Urban residential tree canopy and perceived stress among pregnant women.

OBJECTIVE: To examine the association of urban residential tree canopy cover with perceived stress in a cohort of pregnant women in Philadelphia, PA, and explore whether this association differed among participants with a history of anxiety and depression. STUDY DESIGN: We performed a secondary analysis of 1294 participants of the Motherhood & Microbiome (M&M) pregnancy cohort who lived in Philadelphia, with first visit perceived stress (Cohen's Perceived Stress Scale, PSS-14), and key covariate data. Tree canopy cover was calculated as percent cover within 100 and 500 m radii buffers around participants' homes. We performed multilevel mixed effects linear regression models, with perceived stress as the dependent variable. The main independent variable was tree canopy coverage. Individual-level covariates included season of last menstrual period, history of depression or anxiety, race/ethnicity, insurance, parity, and age. Census tract neighborhood deprivation index was used to account for area-level socioeconomic confounding variables. We also examined whether a history of anxiety or depression, modified the association between tree canopy coverage and perceived stress. RESULTS: Most participants were non-Hispanic Black (70.6%, n = 913), on Medicaid or uninsured (60.4%, n = 781), and 15.8% (n = 204) of participants had a prior history of depression or anxiety. We did not detect associations between tree canopy coverage and perceived stress overall. However, we detected effect modification; among participants with a history of depression or anxiety, each standard deviation increase in tree canopy cover was associated with lower PSS-14 in 100 m buffers (ß -1.0, 95% CI -1.8, -0.2), but not among participants with no histories of depression or anxiety (ß 0.2, 95% CI -0.3, 0.7) (interaction P = 0.007). Results were similar in directionality but not statistically significant within 500 m buffers. CONCLUSION: Residential tree canopy coverage was associated with reduced perceived stress among urban-dwelling pregnant women with history of anxiety or depression. Future studies of the effects of greenness and other stress-reducing efforts should consider underlying mental health conditions as effect modifiers.

Characterizing anxiety at the first encounter in women presenting to the clinic: the CAFÉ study.

BACKGROUND: Clinically based anxiety questionnaires measure 2 forms of anxiety that are known as state anxiety and trait anxiety. State anxiety is temporary and is sensitive to change; trait anxiety is a generalized propensity to be anxious. OBJECTIVE: Our study aims to characterize the reasons for anxiety among women about the initial consultation for their pelvic floor disorders to measure change in participant state anxiety after the visit and to correlate improvement in anxiety with visit satisfaction. STUDY DESIGN: All new patients at our tertiary urogynecology clinic were invited to participate. After giving consent, participants completed pre- and postvisit questionnaires. Providers were blinded to pre- and postvisit questionnaire responses. The previsit questionnaires included the Pelvic Floor Distress Inventory, the Generalized Anxiety Disorder-7, and the 6-item short form of the Spielberg State Trait Anxiety Inventory. Participants were also asked to list their previsit anxieties. The postvisit questionnaires comprised of the Spielberg State Trait Anxiety Inventory, patient global impression of improvement of participant anxiety, patient satisfaction, and the participant's perception of whether her anxiety was addressed during the visit. The anxieties listed by participants were then reviewed independently and categorized by 2 of the authors. A separate panel arbitrated when there were disagreements among anxiety categories. RESULTS: Fifty primarily white (66%) women with a median age of 53 years (interquartile range, 41-66) completed the study. The visit diagnoses included stress urinary incontinence (54%), urge urinary incontinence (46%), myofascial pain (28%), pelvic organ prolapse (20%), and recurrent urinary tract infection (12%). Less than one-quarter of participants (22%) had a history of anxiety diagnosis. The average previsit Spielberg State Trait Anxiety Inventory score was 42.9 (standard deviation, 11.98) which decreased by an average of 12.60 points in the postvisit (95% confidence interval, -16.56 to -8.64; P<.001). Postvisit decreased anxiety was associated with improvements in the patient global impression of improvement anxiety (P<.001) and participants' perception that their anxiety symptoms had been addressed completely (P=.045). The most reported causes for consultation related anxiety were lack of knowledge of diagnosis and ramifications, personal or social issues, and fear of the physical examination. Participants reported that improvements in anxiety were related to patient education and reassurance, medical staff appreciation, and acceptable treatment plan. Participants who reported complete satisfaction demonstrated a greater decrease in the postvisit Spielberg State Trait Anxiety Inventory scores compared with the participants who did not report complete satisfaction (P=.045). Changes in the Spielberg State Trait Anxiety Inventory score were not associated with the Pelvic Floor Distress Inventory (P=.35) or Generalized Anxiety Disorder-7 scores (P=.78). CONCLUSION: Women with the highest satisfaction after their initial urogynecology visit also demonstrated the largest decreases in anxiety after the visit. Changes in anxiety scores were not correlated with the Pelvic Floor Distress Inventory or with measures of generalized anxiety (Generalized Anxiety Disorder-7). Recognizing and addressing patient anxiety may help physicians better treat their patients and improve overall patient satisfaction.

