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1.  Intra-abdominal injury following blunt trauma becomes clinically apparent within 9 hours 
The diagnosis of blunt abdominal trauma can be challenging and resource intensive. Observation with serial clinical assessments plays a major role in the evaluation of these patients, but the time required for intra-abdominal injury to become clinically apparent is unknown. The purpose of this study was to determine the amount of time required for an intra-abdominal injury to become clinically apparent after blunt abdominal trauma via physical examination or commonly followed clinical values.
A retrospective review of patients who sustained blunt trauma resulting in intra-abdominal injury between June 2010 and June 2012 at a Level 1 academic trauma center was performed. Patient demographics, injuries, and the amount of time from emergency department admission to sign or symptom development and subsequent diagnosis were recorded. All diagnoses were made by computed tomography or at the time of surgery. Patient transfers from other hospitals were excluded.
Of 3,574 blunt trauma patients admitted to the hospital, 285 (8%) experienced intra-abdominal injuries. The mean (SD) age was 36(17) years, the majority were male (194 patients, 68%) and the mean (SD) Injury Severity Score (ISS) was 21 (14). The mean (SD) time from admission to diagnosis via computed tomography or surgery was 74 (55) minutes. Eighty patients (28%) required either surgery (78 patients, 17%) or radiographic embolization (2 patients, 0.7%) for their injury. All patients who required intervention demonstrated a sign or symptom of their intra-abdominal injury within 60 minutes of arrival, although two patients were intervened upon in a delayed fashion. All patients with a blunt intra-abdominal injury manifested a clinical sign or symptom of their intra-abdominal injury, resulting in their diagnosis within 8 hours 25 minutes of arrival to the hospital.
All diagnosed intra-abdominal injuries from blunt trauma manifested clinical signs or symptoms that could prompt imaging or intervention, leading to their diagnosis within 8 hours 25 minutes of arrival to the hospital. All patients who required an intervention for their injury manifested a sign or symptom of their injury within 60 minutes of arrival.
Level of Evidence
Therapeutic study, level IV Epidemiologic study, level III.
PMCID: PMC4091734  PMID: 24662866
Blunt trauma; intra-abdominal injury; 8 hours; 60 minutes; clinically apparent
2.  Clinical Presentation and Self-Reported Patterns of Pain and Function in Patients with Plantar Heel Pain 
Plantar heel pain is a common disorder of the foot for which patients seek medical treatment. The purpose of this study is to explore the relationship between duration of symptoms in plantar fasciitis patients and demographic factors, the intensity and location of pain, extent of previous treatment and self reported pain and function.
The charts of patients presenting with plantar heel pain between June 2008 and October 2010 were reviewed retrospectively and 182 patients with a primary diagnosis of plantar fasciitis were identified. Patients with symptoms less than 6 months were identified as acute and patients with symptoms greater than or equal to six months were defined as having chronic symptoms. Comparisons based on duration of symptoms were performed for age, gender, BMI, comorbidities, pain location and intensity, and a functional score measured by the Foot and Ankle Ability Measure (FAAM).
The two groups were similar in age, BMI, gender, and comorbidities. Pain severity, as measured by a VAS, was not statistically significant between the two groups (6.6 and 6.2). The acute and chronic groups of patients reported similar levels of function on both the activity of daily living (62 and 65) and sports (47 and 45) subscales of the FAAM. Patients in the chronic group were more likely to have seen more providers and tried more treatment options for this condition.
As plantar fasciitis symptoms extend beyond 6 months, patients do not experience increasing pain intensity or functional limitation. No specific risk factors have been identified to indicate a risk of developing chronic symptoms.
PMCID: PMC4083061  PMID: 22995253
plantar fasciitis; heel pain; functional limitation
3.  Enantioselective synthesis of hindered cyclic dialkyl ethers via catalytic oxa-Michael/Michael desymmetrization† 
An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and α,β-unsaturated aldehydes provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the concomitant formation of four contiguous stereocenters in a single step. The highly functionalized bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection and serve as valuable precursors for further manipulation.
