Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

Application of a life table approach to assess duration of BNT162b2 vaccine-derived immunity by age using COVID-19 case surveillance data during the Omicron variant period.

BACKGROUND: SARS-CoV-2 Omicron variants have the potential to impact vaccine effectiveness and duration of vaccine-derived immunity. We analyzed U.S. multi-jurisdictional COVID-19 vaccine breakthrough surveillance data to examine potential waning of protection against SARS-CoV-2 infection for the Pfizer-BioNTech (BNT162b) primary vaccination series by age. METHODS: Weekly numbers of SARS-CoV-2 infections during January 16, 2022-May 28, 2022 were analyzed by age group from 22 U.S. jurisdictions that routinely linked COVID-19 case surveillance and immunization data. A life table approach incorporating line-listed and aggregated COVID-19 case datasets with vaccine administration and U.S. Census data was used to estimate hazard rates of SARS-CoV-2 infections, hazard rate ratios (HRR) and percent reductions in hazard rate comparing unvaccinated people to people vaccinated with a Pfizer-BioNTech primary series only, by age group and time since vaccination. RESULTS: The percent reduction in hazard rates for persons 2 weeks after vaccination with a Pfizer-BioNTech primary series compared with unvaccinated persons was lowest among children aged 5-11 years at 35.5% (95% CI: 33.3%, 37.6%) compared to the older age groups, which ranged from 68.7%-89.6%. By 19 weeks after vaccination, all age groups showed decreases in the percent reduction in the hazard rates compared with unvaccinated people; with the largest declines observed among those aged 5-11 and 12-17 years and more modest declines observed among those 18 years and older. CONCLUSIONS: The decline in vaccine protection against SARS-CoV-2 infection observed in this study is consistent with other studies and demonstrates that national case surveillance data were useful for assessing early signals in age-specific waning of vaccine protection during the initial period of SARS-CoV-2 Omicron variant predominance. The potential for waning immunity during the Omicron period emphasizes the importance of continued monitoring and consideration of optimal timing and provision of booster doses in the future.

Trends in Laboratory-Confirmed SARS-CoV-2 Reinfections and Associated Hospitalizations and Deaths Among Adults Aged ≥18 Years - 18 U.S. Jurisdictions, September 2021-December 2022.

Although reinfections with SARS-CoV-2 have occurred in the United States with increasing frequency, U.S. epidemiologic trends in reinfections and associated severe outcomes have not been characterized. Weekly counts of SARS-CoV-2 reinfections, total infections, and associated hospitalizations and deaths reported by 18 U.S. jurisdictions during September 5, 2021-December 31, 2022, were analyzed overall, by age group, and by five periods of SARS-CoV-2 variant predominance (Delta and Omicron [BA.1, BA.2, BA.4/BA.5, and BQ.1/BQ.1.1]). Among reported reinfections, weekly trends in the median intervals between infections and frequencies of predominant variants during previous infections were calculated. As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods; during the same periods, increases in the percentages of reinfections among COVID-19-associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial. Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18-49 years compared with those among adults aged ≥50 years. The median interval between infections ranged from 269 to 411 days by week, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. To prevent severe COVID-19 outcomes, including those following reinfection, CDC recommends staying up to date with COVID-19 vaccination and receiving timely antiviral treatments, when eligible.

Estimated preventable COVID-19-associated deaths due to non-vaccination in the United States.

While some studies have previously estimated lives saved by COVID-19 vaccination, we estimate how many deaths could have been averted by vaccination in the US but were not because of a failure to vaccinate. We used a simple method based on a nationally representative dataset to estimate the preventable deaths among unvaccinated individuals in the US from May 30, 2021 to September 3, 2022 adjusted for the effects of age and time. We estimated that at least 232,000 deaths could have been prevented among unvaccinated adults during the 15 months had they been vaccinated with at least a primary series. While uncertainties exist regarding the exact number of preventable deaths and more granular data are needed on other factors causing differences in death rates between the vaccinated and unvaccinated groups to inform these estimates, this method is a rapid assessment on vaccine-preventable deaths due to SARS-CoV-2 that has crucial public health implications. The same rapid method can be used for future public health emergencies.

