A study of pregnancy rates in "cleared" male factor couples.

BACKGROUND: Among couples with male factor infertility, the natural pregnancy rates associated with classic male factor treatments are well described. In couples with unexplained infertility, the proportion due to occult male factor is unclear. We hypothesized that many men diagnosed with unexplained infertility are actually fertile. We describe the 1-year natural pregnancy rates among couples in whom the male partner has been "cleared" of infertility on urologic evaluation. METHODS: Consecutive infertile couples were recruited from a single practice (PJT) over a 3-year period. A thorough male factor evaluation was performed, including a history, physical examination and 2 semen analyses. Based on this assessment, male partners in whom bulk semen parameters were normal were "cleared" from further evaluation. Lifestyle modifications were allowed, but no medical or surgical treatments were offered. The presence or absence of a female factor evaluation was not required for study inclusion. Subjects were followed for 12 months or until a pregnancy was achieved. Subjects were contacted via telesurvery 1-year later and pregnancy status ascertained. Simple descriptive statistics were used to evaluate the significance of observations. RESULTS: Fifty-four men were enrolled in the study. The mean duration of infertility was 1.5 years (range, 0.4 to 4.0 years) and the mean male and female partner ages were 38.6 and 35.1 years, respectively. On evaluation, 40% of men were noted to have significant fertility risks that included a clinical varicocele, exposures, and androgen altering medications. Among n=31 couples with known pregnancy outcomes, 20/31 (65%) conceived naturally at a mean of 9 months after evaluation (range, 3-30 mos). Another 1/31 (3%) couples conceived with intrauterine insemination (IUI) and 4/31 (13%) conceived with IVF-ICSI. CONCLUSIONS: A significant proportion of men diagnosed with unexplained infertility have lifestyle risk factors on urologic evaluation. Care in the form of counseling at-risk patients regarding lifestyle issues, in the absence of formal treatment, may have value in improving the fertility potential in this population. Indeed, natural conception rates among men identified with unexplained infertility are substantial and suggest that many of these men are truly fertile.

A Protocol-Driven Reduction in Surgical Site Infections After Colon Surgery.

BACKGROUND: Surgical site infection (SSI) is an established quality indicator and predictor for adverse patient outcomes. Multiple strategies have been established to reduce SSI; however, optimum protocol remains unclear. The aim of the study was to assess the impact of established protocol on SSI after colon surgery. METHODS: We established a colon SSI bundle in 2017, which includes a chlorhexidine prescrub followed by chloraPrep, betadine wound wash, antibiotic infused irrigation, use of closure tray, and incision coverage with silver impregnated dressing. Retrospective analysis of a 2-y (2016-2017) prospectively collected before and after analysis of all patients undergoing elective colon surgery was performed. Patients were divided into two groups: preprotocol (PP: year 2016) and postprotocol (PoP: year 2017). Patients in the two groups were matched using propensity score matching for age, gender, comorbidities, Anesthesiology Severity Score, indication of procedure, and procedure type. Outcome measures were SSI, hospital length of stay, and readmission rate. RESULTS: A total of 328 patients were analyzed, and after propensity matching, 94 patients (PP:47 and PoP:47) were included. The mean age was 63.7 ± 16.4 y, 43.6% male, and 44.6% of procedures were performed laparoscopically. There was no difference in demographics, comorbidities, and procedure details between two groups. PoP patients had significantly lower superficial (odds ratio: 0.91 [0.74-0.98]; P = 0.045) and deep SSI (odds ratio:0.97 [0.65-0.99]; P = 0.048) than PP patients. PoP patient had shorter length of stay (P = 0.049) and trend toward lower readmission rate (P = 0.098) compared with PP patients and an 85% reduction in the Centers for Medicare and Medicaid Services standardized infection rate. CONCLUSIONS: Protocol-driven patient care improves patient outcomes. SSI bundle reduced SSI in patient undergoing colon surgery. Establishing national SSI bundles will help standardize care and help optimize patient outcomes.

Restricting Intraoperative Fluid Volume Allows Earlier Return of Bowel Function After Colon and Rectal Surgery.

