Prognostic significance of lymphovascular space invasion for stage IA1 and IA2 cervical cancer.

BACKGROUND: Data regarding the prognostic significance of lymphovascular space invasion (LVSI) for stage IA1 and IA2 cervical cancer are limited. Specifically, the role of LVSI as an independent risk factor for mortality in stage IA disease has not been shown. OBJECTIVE: We examined the association between LVSI and nodal metastases and survival for women with stage IA1 and IA2 cervical cancer. STUDY DESIGN: We used the National Cancer Database to identify patients with stage IA adenocarcinoma or squamous carcinoma of the cervix from January 2010 through December 2015 for whom LVSI status was known. Mixed-effect log-Poisson models were used to identify predictors of LVSI. Cox proportional hazard models and Kaplan-Meier curves were used to compare all-cause mortality. RESULTS: We identified 3239 patients with stage IA1 and 1049 patients with stage IA2 carcinoma of the cervix. Among patients with stage IA1 and IA2 disease, 10.5% and 18.8% had LVSI, respectively. Less than 1% of patients with stage IA1 disease without LVSI had positive nodes compared with 7.8% of those with LVSI (p<0.001). Lymphatic metastases were identified in 1.7% of stage IA2 cases without LVSI versus 14.6% for those with LVSI (p<0.001). Among both stage IA1 and IA2 patients, squamous histology, grade 3 tumor differentiation, and white race were associated with LVSI (p<0.05 for all). In a univariable model, the hazard ratio for death associated with LVSI was 1.05 (95% CI 0.45 to 2.45) for women with stage IA1 tumors and 2.36 (95% CI 1.04 to 5.33) for those with IA2 neoplasms. CONCLUSIONS: LVSI is associated with lymph node metastases in patients with stage IA cervical cancer. LVSI is associated with decreased survival for women with stage IA2 cervical cancer.

Trends in end-of-life care and health care spending in women with uterine cancer.

BACKGROUND: High-intensity care including hospitalizations, chemotherapy, and other interventions at the end of life is costly and often of little value for cancer patients. Little is known about patterns of end-of-life care and resource utilization for women with uterine cancer. OBJECTIVE: We examined the costs and predictors of aggressive end-of-life care for women with uterine cancer. STUDY DESIGN: In this observational cohort study the Surveillance, Epidemiology, and End Results-Medicare linked database was used to identify women age ≥65 years who died from uterine cancer from 2000 through 2011. Resource utilization in the last month of life including ≥2 hospital admissions, >1 emergency department visit, ≥1 intensive care unit admission, or use of chemotherapy in the last 14 days of life was examined. High-intensity care was defined as the occurrence of any of the above outcomes. Logistic regression models were developed to identify factors associated with high-intensity care. Total Medicare expenditures in the last month of life are reported. RESULTS: Of the 5873 patients identified, the majority had stage IV cancer (30.2%), were white (79.9%), and had endometrioid tumors (47.6%). High-intensity care was rendered to 42.5% of women. During the last month of life, 15.0% had ≥2 hospital admissions, 9.0% had a hospitalization >14 days, 15.3% had >1 emergency department visits, 18.3% had an intensive care unit admission, and 6.6% received chemotherapy in the last 14 days of life. The percentage of women who received high-intensity care was stable over the study period. Characteristics of younger age, black race, higher number of comorbidities, stage IV disease, residence in the eastern United States, and more recent diagnosis were associated with high-intensity care. The median Medicare payment during the last month of life was $7645. Total per beneficiary Medicare payments remained stable from $9656 (interquartile range $3190-15,890) in 2000 to $9208 (interquartile range $3309-18,554) by 2011. The median health care expenditure was 4 times as high for those who received high-intensity care compared to those who did not (median $16,173 vs $4099). CONCLUSION: Among women with uterine cancer, high-intensity care is common in the last month of life, associated with substantial monetary expenditures, and does not appear to be decreasing.

Natural history and outcome of neuroendocrine carcinoma of the cervix.