COVID-19 Incidence and Mortality Among Unvaccinated and Vaccinated Persons Aged ≥12 Years by Receipt of Bivalent Booster Doses and Time Since Vaccination - 24 U.S. Jurisdictions, October 3, 2021-December 24, 2022.

On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance.† During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years; RR = 23.7 and ≥80 years; 10.3) or a monovalent booster (65-79 years; 8.3 and ≥80 years; 4.2). In a second analysis stratified by time since booster vaccination, there was a progressive decline from the Delta period (RR = 50.7) to the early BA.4/BA.5 period (7.4) in relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.

Pediatric Emergency Department Visits Before and During the COVID-19 Pandemic - United States, January 2019-January 2022.

Emergency departments (EDs) in the United States remain a frontline resource for pediatric health care emergencies during the COVID-19 pandemic; however, patterns of health-seeking behavior have changed during the pandemic (1,2). CDC examined changes in U.S. ED visit trends to assess the continued impact of the pandemic on visits among children and adolescents aged 0-17 years (pediatric ED visits). Compared with 2019, pediatric ED visits declined by 51% during 2020, 22% during 2021, and 23% during January 2022. Although visits for non-COVID-19 respiratory illnesses mostly declined, the proportion of visits for some respiratory conditions increased during January 2022 compared with 2019. Weekly number and proportion of ED visits increased for certain types of injuries (e.g., drug poisonings, self-harm, and firearm injuries) and some chronic diseases, with variation by pandemic year and age group. Visits related to behavioral concerns increased across pandemic years, particularly among older children and adolescents. Health care providers and families should remain vigilant for potential indirect impacts of the COVID-19 pandemic, including health conditions resulting from delayed care, and increasing emotional distress and behavioral health concerns among children and adolescents.

Pediatric Emergency Department Visits Associated with Mental Health Conditions Before and During the COVID-19 Pandemic - United States, January 2019-January 2022.

In 2021, a national emergency* for children's mental health was declared by several pediatric health organizations, and the U.S. Surgeon General released an advisory† on mental health among youths. These actions resulted from ongoing concerns about children's mental health in the United States, which was exacerbated by the COVID-19 pandemic (1,2). During March-October 2020, among all emergency department (ED) visits, the proportion of mental health-related visits increased by 24% among U.S. children aged 5-11 years and 31% among adolescents aged 12-17 years, compared with 2019 (2). CDC examined changes in U.S. pediatric ED visits for overall mental health conditions (MHCs) and ED visits associated with specific MHCs (depression; anxiety; disruptive behavioral and impulse-control disorders; attention-deficit/hyperactivity disorder; trauma and stressor-related disorders; bipolar disorders; eating disorders; tic disorders; and obsessive-compulsive disorders [OCD]) during 2019 through January 2022 among children and adolescents aged 0-17 years, overall and by sex and age. After declines in weekly visits associated with MHCs among those aged 0-17 years during 2020, weekly numbers of ED visits for MHCs overall and for specific MHCs varied by age and sex during 2021 and January 2022, when compared with corresponding weeks in 2019. Among adolescent females aged 12-17 years, weekly visits increased for two of nine MHCs during 2020 (eating disorders and tic disorders), for four of nine MHCs during 2021 (depression, eating disorders, tic disorders, and OCD), and for five of nine MHCs during January 2022 (anxiety, trauma and stressor-related disorders, eating disorders, tic disorders, and OCD), and overall MHC visits during January 2022, compared with 2019. Early identification and expanded evidence-based prevention and intervention strategies are critical to improving children's and adolescents' mental health (1-3), especially among adolescent females, who might have increased need.

COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence - 25 U.S. Jurisdictions, April 4-December 25, 2021.

