Intraosseous access in the obese patient: assessing the need for extended needle length.

BACKGROUND: Intraosseous (IO) access can be complicated by obesity. Successful placement of a 25 mm IO needle is unlikely when soft tissue depth exceeds 20 mm. OBJECTIVES: The authors examined the relationship between body mass index (BMI), the ability to palpate the tibial tuberosity (TT), and soft tissue depth at recommended IO insertion sites. METHODS: Obese emergency department patients were assessed for a palpable TT and received ultrasound measurement of the soft tissue depth at recommended IO insertion sites. Linear and logistic regression were used to determine cut-off BMI values predicting soft tissue depth >20 mm. RESULTS: Seventy-five patients were enrolled with a mean BMI of 47.2. The mean soft tissue depth at the proximal humerus, proximal tibial, and distal tibial were 29.6 [95% CI 27.5-31.7] mm, 11.0 [8.9-13.0] mm, and 10.7 [9.4-12.1] mm, respectively. In 5 patients without a palpable TT the soft tissue depth exceeded 20 mm at all three anatomic sites. A BMI ≥43 and BMI ≥60 predicted a soft tissue depth >20 mm at the proximal tibia and distal tibia, respectively, while no reliable BMI cut-off was identified at the proximal humerus. CONCLUSIONS: In obese adults with a palpable TT or BMI ≤43 a 25 mm IO needle is likely adequate at the proximal and distal tibial insertion sites. Empiric use of an extended 45 mm IO needle is advisable at the proximal humeral insertion site in obese patients.

Feeding characteristics of healthy infants without reported feeding impairments throughout the first month of life.

OBJECTIVE: Elucidate characteristics of feeding performance in healthy infants without reported feeding problems throughout the first month of life. STUDY DESIGN: Feeding was monitored in 61 healthy infants by caregiver report for 48 h a week from birth to 4 weeks old. Outcomes included feeding modality, how much they consumed, how long the feed lasted, and how many coughing episodes the infant exhibited. Data were analyzed with descriptive and non-parametric statistics. RESULT: The majority of infants (68%) exhibited at least one problematic feeding behavior. Infants consumed 68 ml/feed over 20 min, though the milk volumes and feed durations were highly variable. Coughing occurred an average of 2 feeds per day. No significant change in coughing was observed throughout the first month of life (p = 0.64). Infants coughed significantly less during breast feeds than bottle feeds (p = 0.02). CONCLUSION: Healthy term infants exhibit what appear to be normal developmental imperfections in feeding performance throughout the first month of life.

Redox control of a ring-opening polymerization catalyst.

The activity of an yttrium alkoxide complex supported by a ferrocene-based ligand was controlled using redox reagents during the ring-opening polymerization of L-lactide. The oxidized complex was characterized by X-ray crystallography and (1)H NMR, XANES, and Mössbauer spectroscopy. Switching in situ between the oxidized and reduced yttrium complexes resulted in a change in the rate of polymerization of L-lactide. Synthesized polymers were analyzed by gel permeation chromatography. Polymerization of trimethylene carbonate was also performed with the reduced and oxidized forms of an indium alkoxide complex. The indium system showed the opposite behavior to that of yttrium, revealing a metal-based dependency on the rate of polymerization.

Genetic variation associated with bortezomib-induced peripheral neuropathy.

OBJECTIVE: To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN). METHODS: Two thousand and sixteen single-nucleotide polymorphisms (SNPs) were genotyped in 139 samples from myeloma patients treated with bortezomib-melphalan-prednisone in the VISTA phase 3 trial. Single-marker association analysis for PN onset and time/cumulative dose to PN onset using the Cox proportional hazards model and multiple covariates was performed under additive, dominant, and recessive genotypic models, followed by correction for multiplicity. Associations were also pursued in a cohort of 212 samples from patients treated with bortezomib-dexamethasone in the IFM 2005-01 phase 3 trial. RESULTS: In the VISTA cohort, after Bonferroni correction, two SNPs significantly associated with time to onset of PN [CTLA4 rs4553808, false discovery rate (FDR)=0.002] and time to onset of grade of at least 2 PN (PSMB1 rs1474642, FDR=0.014). Using FDR less than 0.05 as the threshold, two additional SNPs significantly associated with time to onset of grade of at least 2 (CTSS rs12568757, FDR=0.027) or grade of at least 3 PN (GJE1 rs11974610, FDR=0.041). DYNC1I1 rs916758 significantly associated (FDR=0.012) with cumulative dose to onset of grade of at least 2 PN. These associations were generally not detected in the IFM 2005-01 cohort, although CTLA4 rs4553808 showed the same trend in association with time to onset (P=0.138). In addition, in the IFM 2005-01 cohort, TCF4 rs1261134 significantly associated with onset of any neurologic event (FDR=0.048). CONCLUSION: Genes associated with immune function (CTLA4, CTSS), reflexive coupling within Schwann cells (GJE1), drug binding (PSMB1), and neuron function (TCF4, DYNC1I1) associated with bortezomib-induced PN in this study.

Synthesis and characterization of cerium and yttrium alkoxide complexes supported by ferrocene-based chelating ligands.

Two series of Schiff base metal complexes were investigated, where each series was supported by an ancillary ligand incorporating a ferrocene backbone and different N=X functionalities. One ligand is based on an imine, while the other is based on an iminophosphorane group. Cerium(IV), cerium(III), and yttrium(III) alkoxide complexes supported by the two ligands were synthesized. All metal complexes were characterized by cyclic voltammetry. Additionally, NMR, Mössbauer, X-ray absorption near-edge structure (XANES), and absorption spectroscopies were used. The experimental data indicate that iron remains in the +2 oxidation state and that cerium(IV) does not engage in a redox behavior with the ancillary ligand.

Standardizing Point-of-Care Ultrasound Credentialing Across a Large Health Care System.

BACKGROUND: Point-of-care ultrasound (POCUS) is becoming prevalent in the daily practice of bedside clinicians. As large health care systems standardize practice patterns, an organized approach of credentialing physicians in POCUS is paramount for quality and patient safety. This study describes a systematic approach of credentialing a diverse group of community emergency physicians (EPs) across a large health care system. METHODS: A multimodal POCUS credentialing initiative for EPs was implemented across 11 hospitals between January 1, 2017, and July 1, 2018, that included (1) standardization of POCUS credentialing for all hospitals in the system, (2) tiered POCUS credentialing (Basic and Intermediate) for manageable attainment of goals with a required POCUS course, (3) automatic privileges for EPs who completed residency or practice-based POCUS pathways prior to employment, and (4) implementation of a practice-based pathway for competency assessment for noncredentialed physicians. Key factors for implementation included executive administrative support, dedicated POCUS courses, equipment standardization, a robust electronic medical record capable of logging training scans, and competency assessment for attainment of privileges. RESULTS: Through the initiative, 78/106 EPs achieved Intermediate credentialing, and 28/106 were without POCUS privileges. All 28 noncredentialed EPs completed the required Basic POCUS course. Almost half (13/28) completed the initiative and became credentialed. From 2016 to 2018, the number of EPs performing scans increased from 52 to 112, and the number of POCUS scans increased from 928 to 3,007. CONCLUSION: A standardized POCUS credentialing initiative can be successfully implemented in large health care systems. Other specialties can use this initiative to implement POCUS into their daily practice.

Cerium(IV) catalysts for the ring-opening polymerization of lactide.

A rare example of a cerium(IV) alkoxide catalyst for lactide polymerization is reported. The lactide polymerization activity of the new cerium(IV) complex supported by a ferrocene Schiff base ligand, salfen, is compared to the activity of the yttrium analogue and to that of Ce(O(t)Bu)(4)(THF)(2). The complex Ce(salfen)(O(t)Bu)(2) is less active than Ce(O(t)Bu)(4)(THF)(2) and the corresponding yttrium(III) alkoxide, Y(salfen)(O(t)Bu)(THF). The different activity was correlated with the Mulliken charges calculated by density functional theory for the two complexes.

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

AIMS: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. PATIENTS & METHODS: Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. RESULTS: The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. CONCLUSION: This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.

Structural studies of Vgamma2Vdelta2 T cell phosphoantigens.

Human gammadelta T cells containing the Vgamma2Vdelta2 (Vgamma9Vdelta2) T cell receptor are stimulated by a broad variety of small, phosphorus-containing antigenic molecules called phosphoantigens. The structures of several species present in both Mycobacteria (TUBags1-4) and in Escherichia coli have been reported to contain a formyl-alkyl diphosphate core. Here we report the synthesis of the lead member of the series, 3-formyl-1-butyl diphosphate. This compound has low activity for gammadelta T cell stimulation, unlike its highly active isomer (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate, necessitating a revision of the structure of TUBag1. Likewise, the structure of the species identified as the pentyl analog (TUBag 2) is revised to 6-phosphogluconate. These results indicate that neither TUBag1 nor the m/e 275 species proposed for TUBag2 are 3-formyl-1-alkyl diphosphates, leading to the conclusion that none of the natural phosphoantigens (TUBags1-4) possess the structures reported previously.

Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosoma brucei soluble vacuolar pyrophosphatase.

Trypanosoma brucei, the causative agent of African trypanosomiasis, contains a soluble, vacuolar pyrophosphatase, TbVSP1, not present in humans, which is essential for the growth of bloodstream forms in their mammalian host. Here, we report the inhibition of a recombinant TbVSP1 expressed in Escherichia coli by a panel of 81 bisphosphonates. The IC50 values were found to vary from approximately 2 to 850 microM. We then used 3D QSAR (comparative molecular field and comparative molecular similarity index; CoMFA and CoMSIA) methods to analyze the enzyme inhibition results. The R2 values for the experimental versus the QSAR-predicted activities were 0.78 or 0.61 for CoMFA and 0.79 or 0.68 for CoMSIA, for two different alignments. The root-mean-square (rms) pIC50 error for the best CoMFA model was 0.41 for five test sets of five activity predictions, which translates to a factor of approximately 2.6 error in IC50 prediction. For CoMSIA, the rms pIC50 error and error factors were 0.35 and 2.2, respectively. In general, the most active compounds contained both a single aromatic ring and a hydrogen bond donor feature. Thirteen of the more potent compounds were then tested in vivo in a mouse model of T. brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest.

Urine processing impacts uric acid level in HIV-infected adults: implications for diagnosing tenofovir-associated proximal tubulopathy.

Urine specimens are valuable to investigate kidney disease and antiretroviral nephrotoxicity. We observed large rust-colored pellets in some urine specimens after overnight storage at 4°C. Testing of supernatant under varying conditions demonstrated that this phenomenon reflects supersaturation and precipitation of uric acid in samples with high uric acid concentration. Delays in processing, even with refrigeration, may decrease the sensitivity of urine uric acid testing, with implications for the evaluation of proximal tubulopathy related to tenofovir.

Redox control of a polymerization catalyst by changing the oxidation state of the metal center.

The activity of cerium alkoxide complexes supported by a Schiff base ligand was controlled using redox reagents during the ring-opening polymerization of L-lactide. The rate of L-lactide polymerization was modified by switching in situ between the cerium(III) and cerium(IV) species.

Synthesis of chiral phosphoantigens and their activity in gamma delta T cell stimulation.

Gammadelta T cells expressing Vgamma2Vdelta2 T cell receptors are activated by a broad range of phosphorus-containing small molecules, termed phosphoantigens, and are of interest in the context of the chemotherapy of B cell malignancies. Here, we report the synthesis of four pairs of chiral phosphoantigens: the bromohydrins of isopentenyl diphosphate (Phosphostim), the epoxides of isopentenyl diphosphate (EIPP); and the corresponding bromohydrin and epoxide analogs of but-3-enyl diphosphate. The ability of each compound to stimulate human Vgamma2Vdelta2 T cells was determined by TNF-alpha release and cell proliferation. In these assays, the (R)-bromohydrin diphosphates were, on average, about twice as active as the (S)-bromohydrin diphosphates. In contrast, the (S)-form of EIPP was about twice as active as (R)-EIPP. The activities of the epoxy but-3-enyl diphosphates were both very low. These results suggest that chiral phosphoantigens, as opposed to racemic mixtures, may have utility in immunotherapy.