The mechanism by which strictly CCR5 using HIV-1 clade C variants exacerbate disease progression in absence of coreceptor switch is not clearly known. We previously reported HIV-1 cladeC envelopes (Env) obtained from late stage Indian patients with expanded coreceptor tropism. Here we compared such Envs (having expanded coreceptor tropism) with strictly CCR5 using Envs also obtained from late stage in their capacity to utilize CD4 and CCR5 for productive entry. We found that while envelopes with low CD4 dependence tend to infect primary CD4(+) T cells better than those required optimum CD4 for entry, no significant association was found between low CD4 usage and infectivity of primary CD4(+) T cells by Env-pseudotyped viruses and theirsensitivity to CCR5 antagonist TAK-779. Interestingly, Envs that readily infected HeLa cells expressing low CD4 showed relative resistance to T20 indicating that conformational intermediates of these envelopes remained for a shorter period of time than is required for efficient inhibition by T20.

Identification of vulnerability in the HIV-1 envelope (Env) will aid in Env-based vaccine design. We recently found an HIV-1 clade C Env clone (4-2.J45) amplified from a recently infected Indian patient showing exceptional neutralization sensitivity to autologous plasma in contrast to other autologous Envs obtained at the same time point. By constructing chimeric Envs and fine mapping between sensitive and resistant Env clones, we found that substitution of highly conserved isoleucine (I) with methionine (M) (ATA to ATG) at position 424 in the C4 domain conferred enhanced neutralization sensitivity of Env-pseudotyped viruses to autologous and heterologous plasma antibodies. When tested against monoclonal antibodies targeting different sites in gp120 and gp41, Envs expressing M424 showed significant sensitivity to anti-V3 monoclonal antibodies and modestly to sCD4 and b12. Substitution of I424M in unrelated Envs also showed similar neutralization phenotype, indicating that M424 in C4 region induces exposure of neutralizing epitopes particularly in CD4 binding sites and V3 loop.

We calculated the incremental cost per quit of a telephone care intervention versus usual care using the provider's perspective. The study population was 819 smokers at five US Veterans Affairs (VA) primary care clinics. They enrolled in the clinical trial between June 2001 and December 2002. After 12 months the participants were assessed for short- and long-term abstinence over the previous six months. VA records were used to extract the cost of VA services over 12 months, and the cost of care purchased by the VA from others. Intervention costs were derived through micro-costing. On average, the intervention cost $142 per person, excluding medications. The average cost of all VA-funded medical care during the study period was $8959 in the telephone-care arm and $7939 in the usual care arm (P = 0.37). Under a standard intent-to-treat analysis the average cost per quit was $11,408 and thus the intervention was cost-effective by conventional standards.

Abstract

BACKGROUND:

While studies have demonstrated higher medium-term mortality for community-acquired pneumonia (CAP), mortality and costs have not been characterized for healthcare-associated pneumonia (HCAP) over a 1-year period.

METHODS:

We conducted a retrospective cohort study to evaluate mortality rates and health system costs for patients with CAP or HCAP during initial hospitalization and for 1 year after hospital discharge. We selected 50 758 patients admitted to the Veterans Affairs (VA) healthcare system between October 2003 and May 2007. Main outcome measures included hospital, post-discharge, and cumulative mortality rates and cost during initial hospitalization and at 12 months following discharge.

RESULTS:

Hospital and 1-year HCAP mortality were nearly twice that of CAP. HCAP was an independent predictor for hospital mortality (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.49-1.76) and 1-year mortality (OR 1.99, 95% CI 1.87-2.11) when controlling for demographics, comorbidities, pneumonia severity, and factors associated with multidrug-resistant infection, including immune suppression, previous antibiotic treatment, and aspiration pneumonia. HCAP patients consistently had higher mortality in each stratum of the Charlson-Deyo-Quan comorbidity index. HCAP patients incurred significantly greater cost during the initial hospital stay and in the following 12 months. Demographics and comorbid conditions, particularly aspiration pneumonia, accounted for 19-33% of this difference.

CONCLUSION:

HCAP represents a distinct category of pneumonia with particularly poor survival up to 1 year after hospital discharge. While comorbidities, pneumonia severity, and risk factors for multidrug-resistant infection may interact to produce even higher mortality compared to CAP, they alone do not explain the observed differences.

