiol.

BACKGROUND: Inflammation has been proposed to contribute to the decline in adult hippocampal neurogenesis. Proinflammatory cytokines activate transcription of chemokine growth-regulated oncogene α (Gro1) in human and murine hippocampal neuronal progenitor cells (NPC). The goal of this study was to investigate the effects of Gro1 on hippocampal neurogenesis in the presence of inflammation. METHODS: Human hippocampal NPC were transfected with lentivirus expressing Gro1, and murine NPC and hippocampal neuronal HT-22 cells were treated with Gro1 protein. A plasmid expressing mGro1 was electroporated in the hippocampus of newborn mice that were sacrificed 10 days later. Adult male and female mice were injected with lipopolysaccharide (LPS; 1 mg/kg, i.p in five daily injections) or normal saline. Adult male mice were implanted with pellets releasing 17-ß estradiol (E2; 2.5 mg/pellet, 41.666 µg/day release) or placebo for 6 weeks and challenged with LPS or normal saline as above. In both experiments, mice were sacrificed 3 h after the last injection. Hippocampal markers of neurogenesis were assessed in vitro and in vivo by Western blot, real-time PCR, and immunohisto/cytochemistry. RESULTS: Gro1 induced premature senescence in NPC and HT-22 cells, activating senescence-associated ß-galactosidase and the cell cycle inhibitor p16 and suppressing neuroblast proliferation and expression of doublecortin (DCX) and neuron-specific class III beta-tubulin (Tuj-1), both neuroblast markers, while promoting proliferation of neural glial antigen 2 (Ng2)-positive oligodendrocytes. Gro1 overexpression in the hippocampus of newborn mice resulted in decreased neuroblast development, as evidenced by decreased DCX expression and increased expression of platelet-derived growth factor α receptor (PDGFαR), a marker of oligodendrocyte precursors. In adult mice, Gro1 was induced in response to LPS treatment in male but not in female hippocampus, with a subsequent decrease in neurogenesis and activation of oligodendrocyte progenitors. No changes in neurogenesis were observed in females. Treatment with E2 blunted LPS-induced Gro1 in the male hippocampus. CONCLUSIONS: Inflammation-induced Gro1 triggers neuroblast senescence, thus suppressing new neuron development in the hippocampus. Sex-dependent differences in Gro1 response are attributed to estradiol, which blunts these changes, protecting the female hippocampus from the deleterious effects of inflammation-induced Gro1 on neurogenesis.

Interrelationship of Primary Virus Replication, Level of Latency, and Time to Reactivation in the Trigeminal Ganglia of Latently Infected Mice.

UNLABELLED: We sought to determine the possibility of an interrelationship between primary virus replication in the eye, the level of viral DNA in the trigeminal ganglia (TG) during latency, and the amount of virus reactivation following ocular herpes simplex virus type 1 (HSV-1) infection. Mice were infected with virulent (McKrae) or avirulent (KOS and RE) strains of HSV-1, and virus titers in the eyes and TG during primary infection, level of viral gB DNA in TG on day 28 postinfection (p.i.), and virus reactivation on day 28 p.i. as measured by explant reactivation were calculated. Our results suggest that the avirulent strains of HSV-1, even after corneal scarification, had lower virus titers in the eye, had less latency in the TG, and took a longer time to reactivate than virulent strains of HSV-1. The time to explant reactivation of avirulent strains of HSV-1 was similar to that of the virulent LAT((-)) McKrae-derived mutant. The viral dose with the McKrae strain of HSV-1 affected the level of viral DNA and time to explant reactivation. Overall, our results suggest that there is no absolute correlation between primary virus titer in the eye and TG and the level of viral DNA in latent TG and time to reactivation. IMPORTANCE: Very little is known regarding the interrelationship between primary virus replication in the eye, the level of latency in TG, and the time to reactivate in the mouse model. This study was designed to answer these questions. Our results point to the absence of any correlation between the level of primary virus replication and the level of viral DNA during latency, and neither was an indicator of how rapidly the virus reactivated following explant TG-induced reactivation.