OBJECTIVE: Neuroendocrine carcinomas of the cervix (NECC) are rare and thought to be aggressive. We performed a population-based analysis to examine the natural history, treatment patterns and outcomes of women with NECC compared to squamous cell carcinoma (SCCC) and adenocarcinoma (AC) of the cervix. METHODS: The National Cancer Database (NCDB) was utilized to identify women with NECC, SCCC, and AC treated from 1998 to 2011. Clinical, demographic, and treatment characteristics were compared between the groups. The association between tumor histology and survival was examined using Kaplan-Meier analyses and multivariable Cox proportional hazards regression models. RESULTS: We identified 127,332 patients, including 1,896 (1.5%) with NECC and 101,240 (79.5%) with SCCC and 24,196 (19.0%) with AC. Patients with NECC were younger, more often white, commercially insured, and diagnosed with metastatic disease at presentation compared to women with SCCC. Patients with early-stage NECC were more likely to receive adjuvant chemotherapy and radiation after surgery (P<0.05 for both). In multivariable models stratified by stage and adjusted for clinical and demographic characteristics, the risk of death was higher for patients with NECC compared to SCCC for all stages of disease: stages IB-IIA (HR=2.96; 95% CI, 2.48-3.52), stages IIB-IVA (HR=1.70; 95% CI, 1.45-1.99) and stage IVB (HR=1.14; 95% CI, 0.91-1.43). CONCLUSION: NECC are aggressive tumors associated with an increased risk of death. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease.

Overuse of external beam radiotherapy for stage I endometrial cancer.

BACKGROUND: Radiation therapy has long been part of the treatment of endometrial cancer. Despite the long history of radiation use, prospective trials in the United States and Europe have been unable to demonstrate a survival benefit with adjuvant radiotherapy compared with observation. Whereas radiation has been associated with a decreased rate of locoregional failure, the treatment is also associated with substantial toxicity. However, a randomized trial published in 2010 demonstrated that, compared with external beam radiation therapy (EBRT), vaginal brachytherapy was less toxic and as effective in reducing locoregional relapses. OBJECTIVE: We examined patterns of use of external beam radiation therapy for women with high intermediate risk endometrial cancer. STUDY DESIGN: We examined the use of external beam radiation therapy in women registered in the National Cancer Data Base with high intermediate risk, stage I endometrial cancer treated from 2008 through 2012. High intermediate risk was defined as age > 60 years with a stage IA, grade 3 tumors or stage IB, grade 1 or 2 tumors. Multivariable models of EBRT use were developed. RESULTS: Among 8242 women, 915 (11.1%) received EBRT, 2614 (31.7%) were treated with brachytherapy, and 4713 (57.2%) did not receive any adjuvant radiation. The use of EBRT was 18.1% in 2008 and declined to 8.6% in 2012, whereas the use of brachytherapy rose each year from 26.5% in 2008 to 37.6% in 2012 (P < .0001). External beam radiation was administered to 7.9% of patients with stage IA/grade 3 tumors, 8.8% of those with stage IB/grade 1 cancers, and to 15.2% of women with stage IB/grade 2 neoplasms (P < .0001). EBRT was utilized in 10.1% of women who underwent lymphadenectomy compared with 22.0% who did not undergo lymphadenectomy (P < .0001). In a multivariable model, black women were more likely to receive EBRT than white women (relative risk [RR], 1.33; 95% confidence interval [CI], 1.03-1.70). Similarly, patients in the eastern United States, those treated at community cancer centers and comprehensive community cancer programs, patients in metropolitan areas, and those diagnosed in earlier years were more likely to undergo EBRT. Patients with stage IB/grade 2 tumors (RR, 1.96; 95% CI, 1.65-2.32) were more likely to receive EBRT than those with stage IA/grade 3 neoplasms. Those women who did not undergo lymphadenectomy were more than twice as likely to receive EBRT compared with those who had a lymphadenectomy (RR, 2.32; 95% CI, 1.99-2.72). CONCLUSION: Despite data from randomized trials, approximately 9% of women with high intermediate risk of endometrial cancer continue to receive EBRT. Performance of lymphadenectomy is associated with a lower likelihood of external beam radiation therapy.

