Cyclic AMP response element-binding protein is required in excitatory neurons in the forebrain to sustain wakefulness.

The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB promotes the transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the Cre/lox system to conditionally delete CREB in the forebrain (FB) and in the locus coeruleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that FB-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement sleep. Mice lacking CREB in the FB were unable to sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the FB but not in the LC to promote and stabilize wakefulness.

Trends in Use and Survival Associated With Fertility-Sparing Trachelectomy for Young Women With Early-Stage Cervical Cancer.

OBJECTIVE: To assess the trends in use of trachelectomy in the United States and to examine the outcomes of the procedure compared with hysterectomy in young women with cervical cancer. METHODS: Data were analyzed from women younger than 50 years of age with stage IA2-IB2 cervical cancer treated with hysterectomy or trachelectomy from 2004 to 2014 who were registered in the National Cancer Database. After propensity score matching, we used Cox proportional hazard models to examine the association between treatment and survival. RESULTS: We identified 15,150 patients with cervical cancer, including 14,714 (97.1%) who underwent hysterectomy and 436 (2.9%) who underwent trachelectomy. Trachelectomy rates increased from 1.5% in 2004 to 3.8% by 2014 (P<.001). The greatest increase in the rate of trachelectomy was seen in women younger than 30 years of age (4.6% in 2004 to 17.0% in 2014, P<.001). Among women who underwent trachelectomy, 29.6% had tumors greater than 2 cm in diameter. In a multivariable model, younger women and those more recently diagnosed were more likely to undergo trachelectomy, whereas Medicaid recipients (risk ratio 0.39, 95% CI 0.28-0.54) and the uninsured (risk ratio 0.67, 95% CI 0.45-1.00) were less likely to undergo trachelectomy. After propensity score matching, there was no association between trachelectomy and the risk of mortality (hazard ratio 1.24, 95% CI 0.70-2.22) (mortality rate was 6.0% for hysterectomy vs 5.2% for trachelectomy). Similarly, 5-year survival rates were similar between trachelectomy and hysterectomy for all of the stages examined. CONCLUSIONS: Use of trachelectomy for early-stage cervical cancer has increased in the United States, particularly among women younger than 30 years of age. Within this population, survival is similar for trachelectomy and hysterectomy.

Risk of Occult Uterine Sarcoma in Presumed Uterine Fibroids.

Symptomatic fibroids are a common indication for hysterectomy or myomectomy. Although rare, unexpected gynecologic malignancies in presumed fibroids have been documented. In cases where tissue retrieval is performed through morcellation, there is increasing concern that intra-abdominal dispersion of occult uterine malignancies may lead to peritoneal dissemination and worse outcomes. We examined the available literature to determine the prevalence of all uterine cancers in women undergoing hysterectomy or myomectomy for benign uterine disease, with attention to the risk of morcellating occult uterine sarcomas. We also reviewed the available tools for preoperative discrimination between benign and malignant uterine disease.

Economic and Survival Implications of Use of Electric Power Morcellation for Hysterectomy for Presumed Benign Gynecologic Disease.

BACKGROUND: Electric power morcellation during laparoscopic hysterectomy allows some women to undergo minimally invasive surgery but may disrupt underlying occult malignancies and increase the risk of tumor dissemination. METHODS: We developed a state transition Markov cohort simulation model of the risks and benefits of hysterectomy (abdominal, laparoscopic, and laparoscopic with electric power morcellation) for women with presumed benign gynecologic disease. The model considered perioperative morbidity, mortality, risk of cancer and dissemination, and outcomes in women with an underlying malignancy. We explored the effectiveness from a societal perspective stratified by age (<40, 40-49, 50-59, and ≥60 years). RESULTS: Under all scenarios, modeled laparoscopic hysterectomy without morcellation was the most beneficial strategy. Laparoscopic hysterectomy with morcellation was associated with 80.83 more intraoperative complications, 199.64 fewer perioperative complications, and 241.80 fewer readmissions than abdominal hysterectomy per 10 000 women. Per 10 000 women younger than age 40 years, laparoscopic hysterectomy with morcellation was associated with 1.57 more cases of disseminated cancer and 0.97 fewer deaths than abdominal hysterectomy. The excess cases of disseminated cancer per 10 000 women with morcellation compared with abdominal hysterectomy increased with age to 47.54 per 10 000 in women age 60 years and older. Compared with abdominal hysterectomy, this resulted in 0.30 (age 40-49 years), 5.07 (age 50-59 years), and 18.14 (age 60 years and older) excess deaths per 10 000 women in the respective age groups. CONCLUSION: Laparoscopic hysterectomy without morcellation is the most beneficial approach of the three methods of hysterectomy studied. In older women, the risks of electric power morcellation may outweigh the benefits of minimally invasive hysterectomy.

Use of Electric Power Morcellation and Prevalence of Underlying Cancer in Women Who Undergo Myomectomy.

