Hounsfield Unit-Calculated Bone Mineral Density Loss Following Combat-Related Lower Extremity Amputations.

BACKGROUND: After combat-related lower extremity amputations, patients rapidly lose bone mineral density (BMD). As serial dual x-ray absorptiometry (DXA) scans are rarely performed in this setting, it is difficult to determine the timeline for bone loss and recovery or the role of interventions. However, a strong correlation has been demonstrated between DXA BMD and computed tomography (CT) signal attenuation. We sought to leverage multiple CT scans obtained after trauma to develop a predictive model for BMD after combat-related lower extremity amputations. METHODS: We reviewed amputations performed within the United States military between 2003 and 2016 in patients with multiple CT scans. We collected pertinent clinical information, including amputation level(s), complications, and time to weight-bearing. The primary outcome measure was the development of low BMD, estimated in Hounsfield units (HU) from CT scans with use of a previously validated method. One hundred and twenty-eight patients with 613 femoral neck CT scans were available for analysis. A least absolute shrinkage and selection operator (LASSO) multiple logistic regression analysis was applied to determine the effects of modifiable and non-modifiable variables on BMD. A random-effects model was applied to determine which factors were most predictive of low BMD and to quantify their effects. RESULTS: Both amputated and non-amputated extremities demonstrated substantial BMD loss, which stabilized approximately 3 years after the injury. Loss of BMD followed a logarithmic pattern, stabilizing after 1,000 days. On average, amputated limbs lost approximately 100 HU of BMD after 1,000 days. Other factors identified by the mixed-effects model included nonambulatory status (-33.5 HU), age at injury (-3.4 HU per year), surgical complications delaying weight-bearing (-21.3 HU), transtibial amputation (20.9 HU), and active vitamin-D treatment (-19.7 HU). CONCLUSIONS: Patients with combat-related lower extremity amputations experience an initially rapid decline in BMD in both intact and amputated limbs as a result of both modifiable and non-modifiable influences, including time to walking, amputation level, surgical complications, and age. The paradoxical association of vitamin-D supplementation with lower HU likely reflects this treatment being assigned to patients with low BMD. This model may assist with clinical decision-making prior to performing lower extremity amputation and also may assist providers with postoperative decision-making to optimize management for prophylaxis against osteoporosis. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Cellular microRNAs correlate with clinical parameters in multiple injury patients.

INTRODUCTION: The pathophysiology of the inflammatory response after major trauma is complex, and the magnitude correlates with severity of tissue injury and outcomes. Study of infection-mediated immune pathways has demonstrated that cellular microRNAs may modulate the inflammatory response. The authors hypothesize that the expression of microRNAs would correlate to complicated recoveries in polytrauma patients (PtPs). METHODS: Polytrauma patients enrolled in the prospective observational Tissue and Data Acquisition Protocol with Injury Severity Score of >15 were selected for this study. Polytrauma patients were divided into complicated recoveries and uncomplicated recovery groups. Polytrauma patients' blood samples were obtained at the time of admission (T0). Established biomarkers of systemic inflammation, including cytokines and chemokines, were measured using multiplexed Luminex-based methods, and novel microRNAs were measured in plasma samples using multiplex RNA hybridization. RESULTS: Polytrauma patients (n = 180) had high Injury Severity Score (26 [20-34]) and complicated recovery rate of 33%. MicroRNAs were lower in PtPs at T0 compared with healthy controls, and bivariate analysis demonstrated that variations of microRNAs correlated with age, race, comorbidities, venous thromboembolism, pulmonary complications, complicated recovery, and mortality. Positive correlations were noted between microRNAs and interleukin 10, vascular endothelial growth factor, Acute Physiology and Chronic Health Evaluation, and Sequential Organ Failure Assessment scores. Multivariable Lasso regression analysis of predictors of complicated recovery based on microRNAs, cytokines, and chemokines revealed that miR-21-3p and monocyte chemoattractant protein-1 were predictive of complicated recovery with an area under the curve of 0.78. CONCLUSION: Systemic microRNAs were associated with poor outcomes in PtPs, and results are consistent with previously described trends in critically ill patients. These early biomarkers of inflammation might provide predictive utility in early complicated recovery diagnosis and prognosis. Because of their potential to regulate immune responses, microRNAs may provide therapeutic targets for immunomodulation. LEVEL OF EVIDENCE: Diagnostic Tests/Criteria; Level II.

Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.