Summary

Cardiac arrhythmias during sleep are relatively common and include a diverse etiology, from benign sinus bradycardia to potentially fatal ventricular arrhythmias. Predisposing factors include obstructive sleep apnea and cardiac disease. Rapid eye movement (REM)-related bradyarrhythmia syndrome (including sinus arrest and complete atrioventricular block with ventricular asystole) in the absence of an underlying cardiac or physiologic sleep disorder was first described in the early 1980s. Although uncertain, the underlying pathophysiology likely reflects abnormal autonomic neural-cardiac inputs during REM sleep. The autonomic nervous system (ANS) is a known key modulator of heart rate fluctuations and rhythm during sleep and nocturnal heart rate reflects a balance between the sympathetic-parasympathetic systems. Whether the primary trigger for REM-related bradyarrhythmias reflects abnormal centrally mediated control of the ANS during REM sleep or anomalous baroreflex parasympathetic influences is unknown. This review focuses on the salient features of the REM-related bradyarrhythmia syndrome and explores potential mechanisms with a particular assessment of the relationship between the ANS and nocturnal heart rate fluctuations.

Abstract

Morbid obesity is associated with excessive daytime sleepiness and reduced health-related quality of life. We prospectively evaluated the pre- and postoperative responses of bariatric surgery recipients with the Epworth Sleepiness Scale (ESS) and the Short Form-12. Participants (n = 223; 79% women) with a mean body mass index (BMI) and ESS of 44.8 ± 7.9 kg/m(2) and 7.9 ± 4.5, respectively, received a vertical gastrectomy (76%) or Roux-en-Y gastric bypass (12%). Preoperatively, 30% of patients complained of excessive daytime sleepiness (ESS > 10). Patients with preoperative excessive daytime sleepiness were more obese (p = 0.002), had higher fasting glucose levels (p = 0.02), more likely to have a diagnosis of sleep-disordered breathing (p < 0.001), report snoring (p < 0.001), and had lower health-related quality of life measures particularly physical function (p < 0.001), depression (p = 0.006), and sexual satisfaction (p = 0.04) than non-sleepy patients. At 12-months postoperatively, most patients experienced a significant reduction in BMI (28.6 ± 5.5 kg/m(2), p < 0.001) and excessive daytime sleepiness (mean ESS 5.3 ± 3.3, p < 0.001). Patients with a clinically relevant improvement in the ESS at 12-months post-operatively had greater improvements in physical function (p = 0.009) and snoring (p = 0.010) and were more likely still using positive airway pressure therapy (p = 0.032) than patients without a clinically relevant improvement. Statistically and clinically significant improvements in all health-related quality of life measures were noted at 24 months. Bariatric surgery is associated with dramatic weight loss and improvements in physical functioning and daytime sleepiness.

Author information: IOM (Institute of Medicine) and NRC (National Research Council). (Committee: Goldstein BD, DeSimone JM, Ascher MS, Buehler JW, Cook KS, Crouch NA, Doyle FJ, Foldy S, Gursky EA, Hoffman S, Johnson CB, Keim P, Kellerman AL, Kleinman KP, Layton M, Lee EK, Mayor SD, Moshier TF, Murphy FA, Murray RW, Owens DK, Pollock SM, Resnick IG, Schaudies RP, Schultz JS)

Following the attacks of September 11, 2001 and the anthrax letters, the ability to detect biological threats as quickly as possible became a top priority. In 2003 the Department of Homeland Security (DHS) introduced the BioWatch program--a federal monitoring system intended to speed detection of specific biological agents that could be released in aerosolized form during a biological attack. 

The present volume evaluates the costs and merits of both the current BioWatch program and the plans for a new generation of BioWatch devices. BioWatch and Public Health Surveillance also examines infectious disease surveillance through hospitals and public health agencies in the United States, and considers whether BioWatch and traditional infectious disease surveillance are redundant or complementary.

BACKGROUND: Induction of labor is on the rise in the U.S., increasing from 9.5 percent in 1990 to 22.1 percent in 2004. Although, it is not entirely clear what proportion of these inductions are elective (i.e. without a medical indication), the overall rate of induction of labor is rising faster than the rate of pregnancy complications that would lead to a medically indicated induction. However, the maternal and neonatal effects of induction of labor are unclear. Many studies compare women with induction of labor to those in spontaneous labor. This is problematic, because at any point in the management of the woman with a term gestation, the clinician has the choice between induction of labor and expectant management, not spontaneous labor. Expectant management of the pregnancy involves nonintervention at any particular point in time and allowing the pregnancy to progress to a future gestational age. Thus, women undergoing expectant management may go into spontaneous labor or may require indicated induction of labor at a future gestational age.

OBJECTIVES: The Stanford-UCSF Evidence-Based Practice Center examined the evidence regarding four Key Questions: What evidence describes the maternal risks of elective induction versus expectant management? What evidence describes the fetal/neonatal risks of elective induction versus expectant management? What is the evidence that certain physical conditions/patient characteristics are predictive of a successful induction of labor? How is a failed induction defined?