PMCID: PMC3964814  PMID: 24683449
4.  Implementation and evaluation of the 5As framework of obesity management in primary care: design of the 5As Team (5AsT) randomized control trial 
Obesity is a pressing public health concern, which frequently presents in primary care. With the explosive obesity epidemic, there is an urgent need to maximize effective management in primary care. The 5As of Obesity Management™ (5As) are a collection of knowledge tools developed by the Canadian Obesity Network. Low rates of obesity management visits in primary care suggest provider behaviour may be an important variable. The goal of the present study is to increase frequency and quality of obesity management in primary care using the 5As Team (5AsT) intervention to change provider behaviour.
The 5AsT trial is a theoretically informed, pragmatic randomized controlled trial with mixed methods evaluation. Clinic-based multidisciplinary teams (RN/NP, mental health, dietitians) will be randomized to control or the 5AsT intervention group, to participate in biweekly learning collaborative sessions supported by internal and external practice facilitation. The learning collaborative content addresses provider-identified barriers to effective obesity management in primary care. Evidence-based shared decision making tools will be co-developed and iteratively tested by practitioners. Evaluation will be informed by the RE-AIM framework. The primary outcome measure, to which participants are blinded, is number of weight management visits/full-time equivalent (FTE) position. Patient-level outcomes will also be assessed, through a longitudinal cohort study of patients from randomized practices. Patient outcomes include clinical (e.g., body mass index [BMI], blood pressure), health-related quality of life (SF-12, EQ5D), and satisfaction with care. Qualitative data collected from providers and patients will be evaluated using thematic analysis to understand the context, implementation and effectiveness of the 5AsT program.
The 5AsT trial will provide a wide range of insights into current practices, knowledge gaps and barriers that limit obesity management in primary practice. The use of existing resources, collaborative design, practice facilitation, and integrated feedback loops cultivate an applicable, adaptable and sustainable approach to increasing the quantity and quality of weight management visits in primary care.
Trial registration
PMCID: PMC4076432  PMID: 24947045
Primary healthcare; Obesity; Randomized control trial; Evaluation studies; Family medicine; Practice facilitation
5.  Resistance to tenofovir-based regimens during treatment failure of subtype C HIV-1 in South Africa 
Antiviral therapy  2013;18(7):915-920.
Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principle TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV.
Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virologic failure (defined as an HIV RNA >1000 c/mL) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors.
Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major NNRTI mutations in 24 (57%), and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA log10 3.3 versus 4.2 c/mL) and prior stavudine exposure. An additional 5 patients had minority K65R populations identified by allele-specific PCR.
These data suggest that the K65R prevalence at virologic failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype C infected patients with up to 6 months of failure of a TDF-containing regimen.
PMCID: PMC4046272  PMID: 23751421
6.  Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury 
Neurobiology of disease  2013;54:329-338.
Oxidative stress is generated in several peripheral nerve injury models. In response to oxidative stress, the transcription factor Nrf2 is activated to induce expression of antioxidant responsive element (ARE) genes. The role of Nrf2 in peripheral nerve injury has not been studied to date. In this study, we used a sciatic nerve crush model to examine how deletion of Nrf2 affects peripheral nerve degeneration and regeneration. Our study demonstrated that functional recovery in the Nrf2-/- mice were impaired compared to the wild type mice after sciatic nerve crush. Larger myelin debris were present in the distal nerve stump of the Nrf2-/- mice than in the wild type mice. The presence of larger myelin debris in the Nrf2-/- mice coincides with less macrophages accumulation in the distal nerve stump. Less accumulation of macrophages may have contributed to slower clearance of myelin and thus resulted in the presence of larger myelin debris. Meanwhile, axonal regeneration is comparatively lower in the Nrf2-/- mice than in the wild type mice. Even after 3 months post the injury, more thinly myelinated axon fibers were present in the Nrf2-/- mice than in the wild type mice. Taken collectively, these data support the concept of therapeutic intervention with Nrf2 activators following nerve injury.
