Outcomes of Extended-Infusion Piperacillin/Tazobactam in Pediatric Patients.

Poster presented at: ID Week 2013, October 2013, San Francisco, California

Delayed evaluation of combat-related penetrating neck trauma

ObjectiveThe approach to penetrating trauma of the head and neck has undergone significant evolution and offers unique challenges during wartime. Military munitions produce complex injury patterns that challenge conventional diagnosis and management. Mass casualties may not allow for routine exploration of all stable cervical blast injuries. The objective of this study was to review the delayed evaluation of combat-related penetrating neck trauma in patients after evacuation to the United States.MethodFrom February 2003 through April 2005, a series of patients with military-associated penetrating cervical trauma were evacuated to a single institution, prospectively entered into a database, and retrospectively reviewed.ResultsSuspected vascular injury from penetrating neck trauma occurred in 63 patients. Injuries were to zone II in 33%, zone III in 33%, and zone I in 11%. The remaining injuries involved multiple zones, including the lower face or posterior neck. Explosive devices wounded 50 patients (79%), 13 (21%) had high-velocity gunshot wounds, and 19 (30%) had associated intracranial or cervical spine injury. Of the 39 patients (62%) who underwent emergent neck exploration in Iraq or Afghanistan, 21 had 24 injuries requiring ligation (18), vein interposition or primary repair (4), polytetrafluoroethylene (PTFE) graft interposition (1), or patch angioplasty (1). Injuries occurred to the carotid, vertebral, or innominate arteries, or the jugular vein. After evacuation to the United States, all patients underwent radiologic evaluation of the head and neck vasculature. Computed tomography angiography was performed in 45 patients (71%), including six zone II injuries without prior exploration. Forty (63%) underwent diagnostic arteriography that detected pseudoaneurysms (5) or occlusions (8) of the carotid and vertebral arteries. No occult venous injuries were noted. Delayed evaluation resulted in the detection of 12 additional occult injuries and one graft thrombosis in 11 patients. Management included observation (5), vein or PTFE graft repair (3), coil embolization (2), or ligation (1).ConclusionsPenetrating multiple fragment injury to the head and neck is common during wartime. Computed tomography angiography is useful in the delayed evaluation of stable patients, but retained fragments produce suboptimal imaging in the zone of injury. Arteriography remains the imaging study of choice to evaluate for cervical vascular trauma, and its use should be liberalized for combat injuries. Stable injuries may not require immediate neck exploration; however, the high prevalence of occult injuries discovered in this review underscores the need for a complete re-evaluation upon return to the United States

Morbid Obesity as a Risk Factor for Hospitalization and Death Due to 2009 Pandemic Influenza A(H1N1) Disease

BACKGROUND: Severe illness due to 2009 pandemic A(H1N1) infection has been reported among persons who are obese or morbidly obese. We assessed whether obesity is a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1), independent of chronic medical conditions considered by the Advisory Committee on Immunization Practices (ACIP) to increase the risk of influenza-related complications. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-cohort design to compare cases of hospitalizations and deaths from 2009 pandemic A(H1N1) influenza occurring between April-July, 2009, with a cohort of the U.S. population estimated from the 2003-2006 National Health and Nutrition Examination Survey (NHANES); pregnant women and children <2 years old were excluded. For hospitalizations, we defined categories of relative weight by body mass index (BMI, kg/m(2)); for deaths, obesity or morbid obesity was recorded on medical charts, and death certificates. Odds ratio (OR) of being in each BMI category was determined; normal weight was the reference category. Overall, 361 hospitalizations and 233 deaths included information to determine BMI category and presence of ACIP-recognized medical conditions. Among >or=20 year olds, hospitalization was associated with being morbidly obese (BMI>or=40) for individuals with ACIP-recognized chronic conditions (OR = 4.9, 95% CI 2.4-9.9) and without ACIP-recognized chronic conditions (OR = 4.7, 95%CI 1.3-17.2). Among 2-19 year olds, hospitalization was associated with being underweight (BMI<or=5(th) percentile) among those with (OR = 12.5, 95%CI 3.4-45.5) and without (OR = 5.5, 95%CI 1.3-22.5) ACIP-recognized chronic conditions. Death was not associated with BMI category among individuals 2-19 years old. Among individuals aged >or=20 years without ACIP-recognized chronic medical conditions death was associated with obesity (OR = 3.1, 95%CI: 1.5-6.6) and morbid obesity (OR = 7.6, 95%CI 2.1-27.9). CONCLUSIONS/SIGNIFICANCE: Our findings support observations that morbid obesity may be associated with hospitalization and possibly death due to 2009 pandemic H1N1 infection. These complications could be prevented by early antiviral therapy and vaccination

Prevalence of 2009 Pandemic Influenza A (H1N1) Virus Antibodies, Tampa Bay Florida — November–December, 2009