METHODS: We performed a systematic review to answer the Key Questions. We searched MEDLINE(1966-2007) and bibliographies of prior systematic reviews and the included studies for English language studies of maternal and fetal outcomes after elective induction of labor. We evaluated the quality of included studies. When possible, we synthesized study data using random effects models. We also evaluated the potential clinical outcomes and cost-effectiveness of elective induction of labor versus expectant management of pregnancy labor at 41, 40, and 39 weeks' gestation using decision-analytic models.

RESULTS: Our searches identified 3,722 potentially relevant articles, of which 76 articles met inclusion criteria. Nine RCTs compared expectant management with elective induction of labor. We found that overall, expectant management of pregnancy was associated with an approximately 22 percent higher odds of cesarean delivery than elective induction of labor (OR 1.22, 95 percent CI 1.07-1.39; absolute risk difference 1.9, 95 percent CI: 0.2-3.7 percent). The majority of these studies were in women at or beyond 41 weeks of gestation (OR 1.21, 95 percent CI 1.01-1.46). In studies of women at or beyond 41 weeks of gestation, the evidence was rated as moderate because of the size and number of studies and consistency of the findings. Among women less than 41 weeks of gestation, there were three trials which reported no difference in risk of cesarean delivery among women who were induced as compared to expectant management (OR 1.73; 95 percent CI: 0.67-4.5, P=0.26), but all of these trials were small, non-U.S., older, and of poor quality. When we stratified the analysis by country, we found that the odds of cesarean delivery were higher in women who were expectantly managed compared to elective induction of labor in studies conducted outside the U.S. (OR 1.22; 95 percent CI 1.05-1.40) but were not statistically different in studies conducted in the U.S. (OR 1.28; 95 percent CI 0.65-2.49). Women who were expectantly managed were also more likely to have meconium-stained amniotic fluid than those who were electively induced (OR 2.04; 95 percent CI: 1.34-3.09). Observational studies reported a consistently lower risk of cesarean delivery among women who underwent spontaneous labor (6 percent) compared with women who had an elective induction of labor (8 percent) with a statistically significant decrease when combined (OR 0.63; 95 percent CI: 0.49-0.79), but again utilized the wrong control group and did not appropriately adjust for gestational age. We found moderate to high quality evidence that increased parity, a more favorable cervical status as assessed by a higher Bishop score, and decreased gestational age were associated with successful labor induction (58 percent of the included studies defined success as achieving a vaginal delivery anytime after the onset of the induction of labor; in these instances, induction was considered a failure when it led to a cesarean delivery). In the decision analytic model, we utilized a baseline assumption of no difference in cesarean delivery between the two arms as there was no statistically significant difference in the U.S. studies or in women prior to 41 0/7 weeks of gestation. In each of the models, women who were electively induced had better overall outcomes among both mothers and neonates as estimated by total quality-adjusted life years (QALYs) as well as by reduction in specific perinatal outcomes such as shoulder dystocia, meconium aspiration syndrome, and preeclampsia. Additionally, induction of labor was cost-effective at $10,789 per QALY with elective induction of labor at 41 weeks of gestation, $9,932 per QALY at 40 weeks of gestation, and $20,222 per QALY at 39 weeks of gestation utilizing a cost-effectiveness threshold of $50,000 per QALY. At 41 weeks of gestation, these results were generally robust to variations in the assumed ranges in univariate and multi-way sensitivity analyses. However, the findings of cost-effectiveness at 40 and 39 weeks of gestation were not robust to the ranges of the assumptions. In addition, the strength of evidence for some model inputs was low, therefore our analyses are exploratory rather than definitive.

CONCLUSIONS: Randomized controlled trials suggest that elective induction of labor at 41 weeks of gestation and beyond may be associated with a decrease in both the risk of cesarean delivery and of meconium-stained amniotic fluid. The evidence regarding elective induction of labor prior to 41 weeks of gestation is insufficient to draw any conclusion. There is a paucity of information from prospective RCTs examining other maternal or neonatal outcomes in the setting of elective induction of labor. Observational studies found higher rates of cesarean delivery with elective induction of labor, but compared women undergoing induction of labor to women in spontaneous labor and were subject to potential confounding bias, particularly from gestational age. Such studies do not inform the question of how elective induction of labor affects maternal or neonatal outcomes. Elective induction of labor at 41 weeks of gestation and potentially earlier also appears to be a cost-effective intervention, but because of the need for further data to populate these models our analyses are not definitive. Despite the evidence from the prospective, RCTs reported above, there are concerns about the translation of such findings into actual practice, thus, there is a great need for studying the translation of such research into settings where the majority of obstetric care is provided.