Surgical management of pelvic organ prolapse.

Despite pelvic organ prolapse being a universal problem experienced in nearly 50% of parous women, the surgical management of vaginal prolapse remains an enigma to many, with wide variation in the rates and types of intervention performed. As part of the 6th International Consultation on Incontinence (ICI) our committee, charged with producing an evidence-based report on the surgical management of prolapse, produced a pathway for the surgical management of prolapse. The 2017 ICI surgical management of prolapse evidence-based pathway will be presented and summarized. Weaknesses of the data and pathway will be discussed and avenues for future research proposed.

Estimation of causal effects of binary treatments in unconfounded studies with one continuous covariate.

The estimation of causal effects in nonrandomized studies should comprise two distinct phases: design, with no outcome data available; and analysis of the outcome data according to a specified protocol. Here, we review and compare point and interval estimates of common statistical procedures for estimating causal effects (i.e. matching, subclassification, weighting, and model-based adjustment) with a scalar continuous covariate and a scalar continuous outcome. We show, using an extensive simulation, that some highly advocated methods have poor operating characteristics. In many conditions, matching for the point estimate combined with within-group matching for sampling variance estimation, with or without covariance adjustment, appears to be the most efficient valid method of those evaluated. These results provide new conclusions and advice regarding the merits of currently used procedures.

Error adjustments for file linking methods using encrypted unique client identifier (eUCI) with application to recently released prisoners who are HIV+.

Incarceration provides an opportunity to test for HIV, provide treatment such as highly active anti-retroviral therapy, as well as link infected persons to comprehensive HIV care upon their release. A key factor in assessing the success of a program that links released individuals to care is the time from release to receiving care in the community (linkage time). To estimate the linkage time, records from correction systems are linked to Ryan White Clinic data using encrypted Unique Client Identifier (eUCI). Most of the records that were linked using eUCI belong to the same individual; however, in some cases, it may link records incorrectly, or not identify records that should have been linked. We propose a Bayesian procedure that relies on the relationships between variables that appear in either of the data sources, as well as variables that exists in both to identify correctly linked records among all linked records. The procedure generates K datasets in which each pair of linked records is identified as a true link or a false link. The K datasets are analyzed independently, and the results are combined using Rubin's multiple imputation rules. A small validation dataset is used to examine different statistical models and to inform the prior distributions of the parameters. In comparison with previously proposed methods, the proposed method utilizes all of the available data and is both flexible and computationally efficient. In addition, this approach can be applied in other file linking applications.

Increased morbidity in combined abdominal sacrocolpopexy and abdominoplasty procedures.

INTRODUCTION AND HYPOTHESIS: This study was performed to determine whether abdominoplasty combined with abdominal sacrocolpopexy (ASC + A) increases perioperative morbidity compared with ASC alone. We hypothesized that patients undergoing combined procedures would have increased complications. METHODS: This was a multicenter, retrospective cohort study of all women undergoing ASC + A from 2002 to 2010 at Washington Hospital Center and Johns Hopkins University. We selected two women undergoing ASC alone for comparison with each ASC + A patient. Baseline demographics, surgical data, length of hospitalization, and perioperative complications were recorded. The primary outcome was any major complication within 6 weeks of surgery, including intraoperative complications, pulmonary embolism (PE), deep venous thrombosis (DVT), cardiac compromise, intensive care unit (ICU) admission, reoperation, and readmission. Surgical data and minor complications were also compared. RESULTS: Twenty-six ASC + A patients and 52 ASC patients were identified. There were no significant differences in baseline characteristics between groups. Patients with ASC + A had longer operating times (337 vs 261 min, p < 0.01), more intravenous fluid administration intraoperatively (4,665 vs 3181 ml, p < 0.01), and longer hospital stays (3.7 vs 2.7 days, p < 0.01). Major complications occurred in 23 % of the ASC + A group compared with 12 % of the ASC group (p = 0.20). The ASC + A group had greater declines in hematocrit levels and higher rates of PE, ICU admission, and blood transfusion, all of which were statistically significant. CONCLUSIONS: ASC + A increases length of stay and perioperative complications, such as PE, ICU admission, and blood transfusion, compared with ASC alone. Surgeons should consider recommending interval abdominoplasty due to increased morbidity risk with a combined procedure.