PMCID: PMC3628945  PMID: 23328769
Nrf2; sciatic nerve crush; myelin clearance; axonal regeneration; remyelination
7.  Kinetics and Kinematics after the Bridle Procedure for Treatment of Traumatic Foot Drop 
The Bridle procedure restores active ankle dorsiflexion through a tri-tendon anastamosis of the tibialis posterior, transferred to the dorsum of the foot, with the peroneus longus and tibialis anterior tendon. Inter-segmental foot motion after the Bridle procedure has not been measured. The purpose of this study is to report kinetic and kinematic variables during walking and heel rise in patients after the Bridle procedure.
18 Bridle and 10 control participants were studied. Walking and heel rise kinetic and kinematic variables were collected and compared using an ANOVA.
During walking the Bridle group, compared with controls, had reduced ankle power at push off [2.3 (SD 0.7) W/kg, 3.4 (SD 0.6) W/kg, respectively, P<.01], less hallux extension during swing [−13 (SD 7)°, 15 (SD6)°, respectively, P<.01] and slightly less ankle dorsiflexion during swing [6 (SD4)°, 9 (SD 2)°, respectively, P=.03]. During heel rise the Bridle group had 4 (SD 6)° of forefoot on hindfoot dorsiflexion compared to 8 (SD 3)° of plantarflexion in the controls (P<.01).
This study provides evidence that the Bridle procedure restores the majority of dorsiflexion motion during swing. However, plantarflexor function during push off and hallux extension during swing were reduced during walking in the Bridle group. Abnormal mid-tarsal joint motion, forefoot on hindfoot dorsiflexion instead of plantarflexion, was identified in the Bridle group during the more challenging heel rise task. Intervention after the Bridle procedure must maximize ankle plantarflexor function and midfoot motion should be examined during challenging tasks.
PMCID: PMC3934630  PMID: 23684087
8.  Asymmetric Synthesis of anti-β-Amino-α-Hydroxy Esters via Dynamic Kinetic Resolution of β-Amino-α-Keto Esters 
Organic letters  2013;15(10):2446-2449.
A method for the asymmetric synthesis of enantioenriched anti-α-hydroxy-β-amino acid derivatives by enantioconvergent reduction of the corresponding racemic α-keto esters is presented. The requisite α-keto esters are prepared via Mannich addition of ethyl diazoacetate to imines followed by oxidation of the diazo group with Oxone®. Implementation of a recently-developed dynamic kinetic resolution of β-substituted-α-keto esters via Ru(II)-catalyzed asymmetric transfer hydrogenation provides the title motif in routinely high diastereo- and enantioselectivity.
PMCID: PMC3766400  PMID: 23631467
9.  Comparing the EQ-5D 3L and 5L: measurement properties and association with chronic conditions and multimorbidity in the general population 
Studies comparing the measurement properties of EQ-5D 3L (3L) and EQ-5D 5L (5L) are limited to specific patient populations with small sample sizes. Using a general population sample, we compared 3L and 5L in terms of their measurement properties and association with number of chronic conditions, including multimorbidity – the concurrent occurrence of two or more chronic conditions.
Data were available from two consecutive cycles of a cross-sectional telephone interview survey using 3L (2010 cycle) and 5L (2012 cycle), in the general population of adults (age ≥ 18 years) in Alberta, Canada. Measurement properties were compared by determining their feasibility, ceiling effect, and discriminatory power (Shannon indices) for 3L and 5L. Linear regression models were fitted to test the associations between multimorbidity and EQ-5D index score.