IMPORTANCE: Myomectomy, the excision of uterine leiomyoma, is now commonly performed via minimally invasive surgery. Electric power morcellation, or fragmentation of the leiomyoma with a mechanical device, may be used to facilitate extraction of the leiomyoma. OBJECTIVE: To analyze the prevalence of underlying cancer and precancerous changes in women who underwent myomectomy with and without electric power uterine morcellation. DESIGN, SETTING, AND PARTICIPANTS: We used a US nationwide database to retrospectively analyze women who underwent myomectomy at 496 hospitals from January 2006 to December 2012. Use of electric power morcellation at the time of myomectomy was investigated. The prevalence of uterine cancer, uterine neoplasms of uncertain malignant potential, and endometrial hyperplasia were estimated. Multivariable mixed-effects regression models were developed to examine predictors of use of electric power morcellation and factors associated with adverse pathologic outcomes. MAIN OUTCOMES AND MEASURES: Use of electric power morcellation at the time of myomectomy was examined. The occurrence of uterine cancer and precancerous uterine lesions was determined. RESULTS: The cohort consisted of 41 777 women who underwent myomectomy at 496 hospitals and included 3220 (7.7%) who had electric power morcellation. Uterine cancer was identified in 73 (1 in 528) women who underwent myomectomy without electric power morcellation (0.19%; 95% CI, 0.15%-0.23%) and in 3 (1 in 1073) women who underwent electric power morcellation (0.09%; 95% CI, 0.02%-0.27%). The corresponding rates of any pathologic finding (cancer, tumors of uncertain malignant potential, or endometrial hyperplasia) were 0.67% (n = 257) (95% CI, 0.59%-0.75%) (1 in 150) and 0.43% (n = 14) (95% CI, 0.21%-0.66%) (1 in 230), respectively. Advanced age was the strongest risk factor for uterine cancer. CONCLUSIONS AND RELEVANCE: The prevalence of cancers and precancerous abnormalities of the uterus in women who undergo myomectomy with or without electric power morcellation is low overall, but risk increases with age. Electric power morcellation should be used with caution in older women undergoing myomectomy.

Organizational characteristics of HIV/syphilis testing services for men who have sex with men in South China: a social entrepreneurship analysis and implications for creating sustainable service models.

BACKGROUND: UNAIDS has called for greater HIV/syphilis testing worldwide just as local HIV/syphilis testing programs are cut or altered. New models are needed to make HIV/syphilis testing services sustainable while retaining their essential public health function. Social entrepreneurship, using business principles to promote a social cause, provides a framework to pilot programs that sustainably expand testing. Drawing on fieldwork in two South Chinese cities, we examined organizational and financial characteristics of current HIV/syphilis testing systems for men who have sex with men (MSM) in addition to new pilot programs focused on revenue-generation for sustainability. METHODS: We undertook a qualitative study to explore organizational and financial characteristics of HIV/syphilis testing for MSM. Data were collected from men who have sex with men and policy stakeholders in Guangzhou and Hong Kong. Framework analysis was used to identify themes and then code the data. RESULTS: Our qualitative research study included MSM and policy stakeholders (n = 84). HIV/syphilis testing services were implemented at a wide range of organizations which we grouped broadly as independent community-based organizations (CBOs), independent clinics, and hybrid CBO-clinic sites. From an organizational perspective, hybrid CBO-clinic sites offered the inclusive environment of an MSM CBO linked to the technical capacity and trained staff of a clinic. From a financial perspective, stakeholders expressed concern about the sustainability and effectiveness of sexual health services reliant on external funding. We identified four hybrid CBO-clinic organizations that launched pilot testing programs in order to generate revenue while expanding HIV testing. CONCLUSION: Many MSM CBOs are searching for new organizational models to account for decreased external support. Hybrid CBO-clinic organizations create a strong foundation to increase HIV/syphilis testing using social entrepreneurship models in China.

Incentivizing HIV/STI testing: a systematic review of the literature.

Suboptimal HIV/STI testing uptake has a profound impact on morbidity and mortality. Incentives have been effective in other areas of medicine and may improve HIV/STI testing uptake rates. This study reviewed the effects of incentives on HIV/STI testing uptake. A systematic search of seven databases was undertaken. Testing uptake was defined as test implementation and/or test result retrieval. Incentives were defined as monetary or non-monetary rewards or free-of-charge testing vouchers. Seven studies were included. All seven studies demonstrated higher rates of uptake in an incentivized group. Incentives offered at a non-clinical setting demonstrated more significant differences in uptake rates compared to incentives offered at a clinical setting. Incentivizing HIV/STI testing uptake, especially testing at a non-clinical setting, may be a useful tool to modify health behavior. Further research is needed to understand how incentives could be an effective component within a comprehensive HIV/STI control strategy.

Microenterprise development interventions for sexual risk reduction: a systematic review.

Comprehensive interventions that address both individual and structural determinants associated with HIV/STI risk are gaining increasing attention over the past decade. Microenterprise development offers an appealing model for HIV prevention by addressing poverty and gender equality. This study systematically reviewed the effects of microenterprise development interventions on HIV/STI incidence and sexual risk behaviors. Microenterprise development was defined as developing small business capacity among individuals to alleviate poverty. Seven eligible research studies representing five interventions were identified and included in this review. All of the studies targeted women, and three focused on sex workers. None measured biomarker outcomes. All three sex worker studies showed significant reduction in sexual risk behaviors when compared to the control group. Non-sex worker studies showed limited changes in sexual risk behavior. This review indicates the potential utility of microenterprise development in HIV risk reduction programs. More research is needed to determine how microenterprise development can be effectively incorporated in comprehensive HIV control strategies.

Central pontine myelinolysis: a case report and clinical-pathological review.

An 11-yr-old child presented with acute mental status changes and spastic quadriplegia after orthotopic liver transplantation. Magnetic resonance (MR) imaging findings were consistent with central pontine and EPM. Initial immunosuppression included tacrolimus, mycophenolate mofetil, and corticosteroids. Given that neurotoxicity is a well-established side effect of CNI, the patient was converted to rapamycin and subsequently experienced significant neurologic recovery. The temporal resolution of the patient's symptoms suggests that prompt recognition of central pontine and EPM and conversion from tacrolimus to rapamycin during the early post-operative course may have therapeutic benefits for patients undergoing pediatric transplant with CNI-related neurotoxicity.