Defining the Need for Causal Inference to Understand the Impact of Social Determinants of Health: A Primer on Behalf of the Consortium for the Holistic Assessment of Risk in Transplantation (CHART).

Objective: This study aims to introduce key concepts and methods that inform the design of studies that seek to quantify the causal effect of social determinants of health (SDOH) on access to and outcomes following organ transplant. Background: The causal pathways between SDOH and transplant outcomes are poorly understood. This is partially due to the unstandardized and incomplete capture of the complex interactions between patients, their neighborhood environments, the tertiary care system, and structural factors that impact access and outcomes. Designing studies to quantify the causal impact of these factors on transplant access and outcomes requires an understanding of the fundamental concepts of causal inference. Methods: We present an overview of fundamental concepts in causal inference, including the potential outcomes framework and direct acyclic graphs. We discuss how to conceptualize SDOH in a causal framework and provide applied examples to illustrate how bias is introduced. Results: There is a need for direct measures of SDOH, increased measurement of latent and mediating variables, and multi-level frameworks for research that examine health inequities across multiple health systems to generalize results. We illustrate that biases can arise due to socioeconomic status, race/ethnicity, and incongruencies in language between the patient and clinician. Conclusions: Progress towards an equitable transplant system requires establishing causal pathways between psychosocial risk factors, access, and outcomes. This is predicated on accurate and precise quantification of social risk, best facilitated by improved organization of health system data and multicenter efforts to collect and learn from it in ways relevant to specialties and service lines.

Time Period of Treatment's Effect on the Association Between Race and Survival in Patients With Malignant Colorectal Adenocarcinoma.

BACKGROUND: Colorectal cancer is one of the most common malignancies diagnosed in the United States, with 126,240 new cases diagnosed in 2020. Past studies have shown that disparities may exist between certain patient populations, but it is unknown how they are affected over time as treatments evolve. The purpose of this study was to determine whether the decade of treatment modifies the association between race and five-year survival in adults diagnosed and treated for malignant colorectal adenocarcinomas since the 1970s. METHODS: This was a non-concurrent retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The inclusion criteria involved patients with primary malignant colorectal adenocarcinoma between the years 1975 and 2018. Exclusion criteria included previous malignancies or missing information on any of the variables. The exposure variable was the patient's race, and the main outcome variable was average five-year survival rates. The effect modifier was the time period in which the patient received treatment. The covariates of the study included age, sex, Hispanic status, surgical intervention recommendation, and disease stage. Unadjusted and adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated using Cox regression models. RESULTS: As the interaction term between race/ethnicity and year of diagnosis was statistically significant, the data were stratified according to year of diagnosis. Black patients in both time periods had a higher mortality rate from malignant colorectal carcinoma after adjustment for the covariates (1975-1990: HR 1.10, 95% CI 1.06-1.15; 1991-2018: HR 1.19, 95% CI 1.16-1.23) when compared with White patients. American Indian, Alaskan Native, and Asian patients were found to have lower mortality in both time periods when compared with White patients (1975-1990: HR 0.90, 95% CI 0.85-0.95; 1991-2018: HR 0.93, 95% CI 0.89-0.96). CONCLUSION: Our data found that despite the evolution in the standard of care treatment for malignant colorectal adenocarcinoma since the year 1975, Black patients had lower five-year survival rates when compared with their White counterparts as well as increased rates of being diagnosed with this disease. Overall, addressing these disparities in colorectal cancer outcomes is critical for improving public health and reducing healthcare costs.

"La Perla Del Mar": A Case Report on Subcutaneous Penile Implants.