LASER RESENSITIZATION OF MEDICALLY UNRESPONSIVE NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Efficacy and Implications.

PURPOSE: Drug tolerance is the most common cause of treatment failure in neovascular age-related macular degeneration. "Low-intensity/high-density" subthreshold diode micropulse laser (SDM) has been reported effective for a number of retinal disorders without adverse effects. It has been proposed that SDM normalizes retinal pigment epithelial function. On this basis, it has been postulated that SDM treatment might restore responsiveness to anti-vascular endothelial growth factor drugs in drug-tolerant eyes. METHODS: Subthreshold diode micropulse laser treatment was performed in consecutive eyes unresponsive to all anti-vascular endothelial growth factor drugs, including at least three consecutive ineffective aflibercept injections. Monthly aflibercept was resumed 1 month after SDM treatment. RESULTS: Thirteen eyes of 12 patients, aged 73 to 97 years (average, 84 years), receiving 16 to 67 (average, 34) anti-vascular endothelial growth factor injections before SDM treatment were included and followed for 3 months to 7 months (average, 5 months) after SDM treatment. After SDM treatment and resumption of aflibercept, 92% (12 of 13) of eyes improved, with complete resolution of macular exudation in 69% (9 of 13). Visual acuity remained unchanged. Central and maximum macular thicknesses significantly improved. CONCLUSION: Subthreshold diode micropulse laser treatment restored drug response in drug-tolerant eyes with neovascular age-related macular degeneration. Based on these findings, a theory of SDM action is proposed, suggesting a wider role for SDM as retinal reparative/protective therapy.

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin.

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.

A phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of talactoferrin in patients with severe sepsis.

OBJECTIVES: Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial. SETTING: Adult ICUs and emergency departments in the United States. PATIENTS: One hundred ninety-four adults within 24 hrs of the onset of severe sepsis. INTERVENTIONS: Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU. MEASUREMENTS AND MAIN RESULTS: Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo. CONCLUSIONS: Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

Rhinovirus-induced barrier dysfunction in polarized airway epithelial cells is mediated by NADPH oxidase 1.

Previously, we showed that rhinovirus (RV), which is responsible for the majority of common colds, disrupts airway epithelial barrier function, as evidenced by reduced transepithelial resistance (R(T)), dissociation of zona occludins 1 (ZO-1) from the tight junction complex, and bacterial transmigration across polarized cells. We also showed that RV replication is required for barrier function disruption. However, the underlying biochemical mechanisms are not known. In the present study, we found that a double-stranded RNA (dsRNA) mimetic, poly(I:C), induced tight junction breakdown and facilitated bacterial transmigration across polarized airway epithelial cells, similar to the case with RV. We also found that RV and poly(I:C) each stimulated Rac1 activation, reactive oxygen species (ROS) generation, and Rac1-dependent NADPH oxidase 1 (NOX1) activity. Inhibitors of Rac1 (NSC23766), NOX (diphenylene iodonium), and NOX1 (small interfering RNA [siRNA]) each blocked the disruptive effects of RV and poly(I:C) on R(T), as well as the dissociation of ZO-1 and occludin from the tight junction complex. Finally, we found that Toll-like receptor 3 (TLR3) is not required for either poly(I:C)- or RV-induced reductions in R(T). Based on these results, we concluded that Rac1-dependent NOX1 activity is required for RV- or poly(I:C)-induced ROS generation, which in turn disrupts the barrier function of polarized airway epithelia. Furthermore, these data suggest that dsRNA generated during RV replication is sufficient to disrupt barrier function.

Qualitative analysis of gynecologic oncology patients' experience with treatment holidays.