OBJECTIVES: To evaluate early activation of latent viruses in polytrauma patients and consider prognostic value of viral micro-RNAs in these patients. DESIGN: This was a subset analysis from a prospectively collected multicenter trauma database. Blood samples were obtained upon admission to the trauma bay (T0), and trauma metrics and recovery data were collected. SETTING: Two civilian Level 1 Trauma Centers and one Military Treatment Facility. PATIENTS: Adult polytrauma patients with Injury Severity Scores greater than or equal to 16 and available T0 plasma samples were included in this study. Patients with ICU admission greater than 14 days, mechanical ventilation greater than 7 days, or mortality within 28 days were considered to have a complicated recovery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Polytrauma patients (n = 180) were identified, and complicated recovery was noted in 33%. Plasma samples from T0 underwent reverse transcriptase-quantitative polymerase chain reaction analysis for Kaposi's sarcoma-associated herpesvirus micro-RNAs (miR-K12_10b and miRK-12-12) and Epstein-Barr virus-associated micro-RNA (miR-BHRF-1), as well as Luminex multiplex array analysis for established mediators of inflammation. Ninety-eight percent of polytrauma patients were found to have detectable Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus micro-RNAs at T0, whereas healthy controls demonstrated 0% and 100% detection rate for Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, respectively. Univariate analysis revealed associations between viral micro-RNAs and polytrauma patients' age, race, and postinjury complications. Multivariate least absolute shrinkage and selection operator analysis of clinical variables and systemic biomarkers at T0 revealed that interleukin-10 was the strongest predictor of all viral micro-RNAs. Multivariate least absolute shrinkage and selection operator analysis of systemic biomarkers as predictors of complicated recovery at T0 demonstrated that miR-BHRF-1, miR-K12-12, monocyte chemoattractant protein-1, and hepatocyte growth factor were independent predictors of complicated recovery with a model complicated recovery prediction area under the curve of 0.81. CONCLUSIONS: Viral micro-RNAs were detected within hours of injury and correlated with poor outcomes in polytrauma patients. Our findings suggest that transcription of viral micro-RNAs occurs early in the response to trauma and may be associated with the biological processes involved in polytrauma-induced complicated recovery.

Patient-Specific Precision Injury Signatures to Optimize Orthopaedic Interventions in Multiply Injured Patients (PRECISE STUDY).

SUMMARY: Optimal timing and procedure selection that define staged treatment strategies can affect outcomes dramatically and remain an area of major debate in the treatment of multiply injured orthopaedic trauma patients. Decisions regarding timing and choice of orthopaedic procedure(s) are currently based on the physiologic condition of the patient, resource availability, and the expected magnitude of the intervention. Surgical decision-making algorithms rarely rely on precision-type data that account for demographics, magnitude of injury, and the physiologic/immunologic response to injury on a patient-specific basis. This study is a multicenter prospective investigation that will work toward developing a precision medicine approach to managing multiply injured patients by incorporating patient-specific indices that quantify (1) mechanical tissue damage volume; (2) cumulative hypoperfusion; (3) immunologic response; and (4) demographics. These indices will formulate a precision injury signature, unique to each patient, which will be explored for correspondence to outcomes and response to surgical interventions. The impact of the timing and magnitude of initial and staged surgical interventions on patient-specific physiologic and immunologic responses will be evaluated and described. The primary goal of the study will be the development of data-driven models that will inform clinical decision-making tools that can be used to predict outcomes and guide intervention decisions.

Tranexamic acid administration and pulmonary embolism in combat casualties with orthopaedic injuries.

In combat casualty care, tranexamic acid (TXA) is administered as part of initial resuscitation effort; however, conflicting data exist as to whether TXA contributes to increased risk of venous thromboembolism (VTE). The purpose of this study is to determine what factors increase risk of pulmonary embolism after combat-related orthopaedic trauma and whether administration of TXA is an independent risk factor for major thromboembolic events. SETTING: United States Military Trauma Centers. PATIENTS: Combat casualties with orthopaedic injuries treated at any US military trauma center for traumatic injuries sustained from January 2011 through December 2015. In total, 493 patients were identified. INTERVENTION: None. MAIN OUTCOME MEASURES: Occurrence of major thromboembolic events, defined as segmental or greater pulmonary embolism or thromboembolism-associated pulseless electrical activity. RESULTS: Regression analysis revealed TXA administration, traumatic amputation, acute kidney failure, and hypertension to be associated with the development of a major thromboembolic event for all models. Injury characteristics independently associated with risk of major VTE were Injury Severity Score 23 or greater, traumatic amputation, and vertebral fracture. The best performing model utilized had an area under curve  = 0.84, a sensitivity=0.72, and a specificity=0.84. CONCLUSIONS: TXA is an independent risk factor for major VTE after combat-related Orthopaedic injury. Injury factors including severe trauma, major extremity amputation, and vertebral fracture should prompt suspicion for increased risk of major thromboembolic events and increased threshold for TXA use if no major hemorrhage is present. LEVEL OF EVIDENCE: III, Prognostic Study.