The purpose of this report is to alert and inform the medical community about the presence and practice of subcutaneous penile implants (SPIs), which are used with the intent of increasing sexual pleasure. This case aspires to deflect plausible misconceptions in the specific populations who use the SPIs. This case study was performed in January 2023 at a tertiary care center in Miami, Florida. A 61-year-old Cuban male admitted for a routine hernia repair with an incidental finding of a benign SPI was interviewed and examined; an extended collection of historical information regarding the patient's penile implant was ascertained. The patient stated that there was a tradition among the men and adolescent individuals living along coastal cities/towns of Cuba such as Havana and Matanzas who would elect to have pieces of stones or gems or any solid objects shaped and molded into round objects that are used for the intent of increasing sexual pleasure. The patient referred to the implant as "La Perla Del Mar," which translates directly into "Pearl of the Sea." Upon visualization of the nodule on examination, a differential diagnosis may include infection (such as syphilis), granulomas, sarcoidosis, dermatofibroma, epithelial inclusion cyst, or malignancy. However, an appropriate workup informed us about the penile implant. Clinicians should employ caution in investigating a penile nodule by taking a detailed social and sexual history and physical exam from the patient if possible. This case and the literature review cited to bolster the notion of a lack of chronic symptoms due to the inserted objects. Several provocations for the implantation of an artificial penile nodule, in this case, maybe extrapolated, such as the desire for a prospective partner's pleasure/displeasure, group identification, or masculine embodiment. The main takeaways from this case report are the considerations that should be taken in the older Caribbean population for patients with the "Perla Del Mar" implantation and bolstering the notion of complete sexual education for clinicians regarding specific populations to enhance patient care.

Yttrium-90 Radioembolization of Unresectable Intrahepatic Cholangiocarcinoma: Long-Term Follow-up for a 136-Patient Cohort.

PURPOSE: Unresectable intrahepatic cholangiocarcinoma (ICC) signifies a poor prognosis with limited treatment options beyond systemic chemotherapy. This study's purpose was to evaluate the safety, efficacy, and potential for downstaging to resection of yttrium-90 (Y90) radioembolization for treatment of unresectable ICC. MATERIALS AND METHODS: From 2004 to 2020, 136 patients with unresectable ICC were treated with radioembolization at a single institution. Retrospective review was performed of a prospectively collected database. Outcomes were (1) biochemical and clinical toxicities, (2) local tumor response, (3) time to progression, and (4) overall survival (OS) after Y90. Univariate/multivariate survival analyses were performed. A subgroup analysis was performed to calculate post-resection recurrence and OS in patients downstaged to resection after Y90. RESULTS: Grade 3+ clinical and biochemical toxicities were 7.6% (n = 10) and 4.9% (n = 6), respectively. Best index lesion response was complete response in 2 (1.5%), partial response in 42 (32.1%), stable disease in 82 (62.6%), and progressive disease in 5 (3.8%) patients. Median OS was 14.2 months. Solitary tumor (P < 0.001), absence of vascular involvement (P = 0.009), and higher serum albumin (P < 0.001) were independently associated with improved OS. Eleven patients (8.1%) were downstaged to resection and 2 patients (1.5%) were bridged to transplant. R0-resection was achieved in 8/11 (72.7%). Post-resection median recurrence and OS were 26.3 months and 39.9 months, respectively. CONCLUSION: Y90 has an acceptable safety profile and high local disease control rates for the treatment of unresectable ICC. Downstaging to resection with > 3 years survival supports the therapeutic role of Y90 for unresectable ICC. LEVEL OF EVIDENCE: Level 3, single-arm single-center cohort study.

Single Center Experience with Incidence, Impact and Predictors of Biliary Complications in Donation After Circulatory Death Liver Transplantation.

Introduction: Utilizing allografts from donors after cardiac death (DCD) has improved organ availability, and DCD livers comprise a growing proportion of transplantations. However, it has been suggested that DCD transplantations have worse outcomes. Research Questions: We aimed to characterize outcomes in a large cohort of DCD transplantations, identify trends in outcomes over time, and identify factors associated with the development of biliary complications. Design: We conducted an observational retrospective cohort study of patients receiving DCD liver allografts within a large academic teaching hospital with a high transplantation volume. Consecutive patients who underwent Type III DCD liver transplantation from 2006-2016 were included in our cohort. Re-transplantations and multi-organ transplant recipients were excluded. Results: Ninety-six type III DCD transplantations occurred between 2006-2016. We report a 1one-year patient survival of 90.6% (87) and a 5five-year patient survival of 69.8% (67). Twenty-nine (30.2%) patients experienced any biliary complication in the first year following discharge, with 17 (17.7%) experiencing ischemic cholangiopathy. Five-year patient (P = 0.04) and graft (P = 0.005) survival improved over time. Post-operative biliary complications experienced during index admission and prior to discharge were found to be associated with the development of biliary complications (P = 0.005) and ischemic cholangiopathy (P = 0.01) following discharge. Conclusion: Our data suggested that outcomes using DCD allografts have improved, however biliary complications remain a significant issue in DCD transplantation. Patients who experienced post-operative biliary complications during index admission may require more frequent screening to allow the initiation of earlier treatment for biliary complications.