Bladder urinary oxygen tension is correlated with urinary microbiota composition.

INTRODUCTION AND HYPOTHESIS: Presence of microbial communities (microbiota) in an organ system depends on environmental factors, such as oxygen availability. We describe a novel technique to measure bladder urine oxygen tension (BUOT) in ambulatory women and use that technique to compare BUOT values to female urinary microbiota and participant urinary signs and symptoms. METHODS: Ambulatory female urogynecology patients presenting for clinical care who were willing to undergo transurethral catheterization underwent BUOT determination with a non-invasive flow-through oxygen sensor. To detect urinary microbiota in the bladder, 16S rRNA gene sequencing was performed on catheterized urine. Multivariate statistical analyses were performed to examine potential correlations among BUOT, urinary microbiota compositions and clinical variables. RESULTS: Significant variation in BUOT existed between individuals (range: 0.47-51.5 mmHg; median: 23.1 ± 13.5). Microbiota compositions were associated with BUOT (p = 0.03). BUOT was significantly lower in urines that were nitrite negative on dipstick analysis (p = 0.0001) and in participants who answered yes to having urinary leakage on the validated Urinary Distress Inventory (p = 0.01). CONCLUSIONS: BUOTs can be measured in ambulatory women. For urogynecology patients, a wide range of values exist. BUOT may be associated with the presence of urinary microbiota and resultant signs and symptoms.

Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior.

Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects.

Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease.

Overactivation of Src has been linked to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). This phase 2, multisite study assessed the efficacy and safety of bosutinib, an oral dual Src/Bcr-Abl tyrosine kinase inhibitor, in patients with ADPKD. Patients with ADPKD, eGFR≥60 ml/min per 1.73 m2, and total kidney volume ≥750 ml were randomized 1:1:1 to bosutinib 200 mg/d, bosutinib 400 mg/d, or placebo for ≤24 months. The primary endpoint was annualized rate of kidney enlargement in patients treated for ≥2 weeks who had at least one postbaseline magnetic resonance imaging scan that was preceded by a 30-day washout (modified intent-to-treat population). Of 172 enrolled patients, 169 received at least one study dose. Per protocol amendment, doses for 24 patients who initially received bosutinib at 400 mg/d were later reduced to 200 mg/d. The annual rate of kidney enlargement was reduced by 66% for bosutinib 200 mg/d versus placebo (1.63% versus 4.74%, respectively; P=0.01) and by 82% for pooled bosutinib versus placebo (0.84% versus 4.74%, respectively; P<0.001). Over the treatment period, patients receiving placebo or bosutinib had similar annualized eGFR decline. Gastrointestinal and liver-related adverse events were the most frequent toxicities. In conclusion, compared with placebo, bosutinib at 200 mg/d reduced kidney growth in patients with ADPKD. The overall gastrointestinal and liver toxicity profile was consistent with the profile in prior studies of bosutinib; no new toxicities were identified. (ClinicalTrials.gov: NCT01233869).

A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia.

Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.

Variation in NICU Head CT Utilization Among U.S. Children's Hospitals.

OBJECTIVES: Evaluate nationwide 12-year trend and hospital-level variation in head computed tomography (CT) utilization among infants admitted to pediatric hospital NICUs. We hypothesized there was significant variation in utilization. METHODS: We conducted a retrospective cohort study examining head CT utilization for infants admitted to the NICU within 31 United States children's hospitals within the Pediatric Health Information System database between 2010 and 2021. Mixed effects logistic regression was used to estimate head CT, head MRI, and head ultrasound utilization (% of admissions) by year. Risk-adjusted hospital head CT rates were examined within the 2021 cohort. RESULTS: Between 2010 and 2021, there were 338 644 NICU admissions, of which 10 052 included head CT (3.0%). Overall, head CT utilization decreased (4.9% in 2010 to 2.6% in 2021, P < .0001), with a concomitant increase in head MRI (12.1% to 18.7%, P < .0001) and head ultrasound (41.3% to 43.4%, P < .0001) utilization. In 2021, significant variation in risk-adjusted head CT utilization was noted across centers, with hospital head CT rates ranging from 0% to 10% of admissions. Greatest hospital-level variation was noted for patients with codes for seizure or encephalopathy (hospital head CT rate interquartile range [IQR] = 11.6%; 50th percentile = 12.0%), ventriculoperitoneal shunt (IQR = 10.8%; 50th percentile = 15.4%), and infection (IQR = 10.1%; 50th percentile = 7.5%). CONCLUSIONS: Head CT utilization within pediatric hospital NICUs has declined over the past 12-years, but substantial hospital-level variation remains. Development of CT stewardship guidelines may help decrease variation and reduce infant radiation exposure.