A multi-registry analysis of military and civilian penetrating cervical carotid artery injury.

INTRODUCTION: Penetrating cervical carotid artery injury is an uncommon but high-stake scenario associated with stroke and death. The objective of this study was to characterize and compare penetrating carotid injury in the military and civilian setting, as well as provide considerations for management. METHODS: Cohorts with penetrating cervical carotid artery injury from the Department of Defense Trauma Registry (2002-2015) and the American Association for the Surgery of Trauma Prospective Observation Vascular Injury Treatment Registry (2012-2018) were analyzed. A least absolute shrinkage and selection operator multivariate analysis using random forest-based imputation was performed to identify risk factors affecting stroke and mortality. RESULTS: There were a total of 157 patients included in the study, of which 56 (35.7%) were military and 101 (64.3%) were civilian. The military cohort was more likely to have been managed with open surgery (87.5% vs. 44.6%, p < 0.001) and to have had any procedure to restore or maintain flow to the brain (71.4% vs. 35.6%, p < 0.001), while the civilian cohort was more likely to undergo nonoperative management (45.5% vs. 12.5%, p < 0.001). Stroke rate was higher within the military cohort (41.1% vs. 13.9%, p < 0.001); however, mortality did not differ between the groups (12.5% vs. 17.8%, p = 0.52). On multivariate analysis, predictors for stroke were presence of a battle injury (log odds, 2.1; p < 0.001) and internal or common carotid artery ligation (log odds 1.5, p = 0.009). For mortality outcome, protective factors included a high Glasgow Coma Scale on admission (log odds, -0.21 per point; p < 0.001). Increased admission Injury Severity Score was a predictor of mortality (log odds, 0.05 per point; p = 0.005). CONCLUSION: The stroke rate was higher in the military cohort, possibly reflecting complexity of injury; however, there was no difference in mortality between military and civilian patients. For significant injuries, concerted efforts should be made at carotid reconstruction to reduce the occurrence of stroke. LEVEL OF EVIDENCE: Retrospective cohort analysis, level III.

The Enhanced Recovery After Surgery (ERAS) Elements that Most Greatly Impact Length of Stay and Readmission.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been shown to decrease length of stay (LOS) and improve patient outcomes in a wide variety of surgical fields; however, barriers exist preventing the implementation of all elements. We hypothesize that a subset of ERAS elements are most influential on LOS and readmission following colorectal surgery. STUDY DESIGN: A retrospective review of 840 patients was performed and their compliance with 24 ERAS components evaluated. Two independent machine-learning statistical algorithms were employed to determine which subset of ERAS elements was most impactful on LOS <3 days and hospital readmission. RESULTS: Increasing compliance with ERAS elements had an inverse linear relationship with LOS. Open (vs minimally invasive) surgery was associated with increased LOS. Early mobilization and multimodal pain management are the elements most protective against increased LOS. Readmissions increase with the number of morphine milligram equivalents (MME)/day. The subset of patients who underwent minimally invasive procedures, had multimodal pain control, and less than 16 MME per day were least likely (23%) to have >3-day LOS. Those patients who underwent an open procedure with less than 15 ERAS elements completed were most likely (84%) to have >3-day LOS. CONCLUSION: While increasing compliance with ERAS protocols and minimally invasive procedures decrease LOS and readmission overall, a subset of components-multimodal pain control, limited opioid use, and early mobilization-was most associated with decreased LOS and readmission. This study provides guidance on which ERAS elements should be emphasized.

Evolution of Advanced Chronic Lymphoid Leukemia Unveiled by Single-Cell Transcriptomics: A Case Report.

Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.

Decreasing Opioid Use Postpartum: A Quality Improvement Initiative.