Preclinical studies of efficacy thresholds and tolerability of a clinically ready lentiviral vector for pyruvate kinase deficiency treatment.

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder caused by mutations in the PKLR gene. PKD is characterized by non-spherocytic hemolytic anemia of variable severity and may be fatal in some cases during early childhood. Although not considered the standard of care, allogeneic stem cell transplantation has been shown as a potentially curative treatment, limited by donor availability, toxicity, and incomplete engraftment. Preclinical studies were conducted to define conditions to enable consistent therapeutic reversal, which were based on our previous data on lentiviral gene therapy for PKD. Improvement of erythroid parameters was identified by the presence of 20%-30% healthy donor cells. A minimum vector copy number (VCN) of 0.2-0.3 was required to correct PKD when corrected cells were transplanted in a mouse model for PKD. Biodistribution and pharmacokinetics studies, with the aim of conducting a global gene therapy clinical trial for PKD patients (RP-L301-0119), demonstrated that genetically corrected cells do not confer additional side effects. Moreover, a clinically compatible transduction protocol with mobilized peripheral blood CD34+ cells was optimized, thus facilitating the efficient transduction on human cells capable of repopulating the hematopoiesis of immunodeficient mice. We established conditions for a curative lentiviral vector gene therapy protocol for PKD.

Differential tissue distribution of discrete typing units after drug combination therapy in experimental Trypanosoma cruzi mixed infection.

The aim of the present work was to evaluate the distribution of the different clones of the parasite prevailing after treatment with benznidazole (BZ) and clomipramine (CLO), in mice infected with Trypanosoma cruzi, Casibla isolate which consists of a mixture of two discrete typing units (DTUs). Albino Swiss mice were infected and treated with high and low concentrations of BZ (100 or 6.25 mg/kg), CLO (5 or 1.25 mg/kg), or the combination of both low doses (BZ6.25 + CLO1.25), during the acute phase of experimental infection. Treatment efficacy was evaluated by comparing parasitaemia, survival and tissular parasite presence. For DTUs genotyping, blood, skeletal and cardiac muscle samples were analysed by multiplex quantitative polymerase chain reaction. The combined treatment had similar outcomes to BZ6.25; BZ100 was the most effective treatment, but it failed to reach parasite clearance and produced greater histological alterations. Non-treated mice and the ones treated with monotherapies showed both DTUs while BZ6.25 + CLO1.25 treated mice showed only TcVI parasites in all the tissues studied. These findings suggest that the treatment may modify the distribution of infecting DTUs in host tissues. Coinfection with T. cruzi clones belonging to different DTUs reveals a complex scenario for the treatment of Chagas disease and search for new therapies.