Estimating energy expenditure in mice using an energy balance technique.

OBJECTIVE: To compare, in mice, the accuracy of estimates of energy expenditure (EE) using an energy balance technique (TEEbal: food energy intake and body composition change) vs indirect calorimetry (TEEIC). SUBJECTS: In 32 male C57BL/6J mice, EE was estimated using an energy balance (caloric intake minus change in body energy stores) method over a 37-day period. EE was also measured in the same animals by indirect calorimetry. These measures were compared. RESULTS: The two methods were highly correlated (r(2)=0.87: TEEbal=1.07*TEEIC-0.22, P<0.0001). By Bland-Altman analysis, TEEbal estimates were slightly higher (4.6±1.5%; P<0.05) than TEEIC estimates (Bias=0.55 kcal per 24 h). CONCLUSION: TEEbal can be performed in 'home cages' and provides an accurate integrated long-term measurement of EE while minimizing potentially confounding stress that may accompany the use of indirect calorimetry systems. The technique can also be used to assess long-term energy intake.

Robust estimation of causal effects of binary treatments in unconfounded studies with dichotomous outcomes.

The estimation of causal effects has been the subject of extensive research. In unconfounded studies with a dichotomous outcome, Y, Cangul, Chretien, Gutman and Rubin (2009) demonstrated that logistic regression for a scalar continuous covariate X is generally statistically invalid for testing null treatment effects when the distributions of X in the treated and control populations differ and the logistic model for Y given X is misspecified. In addition, they showed that an approximately valid statistical test can be generally obtained by discretizing X followed by regression adjustment within each interval defined by the discretized X. This paper extends the work of Cangul et al. 2009 in three major directions. First, we consider additional estimation procedures, including a new one that is based on two independent splines and multiple imputation; second, we consider additional distributional factors; and third, we examine the performance of the procedures when the treatment effect is non-null. Of all the methods considered and in most of the experimental conditions that were examined, our proposed new methodology appears to work best in terms of point and interval estimation.

Peroxisome proliferator-activated receptor α (PPARα) activation advances locomotor activity and feeding daily rhythms in mice.

Peroxisome proliferator-activated receptors (PPARs) are key mediators of energy homeostasis, and lipid and glucose metabolism that exhibit circadian expression. PPAR activating drugs are used clinically as lipid and glucose-lowering drugs. We evaluated the effect of long-term (11 weeks) PPARα and PPARγ activation using bezafibrate and rosiglitazone, respectively, on metabolism, locomotor activity and feeding rhythms of non-obese mice. We found that bezafibrate, but not rosiglitazone, led to no weight gain and a slight weight loss with reduced epididymal fat pads. Although rosiglitazone had a minor effect on 24-h food intake rhythm, bezafibrate treatment was accompanied by increased amplitude and an advanced acrophase of the 24-h feeding rhythm. Similarly, unlike rosiglitazone, bezafibrate treatment was accompanied by a significantly advanced acrophase of locomotor activity rhythm under constant darkness conditions. As disrupted circadian rhythms lead to obesity, PPARα activation can serve as a clinical target for the modulation of both circadian rhythms and metabolism.

Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

WITHDRAWN: A comment on the application of statistical process control in the surgical arena.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Spontaneous caloric restriction associated with increased leptin levels in obesity-resistant αMUPA mice.

BACKGROUND: αMUPA mice carry as a transgene the cDNA encoding urokinase-type plasminogen activator, a member of the plasminogen/plasmin system that functions in fibrinolysis and extracellular proteolysis. These mice spontaneously consume less food when fed ad libitum and live longer compared with wild-type (WT) control mice. αMUPA mice are obesity resistant and they share many similarities with calorically restricted animals. However, extensive metabolic characterization of this unique transgenic model has never been performed. METHOD: Metabolism of αMUPA mice was analyzed by measuring hormone, lipid and glucose levels in the serum, as well as gene and protein expression levels in the liver, hypothalamus and brainstem. RESULTS: αMUPA mice were found to be leaner than WT mice mainly because of reduced fat depots. Serum analyses showed that αMUPA mice have high levels of the anorexigenic hormones insulin and leptin, and low levels of the orexigenic hormone ghrelin. Analyses of brain neuropeptides showed that the transcript of the anorexigenic neuropeptide Pomc is highly expressed in the brainstem, whereas the expression of the orexigenic neuropeptides Npy, Orexin and Mch is blunted in the hypothalamus of αMUPA mice. In addition, adenosine monophosphate (AMP)-activated protein kinase (AMPK) levels were higher in the liver and lower in the hypothalamus, thus promoting simultaneously central reduction in appetite and peripheral loss of fat. The levels of SIRT1 were low in the liver, but high in the hypothalamus, a feature that αMUPA mice share with calorically restricted animals. CONCLUSION: Taken together, αMUPA mice exhibit a unique metabolic phenotype of low-calorie intake and high leptin levels, and could serve as a model for both spontaneous calorie restriction and resistance to obesity.