BACKGROUND: Return of bowel function (ROBF) after abdominal surgery is an important determinant of patient outcomes. The role of intraoperative fluids (IOFs) in colon surgery remains unclear. The aim of this study was to assess the impact of IOF on ROBF in patients undergoing colon surgery. We hypothesized that minimizing IOFs allows earlier ROBF. METHODS: A 2-year (2016-2017) retrospective analysis of all patients undergoing elective colon resection was performed at our tertiary hospital using a protocol limiting IOF and postoperative narcotics. Patients were divided into two groups: preprotocol (2016) and postprotocol (PoP) (2017). Patients were matched using propensity score matching for age, gender, comorbidities, Anesthesiology Severity Score, indication for procedure, and procedure type. The outcome measured was ROBF. Secondary outcome measures were complication rates and hospital length of stay. RESULTS: A total of 360 patients were analyzed. After propensity matching, 90 patients (preprotocol: 45; PoP: 45) were included. The mean age was 62.2 ± 14.8 y, 43.3% male, and 44.4% of procedures were performed laparoscopically. There was no difference in demographics and comorbidities between groups. PoP patients received lower IOF (P = 0.036, 2016: 1198.8 ± 1096.5 mL, 2017: 2176.7 ± 1458.3 mL) and lower postoperative narcotics (P = 0.042). PoP patients had earlier ROBF 2[2-4], 4[3-5] (odds ratio: 1.18 [1.05-1.52], P = 0.04), shorter length of stay 3[2-5] d versus 5[4-7] (odds ratio: 1.11 [1.09-1.89], P = 0.043), and trended toward lower complication rates (P = 0.09). CONCLUSIONS: IOF volume independently impacts ROBF after colon surgery. Restricting IOF allows for earlier bowel function and shorter hospital stay. Further studies defining optimum fluid management impacting ROBF may help optimize patient care.

Dual Prosthetic Implantation After Radical Cystoprostatectomy and Neobladder: Outcomes of the Inflatable Penile Prosthesis and Artificial Urinary Sphincter in Bladder Cancer Survivors.

OBJECTIVES: To determine the impact of radical cystectomy and orthotopic neobladder (NB) diversion on device-related outcomes in patients who undergo subsequent placement of both, an artificial urinary sphincter (AUS) and 3-piece inflatable penile prosthesis. MATERIALS AND METHODS: Using an institutional prosthetic database, we identified 39 patients who underwent radical cystectomy and NB and subsequent implantation of both prosthetic devices from 2003 to 2017. Patient demographics, perioperative data, and postoperative outcomes including prosthetic infection, mechanical failure, revision surgery, and functional outcomes were examined and compared to an appropriate matched group of patients (n = 48, non-neobladder group). RESULTS: No intraoperative complications were observed. After median follow-up of 94 months (12-177 months), 1 patient developed an infection of their penile prosthesis and 4 patients developed an erosion of their AUS. In each case, the infection did not involve the other device. Two patients required revision surgery of their penile prosthesis due to mechanical failure (reservoir leak, n = 1; cylinder aneurysm, n = 1). Twenty-one patients underwent elective revision surgery to improve continence (cuff downsizing, n = 18; pressure-regulating balloon exchange, n = 3). There were 6 cases of AUS mechanical failure. No reservoir-related complications such as herniation or erosion were observed. Compared to the control group of non-neobladder patients, there were no significant differences in prosthetic infection, mechanical failure, and revision surgery. CONCLUSION: The AUS and 3-piece inflatable penile prosthesis can coexist safely in patients with NB without an increased risk of device-related complications.

Assessing trends in urinary diversion after radical cystectomy for bladder cancer in the United States.

OBJECTIVES: We assessed recent trends in both urinary diversion after radical cystectomy for bladder cancer in the United States and patient- and hospital-related characteristics. We also identified variables associated with undergoing continent diversion. MATERIALS AND METHODS: We queried the National Cancer Database and identified 27,170 patients who underwent radical cystectomy with urinary diversion from 2004 to 2013. Patient demographics, socioeconomic variables, and hospital-related factors were compared between incontinent and continent diversion and trended over time. Multivariable logistic regression was used to identify variables associated with undergoing continent diversion. RESULTS: Overall, 23,224 (85.5%) and 3,946 (14.5%) patients underwent incontinent and continent diversion, respectively. Continent diversion declined from 17.2% in 2004 to 2006 to 12.1% in 2010 to 2013 (P < 0.01). When analyzing high-volume facilities, those performing ≥75% minimally invasive radical cystectomy had fewer continent diversions (10.2%) compared to centers with higher rate of open approach (19.7%), P < 0.01. Higher income, facility located in the West, academic programs, high-volume facilities, and patients traveling >60 miles for care were significantly associated with undergoing continent diversion. Rate of continent diversion has declined in most patient- and hospital-related subgroups. Compared to 2004 to 2006, patients in 2010 to 2013 were more likely to be older, have more comorbidities, and be operated on at a high-volume academic facility. CONCLUSION: The rate of continent diversion has declined to 12.1% in the United States. Hospital volume and type, patient income, distance traveled for care, and geography are significantly associated with undergoing continent diversion. Even among high-volume and academic centers, the rate of continent diversion is declining.

Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells.