High-Dose Celecoxib for Pain After Pediatric Tonsillectomy: A Randomized Controlled Trial.

OBJECTIVE: Pediatric tonsillectomy causes significant postoperative pain. Newer nonsteroidal anti-inflammatory drugs such as celecoxib control pain without increasing bleeding risk, but in prior studies provided only modest pain reduction at standard doses. We aimed to determine if high-dose celecoxib (double the usual pediatric dose) is effective for pain, without increasing bleeding or other risks. STUDY DESIGN: Randomized double-blind trial. SETTING: Pediatric tertiary center. METHODS: Children aged 3 to 11 years undergoing total tonsillectomy were randomized to receive celecoxib (6 mg/kg/dose) or placebo, twice daily, for up to 10 days. All cases were supplemented with acetaminophen and oxycodone as needed. All participants and personnel were blinded to treatment group. Subjects recorded coanalgesic consumption, pain, diet, and activity. RESULTS: The celecoxib group (n = 68) consumed 0.72 mg/kg of oxycodone, as compared with 1.12 mg/kg in the placebo group (n = 62), a 36% difference that was not significant. However, multivariate analysis by treatment group, separate from pain levels, confirmed that this reduction was due to celecoxib treatment (P = .03). In subjects with more prolonged pain (n = 88), celecoxib reduced consumption by 52% (P = .02). Celecoxib showed greater benefit for subjects in the prolonged pain group than for those in the lesser pain group (P = .006). Incidence of adverse events was similar between groups. Minor hemorrhage occurred in 4.6% (5 placebo, 3 celecoxib). CONCLUSION: High-dose celecoxib is effective in controlling pain after tonsillectomy, with no adverse effects in this relatively small sample. It reduces narcotic consumption, and its impact appears greater in children with higher degrees of pain. Celecoxib can be considered an effective alternative to ibuprofen after tonsillectomy. This trial was registered at ClinicalTrials.gov: NCT02934191.

The impact of a sacroiliac joint belt on function and pain using the active straight leg raise in pregnancy-related pelvic girdle pain.

INTRODUCTION: Pelvic girdle pain (PGP) is the most common musculoskeletal concern in pregnancy. The Active Straight Leg Raise (ASLR) test is diagnostic. Sacroiliac joint (SIJ) belts are included in multimodal therapy, but there is no established predictive measure to determine which pregnant women will benefit. OBJECTIVE: To determine if the ASLR score is immediately reduced by SIJ belt application and whether PGP pain and function improves after 4 weeks of belt use. DESIGN: Prospective observational cohort study. SETTING: Academic medical center. PARTICIPANTS: Pregnant women at least 18 years of age in the second or third trimester of pregnancy with posterior PGP and ASLR score of 2 to 10. INTERVENTIONS: Four-week SIJ belt use. MAIN OUTCOME MEASURES: ASLR, Numerical Rating Scale (NRS), Pelvic Girdle Questionnaire (PGQ), Perceived Global Impression of Improvement (PGII). RESULTS: Sixty-three women enrolled. On multivariable analysis, immediate belted ASLR score was -2.70 points lower than the non-belted ASLR score (P < .001). Four weeks later there was significant improvement in the ASLR score with a belt (Mdiff = -0.99; P = .001) and without a belt (Mdiff = -1.94; P < .001); the decline was more precipitous for the non-belted response (Mdiff = -0.96; P = .02). Current NRS pain scores declined from baseline by approximately -0.94 points (P < .001). This decline did not depend on ASLR scores (interaction P = .43) or wearing a belt at the time of testing (interaction P = .51). Similar conclusions held for participants' usual NRS score and average PGQ score. After 4 weeks, 82% reported improvement based on the PGII. CONCLUSIONS: SIJ belts are a safe, well-tolerated, and effective therapeutic option for pregnancy-related PGP. The ASLR score is immediately reduced following SIJ belt application but does not predict pain score 4 weeks later. SIJ belt leads to significant improvements in pain and function over time.