OBJECTIVE: Patients with advanced or recurrent gynecologic malignancies occasionally take breaks from systemic treatment colloquially referred to as "treatment holidays" or "chemotherapy holidays." There are no data from the patient perspective that help describe this experience. METHODS: Patients with recurrent or advanced primary gynecologic malignancies who had decided to enter a treatment holiday were recruited and interviewed. A treatment holiday was defined as a planned temporary break or delay in treatment for a patient with recurrent or advanced primary gynecologic malignancy for reasons other than pursuit of hospice or best supportive care, research protocol violation or unacceptable toxicity. Interviews were audiotaped, transcribed and then analyzed using an inductive thematic analysis. RESULTS: Of 6 total patients identified for participation, 5 completed interviews with ages ranging from 57 to 80 years. Two participants returned to their previous treatment regimen after their holiday therapy, two switched therapies, and one remained on an extended break from systemic treatment. Treatment holidays were experienced as a break from the physical and psychological routine of being a cancer patient, but also brought about feelings of a lack of structure, uncertainty, and led to a confrontation with mortality issues. Overall, participants had favorable experiences which were initiated by their providers in whom they had a deep sense of trust. CONCLUSION: Patients experience treatment holidays as a positive and valuable break from the physical and psychosocial routine of cancer treatment and illness. These experiences produce distinct emotional needs that clinicians should address to best support patients electing treatment holidays.

The impact of the ban on elective surgery in New York City during the coronavirus outbreak on gynecologic oncology patient care.

Introduction: Elective surgical procedures were suspended during the coronavirus disease pandemic (COVID-19) in New York City (NYC) between March 16 and June 15, 2020. This study characterizes the impact of the ban on surgical delays for patients scheduled for surgery during this first wave of the COVID-19 outbreak. Methods: Patients who were scheduled for surgical treatment of malignant or pre-invasive disease by gynecologic oncologists at three NYC hospitals during NYC's ban on elective surgery were included. Outcomes of interest were the percentage of patients experiencing surgical delay and the nature of delays. Kruskal-Wallis, chi-square, and logistic regression tests were performed with significance set at p < 0.05. Results: Of the 145 patients with malignant or pre-invasive diseases scheduled for surgery during the ban on elective surgery, 40% of patients experienced one or more surgical delays, 10% experienced two or more and 1% experienced three surgical delays. Of patients experiencing an initial delay, 77% were hospital-initiated and 11% were due to known or suspected personal COVID-19. Overall, 81% of patients completed their planned treatment, and 93% of patients underwent their initially planned surgery. Among patients for whom adjuvant therapy was recommended, 67% completed their planned treatment, and the most common reasons for not completing treatment were medically indicated followed by concerns regarding COVID-19. Conclusion: During the ban on elective surgery in NYC during the first outbreak of the COVID-19 pandemic, many patients experienced minor surgical delays, but most patients obtained appropriate, timely care with either surgery or alternative treatment.

Impact of the COVID-19 Pandemic on the Behavioral Health of People With Intellectual and Developmental Disabilities.

OBJECTIVE: The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD). METHODS: A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors' clinical networks and IDD-affiliated organizations from March to June 2021. RESULTS: In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%). CONCLUSIONS: COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.

CCNE1 amplification among metastatic sites in patients with gynecologic high-grade serous carcinoma.

OBJECTIVE: We sought to characterize the variability of CCNE1 amplification among metastatic sites of CCNE1 amplified high grade serous carcinoma (HGSC) cases to investigate the feasibility of targeting this alteration for therapeutic purposes. METHODS: Patients with CCNE1 amplified HGSC who underwent surgical cytoreduction with metastatic sites were identified from institutional molecular profiling reports and a population of HGSC cases screened using digital droplet PCR (ddPCR). Cases with normal CCNE1 copy number were included as controls. Slides from metastatic sites were cut from formalin-fixed paraffin-embedded tissue blocks, dissected for tumor of > 50% purity, and underwent DNA extraction. CCNE1 copy number was determined by ddPCR. Tumor purity was confirmed with mutant TP53 allele fraction from targeted massively parallel sequencing. RESULTS: Four of 15 patients from an institutional database screened by ddPCR were found to have CCNE1 amplification. Three additional patients were identified from a query of institutional commercial clinical reports. Among these 7 CCNE1 amplified cases (2 uterine, 5 ovarian), 5 showed preservation of CCNE1 amplification (copy number > 5) among all metastatic sites. The remaining 2 cases had multiple metastatic sites without preserved CCNE1 amplification. Non-amplified cases had predominantly normal CCNE1 copy number across metastatic sites. CONCLUSIONS: CCNE1 amplification is an early genomic event in HGSC and is preserved in most metastatic sites suggesting a uniform response to pathway targeting therapies.