Data were available for 4946 (2010) and 4752 (2012) survey respondents with information on HRQL. Compared to 3L, 5L showed lower ceiling effect (32.3% versus 42.1%), higher absolute discriminatory power (Shannon index, mean 0.79 versus 0.52) and higher relative discriminatory power (Shannon Evenness index, mean 0.09 versus 0.06 for 3L). Despite these differences, similar relationships of lower HRQL with greater multimorbidity were observed for the 3L (ß = −0.13, 95% CI −0.15; −0.11) and 5L (ß = −0.12, 95% CI −0.13; −0.11).
Using a general population sample, the EQ-5D 5L showed better measurement properties than the EQ-5D 3L. Nonetheless, clinically important differences in HRQL associated with multimorbidity were similar in magnitude using both versions of EQ-5D.
PMCID: PMC4030014  PMID: 24885017
EQ-5D; Quality of life; Multimorbidity; Health related quality of life; Chronic diseases; Shannon index; Canada
10.  Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study 
Leukemia & lymphoma  2008;49(11):2081-2090.
The proliferation index in mantle cell lymphoma (MCL) has not been validated in the context of aggressive therapy regimens in the rituximab era. We assessed Ki67 and PIM1 (a cell cycle-related gene upregulated in blastoid MCL) expression by immunohistochemistry in a phase II study Cancer and Leukemia Group B 59909 of aggressive chemotherapy and rituximab followed by autologous stem cell transplantation plus rituximab in untreated MCL patients < 70 years of age. As a continuous variable or using a cutoff of 35%, higher image analysis (IA Ki67, n = 52) was associated with shorter progression free survival (PFS) (P ≤ 0.030) and event free survival (EFS) (P ≤ 0.017). PIM1 expression (n = 50) was associated with PFS (P = 0.033) and EFS (P = 0.043). Bivariate Cox models showed IA Ki67 and PIM1 were independent of clinical factors. High Ki67 (> 35%) is an important independent prognostic marker in aggressively treated MCL in the rituximab era. PIM1 expression predicts poor outcome and, given its potential role as a therapeutic target, deserves further study.
PMCID: PMC4011712  PMID: 19021050
Mantle cell lymphoma; prognosis; Ki67; PIM1; clinical trial; transplant
11.  Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway 
Bioorganic & medicinal chemistry  2013;21(9):2618-2622.
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in-vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H2O2 induced cell death.
PMCID: PMC3670146  PMID: 23507152
Nuclear factor E2-related factor 2; antioxidant response element; sage; neuroprotection; phenolic diterpenes; carnosic acid; carnosol
12.  Transthyretin as both Sensor and Scavenger of Aβ Oligomers 
Biochemistry  2013;52(17):2849-2861.
Transthyretin (TTR) is a homotetrameric transport protein, assembled from monomers that each contains two four-stranded β-sheets and a short α-helix and loop. In the tetramer, the ‘inner’ β-sheet forms a hydrophobic pocket while the helix and loop are solvent-exposed. Beta-amyloid (Aβ) aggregates bind to TTR, and the binding is significantly reduced in mutants L82A (on the loop) and L110A (on the inner β-sheet). Protection against Aβ toxicity was demonstrated for wild-type TTR but not L82A or L110A, providing a direct link between TTR-Aβ binding, and TTR-mediated cytoprotection. Protection is afforded at substoichiometric (1:100) TTR:Aβ molar ratios, and binding of Aβ to TTR is highest for partially aggregated materials and decreased for freshly-prepared or heavily aggregated Aβ, suggesting that TTR binds selectively to soluble toxic Aβ aggregates. A novel technique, nanoparticle tracking, is used to show that TTR arrests Aβ aggregation by both preventing formation of new aggregates and inhibiting growth of existing aggregates. TTR tetramers are normally quite stable; tetrameric structure is necessary for the protein’s transport functions, and mutations that decrease tetramer stability have been linked to TTR amyloid diseases. However, TTR monomers bind more Aβ than do tetramers, presumably because the hydrophobic ‘inner’ sheet is solvent-exposed upon tetramer disassembly. Wild-type and L110A tetramers, but not L82A, were destabilized when co-incubated with Aβ, suggesting that Aβ binding to L82 triggers tetramer dissociation. Taken together, these results suggest a novel mechanism of action for TTR: the EF helix/loop ‘senses’ the presence of soluble toxic Aβ oligomers, triggering destabilization of TTR tetramers and exposure of the hydrophobic inner sheet, which then ‘scavenges’ these toxic oligomers and prevents them from causing cell death
PMCID: PMC3658121  PMID: 23570378
14.  Inflammation and the Host Response to Injury, a Large-Scale Collaborative Project: Patient-Oriented Research Core—Standard Operating Procedures for Clinical Care VII—Guidelines for Antibiotic Administration in Severely Injured Patients 
The Journal of trauma  2008;65(6):1511-1519.