BACKGROUND: In 2009, a novel influenza virus (2009 pandemic influenza A (H1N1) virus (pH1N1)) caused significant disease in the United States. Most states, including Florida, experienced a large fall wave of disease from September through November, after which disease activity decreased substantially. We determined the prevalence of antibodies due to the pH1N1 virus in Florida after influenza activity had peaked and estimated the proportion of the population infected with pH1N1 virus during the pandemic. METHODS: During November-December 2009, we collected leftover serum from a blood bank, a pediatric children's hospital and a pediatric outpatient clinic in Tampa Bay Florida. Serum was tested for pH1N1 virus antibodies using the hemagglutination-inhibition (HI) assay. HI titers ≥40 were considered seropositive. We adjusted seroprevalence results to account for previously established HI assay specificity and sensitivity and employed a simple statistical model to estimate the proportion of seropositivity due to pH1N1 virus infection and vaccination. RESULTS: During the study time period, the overall seroprevalence in Tampa Bay, Florida was 25%, increasing to 30% after adjusting for HI assay sensitivity and specificity. We estimated that 5.9% of the population had vaccine-induced seropositivity while 25% had seropositivity secondary to pH1N1 virus infection. The highest cumulative incidence of pH1N1 virus infection was among children aged 5-17 years (53%) and young adults aged 18-24 years (47%), while adults aged ≥50 years had the lowest cumulative incidence (11-13%) of pH1N1 virus infection. CONCLUSIONS: After the peak of the fall wave of the pandemic, an estimated one quarter of the Tampa Bay population had been infected with the pH1N1 virus. Consistent with epidemiologic trends observed during the pandemic, the highest burdens of disease were among school-aged children and young adults

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

Quantitative Proteomic and Interaction Network Analysis of Cisplatin Resistance in HeLa Cells

Cisplatin along with other platinum based drugs are some of the most widely used chemotherapeutic agents. However drug resistance is a major problem for the successful chemotherapeutic treatment of cancer. Current evidence suggests that drug resistance is a multifactorial problem due to changes in the expression levels and activity of a wide number of proteins. A majority of the studies to date have quantified mRNA levels between drug resistant and drug sensitive cell lines. Unfortunately mRNA levels do not always correlate with protein expression levels due to post-transcriptional changes in protein abundance. Therefore global quantitative proteomics screens are needed to identify the protein targets that are differentially expressed in drug resistant cell lines. Here we employ a quantitative proteomics technique using stable isotope labeling with amino acids in cell culture (SILAC) coupled with mass spectrometry to quantify changes in protein levels between cisplatin resistant (HeLa/CDDP) and sensitive HeLa cells in an unbiased fashion. A total of 856 proteins were identified and quantified, with 374 displaying significantly altered expression levels between the cell lines. Expression level data was then integrated with a network of protein-protein interactions, and biological pathways to obtain a systems level view of proteome changes which occur with cisplatin resistance. Several of these proteins have been previously implicated in resistance towards platinum-based and other drugs, while many represent new potential markers or therapeutic targets

Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development

Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10−12). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development

Multiple FadD Acyl-CoA Synthetases Contribute to Differential Fatty Acid Degradation and Virulence in Pseudomonas aeruginosa

A close interconnection between nutrient metabolism and virulence factor expression contributes to the pathophysiology of Pseudomonas aeruginosa as a successful pathogen. P. aeruginosa fatty acid (FA) degradation is complicated with multiple acyl-CoA synthetase homologs (FadDs) expressed in vivo in lung tissue during cystic fibrosis infections. The promoters of two genetically linked P. aeruginosa fadD genes (fadD1 and fadD2) were mapped and northern blot analysis indicated they could exist on two different transcripts. These FadDs contain ATP/AMP signature and FA-binding motifs highly homologous to those of the Escherichia coli FadD. Upon introduction into an E. coli fadD-/fadR- double mutant, both P. aeruginosa fadDs functionally complemented the E. coli fadD-/fadR- mutant, allowing degradation of different chain-length FAs. Chromosomal mutagenesis, growth analysis, induction studies, and determination of kinetic parameters suggested that FadD1 has a substrate preference for long-chain FAs while FadD2 prefers shorter-chain FAs. When compared to the wild type strain, the fadD2 mutant exhibited decreased production of lipase, protease, rhamnolipid and phospholipase, and retardation of both swimming and swarming motilities. Interestingly, fadD1 mutant showed only increased swarming motility. Growth analysis of the fadD mutants showed noticeable deficiencies in utilizing FAs and phosphatidylcholine (major components of lung surfactant) as the sole carbon source. This defect translated into decreased in vivo fitness of P. aeruginosa in a BALB/c mouse lung infection model, supporting the role of lipids as a significant nutrient source for this bacterium in vivo

Why organizational and community diversity matter:Representativeness and the Emergence of Incivility and Organizational Performance

Integrating sociological and psychological perspectives, this research considers the value of organizational ethnic diversity as a function of community diversity. Employee and patient surveys, census data, and performance indexes relevant to 142 hospitals in the United Kingdom suggest that intraorganizational ethnic diversity is associated with reduced civility toward patients. However, the degree to which organizational demography was representative of community demography was positively related to civility experienced by patients and ultimately enhanced organizational performance. These findings underscore the understudied effects of community context and imply that intergroup biases manifested in incivility toward out-group members hinder organizational performance

Initial sequencing and analysis of the human genome

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62798/1/409860a0.pd