OBJECTIVE: To estimate the effects of an inpatient initiative to decrease opioid use among women admitted to labor and delivery. METHODS: We created a multimodal pain power plan with standard therapeutic postpartum activity goals rather than pain goals, tiered order sets with scheduled administration of nonsteroidal antiinflammatory drugs (NSAIDs), and embedded changes into the electronic health record. Before the multimodal pain power plan launch, pain was assessed on a 10-point scale; women received NSAIDs for pain levels of 3 or less and opioids for pain levels higher than 3. For this analysis, we included women who delivered at 5 hospitals in the 10 months before and 12 months after the multimodal pain power plan launch. Women with prior substance use disorder or complicated deliveries were excluded and we stratified analyses into women who delivered vaginally compared with by cesarean. Opioid use was converted to morphine milligram equivalent (MME). Women rated pain control in 24-hour blocks using individually ascertained cutoffs. A multivariable regression analysis was performed, and adjusted odds ratios are reported. RESULTS: We compared the 6,892 women who delivered 10 months before the pain power plan launch to the 7,527 who delivered in the 12 months after the launch. The mean cohort age was 29.6±6.0 years; the majority (75%) were white. Risk of opioid use decreased by 26% among women who delivered vaginally (risk ratio [RR] 0.74; 95% CI [0.68, 0.81]) and 18% among women who delivered by cesarean (RR 0.82; 95% CI [0.72, 0.92]). Among women who received opioids, mean MME use decreased 21% (RR 0.79; 95% CI [0.70, 0.88]) and 54% (RR 0.46; 95% CI [0.35, 0.61]) in the vaginal and cesarean delivery groups, respectively. Fewer women reported acceptable pain levels, with decreases of 82-69% (P<.01) and 82-74% (P<.01) in the vaginal and cesarean delivery groups, respectively. Within the postlaunch cesarean delivery group, women also reported that they were less likely to have their pain well controlled on the Hospital Consumer Assessment of Healthcare Providers and Systems questionnaires (82% vs 62%, P <.01). CONCLUSION: A standardized multimodal pain power plan reduced opioid use among a large cohort of women admitted to labor and delivery in Central Texas. Despite meeting functional goals, some women reported increased pain during their hospital stay.

Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study.

OBJECTIVE: To determine whether a single treatment of botulinum toxin A in the forehead (glabellar) region can improve symptoms of depression in patients with major depressive disorder (MDD), as defined by DSM-IV criteria. METHOD: Thirty participants were randomly assigned to receive either placebo or botulinum toxin A (BTA; onabotulinumtoxinA) injections in the forehead. Female participants received 29 units; male participants received 39 units. At week 12, the groups were crossed over. Participants were evaluated at weeks 0, 3, 6, 12, 15, 18, and 24 for improvement in MDD symptoms using the Patient Health Care Questionnaire-9, Beck Depression Inventory (BDI), and 21-Item Hamilton Depression Rating Scale (HDRS-21) objective measurement scales. The primary outcome was the rate of HDRS-21 response, defined as ≥ 50% score reduction from baseline. The study occurred from July 2011 to November 2012. RESULTS: Patients who received BTA at week 0 (BTA-first group) and at week 12 (BTA-second group) had a statistically significant reduction in MDD symptoms as compared to placebo. Improvement in MDD continued over 24 weeks in the group that received BTA first even though the cosmetic effects of BTA wore off at 12 to 16 weeks. HDRS-21 response rates were 55% (6/11) in the BTA-first group, 24% (4/17) in the BTA-second group, and 0% (0/19) in the placebo group (P < .0001). HDRS-21 remission rates (score ≤ 7) were 18% (2/11), 18% (3/17), and 0% (0/19), respectively (P = .057). HDRS-21 scores dropped -46% and -35% in the BTA-first and -second groups versus -2% in the placebo group (P < .0001). The BDI response rate (≥ 50% reduction from baseline) was 45% (5/11) in the BTA-first group, 33% (6/18) in the BTA-second group, and 5% (1/19) in the placebo group (P = .0067). BDI remission rates (score ≤ 9) were 27% (3/11), 33% (6/18), and 5% (1/19), respectively (P = .09). BDI scores dropped -42% and -35% in the BTA-first and -second groups versus -15% in the placebo group (P < .0001). CONCLUSIONS: Botulinum toxin A injection in the glabellar region was associated with significant improvement in depressive symptoms and may be a safe and sustainable intervention in the treatment of MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01392963.

A retrospective review of swallow dysfunction in patients with severe traumatic brain injury.