Serous carcinoma of a prolapsed fallopian tube: A rare cause of a vaginal apex mass.

BACKGROUND: The differential diagnosis for women who present with a vaginal mass after undergoing a hysterectomy is dependent on the indication, type and timing of the hysterectomy. The differential diagnosis includes cervical dysplasia, malignancy, nabothian cysts, prolapsed endocervical polyp/fibroid, abscess, hematoma, granulation tissue, or dehiscence with organ evisceration. CASE: We introduce a case of a woman who presented with a vaginal apex mass and had a remote history of a total hysterectomy for an unknown indication. She was ultimately diagnosed with high grade serous carcinoma of a prolapsed fallopian tube. CONCLUSION: This is the first reported case of serous carcinoma of a prolapsed fallopian tube and highlights the importance of maintaining a wide differential diagnosis for women who present with vaginal apex masses.

Safety and Feasibility of Discharge Without an Opioid Prescription for Patients Undergoing Gynecologic Surgery.

OBJECTIVE: To implement a quality-improvement intervention aimed at reducing unnecessary opioid prescriptions for patients who are undergoing gynecologic surgery. METHODS: This was a retrospective cohort study that included data from the pre- and post-quality-improvement initiative cohorts. Patients at an urban, tertiary academic medical center who were undergoing scheduled minimally invasive surgery and open abdominal surgery by a gynecologic oncologist were included. Patients underwent preoperative counseling, standardization of perioperative analgesia, and a postoperative opioid prescribing algorithm. Descriptive statistics were calculated for demographic and perioperative characteristics, process measures, and outcome measures. RESULTS: A total of 532 abdominal surgeries were analyzed. The total percentage of patients discharged with an opioid prescription decreased from 82.7% (n=229/276) to 23.1% (n=59/256) (P<.001) and was significantly reduced for all routes of surgery. The mean number of opioid tablets prescribed for all patients was significantly reduced from 7.2 tablets (SD=5.7) to 1.8 tablets (SD=4.3) (P<.001). Eighty-three percent of patients (n=97/117) who underwent minimally invasive hysterectomy and were discharged on postoperative day 0 or day 1 were not provided an opioid prescription. Fifty-one percent of patients who underwent laparotomy were discharged without an opioid prescription. The percentage of patients who required an opioid refill or new prescription in the preintervention and postintervention cohorts remained constant (6.5%, n=18/276 vs 5.9%, n=15/256, P=.75), as did postoperative calls for pain (8.3%, n=23/276 vs 10.9%, n=33/256). CONCLUSION: Patients who are undergoing scheduled abdominal gynecologic surgery can be safely discharged without opioid prescriptions with appropriate education and perioperative analgesia prescribing practices. These protocols and prescribing practices profoundly limit opioid prescriptions, which is an important factor in combating the ongoing opioid crisis.

Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.

CONTEXT: Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages. OBJECTIVE: To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. DESIGN, SETTING, AND PATIENTS: Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. INTERVENTIONS: Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days. MAIN OUTCOME MEASURES: Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. RESULTS: There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02). CONCLUSIONS: There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56).

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial.