Previous reports of COVID-19 case, hospitalization, and death rates by vaccination status† indicate that vaccine protection against infection, as well as serious COVID-19 illness for some groups, declined with the emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, and waning of vaccine-induced immunity (1-4). During August-November 2021, CDC recommended§ additional primary COVID-19 vaccine doses among immunocompromised persons and booster doses among persons aged ≥18 years (5). The SARS-CoV-2 B.1.1.529 (Omicron) variant emerged in the United States during December 2021 (6) and by December 25 accounted for 72% of sequenced lineages (7). To assess the impact of full vaccination with additional and booster doses (booster doses),¶ case and death rates and incidence rate ratios (IRRs) were estimated among unvaccinated and fully vaccinated adults by receipt of booster doses during pre-Delta (April-May 2021), Delta emergence (June 2021), Delta predominance (July-November 2021), and Omicron emergence (December 2021) periods in the United States. During 2021, averaged weekly, age-standardized case IRRs among unvaccinated persons compared with fully vaccinated persons decreased from 13.9 pre-Delta to 8.7 as Delta emerged, and to 5.1 during the period of Delta predominance. During October-November, unvaccinated persons had 13.9 and 53.2 times the risks for infection and COVID-19-associated death, respectively, compared with fully vaccinated persons who received booster doses, and 4.0 and 12.7 times the risks compared with fully vaccinated persons without booster doses. When the Omicron variant emerged during December 2021, case IRRs decreased to 4.9 for fully vaccinated persons with booster doses and 2.8 for those without booster doses, relative to October-November 2021. The highest impact of booster doses against infection and death compared with full vaccination without booster doses was recorded among persons aged 50-64 and ≥65 years. Eligible persons should stay up to date with COVID-19 vaccinations.

Covid-19 Rates by Time since Vaccination during Delta Variant Predominance.

BACKGROUND: With the emergence of the delta variant, the United States experienced a rapid increase in Covid-19 cases in 2021. We estimated the risk of breakthrough infection and death by month of vaccination as a proxy for waning immunity during a period of delta variant predominance. METHODS: Covid-19 case and death data from 15 U.S. jurisdictions during January 3 to September 4, 2021 were used to estimate weekly hazard rates among fully vaccinated persons, stratified by age group and vaccine product. Case and death rates during August 1 to September 4, 2021 were presented across four cohorts defined by month of vaccination. Poisson models were used to estimate adjusted rate ratios comparing the earlier cohorts to July rates. RESULTS: During August 1 to September 4, 2021, case rates per 100,000 person-weeks among all vaccine recipients for the January to February, March to April, May to June, and July cohorts were 168.8 (95% confidence interval [CI], 167.5 to 170.1), 123.5 (95% CI, 122.8 to 124.1), 83.6 (95% CI, 82.9 to 84.3), and 63.1 (95% CI, 61.6 to 64.6), respectively. Similar trends were observed by age group for BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccine recipients. Rates for the Ad26.COV2.S (Janssen-Johnson & Johnson) vaccine were higher; however, trends were inconsistent. BNT162b2 vaccine recipients 65 years of age or older had higher death rates among those vaccinated earlier in the year. Protection against death was sustained for the mRNA-1273 vaccine recipients. Across age groups and vaccine types, people who were vaccinated 6 months ago or longer (January-February) were 3.44 (3.36 to 3.53) times more likely to be infected and 1.70 (1.29 to 2.23) times more likely to die from COVID-19 than people vaccinated recently in July 2021. CONCLUSIONS: Our study suggests that protection from SARS-CoV-2 infection among all ages or death among older adults waned with increasing time since vaccination during a period of delta predominance. These results add to the evidence base that supports U.S. booster recommendations, especially for older adults vaccinated with BNT162b2 and recipients of the Ad26.COV2.S vaccine. (Funded by the Centers for Disease Control and Prevention.).

Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status - 13 U.S. Jurisdictions, April 4-July 17, 2021.