Teaching mid-urethral sling surgery to residents: Impact on operative time and postoperative outcomes.

AIMS: The purpose of this study was to determine the impact of resident teaching on outcomes of mid-urethral sling surgery. METHODS: A retrospective review of female patients who underwent an outpatient transobturator (TOT) synthetic mid-urethral sling procedure with and without concomitant prolapse repair by two surgeons (JA, KE) in a tertiary female pelvic medicine practice was performed. Total procedure time (TPT = time from incision to closure including sling placement and any prolapse procedure), estimated blood loss (EBL), and postoperative complications including urinary retention, mesh exposure, reoperation, vaginal bleeding, and leg pain were compared between cases with and without the presence of a resident. RESULTS: One hundred thirty-four women underwent an outpatient transobturator sling procedure. Fifty-seven patients (43%) had a concomitant prolapse procedure. A resident was present at 57% (76/134) of cases. The average observed TPT (±SEM) was 60.6 ± 3.1 min when a resident was present and 46.6 ± 2.5 min when a resident was not present (P = 0.001). However, residents were more likely to be present when concomitant procedures were performed (P = 0.003). After adjusting for this, the presence of a resident increased TPT by an estimated 7.9 ± 2.5 min (P = 0.002). There was no statistical difference in EBL or postoperative complications. CONCLUSIONS: Resident participation in transobturator sling procedures resulted in a statistically significant, although clinically small, increase in operative time and had no significant impact on EBL or postoperative complications.

Surgical flow disruptions during robotic-assisted radical prostatectomy.

INTRODUCTION: We sought to apply the principles of human factors research to robotic-assisted radical prostatectomy to understand where training and integration challenges lead to suboptimal and inefficient care. MATERIALS AND METHODS: Thirty-four robotic-assisted radical prostatectomy and bilateral pelvic lymph node dissections over a 20 week period were observed for flow disruptions (FD) - deviations from optimal care that can compromise safety or efficiency. Other variables - physician experience, trainee involvement, robot model (S versus Si), age, body mass index (BMI), and American Society of Anesthesiologists (ASA) physical status - were used to stratify the data and understand the effect of context. Effects were studied across four operative phases - entry to insufflations, robot docking, surgical intervention, and undocking. FDs were classified into one of nine categories. RESULTS: An average of 9.2 (SD = 3.7) FD/hr were recorded, with the highest rates during robot docking (14.7 [SD = 4.3] FDs/hr). The three most common flow disruptions were disruptions of communication, coordination, and equipment. Physicians with more robotic experience were faster during docking (p < 0.003). Training cases had a greater FD rate (8.5 versus 10.6, p < 0.001), as did the Si model robot (8.2 versus 9.8, p = 0.002). Patient BMI and ASA classification yielded no difference in operative duration, but had phase-specific differences in FD. CONCLUSIONS: Our data reflects the demands placed on the OR team by the patient, equipment, environment and context of a robotic surgical intervention, and suggests opportunities to enhance safety, quality, efficiency, and learning in robotic surgery.

Preoperative Testing for Urethral Sling Surgery for Stress Urinary Incontinence: Overuse, Underuse and Cost Implications.