When the clinical decision to treat a critically ill patient with antibiotics has been made, one must attempt to identify the site of infection based on clinical signs and symptoms, laboratory or diagnostic radiology studies. Identification of site requires, examination of patient, inspection of all wounds, chest radiograph, and calculation of clinical pulmonary infection score if ventilated, obtaining blood cultures, urinalysis, and line change if clinical suspicion of central venous catheter (CVC) source. If it is impossible to identify site, obtain cultures from all accessible suspected sites and initiate empiric, broad spectrum antibiotics. If likely site can be identified answer these questions: Is intra-abdominal site suspected? Is pulmonary source of infection suspected? Is skin, skin structure or soft tissue site suspected? If yes, does the patient have clinical signs suspicion for necrotizing soft tissue infection (NSTI)? Is a CVC infection suspected? Risk factors for more complicated infections are discussed and specific antibiotic recommendations are provided for each type and severity of clinical infection. Decision to continue, discontinue and/or alter antibiotic/antimicrobial treatment should be based on the clinical response to treatment, diagnostic or interventional findings, and culture and sensitivity data, bearing in mind that not all patients with infections will have positive cultures because of limitations of specimen handling, microbiology laboratory variations, time between specimen acquisition and culture, or presence of effective antibiotics at the time that specimens were obtained. It should also be noted that not all patients with increased temperature/WBC have an infection. Discontinuation of antibiotics is appropriate if cultures and other diagnostic studies are negative.
PMCID: PMC4004064  PMID: 19077651
Sepsis; Antibiotic; Bacterial; Infection; Empiric treatment; Antimicrobial; Bacteria; Therapy; De-escalation
15.  Automating BioSense 2.0 Locker Processing for Local Program-Specific Surveillance 
PMCID: PMC4050746
BioSense; user community; automate; code libraries
17.  Dispersed sites of HIV Vif-dependent polyubiquitination in the DNA deaminase APOBEC3F 
Journal of molecular biology  2013;425(7):1172-1182.
APOBEC3F and APOBEC3G are DNA cytosine deaminases that potently restrict Human Immunodeficiency Virus-type 1 replication when the virus is deprived of its accessory protein Vif. Vif counteracts these restriction factors by recruiting APOBEC3F and APOBEC3G to an E3 ubiquitin ligase complex that mediates their polyubiquitination and proteasomal degradation. While previous efforts have identified single amino acid residues in APOBEC3 proteins required for Vif recognition, less is known about the downstream ubiquitin acceptor sites that are targeted. One prior report identified a cluster of polyubiquitinated residues in APOBEC3G and proposed an antiparallel model of APOBEC3G interaction with the Vif-E3 ubiquitin ligase complex wherein Vif binding at one terminus of APOBEC3G orients the opposite terminus for polyubiquitination [Iwatani Y, et al. (2009) PNAS 106(46):19539–19544]. To test the generalizability of this model, we carried out a complete mutagenesis of the lysine residues in APOBEC3F and used a complementary, unbiased proteomic approach to identify ubiquitin acceptor sites targeted by Vif. Our data indicate that internal lysines are the dominant ubiquitin acceptor sites in both APOBEC3F and APOBEC3G. In contrast with the proposed antiparallel model, however, we find that the Vif-dependent polyubiquitination of APOBEC3F and APOBEC3G can occur at multiple acceptor sites dispersed along predicted lysine-enriched surfaces of both the N- and C-terminal deaminase domains. These data suggest an alternative model for binding of APOBEC3 proteins to the Vif-E3 ubiquitin ligase complex and diminish enthusiasm for the amenability of APOBEC3 ubiquitin acceptor sites to therapeutic intervention.