F1FoATP synthase (ATP synthase) is a ubiquitous enzyme complex in eukaryotes. In general it is localized to the mitochondrial inner membrane and serves as the last step in the mitochondrial oxidative phosphorylation of ADP to ATP, utilizing a proton gradient across the inner mitochondrial membrane built by the complexes of the electron transfer chain. However some cell types, including tumors, carry ATP synthase on the cell surface. It was suggested that cell surface ATP synthase helps tumor cells thriving on glycolysis to survive their high acid generation. Angiostatin, aurovertin, resveratrol, and antibodies against the α and ß subunits of ATP synthase were shown to bind and selectively inhibit cell surface ATP synthase, promoting tumor cell death. Here we show that ATP synthase ß (ATP5B) is present on the cell surface of mouse pheochromocytoma cells as well as tumor cells of human SDHB-derived paragangliomas (PGLs), while being virtually absent on chromaffin primary cells from bovine adrenal medulla by confocal microscopy. The cell surface location of ATP5B was verified in the tissue of an SDHB-derived PGL by immunoelectron microscopy. Treatment of mouse pheochromocytoma cells with resveratrol as well as ATP5B antibody led to statistically significant proliferation inhibition. Our data suggest that PGLs carry ATP synthase on their surface that promotes cell survival or proliferation. Thus, cell surface ATP synthase may present a novel therapeutic target in treating metastatic or inoperable PGLs.

The Evolution of Cooperation is Affected by the Persistence of Fitness Effects, the Neighborhood Size and their Interaction.

Evolutionary Game Theory and the Prisoner's Dilemma (PD) Game in particular have been used to study the evolution of cooperation. We consider a population of asexually reproducing, age-structured individuals in a two-dimensional square lattice structure. The individuals employ fixed cooperative or defecting strategies towards their neighbors in repeating interactions to accumulate reproductive fitness. We focus on the effects of the persistence of past interactions and interactive neighborhood size on the evolution of cooperation. We show that larger neighborhood sizes are generally detrimental to cooperation and that the persistence of fitness effects decreases the likelihood of the evolution of cooperation in small neighborhoods. However, for larger neighborhood sizes the persistence effect is reversed. Thus, our study corroborates earlier studies that population structure increases the evolutionary potential for cooperative behavior in a PD paradigm. This finding may explain the heterogeneity of previous results on the effect of neighborhood size and cautions that the persistence of fitness outcomes needs to be considered in analyses of the evolution of cooperative behavior. The persistence of fitness outcomes of pairwise interactions may vary dramatically in biological and social systems and could have profound effects on the evolution of cooperation in various contexts.

Infective endocarditis associated superior mesenteric artery pseudoaneurysm.

BACKGROUND: Since William Osler first described mycotic aneurysms in the setting of endocarditis in 1885, few pseudoaneurysms (PAs) of the superior mesenteric artery (SMA) have been reported in the literature. We report 2 cases of SMA PA related to infective endocarditis that were managed with open surgery. RESULTS: Here we report 2 cases of SMA PAs treated with different surgical techniques. A 59-year-old male with a history of intravenous drug use presented with abdominal pain and was found to have Streptococcus viridans endocarditis and an SMA PA. A laparotomy was performed, and proximal and distal control of the SMA PA was obtained. After ensuring that Doppler signals were still present in the distal mesentery and the entirety of the bowel was viable, the SMA was ligated proximal and distal to the PA. The patient recovered uneventfully. The second case is a 35-year-old female who presented with abdominal pain and was found to have Streptococcos gordonii endocarditis and an SMA PA for which the patient was initially observed. After several weeks, the patient's condition deteriorated and the patient underwent open ligation of the SMA, proximal and distal to the PA, with a bypass from the infrarenal abdominal aorta to a distal unnamed SMA branch and resection of 3 ft of ischemic small bowel. The patient continued to have recurrent bowel ischemia over the next several weeks and ultimately died. CONCLUSIONS: SMA PAs associated with infective endocarditis are rare, but carry a high risk of rupture and associated morbidity and mortality. Delay in surgical management may increase this risk.

Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.

Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.

Gaucher disease (GD), the most common lysosomal storage disorder of humans, is caused by mutations in the gene coding for the enzyme glucocerebrosidase (GCase). Clinical manifestations vary among patients with the three types of GD, and phenotypic heterogeneity occurs even among patients with identical mutations. To gain insight into why phenotypic heterogeneity occurs in GD, we investigated mechanisms underlying the net loss of GCase catalytic activity in cultured skin fibroblasts derived from patients with the three types of GD. The findings indicate that the loss of catalytic activity of GCase correlates with its quantitative reduction, rather than a decrease in functional capacity of mutant enzyme. Use of a proteasome inhibitor, lactacystin, resulted in increased expression of GCase, suggesting a mechanism of protein degradation in GD. Furthermore, reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding, may result in defective maturation of nascent GCase in GD cells. Additionally, increased interaction between GCase and c-Cbl, an E3 ubiquitin ligase, may be involved in the degradation and loss of GCase in GD. The findings suggest that specific molecular mediators involved in GCase maturation and degradation could be responsible for phenotypic variation among patients with the same genotypes and that these mediators could be therapeutically targeted to increase GCase activity in patients with GD.