COVID-19 vaccine breakthrough infection surveillance helps monitor trends in disease incidence and severe outcomes in fully vaccinated persons, including the impact of the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19. Reported COVID-19 cases, hospitalizations, and deaths occurring among persons aged ≥18 years during April 4-July 17, 2021, were analyzed by vaccination status across 13 U.S. jurisdictions that routinely linked case surveillance and immunization registry data. Averaged weekly, age-standardized incidence rate ratios (IRRs) for cases among persons who were not fully vaccinated compared with those among fully vaccinated persons decreased from 11.1 (95% confidence interval [CI] = 7.8-15.8) to 4.6 (95% CI = 2.5-8.5) between two periods when prevalence of the Delta variant was lower (<50% of sequenced isolates; April 4-June 19) and higher (≥50%; June 20-July 17), and IRRs for hospitalizations and deaths decreased between the same two periods, from 13.3 (95% CI = 11.3-15.6) to 10.4 (95% CI = 8.1-13.3) and from 16.6 (95% CI = 13.5-20.4) to 11.3 (95% CI = 9.1-13.9). Findings were consistent with a potential decline in vaccine protection against confirmed SARS-CoV-2 infection and continued strong protection against COVID-19-associated hospitalization and death. Getting vaccinated protects against severe illness from COVID-19, including the Delta variant, and monitoring COVID-19 incidence by vaccination status might provide early signals of changes in vaccine-related protection that can be confirmed through well-controlled vaccine effectiveness (VE) studies.

Choosing wisely: A prospective study of direct to operating room trauma resuscitation including real-time trauma surgeon after-action review.

INTRODUCTION: Although several centers have direct to operating room (DOR) resuscitation programs, there are no published prospective studies on optimal patient selection, interventions, outcomes, or real-time surgeon assessments. METHODS: Direct to operating room cases for 1 year were prospectively enrolled. Demographics, injury types/severity, triage criteria, interventions, and outcomes including Glasgow Outcome Scale score were collected. Detailed time-to-event and sequence data on initial lifesaving interventions (LSIs) or emergent surgeries were analyzed. A structured real-time attending surgeon assessment tool for each case was collected. Direct to operating room activation criteria were grouped into categories: mechanism, physiology, injury pattern, or emergency medical services (EMS) suspicion. RESULTS: There were 104 DOR cases: male, 84%; penetrating, 80%; and severely injured (Injury Severity Score, >15), 39%. The majority (65%) required at least one LSI (median of 7 minutes from arrival), and 41% underwent immediate emergent surgery (median, 26 minutes). Blunt patients were more severely injured and more likely to undergo LSI (86% vs. 59%) but less likely to require emergent surgery (19% vs. 47%, all p < 0.05). Analysis of DOR criteria categories showed unique patterns in each group for interventions and outcomes, with EMS suspicion associated with the lowest need for DOR. Surgeon assessment tool results found that DOR was indicated in 84% and improved care in 63%, with a small subset identified (9%) where DOR had a negative impact. CONCLUSION: Direct to operating room resuscitation facilitated timely emergent interventions in penetrating truncal trauma and a select subset of critically ill blunt patients. Unique intervention/outcome profiles were identified by activation criteria groups, with little utility among activations for EMS suspicion. Real-time surgeon assessment tool identified high- and low-yield DOR groups. LEVEL OF EVIDENCE: Prospective observational study, level III.

Direct to operating room trauma resuscitation: Optimizing patient selection and time-critical outcomes when minutes count.