PMCID: PMC3602375  PMID: 23318957
APOBEC3F; APOBEC3G; HIV; Vif; ubiquitin
18.  Hyperosmolarity attenuates TNFα–mediated pro-inflammatory activation of human pulmonary microvascular endothelial cells 
Shock (Augusta, Ga.)  2013;39(4):366-372.
Firm neutrophil (PMN)-endothelial (EC) adhesion is crucial to the PMN-mediated hyperinflammation observed in acute lung injury. Hypertonic saline (HTS) used for resuscitation of hemorrhagic shock has been associated with a decreased incidence of PMN-mediated lung injury/acute respiratory distress syndrome. We hypothesize that physiologically accessible hypertonic incubation (170mM vs. 140mM, osmolarity ranging from 360-300 mOsm/L) inhibits pro-inflammatory activation of human pulmonary microvascular endothelial cells (HMVECs). Pro-inflammatory activation of HMVECs was investigated in response to TNFα including IL-8 release, ICAM-1 surface expression, PMN adhesion, and signaling mechanisms under both isotonic (control) and hypertonic conditions. Hyperosmolarity alone had no effect on either basal IL-8 release or ICAM-1 surface expression, but did lead to concentration-dependent decreases in TNFα–induced IL-8 release, ICAM-1 surface expression, and PMN:HMVEC adhesion. Conversely, HTS activated p38 mitogen-activated protein kinase (MAPK) and enhanced TNFα activation of p38 MAPK. Despite this basal activation, hyperosmolar incubation attenuated TNFα stimulated IL-8 release and ICAM-1 surface expression and subsequent PMN adherence, while p38 MAPK inhibition did not further influence the effects of hyperosmolar conditions on ICAM-1 surface expression. In addition, TNFα induced NF-kB DNA binding, but HTS conditions attenuated this by 31% (p<0.01). In conclusion, HTS reduces PMN:HMVEC adhesion as well as TNFα-induced pro-inflammatory activation of primary HMVECs via attenuation of NF-kB signaling.
PMCID: PMC3602232  PMID: 23364439
ARDS; neutrophils; NF-kB; p38 MAPK; HMVECs; IL-8; ICAM-1; hypertonic saline
19.  Impact of Minority Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Resistance Genotype After Virologic Failure 
The Journal of Infectious Diseases  2012;207(6):893-897.
Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants increase the risk of virologic failure for first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and preexisting NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.
PMCID: PMC3571444  PMID: 23264671
HIV-1 drug resistance; minority variants; virologic failure; resistance genotyping
20.  Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic 
Science (New York, N.Y.)  2013;340(6129):180-182.
Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally-intricate aminocyclopentitol antibiotic, displays potent anti-prolific properties across multiple phylogenetic domains, but is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Herein, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction/symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals fifteen steps and is immediately amenable for structural analog synthesis.
PMCID: PMC3952063  PMID: 23580525
21.  Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502 
Journal of Clinical Oncology  2012;31(7):923-929.
The purpose of this study was to determine remission induction frequency when bortezomib was combined with daunorubicin and cytarabine in previously untreated older adults with acute myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemotherapy consisting of intermediate-dose cytarabine (Int-DAC).