CONTEXT: Ventilator-associated pneumonia (VAP) causes substantial morbidity. A silver-coated endotracheal tube has been designed to reduce VAP incidence by preventing bacterial colonization and biofilm formation. OBJECTIVE: To determine whether a silver-coated endotracheal tube would reduce the incidence of microbiologically confirmed VAP. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, single-blind, controlled study conducted in 54 centers in North America. A total of 9417 adult patients (> or = 18 years) were screened between 2002 and 2006. A total of 2003 patients expected to require mechanical ventilation for 24 hours or longer were randomized. INTERVENTION: Patients were assigned to undergo intubation with 1 of 2 high-volume, low-pressure endotracheal tubes, similar except for a silver coating on the experimental tube. MAIN OUTCOME MEASURES: Primary outcome was VAP incidence based on quantitative bronchoalveolar lavage fluid culture with 10(4) colony-forming units/mL or greater in patients intubated for 24 hours or longer. Other outcomes were VAP incidence in all intubated patients, time to VAP onset, length of intubation and duration of intensive care unit and hospital stay, mortality, and adverse events. RESULTS: Among patients intubated for 24 hours or longer, rates of microbiologically confirmed VAP were 4.8% (37/766 patients; 95% confidence interval [CI], 3.4%-6.6%) in the group receiving the silver-coated tube and 7.5% (56/743; 95% CI, 5.7%-9.7%) (P = .03) in the group receiving the uncoated tube (all intubated patients, 3.8% [37/968; 95% CI, 2.7%-5.2%] and 5.8% [56/964; 95% CI, 4.4%-7.5%] [P = .04]), with a relative risk reduction of 35.9% (95% CI, 3.6%-69.0%; all intubated patients, 34.2% [95% CI, 1.2%-67.9%]). The silver-coated endotracheal tube was associated with delayed occurrence of VAP (P = .005). No statistically significant between-group differences were observed in durations of intubation, intensive care unit stay, and hospital stay; mortality; and frequency and severity of adverse events. CONCLUSION: Patients receiving a silver-coated endotracheal tube had a statistically significant reduction in the incidence of VAP and delayed time to VAP occurrence compared with those receiving a similar, uncoated tube. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00148642.

Educational Intervention to Improve Code Status Discussion Proficiency Among Obstetrics and Gynecology Residents.

BACKGROUND: Obstetrics and gynecology (OB/GYN) residents receive little formal training in conducting code status discussions (CSDs). OBJECTIVE: We piloted an educational intervention to improve resident confidence and competence at conducting CSDs. DESIGN: The OB/GYN residents at a single institution participated in a 3-part educational program. First, participants reviewed a journal article and completed an online module. Second, they received a didactic lecture followed by a resident-to-resident mock CSD. Finally, participants had a videotaped CSD with a standardized patient (SP). Pre- and postintervention surveys and performance evaluations were analyzed. A subgroup analysis was performed on those with completed data sets. RESULTS: Participants included 24 residents in postgraduate years (PGY) 1 to 4: 85% were female with a mean age of 29 years; 83% completed the entrance survey; 63% completed the SP CSD; and 42% completed of all parts of the intervention. Residents initially felt most prepared to discuss treatment options (3.3/5 on a Likert scale) and less prepared to discuss hospice, end-of-life care, and code status (2.2/5, 2.2/5, and 2.3/5, respectively). Performance during the resident-to-resident CSD was variable with scores (% of skills achieved) ranging from 27% to 93% (mean 64%). Performance at the SP encounter was similar with scores ranging from 40% to 73% (mean 56%). After intervention, residents felt more prepared for CSDs (3.7/5) and end-of-life care (3.9/5). The subgroup analysis failed to show a significant change in skill performance from the first to the second CSD. CONCLUSION: Participants found the components of this intervention helpful and reported improved confidence at conducting CSDs.

Long-term survival after anterior pelvic exenteration and total vaginectomy for recurrent endometrial carcinoma with metastatic inguinal nodes at the time of surgery.

•Pelvic exenteration can be used in patients with multifocal recurrence.•Ability to achieve negative margins remains a necessity for pelvic exenteration.•Individualized treatments are essential for those with recurrent malignancy.