Safety and Efficacy of Segmental Yttrium-90 Radioembolization for Hepatocellular Carcinoma after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To evaluate safety and efficacy of segmental yttrium-90 (Y90) radioembolization for hepatocellular carcinoma (HCC) after transjugular intrahepatic portosystemic shunt (TIPS) placement. The hypothesis was liver sparing segmental Y90 for HCC after TIPS would provide high antitumor response with a tolerable safety profile. MATERIALS AND METHODS: This single-arm retrospective study included 39 patients (16 women, 23 men) with ages 49-81 years old who were treated with Y90. Child-Pugh A/B liver dysfunction was present in 72% (28/39) with a median Model for End-stage Liver Disease score of 18 (95% confidence interval, 16.4-19.4). Primary outcomes were clinical and biochemical toxicities and antitumor imaging response by World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria. Secondary outcomes were orthotopic liver transplantation (OLT), time to progression (TTP), and overall survival (OS) estimates by the Kaplan-Meier method. RESULTS: The 30-day mortality was 0%. Grade 3+ clinical adverse events and grade 3+ hyperbilirubinemia occurred in 5% (2/39) and 0% (0/39), respectively. Imaging response was achieved in 58% (22/38, WHO criteria) and 74% (28/38, EASL criteria), respectively. Median TTP was 16.1 months for any cause and 27.5 months for primary index lesions. OLT was completed in 88% (21/24) of listed patients at a median time of 6.1 months (range, 0.9-11.7 months). Median OS was 31.6 months and 62.9 months censored and uncensored to OLT, respectively. CONCLUSIONS: Segmental Y90 for HCC appears safe and efficacious in patients after TIPS. Preserved transplant eligibility suggests that Y90 is a useful tool for bridging these patients to liver transplantation.

In Vitro and In Vivo Genetic Disease Modeling via NHEJ-Precise Deletions Using CRISPR-Cas9.

The development of advanced gene and cell therapies for the treatment of genetic diseases requires reliable animal and cellular models to test their efficacy. Moreover, the availability of the target human primary cells of these therapies is reduced in many diseases. The development of endonucleases that can cut into specific sites of the cell genome, as well as the repair of the generated break by non-homologous end-joining, results in a variety of outcomes, insertions, deletions, and inversions that can induce the disruption of any specific gene. Among the many methods that have been developed for gene editing, CRISPR-Cas9 technology has become one of the most widely used endonuclease tools due to its easy design and its low cost. It has also been reported that the use of two guides, instead of just the one required, reduces the outcomes of non-homologous end joining mainly to the precise genomic sequences between the cutting sites of the guides used. We have explored this strategy to generate useful cellular and animal models. Different distances between the two guides have been tested (from 8 to 500 bp apart), and using the optimal range of 30-60 bp we have obtained a human primary cellular model of a genetic disease, pyruvate kinase deficiency, where the availability of the target cells is limited. We have also generated an in vivo model of glycolate oxidase (GO) deficiency, which is an enzyme involved in the glyoxylate metabolism following the same strategy. We demonstrate that the use of two-guide CRISPR-Cas9-induced non-homologous end joining is a feasible and useful tool for disease modeling, and it is most relevant to those diseases in which it is difficult to get the cells that will be genetically manipulated.

E-Cigarette or Vaping Product Use-Associated Lung Injury (EVALI) Mimicking COVID-19 Disease.

BACKGROUND: Coronavirus 2 (SARS-CoV-2) is the virus associated with the coronavirus disease (COVID-19) causing a pandemic worldwide in 2020. There are other noninfectious diseases that can present exactly as COVID-19, and the management and approach are completely different, hence the importance of understanding and having a wide differential in patients presenting with similar characteristics. Case Report. A 23-year-old male, with a history of childhood asthma, presented to the Emergency Department in a hospital in south Florida in the USA with complaints of a 2-day duration of subjective fever, chills, dry cough, dyspnea, and myalgia. His vital signs were blood pressure 135/65 mmHg, temperature 39°C, pulse 134 bpm, respiratory rate 22 breaths per minute, and saturation of oxygen 96% in room air. Laboratory analysis was significant for white blood cells 15.3 × 103/µL, ALT 69 U/L, AST 66 U/L, ferritin 375.6 ng/mL, C-reactive protein 27.70 mg/dL, and procalcitonin 1.43 ng/mL. A respiratory pathogen panel (RPP) and a SARS-CoV-2 test were both negative. The patient was given empiric antibiotic treatment and hydroxychloroquine. Two more tests for SARS-CoV-2 were negative, and the patient reported that he smoked marijuana through an e-cigarette. The patient was started on high-dose steroids, and symptoms improved. CONCLUSION: COVID-19 is an emergent lung disease that is affecting the population worldwide; many other noninfectious diseases can mimic its presentations and laboratory characteristics; the importance of having a broad differential diagnosis especially in causing confusion during pandemic times is valuable in the management of patients with such presentations, such as EVALI, and glucocorticoids will be indicated in this circumstances.