In the acute-care setting, it is difficult for clinicians to determine which patients with severe traumatic brain injury will have long-term oropharyngeal dysphagia (>6 weeks) and which patients will begin oral nutrition quickly. Patients frequently remain in the acute-care setting while physicians determine whether to place a percutaneous endoscopic gastrostomy (PEG) tube. To improve the acute-care clinician's ability to predict long-term oropharyngeal dysphagia and subsequent need for PEG tube placement in patients with severe traumatic brain injury [Glascow Coma Scale (GCS) ≤ 8), a novel prediction model was created utilizing clinical information and acute-care swallowing evaluation findings. Five years of retrospective data were obtained from trauma patients at a Level 1 trauma hospital. Of the 375 patients who survived their hospitalization with a GCS ≤ 8, a total of 269 patients received Ranchos Los Amigos (RLA) scores. Of those patients who were scored for RLA, 219 patients underwent swallowing evaluation. Ninety-six of the 219 patients were discharged from the hospital with a feeding tube, and 123 patients were discharged without one. Logistic regression models examined the association between clinical and patient characteristics and whether a patient with severe traumatic brain injury exhibited long-term oropharyngeal dysphagia. Multivariable logistic regression analysis revealed that increased age, low RLA score, tracheostomy tube placement, and aphonia observed on the initial swallowing evaluation significantly increased the odds of being discharged from the acute-care hospital with a feeding tube. The resultant model could be used clinically to guide decision making and to counsel patients and families.

Turning the analysis of obesity-mortality associations upside down: modeling years of life lost through conditional distributions.

OBJECTIVE: We demonstrate the utility of parametric survival analysis. The analysis of longevity as a function of risk factors such as body mass index (BMI; kg/m(2) ), activity levels, and dietary factors is a mainstay of obesity research. Modeling survival through hazard functions, relative risks, or odds of dying with methods such as Cox proportional hazards or logistic regression are the most common approaches and have many advantages. However, they also have disadvantages in terms of the ease of interpretability, especially for non-statisticians; the need for additional data to convert parameter estimates to estimates of years of life lost (YLL); debates about the appropriate time scale in the model; and an inability to estimate median survival time when the censoring rate is too high. DESIGN AND METHODS: We will conduct parametric survival analyses with multiple distributions, including distributions that are known to be poor fits (Gaussian), as well as a newly discovered "Compressed Gaussian"'' distribution. RESULTS: Parametric survival analysis models were able to accurately estimate median survival times in a population-based data set of 15,703 individuals, even for distributions that were not good fits and the censoring rate was high, due to the central limit theorem. CONCLUSIONS: Parametric survival models are able to provide more direct answers, and in our analysis of an obesity-related data set, gave consistent YLL estimates regardless of the distribution used. We recommend increased consideration of parametric survival models in chronic disease and risk factor epidemiology.

A novel generalized normal distribution for human longevity and other negatively skewed data.

Negatively skewed data arise occasionally in statistical practice; perhaps the most familiar example is the distribution of human longevity. Although other generalizations of the normal distribution exist, we demonstrate a new alternative that apparently fits human longevity data better. We propose an alternative approach of a normal distribution whose scale parameter is conditioned on attained age. This approach is consistent with previous findings that longevity conditioned on survival to the modal age behaves like a normal distribution. We derive such a distribution and demonstrate its accuracy in modeling human longevity data from life tables. The new distribution is characterized by 1. An intuitively straightforward genesis; 2. Closed forms for the pdf, cdf, mode, quantile, and hazard functions; and 3. Accessibility to non-statisticians, based on its close relationship to the normal distribution.

A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge.

It has been suggested that poor immunogenicity may explain the lack of vaccine efficacy in preventing or controlling HIV infection in the Step trial. To investigate this issue we vaccinated eight Indian rhesus macaques with a trivalent replication-incompetent adenovirus serotype 5 vaccine expressing SIV Gag, Pol, and Nef using a regimen similar to that employed in the Step trial. We detected broad vaccine-induced CD8(+) (2-7 pool-specific responses) and CD4(+) (5-19 pool-specific responses) T-cell responses in IFN-γ ELISPOT assays at one week post-boost using fresh PBMC. However, using cryopreserved cells at one and four weeks post-boost we observed a reduction in both the number and magnitude of most vaccine-induced responses. This demonstrates that the time points and conditions chosen to perform immune assays may influence the observed breadth and frequency of vaccine-induced T-cell responses. To evaluate protective efficacy, we challenged the immunized macaques, along with naïve controls, with repeated, limiting doses of the heterologous swarm isolate SIVsmE660. Vaccination did not significantly affect acquisition or control of virus replication in vaccinees compared to naïve controls. Post-infection we observed an average of only two anamnestic CD8(+) T-cell responses per animal, which may not have been sufficiently broad to control heterologous virus replication. While the trivalent vaccine regimen induced relatively broad T-cell responses in rhesus macaques, it failed to protect against infection or control viral replication. Our results are consistent with those observed in the Step trial and indicate that SIV immunization and challenge studies in macaque models of HIV infection can be informative in assessing pre-clinical HIV vaccines.