PURPOSE: We identify areas of overuse and underuse in the preoperative evaluation of patients undergoing mid urethral sling surgery. We also estimate the effect of overuse of preoperative testing on health care costs. MATERIALS AND METHODS: We conducted a retrospective review of women who underwent sling surgery with or without concomitant prolapse repair between 2012 and 2013. Physician orders for preoperative electrocardiogram, chest x-ray, basic metabolic panel, complete blood count, coagulation studies and urinalysis were classified as appropriate or inappropriate based on summary guidelines from the American Academy of Family Physicians. The additional costs of inappropriate tests were estimated using the 2014 Medicare clinical laboratory and physician fee schedules. RESULTS: A total of 101 women who underwent mid urethral sling surgery were identified and 346 preoperative tests were ordered. Overall 76% of coagulation profiles, 73% of complete blood counts, 47% of basic metabolic panels, 39% of chest x-rays and 21% of electrocardiograms ordered did not have an appropriate clinical indication. In addition, 6% of electrocardiograms, 22% of chest x-rays and 10% of urinalyses were not ordered despite an appropriate indication. The estimated charges of overused tests were $1,844.15 for the cohort, or $18 per patient. CONCLUSIONS: Preoperative testing is overused as well as underused in patients undergoing sling surgery. The greatest variation occurred with the use of electrocardiograms, chest x-rays and urinalysis. Poor adherence to national guidelines leads to increased health care costs and warrants increased awareness in following evidence-based guidelines.

The Quality of Care Provided to Women with Urinary Incontinence in 2 Clinical Settings.

PURPOSE: Our aim was to test the feasibility of a set of quality of care indicators for urinary incontinence and at the same time measure the care provided to women with urinary incontinence in 2 clinical settings. MATERIALS AND METHODS: This was a pilot test of a set of quality of care indicators. A total of 20 quality of care indicators were previously developed using the RAND Appropriateness Method. These quality of care indicators were used to measure care received for 137 women with a urinary incontinence diagnosis in a 120-physician hospital based multispecialty medical group. We also performed an abstraction of 146 patient records from primary care offices in Southern California. These charts were previously used as part of ACOVE (Assessing Care of Vulnerable Elders Project). As a post-hoc secondary analysis, the 2 populations were compared with respect to quality, as measured by compliance with the quality of care indicators. RESULTS: In the ACOVE population, 37.7% of patients with urinary incontinence underwent a pelvic examination vs 97.8% in the multispecialty medical group. Only 15.6% of cases in the multispecialty medical group and 14.2% in ACOVE (p = 0.86) had documentation that pelvic floor exercises were offered. Relatively few women with a body mass index of greater than 25 kg/m(2) were counseled about weight loss in either population (20.9% multispecialty medical group vs 26.1% ACOVE, p = 0.76). For women undergoing sling surgery, documentation of counseling about risks was lacking and only 9.3% of eligible cases (multispecialty medical group only) had documentation of the risks of mesh. CONCLUSIONS: Quality of care indicators are a feasible means to measure the care provided to women with urinary incontinence. Care varied by population studied and yet deficiencies in care were prevalent in both patient populations studied.

Safety, efficiency and learning curves in robotic surgery: a human factors analysis.

BACKGROUND: Expense, efficiency of use, learning curves, workflow integration and an increased prevalence of serious incidents can all be barriers to adoption. We explored an observational approach and initial diagnostics to enhance total system performance in robotic surgery. METHODS: Eighty-nine robotic surgical cases were observed in multiple operating rooms using two different surgical robots (the S and Si), across several specialties (Urology, Gynecology, and Cardiac Surgery). The main measures were operative duration and rate of flow disruptions-described as 'deviations from the natural progression of an operation thereby potentially compromising safety or efficiency.' Contextual parameters collected were surgeon experience level and training, type of surgery, the model of robot and patient factors. Observations were conducted across four operative phases (operating room pre-incision; robot docking; main surgical intervention; post-console). RESULTS: A mean of 9.62 flow disruptions per hour (95 % CI 8.78-10.46) were predominantly caused by coordination, communication, equipment and training problems. Operative duration and flow disruption rate varied with surgeon experience (p = 0.039; p < 0.001, respectively), training cases (p = 0.012; p = 0.007) and surgical type (both p < 0.001). Flow disruption rates in some phases were also sensitive to the robot model and patient characteristics. CONCLUSIONS: Flow disruption rate is sensitive to system context and generates improvement diagnostics. Complex surgical robotic equipment increases opportunities for technological failures, increases communication requirements for the whole team, and can reduce the ability to maintain vision in the operative field. These data suggest specific opportunities to reduce the training costs and the learning curve.