A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors.

P-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell-redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, first-in-human, dose-escalation study to characterize the safety and tolerability of PF-06671008, towards determining the recommended phase 2 dose. Adult patients with treatment-refractory solid tumors received PF-06671008 (1.5-400 ng/kg) as a weekly intravenous (IV) infusion on a 21-day/3-week cycle. Parallel cohorts evaluated dosing via subcutaneous injection (SC) or an IV-prime dose. Of the 27 patients enrolled in the study, 24 received PF-06671008 IV in escalating doses, two received SC, and one IV-prime. A dose-limiting toxicity of cytokine release syndrome (CRS) occurred in the 400-ng/kg IV group, prompting evaluation of SC and IV-prime schedules. In all, 25/27 patients who received PF-06671008 reported at least one treatment-related adverse event (TRAE); the most common were CRS (21/27), decreased lymphocyte count (9/27), and hypophosphatemia (8/27). Seven patients permanently discontinued treatment due to adverse events and no treatment-related deaths occurred. Cytokine peak concentrations and CRS grade appeared to positively correlate with Cmax. Although the study was terminated due to limited antitumor activity, it provides important insights into understanding and managing immune-related adverse events resulting from this class of molecules. Clinical Trial Registration: URL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.

Preoperative Music Listening in Pelvic Reconstructive Surgery: A Randomized Trial.

OBJECTIVES: We aimed to investigate the effect of music listening on preoperative anxiety compared with usual care in patients undergoing pelvic reconstructive surgery. METHODS: Patients scheduled for pelvic reconstructive surgery were enrolled on the day of surgery. Participants were randomized to either the usual care (control group) or to music listening on headphones (music group) before their surgery. Participants completed the Spielberg State-Trait Anxiety Inventory form Y1 to measure baseline state anxiety levels before surgery and again after 30 minutes of usual care or music listening. The primary outcome was the change in state anxiety score as measured by the State-Trait Anxiety Inventory form Y1. RESULTS: Sixty-nine women completed the study (35 assigned to the control group and 34 assigned to the music group). Analysis of the primary outcome included 66 participants (34 in the control group and 32 in the music group). Improvement in state anxiety was significantly better for patients assigned to music listening (-6.69; SD, 6.98) than for patients assigned to the control group (-1.32; SD, 8.03; P = 0.01). Six weeks postoperatively, patients in the music group (n = 29) reported higher overall satisfaction when compared with those in the control group (n = 31, P = 0.03). CONCLUSION: Patients undergoing pelvic reconstructive surgery present with moderate anxiety on the day of surgery. Allowing patients to listen to their preferred music is a simple intervention that may lower preoperative anxiety and improve satisfaction in this patient population.

Patient Preferences and Knowledge Regarding Hysterectomy: A Study from the Fellows' Pelvic Research Network (FPRN)®.

OBJECTIVE: The purpose of this study was to describe preference for and knowledge of hysterectomy routes in women presenting to urogynecology/gynecology clinics throughout the United States and to determine association with health literacy. Our primary aim was preference for hysterectomy route, and secondary aims were knowledge of basic pelvic structures and function, knowledge of various hysterectomy routes, and baseline health literacy level. METHODS: This multicenter, cross-sectional study was conducted through the Fellows' Pelvic Research Network. Patients' preference and knowledge for hysterectomy routes were assessed at initial presentation to the urogynecology/gynecology clinic with an anonymous, voluntary, self-administered questionnaire along with a validated health literacy test (Medical Term Recognition Test). RESULTS: Two hundred four women participated. Forty-five percent of patients were unsure which hysterectomy modality they would choose. Of patients who selected a preferred modality, 50% selected laparoscopic and 33% selected vaginal. Patients indicated that safety was considered highest priority when selecting route. The mean score for "knowledge about gynecology/hysterectomy" was 68%, with the high literacy group scoring higher compared with the low health literacy group (70% vs 60.1%, P = 0.01). More than 50% of patients incorrectly answered knowledge questions related to vaginal hysterectomy. Majority of the respondents had high health literacy (79.4%). CONCLUSIONS: Patients prefer laparoscopic hysterectomy approach, although have limited understanding of vaginal hysterectomy. Higher health literacy levels are associated with increased knowledge of gynecology and hysterectomy routes, but were not found to influence patient preference for hysterectomy route. Overall, patients have limited knowledge of vaginal hysterectomy.