Is socioeconomic status of the rearing environment causally related to obesity in the offspring?

We attempt to elucidate whether there might be a causal connection between the socioeconomic status (SES) of the rearing environment and obesity in the offspring using data from two large-scale adoption studies: (1) The Copenhagen Adoption Study of Obesity (CASO), and (2) The Survey of Holt Adoptees and Their Families (HOLT). In CASO, the SES of both biological and adoptive parents was known, but all children were adopted. In HOLT, only the SES of the rearing parents was known, but the children could be either biological or adopted. After controlling for relevant covariates (e.g., adoptee age at measurement, adoptee age at transfer, adoptee sex) the raw (unstandardized) regression coefficients for adoptive and biological paternal SES on adoptee body mass index (BMI: kg/m(2)) in CASO were -.22 and -.23, respectively, both statistically significant (p = 0.01). Controlling for parental BMI (both adoptive and biological) reduced the coefficient for biological paternal SES by 44% (p = .034) and the coefficient for adoptive paternal SES by 1%. For HOLT, the regression coefficients for rearing parent SES were -.42 and -.25 for biological and adoptive children, respectively. Controlling for the average BMI of the rearing father and mother (i.e., mid-parental BMI) reduced the SES coefficient by 47% in their biological offspring (p≤.0001), and by 12% in their adoptive offspring (p = .09). Thus, despite the differing structures of the two adoption studies, both suggest that shared genetic diathesis and direct environmental transmission contribute about equally to the association between rearing SES and offspring BMI.

The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge.

It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5(TFP) and TRIM5(CypA) alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.

Can rodent longevity studies be both short and powerful?

Many rodent experiments have assessed effects of diets, drugs, genes, and other factors on life span. A challenge with such experiments is their long duration, typically over 3.5 years given rodent life spans, thus requiring significant time costs until answers are obtained. We collected longevity data from 15 rodent studies and artificially truncated them at 2 years to assess the extent to which one will obtain the same answer regarding mortality effects. When truncated, the point estimates were not significantly different in any study, implying that in most cases, truncated studies yield similar estimates. The median ratio of variances of coefficients for truncated to full-length studies was 3.4, implying that truncated studies with roughly 3.4 times as many rodents will often have equivalent or greater power. Cost calculations suggest that shorter studies will be more expensive but perhaps not so much to not be worth the reduced time.

Drugs associated with more suicidal ideations are also associated with more suicide attempts.

CONTEXT: In randomized controlled trials (RCTs), some drugs, including CB1 antagonists for obesity treatment, have been shown to cause increased suicidal ideation. A key question is whether drugs that increase or are associated with increased suicidal ideations are also associated with suicidal behavior, or whether drug-induced suicidal ideations are unlinked epiphenomena that do not presage the more troubling and potentially irrevocable outcome of suicidal behavior. This is difficult to determine in RCTs because of the rarity of suicidal attempts and completions. OBJECTIVE: To determine whether drugs associated with more suicidal ideations are also associated with more suicide attempts in large spontaneous adverse event (AE) report databases. METHODOLOGY: Generalized linear models with negative binomial distribution were fitted to Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (AERS) data from 2004 to 2008. A total of 1,404,470 AEs from 832 drugs were analyzed as a function of reports of suicidal ideations; other non-suicidal adverse reactions; drug class; proportion of reports from males; and average age of subject for which AE was filed. Drug was treated as the unit of analysis, thus the statistical models effectively had 832 observations. MAIN OUTCOME MEASURES: Reported suicide attempts and completed suicides per drug. RESULTS: 832 drugs, ranging from abacavir to zopiclone, were evaluated. The 832 drugs, as primary suspect drugs in a given adverse event, accounted for over 99.9% of recorded AERS. Suicidal ideations had a significant positive association with suicide attempts (p<.0001) and had an approximately 131-fold stronger magnitude of association than non-suicidal AERs, after adjusting for drug class, gender, and age. CONCLUSIONS: In AE reports, drugs that are associated with increased suicidal ideations are also associated with increased suicidal attempts or completions. This association suggests that drug-induced suicidal ideations observed in RCTs plausibly represent harbingers that presage the more serious suicide attempts and completions and should be a cause for concern.