Patients and Methods
Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m2 on days 1 through 3 and cytarabine 100 mg/m2 by continuous IV infusion on days 1 through 7. Patients who achieved complete remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 gm/m2 on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m2). Dose-limiting toxicities were assessed during the first cycle of consolidation. The relationship between cell surface expression of CD74 and clinical outcome was assessed.
Frequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with CR/CRp (P = .04) but not with disease-free or overall survival.
The addition of bortezomib to standard 3 + 7 daunorubicin and cytarabine induction chemotherapy for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib administered in combination with Int-DAC for remission consolidation was 1.3 mg/m2 and proved tolerable. Further testing of this regimen is planned.
PMCID: PMC3577952  PMID: 23129738
22.  Health Literacy and Health Outcomes in Diabetes: A Systematic Review 
Low health literacy is considered a potential barrier to improving health outcomes in people with diabetes and other chronic conditions, although the evidence has not been previously systematically reviewed.
To identify, appraise, and synthesize research evidence on the relationships between health literacy (functional, interactive, and critical) or numeracy and health outcomes (i.e., knowledge, behavioral and clinical) in people with diabetes.
English-language articles that addressed the relationship between health literacy or numeracy and at least one health outcome in people with diabetes were identified by two reviewers through searching six scientific databases, and hand-searching journals and reference lists.
Seven hundred twenty-three citations were identified and screened, 196 were considered, and 34 publications reporting data from 24 studies met the inclusion criteria and were included in this review. Consistent and sufficient evidence showed a positive association between health literacy and diabetes knowledge (eight studies). There was a lack of consistent evidence on the relationship between health literacy or numeracy and clinical outcomes, e.g., A1C (13 studies), self-reported complications (two studies), and achievement of clinical goals (one study); behavioral outcomes, e.g., self-monitoring of blood glucose (one study), self-efficacy (five studies); or patient-provider interactions (i.e., patient-physician communication, information exchange, decision-making, and trust), and other outcomes. The majority of the studies were from US primary care setting (87.5 %), and there were no randomized or other trials to improve health literacy.
Low health literacy is consistently associated with poorer diabetes knowledge. However, there is little sufficient or consistent evidence suggesting that it is independently associated with processes or outcomes of diabetes-related care. Based on these findings, it may be premature to routinely screen for low health literacy as a means for improving diabetes-related health-related outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2241-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3579965  PMID: 23065575
health literacy; numeracy; diabetes; health outcomes
23.  Anti-Platelet Therapy is Associated With Decreased Transfusion-Associated Risk of Lung Dysfunction, Multiple Organ Failure, and Mortality in Trauma Patients 
Critical care medicine  2013;41(2):399-404.
To determine whether pre-hospital anti-platelet therapy (APT) was associated with reduced incidence of acute lung dysfunction, multiple organ failure (MOF), and mortality in blunt trauma patients.
Secondary analysis of a cohort enrolled in the NIGMS Trauma Glue Grant database.
Multicenter study including 9 US level-1 trauma centers.
A total of 839 severely injured blunt trauma patients at risk for MOF (age >45 years, base deficit > 6 mEq/L or systolic blood pressure < 90 mmHg, who received a blood transfusion). Severe/isolated head injuries were excluded.
Measurements and Main Results
Primary outcomes were lung dysfunction (defined as grades 2–3 by the Denver MOF score), MOF (Denver MOF score>3), and mortality. Patients were documented as on APT if taking acetylsalicylic acid, clopidogrel, and/or ticlopidine. Fifteen percent were taking APT prior to injury. Median injury severity score (ISS) was 30 (interquartile range, IQR: 22–51), mean age 61 ± 0.4 years and median red blood cells (RBC) volume transfused was 1700 ml (IQR: 800–3150ml). Overall, 63% developed lung dysfunction, 19% had MOF, and 21% died. After adjustment for age, gender, comorbidities, blood products, crystalloid/12hrs, presence of any head injury, ISS, and 12hrs base deficit >8 mEq/L, 12 hrs RBC transfusion was associated with a significantly smaller risk of lung dysfunction and MOF among the group receiving APT compared to those not receiving it (lung dysfunction p=0.0116, MOF p=0.0291). In addition, APT had a smaller risk (albeit not significant, p=0.06) of death for patients receiving RBC compared to those not on APT after adjustment for confounders,
Pre-injury APT therapy is associated with a decreased risk of lung dysfunction, MOF, and possibly mortality in high-risk blunt trauma patients who received blood transfusions. These findings suggest platelets have a role in organ dysfunction development and have potential therapeutic implications.