Testing treatment effects in unconfounded studies under model misspecification: logistic regression, discretization, and their combination.

Logistic regression is commonly used to test for treatment effects in observational studies. If the distribution of a continuous covariate differs between treated and control populations, logistic regression yields an invalid hypothesis test even in an uncounfounded study if the link is not logistic. This flaw is not corrected by the commonly used technique of discretizing the covariate into intervals. A valid test can be obtained by discretization followed by regression adjustment within each interval.

Etiology of post-uterosacral suspension neuropathies.

INTRODUCTION AND HYPOTHESIS: The goal of our investigation was to find a neurological explanation for neuropathies reported following some uterosacral ligament suspension (USLS) [2-3]. METHODS: We dissected the neural structures beneath the USL in seven female, adult, embalmed cadavers. We made a literature review to determine the spinal nerve sensory fiber composition of each exposed neural structure and the dermatome(s) that it innervates. We then compared anticipated sensory neuropathies for each neural structure with neuropathies following USLS to determine which neural structure entrapment could explain the reported symptoms. RESULTS: Several neural structures located beneath the uterosacral ligament (USL) are vulnerable to suture entrapment during USLS. Anticipated clinical outcomes of entrapments are discussed. CONCLUSIONS: Entrapment of S2 sensory fibers in the second trunk of the sacral plexus or in the intrapelvic portion of the sciatic nerve is the most plausible etiology for reported neuropathies following USLS.

Complications of treatment of obstetric fistula in the developing world: gynatresia, urinary incontinence, and urinary diversion.

OBJECTIVE: To provide a comprehensive review of the pathophysiology, evaluation, and treatment of gynatresia and urinary incontinence, 2 conditions that can arise following the repair of obstetric fistulas. The article discusses relevant issues with respect to urinary diversion in the treatment of obstetrical fistula and associated urinary incontinence. METHODS: A review was conducted of the existing literature and of the expert recommendations issued at the Gates Institute fistula meeting held in July 2005 at the Johns Hopkins Bloomberg School of Public Health. RESULTS: Gynatresia and urinary incontinence develop in approximately 10% and 16% of patients, respectively, after the first repair. Urinary diversion may be necessary when fistulas cannot be closed vaginally or in cases of severe urinary incontinence following successful closure. Gynatresia, urinary incontinence, and urinary diversion are all associated with morbidity, and they require surgical and nonsurgical expertise for proper management. CONCLUSIONS: Closing the anatomical fistula is not always sufficient, and treatment paradigms must shift toward the prevention and repair of gynatresia and urinary incontinence at the time of the primary operation.

Development of an evolutionarily novel structure: fibroblast growth factor expression in the carapacial ridge of turtle embryos.

The turtle shell, an evolutionarily novel structure, contains a bony exoskeleton that includes a dorsal carapace and a ventral plastron. The development of the carapace is dependent on the carapacial ridge (CR), a bulge in the dorsal flank that contains an ectodermal structure analogous to the apical ectodermal ridge (AER) of the developing limb (Burke. 1989a. J Morphol 199:363-378; Burke. 1989b. Fortschr Zool 35:206-209). Although the CR is thought to mediate the initiation and outgrowth of the carapace, the mechanisms of shell development have not been studied on the molecular level. Here, we present data suggesting that carapace formation is initiated by co-opting genes that had other functions in the ancestral embryo, specifically those of limb outgrowth. However, there is divergence in the signaling repertoire from that involved in limb initiation and outgrowth. In situ hybridizations with antisense riboprobes derived from Trionyx spiniferous fibroblast growth factor-10 (tfgf10) and Trachemys scripta (T. scripta) fibroblast-growth factor 8 (tfgf8) cDNAs were performed on sections of early T. scripta embryos (< 30 days). Expression of tfgf10 was localized to the mesenchyme subjacent to the ectoderm of the CR. In the chick limb bud, FGF10 is known to be expressed in the early limb-forming mesenchyme and is capable of inducing FGF8 in the AER to initiate the outgrowth of the limb bud. Although the expression of tfgf8 was found in the AER of the developing turtle limb, it was not seen in the CR. Thus, the initiation of the carapace is in agreement with FGF10 expression in the CR, but FGF8 does not appear to have a role in mediating early carapace outgrowth.

Targeted drug delivery for brain cancer treatment.

The blood brain barrier (BBB) and the systemic toxicity of conventional chemotherapy present obstacles to the success of future blood-borne drug therapies of brain tumors. The work with polymer-encapsulated cancer drugs suggests an alternative and more focused treatment approach. Our experimental strategy integrates direct intracerebral drug delivery, sustained drug release from liposomes or polymer implants, and increased targeting of the drug either by chemically modifying the drug or by using tumor-specific carriers. This review will present some of the recent work on targeted drug delivery for brain cancer treatment.

Health-related quality of life predictors of survival and hospital utilization.

The health-related quality of life (HRQOL) of 103 end-stage renal disease (ESRD) patients on hemodialysis was studied for prediction of 1-year survival and hospital days in the context of other predictors. Higher HRQOL physical functioning, higher provider-reported functional performance, fewer private religious activities, living with family, black race, and having a diagnosis of hypertension predicted survival. Lower HRQOL energy, higher pain, and not living with family predicted more hospital days. Patients living with family reported more social support and better HRQOL general health, emotional well-being, social health, and quality of social interactions than other patients.

[Self monitoring of capillary blood glucose. Evaluation of long-term results (3 to 7 years)]. / Autocontrol de la glucemia capilar. Evaluación del resultado a largo plazo (3 a 7 años).

We analyzed data provided by 60 diabetic patients (DP) included in a Program (P) of Self Blood Glucose Monitoring (SBGM) which showed an initial adherence of at least 6 months. Total follow-up was 67,293 DP-days (110,504 capillary glycemias). Only 50% of DP's remained for > 3 years. Rates of drop-out (DO) peaked early (3th semester (S) and late (10th. S) mean +/- SE of daily SBGM reported in the preprogram period and during the 1st S on P-SBGM by the future DO was significantly higher (4.25 +/- 0.22) than those reported by their P-SBGM-mates who stayed in the program (3.11 +/- 0.29; p < 0.01). DO showed a higher % of capillary glycemias < 60 mg/dl (hypoglycemia) (5.34 +/- 1.49 vs 2.85 +/- 1.14; p < 0.01). During the 3rd S early DO showed significantly higher Glycosilated Hemoglobin (HbA1) levels (10.4 +/- 0.49%) than late DO (8.19 +/- 0.45%; p < 0.01). HbA1's recorded by the late DO's just before leaving P-SBGM were significantly higher (10.14 +/- 0.61%) than those seen at 2nd/5th S (8.2 +/- 0.2; p < 0.01). However, HbA1's of 1-DO at time of abandoning P-SBGM were comparable to those shown by those DP's who remained (10.14 +/- 0.61 vs 9.46 +/- 0.27%). DP's performed daily SBGM's in 70% of possible days during 4 years and in only 50% afterwards. Daily SBGM's was 3.3 +/- 1 during the first 3 years and 2.1 +/- 0.8 thereafter. Compared to preprogram period, all DP's improved HbA1's (12.5 +/- 0.31 vs 9.46 +/- 0.27; p < 0.001) and mean blood glucose (166 +/- 5.2 vs 146 +/- 3.6; p < 0.01). DP's who reached a faster and more satisfactory degree of glycemic control in earlier stages of P-SBGM showed the highest rates of drop-out. Early identification of such patients, as well as setting of feasable and individualy adjusted goals of glycemic control may improve current compliance of DP's on long term tight control.