BACKGROUND: Although several trauma centers have developed direct to operating room (DOR) trauma resuscitation programs, there is little published data on optimal patient selection, practices, and outcomes. We sought to analyze triage criteria and interventions associated with optimal DOR outcomes and resource utilization. METHODS: Retrospective review of all adult DOR resuscitations for a 6-year period was performed. Triage criteria were analyzed individually and grouped into categories: mechanism, physiology, anatomy/injury, or other. The best univariate and multivariate predictors of requiring lifesaving interventions (LSIs) or emergent surgery (ES) were analyzed. Actual and predicted mortality were compared for all patients and for predefined time-sensitive subgroups. RESULTS: There were 628 DOR patients (5% of all admissions) identified; the majority were male (79%), penetrating mechanism (70%), severely injured (40% ISS >15), and 17% died. Half of patients required LSI and 23% required ES, with significantly greater need for ES and lower need for LSI after penetrating versus blunt injury (p < 0.01). Although injury mechanism criteria triggered most DOR cases and best predicted need for ES, the physiology and anatomy/injury criteria were associated with greater need for LSI and mortality. Observed mortality was significantly lower than predicted mortality with DOR for several key subgroups. Triage schemes for both ES and LSI could be simplified to four to six independent predictors by regression analysis. CONCLUSION: The DOR program identified severely injured trauma patients at increased risk for requiring LSI and/or ES. Different triage variable categories drive the need for ES versus LSI and could be simplified or optimized based on local needs or preferences. Direct to operating room was associated with better than expected survival among specific time-sensitive subgroups. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level IV.

Incidence and recent trends in functional gastrointestinal disorders, active component, U.S. Armed Forces, 2005-2014.

Functional gastrointestinal disorders (FGIDs) are common chronic conditions with an unknown pathophysiology and etiology. FGIDs elevate healthcare costs and cause substantial burden to public health and the military, including diminished readiness, productivity, and quality of life. This retrospective cohort study of active component U.S. military personnel covered a 10-year surveillance period, 2005-2014. The Defense Medical Surveillance System (DMSS) was the data source. Incident cases were identified and rates were calculated and stratified by important covariates. Trends were described over the surveillance period. Incidence rates among deployed personnel were compared to rates in non-deployed personnel, stratified by age and sex. An increasing trend in functional constipation was observed during 2005-2012. Being female, black, in the Army or Air Force, and younger than 20 years of age or 40 years of age or older was associated with higher incidence rates. Deployment-exposed personnel had incidence rates that were 53% higher than those of non-deployed personnel. Elevated rates in personnel younger than 20 years of age and deployed personnel evoke interest concerning readiness and cost implications for the Military Health System. These subgroups should be examined in future studies.

Evaluation of Cervical Spine Clearance by Computed Tomographic Scan Alone in Intoxicated Patients With Blunt Trauma.

IMPORTANCE: Current trauma guidelines dictate that the cervical spine should not be cleared in intoxicated patients, resulting in prolonged immobilization or additional imaging. Modern computed tomography (CT) technology may obviate this and allow for immediate clearance. OBJECTIVE: To analyze cervical spine clearance practices and the utility of CT scans of the cervical spine in intoxicated patients with blunt trauma. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective observational study of 1668 patients with blunt trauma aged 18 years and older who underwent cervical spine CT scans from March 2014 to March 2015 at an American College of Surgeons-verified Level I trauma center. Intoxication was determined by serum alcohol levels and urine drug screens. Physical examination and CT scan findings were evaluated for cervical spine injuries (CSI) and the incidence of missed injuries. MAIN OUTCOMES AND MEASURES: Clinically relevant CSIs requiring cervical stabilization. The hypotheses formed prior to data collection were that cervical CT scans are sensitive and specific enough to diagnose CSIs that require stabilization and that normal CT scans are sufficient to clear CSIs in intoxicated patients. RESULTS: Of 1668 patients, 1103 (66.1%) were male, with a mean (SD) age of 49 (20) years and a mean (SD) Injury Severity Score of 10 (9). Vehicular (734 [44.0%]) and falls (579 [34.7%]) were the most common mechanisms for hospitalization. Intoxication was identified in 632 of 1429 of patients tested (44.2%; 425 [29.7%] by serum alcohol levels and 350 [24.5%] by urine drug screens). Half (316 [50.0%]) were admitted with cervical spine immobilization, and 38 (12%) of these were solely owing to the presence of intoxication. There were 65 abnormal CT scans (10.3%) in the intoxicated group. Among 567 normal CT scans, 4 (0.7%) had central cord syndrome found on initial physical examination, and 1 (0.2%) had a symptomatic unstable ligament injury that was misread as normal on CT scan but was abnormal on magnetic resonance imaging. The 316 patients kept in a cervical collar for intoxication had no missed CSIs but were kept immobilized for a mean (SD) of 12 (19) hours. Computed tomographic scans had an overall negative predictive value of 99.2% for patients with CSIs and a negative predictive value of 99.8% for ruling out CSIs that required immobilization or stabilization. CONCLUSIONS AND RELEVANCE: In this study, alcohol or drug intoxication was common and resulted in significant delays to cervical spine clearance. Computed tomographic scans were highly reliable for identifying all clinically significant CSIs. Spine clearance based on a normal CT scan among intoxicated patients with no gross motor deficits appears to be safe and avoids prolonged and unnecessary immobilization.