PMCID: PMC3557727  PMID: 23263579
Antiplatelet Agents; Trauma; Multiple Organ Failure; Lung Dysfunction; Blood Transfusion
24.  Mental health and the relationship between health promotion counseling and health outcomes in chronic conditions 
Canadian Family Physician  2014;60(2):e113-e120.
To explore the relationship between health promotion counseling (HPC) provided by FPs and health-related quality of life (HRQL) and the use of health care services among patients with chronic conditions, while assessing the effect of mental health on these relationships.
Telephone survey using random-digit dialing.
A total of 1615 participants with chronic conditions.
Main outcome measures
Health promotion counseling provided by FPs, which was assessed using 4 questions; HRQL using the Euro quality of life 5-dimensions (EQ-5D) questionnaire; and the use of health care services assessed with self-reported emergency department (ED) visits and hospitalizations.
Of the 1615 participants with chronic conditions, 55% were female and more than two-thirds were older than age 45 years. Less than two-thirds of participants received HPC from their FPs. In patients without anxiety or depression, those who needed help from their FPs in making changes to prevent illness had a 0.05 lower EQ-5D score than those who did not (P < .001); and those who received diet counseling had a 0.03 higher EQ-5D score than their counterparts did (P = .048). However, these associations were not observed in patients with anxiety or depression. Patients were more likely to have visited EDs if they needed their physicians’ help in making changes to prevent illness (odds ratio 1.43, 95% CI 1.08 to 1.89) and less likely to visit EDs if they had been encouraged by their physicians to talk about their health concerns (odds ratio 0.69, 95% CI 0.52 to 0.91). None of the HPC items was associated with hospitalizations.
Not all patients with chronic conditions are receiving HPC from their FPs. Also, there is an association between HPC and important health outcomes (ie, HRQL and ED visits), but this association is not apparent for those with anxiety or depression.
PMCID: PMC3922579  PMID: 24522689
25.  Bone Mineral Density During Total Contact Cast Immobilization for a Patient With Neuropathic (Charcot) Arthropathy 
Physical therapy  2005;85(3):249-256.
Background and Purpose
Diabetes mellitus (DM)-related neuropathic arthropathy of the foot is a destructive bone and joint process. The effect of cast immobilization and non–weight bearing on bone loss has not been well studied. The purpose of this case report is to describe the changes in bone mineral density (BMD) of the calcaneus in the feet of a patient with acute neuropathic arthropathy during total contact cast immobilization.
Case Description
The patient was a 34-year-old woman with type 1 DM, renal failure requiring dialysis, and a 7-week duration of neuropathic arthropathy of the midfoot. Intervention included total contact casting and minimal to no weight bearing for 10 weeks, with transition to therapeutic footwear. Ultrasound-derived estimates of BMD were taken of both involved and uninvolved calcanei.
Bone mineral density decreased for the involved foot (from 0.25 g/cm2 to 0.20 g/cm2) and increased for the uninvolved foot (from 0.27 g/cm2 to 0.31 g/cm2) during casting.
The low initial BMD and further loss during casting suggest the need for transitional bracing and a well-monitored return to full activity to minimize the risk of recurrence and progression of foot deformity.
PMCID: PMC3901582  PMID: 15733049
Arthropathy; Diabetes mellitus; Foot diseases; Fractures; neurogenic

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