Increasing Age Predicts Increasing Residual Urine Volume.

OBJECTIVES: To determine reference values for postvoid residual (PVR) volume for patients referred to a tertiary urogynecology center. METHODS: After Institutional Review Board approval, we performed a retrospective chart review of all new patients presenting to our referral center. We assessed associations between PVR and patient demographics, pelvic floor symptoms, and physical examination by Wilcoxon rank sum or Kruskal-Wallis tests as appropriate. A multivariable logistic regression model was used to calculate odds ratios for patient characteristics associated with PVR in the top age range-specific decile. RESULTS: Three hundred sixty-one patients were included in the analysis. The median PVR was 20 mL (interquartile range, 1st, 3rd quartiles, 10, 50). Older age was associated with higher PVR (P < 0.001). The median PVR in participants younger than 40 years was 10 mL, ages 40 to 49 years was 18 mL, 50 to 69 years was 20 mL, 70 to 79 years was 38 mL and in women older than 79 years was 50 mL. A multivariable analysis showed that prolapse stage (odds ratio [OR], 3.46 with prolapse stage 2-4 vs stage 0-1; P = 0.001), history of stroke (OR, 7.62; [95% CI 2.17-26.77, P = 0.002]), narcotic use (OR, 2.45; [95% CI 1.01-5.92; P = 0.047]), and urinary frequency (OR, 2.61; [95% CI, 1.14-5.98; P = 0.024]) were risk factors for increased PVR (as defined at >90%ile for age), independent of the age-related elevation. CONCLUSIONS: The majority of patients presenting for urogynecologic evaluation had a low PVR with a median of 20 mL. Postvoid residual was higher for older age groups but nearly all volumes were less than 100 mL. The utility of a PVR measurement is highest for patients with pelvic organ prolapse, urinary frequency, narcotic use, or history of stroke.

Neighborhood Violent Crime and Perceived Stress in Pregnancy.

Stress has been shown to adversely affect pregnancy outcomes. Neighborhood crime rates may serve as one publicly available social determinant of health for pregnancy studies that use registry or electronic health record datasets in which individual-level stress data are not available. We sought to determine whether neighborhood violent crime incidents were associated with measured perceived stress in a largely minority, urban pregnancy cohort. We performed a secondary analysis of the 1309 Philadelphia residents participating in the Motherhood and Microbiome cohort (n = 2000) with both neighborhood violent crime and Cohen's Perceived Stress Scale (PSS-14) data. Generalized linear mixed models accounting for confounding variables and geographic clustering demonstrated that, regardless of race, women with the highest quartile of neighborhood violent crime had significantly elevated odds of high stress compared to women with lower crime. We also found that Black women were more likely to have both the highest quartile of neighborhood violent crime and high stress than non-Black women. Overall, this study demonstrates that neighborhood violent crime is associated with perceived stress in pregnancy. Given disparate exposure to crime and prenatal stress by race, future work is warranted to determine whether urban neighborhood violence and/or stress reduction strategies would improve birth outcome racial disparities.

Complications After Reperitonealization of Mesh at Time of Sacrocolpopexy: A Retrospective Cohort Study.

OBJECTIVES: To determine if there is a difference in rates of surgical complications among patients who have reperitonealization of mesh versus no reperitonealization at time of sacrocolpopexy. METHODS: This was a retrospective cohort study of all patients who underwent sacrocolpopexy at an academic medical center between 2008 and 2017. The medical record was reviewed for the operative method of sacrocolpopexy, concomitant surgeries, intraoperative or postoperative complications, and readmissions. Groups were compared on whether mesh was reperitonealized under pelvic peritoneum or not. RESULTS: A total of 209 patients underwent sacrocolpopexy, with mesh reperitonealization performed in 115 (55%). Demographics were similar in both groups, except race/ethnicity and stage of prolapse. The majority (190 [91%]) of surgeries included concomitant procedures. A total of 18 intraoperative or postoperative complications (8.6%) were recorded. Relative risk of complication with mesh reperitonealization is 0.81 (95% confidence interval, 0.1-1.70). Complications for subjects without mesh reperitonealization included 4 cystostomies, 1 urethrotomy, 3 postoperative ileuses, and 1 small bowel obstruction. Among subjects with mesh reperitonealization, complications included 5 cystotomies, 2 proctotomies, 1 ureteral obstruction, and 1 small bowel obstruction. Rates of hospital readmission among both groups were not significantly different, with 3.2% of subjects without mesh reperitonealization versus 3.5% of mesh reperitonealization patients (P = 0.91) (relative risk, 1.09; 95% confidence interval, 0.38-2.56). CONCLUSIONS: There is no significant difference in rates of complications or readmissions among patients with and without mesh reperitonealization at time of sacrocolpopexy. The only intraoperative complication solely attributed to mesh closure was a case with ureteral obstruction at time of reperitonealization.

Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes.

IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.

Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes.

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.

Broken Sacral Neuromodulation Lead Migration Into the Sigmoid Colon: A Case Report.

Sacral neuromodulation is an effective treatment of urinary incontinence, fecal incontinence, and idiopathic urinary retention. The procedure is considered low risk with overall low complication rates. This report describes a 40-year-old woman who underwent sacral neuromodulation explant and full-system implant for weaning efficacy of her device. During device removal, the tined lead broke and was left in situ. Four months later, she was diagnosed as having a wound infection at the site of the retained lead. Imaging revealed lead fragment migration into the sigmoid colon. A colocutaneous fistula was noted soon thereafter. The retained lead was removed during a colonoscopy and the fistula healed. A retained lead can result in migration through the peritoneum and into the colon. This can be managed with assistance from colorectal or gastroenterology consultants.

Attendance at Prescribed Pelvic Floor Physical Therapy in a Diverse, Urban Urogynecology Population.

BACKGROUND: Pelvic floor physical therapy (PFPT) is a common and effective treatment for several pelvic floor disorders, but there is limited knowledge about adherence to the therapy or what factors influence attendance. OBJECTIVE: To determine rates of PFPT attendance (initiation and completion) as well as correlates of PFPT attendance. DESIGN: Retrospective cohort analysis. SETTING: Urban outpatient clinics at a tertiary medical center treating women with pelvic floor disorders. PARTICIPANTS: Patients prescribed PFPT during the time period January 1, 2014, through January 1, 2015. MAIN OUTCOME MEASUREMENTS: Number of PFPT visits recommended and attended; diagnoses associated with PFPT referral. RESULTS: Two-thirds of participants (66%; 118/180) initiated PFPT but less than one-third (29%; 52/180) completed the full treatment course. On univariate analysis, age, body mass index, diagnosis requiring PFPT treatment, marital or employment status, insurance type, number of comorbidities, incontinence status on examination, and stage of prolapse did not differ between PFPT initiators and noninitiators. Those who self-identified as Hispanic were less likely to initiate PFPT when compared with non-Hispanic patients, although this only trended toward significance (odds ratio 0.40, 95% confidence interval 0.14-1.09; exact P = .078). CONCLUSIONS: Two-thirds (66%) of patients initiated PFPT but less than one-third (29%) completed the treatment course. There appears to be an opportunity to augment PFPT attendance, as well as explore racial disparities in attendance. LEVEL OF EVIDENCE: II.

Does Patient Education Augment Pelvic Floor Physical Therapy Preparedness and Attendance? A Randomized Controlled Trial.

OBJECTIVES: The objective of this study was to evaluate patient attendance and preparedness for pelvic floor physical therapy (PFPT) after comparing standard counseling versus standard counseling plus an educational video. METHODS: A randomized controlled trial of 200 patients in a Female Pelvic Medicine and Reconstructive Surgery practice was performed in a tertiary care referral center. Participants were randomized to 1 of 2 educational modalities after being prescribed PFPT. Women either received standard handout counseling or enhanced video counseling. A sample size of 96 per group (N = 192) was needed to detect a 20% difference in PFPT attendance corresponding to a priori estimates of 50% compliance for the standard counseling group (handout) versus 70% compliance for the enhanced counseling group (handout plus video). Compliance data were assessed at least 3 months after the initial referral to determine attendance at PFPT. RESULTS: Sixty-five percent of patients attended at least 1 PFPT visit, whereas 46.5% completed therapy. There was no difference between the standard and enhanced counseling groups in PFPT attendance (P = 0.056) or in completion of half the recommended visits (P = 0.17). Similarly, level of preparedness after viewing the assigned counseling modality did not differ between standard and enhanced counseling groups. For each additional completed visit, the odds of successfully completing PFPT increased by approximately 38% (odds ratio, 1.38; 95% confidence interval, 1.19-1.59). CONCLUSIONS: The addition of enhanced patient counseling did not improve patient preparedness or odds of attending PFPT. Adherence behaviors surrounding PFPT attendance are multifactorial and require further qualitative research to elucidate barriers to PFPT attendance.