A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51.

The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5-/- mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies.

Phylogenetic analysis of eastern equine encephalitis virus isolates from Florida.

Florida has the highest degree of endemicity for eastern equine encephalitis virus (EEEV) of any state in the United States and is the only state with year-round transmission of EEEV. To further understand the viral population dynamics in Florida, the genome sequence of six EEEV isolates from central Florida were determined. These data were used to identify the most polymorphic regions of the EEEV genome from viruses isolated in Florida. The sequence of these polymorphic regions was then determined for 18 additional Florida isolates collected in four geographically distinct regions over a 20-year period. Phylogenetic analyses of these data suggested a rough temporal association of the Florida isolates, but no clustering by region or by source of the isolate. Some clustering of northeastern isolates with Florida isolates was seen, providing support for the hypothesis that Florida serves as a reservoir for the periodic introduction of EEEV into the northeastern United States.

The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics.

The microtubule-associated protein tau, which becomes hyperphosphorylated and pathologically aggregates in a number of these diseases, is extremely sensitive to manipulations of chaperone signaling. For example, Hsp90 inhibitors can reduce the levels of tau in transgenic mouse models of tauopathy. Because of this, we hypothesized that a number of Hsp90 accessory proteins, termed co-chaperones, could also affect tau stability. Perhaps by identifying these co-chaperones, new therapeutics could be designed to specifically target these proteins and facilitate tau clearance. Here, we report that the co-chaperone Cdc37 can regulate aspects of tau pathogenesis. We found that suppression of Cdc37 destabilized tau, leading to its clearance, whereas Cdc37 overexpression preserved tau. Cdc37 was found to co-localize with tau in neuronal cells and to physically interact with tau from human brain. Moreover, Cdc37 levels significantly increased with age. Cdc37 knockdown altered the phosphorylation profile of tau, an effect that was due in part to reduced tau kinase stability, specifically Cdk5 and Akt. Conversely, GSK3ß and Mark2 were unaffected by Cdc37 modulation. Cdc37 overexpression prevented whereas Cdc37 suppression potentiated tau clearance following Hsp90 inhibition. Thus, Cdc37 can regulate tau in two ways: by directly stabilizing it via Hsp90 and by regulating the stability of distinct tau kinases. We propose that changes in the neuronal levels or activity of Cdc37 could dramatically alter the kinome, leading to profound changes in the tau phosphorylation signature, altering its proteotoxicity and stability.

The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau.

Target-based drug discovery for Alzheimer's disease (AD) centered on modulation of the amyloid ß peptide has met with limited success. Therefore, recent efforts have focused on targeting the microtubule-associated protein tau. Tau pathologically accumulates in more than 15 neurodegenerative diseases and is most closely linked with postsymptomatic progression in AD. We endeavored to identify compounds that decrease tau stability rather than prevent its aggregation. An extract from Myrica cerifera (bayberry/southern wax myrtle) potently reduced both endogenous and overexpressed tau protein levels in cells and murine brain slices. The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency, but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract, with potency approaching the best targeted lead therapies. (+)-aR,11S-Myricanol, isolated from M. cerifera and reported here for the first time as the naturally occurring aglycone, was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD.