Impact of Patient-Reported Penicillin Allergy on Antibiotic Prophylaxis and Surgical Site Infection Among Patients Undergoing Colorectal Surgery.

BACKGROUND: Surgical site infections are a major preventable source of morbidity, mortality, and increased health care expenditures after colorectal surgery. Patients with penicillin allergy may not receive the recommended preoperative antibiotics, putting them at increased risk for surgical site infections. OBJECTIVE: This study aimed to evaluate the impact of patient-reported penicillin allergy on preoperative antibiotic prophylaxis and surgical site infection rates among patients undergoing major colon and rectal procedures. DESIGN: This is a retrospective observational study. SETTING: This study was conducted at a tertiary teaching hospital in Dallas. PATIENTS: Adults undergoing colectomy or proctectomy between July 2012 and July 2019 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were preoperative antibiotic choice and surgical site infection. RESULTS: Among 2198 patients included in the study, 12.26% (n = 307) reported a penicillin allergy. Patients with penicillin allergy were more likely to be white (82%) and female (54%; p < 0.01). The most common type of allergic reaction reported was rash (36.5%), whereas 7.2% of patients reported anaphylaxis. Patients with self-reported penicillin allergy were less likely to receive beta-lactam antibiotics than patients who did not report a penicillin allergy (79.8% vs 96.7%, p < 0.001). Overall, 143 (6.5%) patients had surgical site infections. On multivariable logistic regression, there was no difference in rates of surgical site infection between patients with penicillin allergy vs those without penicillin allergy (adjusted OR 1.14; 95% CI, 0.71-1.82). LIMITATIONS: A limitation of this study was its retrospective study design. CONCLUSIONS: Self-reported penicillin allergy among patients undergoing colorectal surgery is common; however, only a small number of these patients report any serious adverse reactions. Patients with self-reported penicillin allergy are less likely to receive beta-lactam antibiotics and more likely to receive non-beta-lactam antibiotics. However, this does not affect the rate of surgical site infection among these patients, and these patients can be safely prescribed non-beta-lactam antibiotics without negatively impacting surgical site infection rates. See Video Abstract at http://links.lww.com/DCR/B838 .IMPACTO DE LA ALERGIA A LA PENICILINA INFORMADA POR EL PACIENTE EN LA PROFILAXIS ANTIBIÓTICA Y LA INFECCIÓN DEL SITIO OPERATORIO ENTRE PACIENTES DE CIRUGÍA COLORECTAL. ANTECEDENTES: Las infecciones del sitio operatorio son una de las principales fuentes prevenibles de morbilidad, mortalidad y aumento del gasto sanitario después de cirugía colorrectal. Es posible que los pacientes con alergia a la penicilina no reciban los antibióticos preoperatorios recomendados, lo que los pone en mayor riesgo de infecciones en el sitio operatorio. OBJETIVO: Este estudio tuvo como objetivo evaluar el impacto de la alergia a la penicilina informada por el paciente sobre la profilaxis antibiótica preoperatoria y las tasas de infección del sitio operatorio entre pacientes sometidos a procedimientos mayores de colon y recto. DISEO: Estudio observacional retrospectivo. AJUSTE: Hospital universitario terciario en Dallas. PACIENTES: Adultos sometidos a colectomía o proctectomía entre julio de 2012 a julio de 2019. PRINCIPALES MEDIDAS DE DESENLACE: Elección de antibióticos preoperatorios e infección del sitio operatorio. RESULTADOS: Entre los 2198 pacientes incluidos en el estudio, el 12,26% (n = 307) informó alergia a la penicilina. Los pacientes con alergia a la penicilina tenían más probabilidades de ser blancos (82%) y mujeres (54%) ( p < 0,01). El tipo más común de reacción alérgica notificada fue erupción cutánea (36,5%), mientras que el 7,2% de los pacientes notificó anafilaxia. Los pacientes con alergia a la penicilina autoinformada tenían menos probabilidades de recibir antibióticos betalactámicos en comparación con los pacientes que no informaron alergia a la penicilina (79,8% frente a 96,7%, p < 0,001). En general, hubo 143 (6,5%) pacientes con infecciones del sitio operatorio. En la regresión logística multivariable no hubo diferencias en las tasas de infección del sitio operatorio entre los pacientes con alergia a la penicilina frente a los que no tenían alergia a la penicilina (razón de probabilidades ajustada 1,14; intervalo de confianza del 95%, 0,71-1,82). LIMITACIONES: Diseño de estudio retrospectivo. CONCLUSIONES: La alergia a la penicilina autoinformada entre los pacientes de cirugía colorrectal es común, sin embargo, solo un pequeño número de estos pacientes informan reacciones adversas graves. Los pacientes con alergia a la penicilina autoinformada tienen menos probabilidades de recibir antibióticos betalactámicos y más probabilidades de recibir antibióticos no betalactámicos. Sin embargo, esto no afecta la tasa de infección del sitio quirúrgico entre estos pacientes y se les puede recetar de forma segura con antibióticos no betalactámicos sin afectar negativamente las tasas de infección del sitio quirúrgico. Consulte Video Resumen en http://links.lww.com/DCR/B838 . (Traducción-Dr. Juan Carlos Reyes ).

Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury.

Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we used genetic models to determine whether radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM vasculature, and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.

Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti-VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non-EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.

Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34(-)c-kit(+)Sca-1(+)lineage(-) (34(-)KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34(-)KSL cells. Treatment of bone marrow (BM) 34(-)KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.

HOXA9 participates in the transcriptional activation of E-selectin in endothelial cells.

The homeobox gene HOXA9 has recently been shown to be an important regulator of endothelial cell (EC) differentiation and activation in addition to its role in embryonic development and hematopoiesis. In this report, we have determined that the EC-leukocyte adhesion molecule E-selectin is a key target for HOXA9. The depletion of HOXA9 protein in ECs resulted in a significant and specific decrease in tumor necrosis factor alpha (TNF-alpha)-induced E-selectin gene expression. In addition, HOXA9 specifically activated the E-selectin gene promoter in ECs. Progressive deletional analyses together with site-specific mutagenesis of the E-selectin promoter indicated that the Abd-B-like HOX DNA-binding motif, CAATTTTATTAA, located in the proximal region spanning bp -210 to -221 upstream of the transcription start site was crucial for the promoter induction by HOXA9. Both HOXA9 in EC nuclear extract and recombinant HOXA9 protein bound to this sequence in vitro. Moreover, we showed that HOXA9 binds temporally, in a TNF-alpha-dependent manner, to the region containing this Abd-B-like element in vivo. We have thus identified a novel and functionally critical cis-regulatory element for TNF-alpha-mediated transient expression of the E-selectin gene. Further, we provide evidence that HOXA9 acts as an obligate proinflammatory factor by mediating cytokine induction of E-selectin.

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

Effects of Acute Atmospheric Pressure Changes on Dynamic Contour Tonometry and Goldmann Applanation Tonometry in Normal Individuals: A Pilot Study.

PRéCIS:: Intraocular pressure (IOP) measurement differences with Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT) are affected by atmospheric pressure inside a hyperbaric chamber. PURPOSE: To compare IOP measurements obtained with GAT and DCT in 22 normal individuals at different atmospheric pressures simulated in a hyperbaric chamber. METHODS: The IOP of both eyes of 22 healthy volunteers was measured using GAT and DCT at 4 different atmospheric pressure levels.Starting at 1 Queretaro atmospheric pressure (QATM), the IOP was measured with GAT and DCT. The atmospheric pressure was then increased to 1.1 QATM (equivalent to 1032 m above sea level), 1.2 QATM (equivalent to 315 m above sea level), and 1.25 QATM (equivalent to sea level), starting 5 minutes after reaching each level. The limits of agreement between various measurements with each tonometer were calculated using the Bland-Altman plots. RESULTS: The first 4 subjects were used to measure feasibility, consistency, variability, and the time needed for IOP to return to baseline after each atmospheric pressure increase.For the entire 44 eyes, the mean GAT IOP at 1 QATM was 12.23 mm Hg (range, 8 to 20 mm Hg; SD, 2.84) and mean DCT was 16.36 (range, 12.1 to 25.3; SD, 2.84), with a mean 4.14 mm Hg difference (range, -0.1 to 7.5 mm Hg; SD, 1.62; P<0.001).Using the second measurements of the first 4 subjects and those after 5 minutes of adaptation for the rest of the group at 1.1 QATM, mean GAT IOP was 11.05±2.68 mm Hg and mean DCT IOP was 15.60±3.02 mm Hg, for a mean difference between instruments of 4.56±1.81 mm Hg (P<0.001).At 1.2 QATM, mean GAT IOP was 11.14±2.53 mm Hg and mean DCT IOP was 15.39±2.91 mm Hg. The difference between instruments was 4.25±2.12 mm Hg (P<0.001).At 1.25 QATM, the mean GAT IOP was 12.39±3.11 mm Hg and mean DCT IOP was 14.91±2.73 mm Hg. The difference between instruments after 5 minutes of adaptation was 2.53±1.62 mm Hg (P<0.001).Generalized estimating equations for performing linear regression multivariable analysis using atmospheric pressure, expressed as altitude, and age as covariates, shows that the difference between GAT and DCT increases by 1 mm Hg per 673 m of increase of altitude above sea level. Age was not a significant predictor. CONCLUSIONS: Acute changes in atmospheric pressure induce changes in IOP measurements for both GAT and DCT and in different directions. Despite the limitation of sample size, it may be postulated that the difference of IOP measurements between the 2 tonometers increases with lower atmospheric pressures.

Mild to Moderate to Severe: What Drives the Severity of ARDS in Trauma Patients?

Acute respiratory distress syndrome (ARDS) is a complex inflammatory process with multifactorial etiologies. Risk factors for its development have been extensively studied, but factors associated with worsening severity of disease, as defined by the Berlin criteria, are poorly understood. A retrospective chart and trauma registry review identified trauma patients in our surgical intensive care unit who developed ARDS, defined according to the Berlin definition, between 2010 and 2015. The primary outcome was development of mild, moderate, or severe ARDS. A logistic regression model identified risk factors associated with developing ARDS and with worsening severity of disease. Of 2704 total patients, 432 (16%) developed ARDS. Of those, 100 (23%) were categorized as mild, 176 (41%) as moderate, and 156 (36%) as severe. Two thousand two hundred and seventy-two patients who did not develop ARDS served as controls. Male gender, blunt trauma, severe head and chest injuries, and red blood cell as well as total blood product transfusions are independent risk factors associated with ARDS. Worsening severity of disease is associated with severe chest trauma and volume of plasma transfusion. Novel findings in our study include the association between plasma transfusions and specifically severe chest trauma with worsening severity of ARDS in trauma patients.

Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche.

The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells.

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates.

Medications that can mitigate against radiation injury are limited. In this study, we investigated the ability of recombinant human growth hormone (rhGH) to mitigate against radiation injury in mice and nonhuman primates. BALB/c mice were irradiated with 7.5 Gy and treated post-irradiation with rhGH intravenously at a once daily dose of 20 microg/dose for 35 days. rhGH protected 17 out of 28 mice (60.7%) from lethal irradiation while only 3 out of 28 mice (10.7%) survived in the saline control group. A shorter course of 5 days of rhGH post-irradiation produced similar results. Compared with the saline control group, treatment with rhGH on irradiated BALB/c mice significantly accelerated overall hematopoietic recovery. Specifically, the recovery of total white cells, CD4 and CD8 T cell subsets, B cells, NK cells and especially platelets post radiation exposure were significantly accelerated in the rhGH-treated mice. Moreover, treatment with rhGH increased the frequency of hematopoietic stem/progenitor cells as measured by flow cytometry and colony forming unit assays in bone marrow harvested at day 14 after irradiation, suggesting the effects of rhGH are at the hematopoietic stem/progenitor level. rhGH mediated the hematopoietic effects primarily through their niches. Similar data with rhGH were also observed following 2 Gy sublethal irradiation of nonhuman primates. Our data demonstrate that rhGH promotes hematopoietic engraftment and immune recovery post the exposure of ionizing radiation and mitigates against the mortality from lethal irradiation even when administered after exposure.