Comparison of DNA extraction methods and real-time PCR assays for the molecular diagnostics of chronic Chagas disease.

Aim: This work aimed to compare the sensitivity of four protocols for the detection of Trypanosoma cruzi DNA in 98 blood samples from chronic Chagas disease patients. Materials & methods: Two DNA extraction (automated and manual) methods and two T. cruzi satellite DNA qPCRs (with a recent design and the usually used set of primers) were analyzed. Results: Both DNA extraction methods and qPCR assays tested in this work gave comparable qualitative results, although the lowest Ct values were obtained when samples were analyzed using the new set of primers for T. cruzi satellite DNA. Conclusion: Our results encourage the implementation of automated DNA extraction systems and the new T. cruzi qPCR for the molecular diagnostics and treatment response monitoring of chronic Chagas disease patients.

Gene expression dynamic analysis reveals co-activation of Sonic Hedgehog and epidermal growth factor followed by dynamic silencing.

Aberrant activation of the Sonic Hedgehog (SHH) gene is observed in various cancers. Previous studies have shown a "cross-talk" effect between the canonical Hedgehog signaling pathway and the Epidermal Growth Factor (EGF) pathway when SHH is active in the presence of EGF. However, the precise mechanism of the cross-talk effect on the entire gene population has not been investigated. Here, we re-analyzed publicly available data to study how SHH and EGF cooperate to affect the dynamic activity of the gene population. We used genome dynamic analysis to explore the expression profiles under different conditions in a human medulloblastoma cell line. Ordinary differential equations, equipped with solid statistical and computational tools, were exploited to extract the information hidden in the dynamic behavior of the gene population. Our results revealed that EGF stimulation plays a dominant role, overshadowing most of the SHH effects. We also identified cross-talk genes that exhibited expression profiles dissimilar to that seen under SHH or EGF stimulation alone. These unique cross-talk patterns were validated in a cell culture model. These cross-talk genes identified here may serve as valuable markers to study or test for EGF co-stimulatory effects in an SHH+ environment. Furthermore, these cross-talk genes may play roles in cancer progression, thus they may be further explored as cancer treatment targets.

The Diethylcarbamazine Delays and Decreases the NETosis of Polymorphonuclear Cells of Humans with DM Type 2.

Type 2 diabetes mellitus (DM2) is a disease that reports high morbidity and mortality rates worldwide. Between its complications, one of the most important is the development of plantar ulcers. The role of the polymorphonuclear cells (PMNs) is affected by metabolic diseases like DM2. Fifteen years ago, reports about a new mechanism of innate immune response where PMNs generate some kind of webs with their chromatin were published. This mechanism was called NETosis. Also, some researchers have demonstrated that NETosis is responsible for the delay of the ulcer healing both in patients with DM2 and in animal models of DM2. Purified PMNs from healthy and DM2 human volunteers were incubated with diethylcarbamazine (DEC) and then induced to NETosis using phorbol 12-myristate 13-acetate (PMA). In a randomized blind study model, the NETosis was documented by confocal microscopy. On microphotographs, the area of each extracellular neutrophil trap (NET) formed at different times after stimuli with PMA was bounded, and the intensity of fluorescence (IF) from the chromatin dyed with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) was quantified. PMNs from healthy volunteers showed the development of NETs at expected times according to the literature. The same phenomenon was seen in cultures of PMNs from metabolically controlled DM2 volunteers. The use of DEC one hour before of the challenge with PMA delayed the NETosis in both groups. The semiquantitative morphometric analysis of the IF from DAPI, as a measure of PMN's capacity to forming NETs, is consistent with these results. The ANOVA test demonstrated that NETosis was lower and appeared later than expected time, both in PMNs from healthy (p ≤ 0.000001) and from DM2 (p ≤ 0.000477) volunteers. In conclusion, the DEC delays and decreases the NETosis by PMNs from healthy as well as DM2 people.

A Case of Pulmonary Histoplasmosis Presenting with Hypercalcemia and Altered Mental Status in a Patient Following Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Histoplasmosis results from the inhalation of spores from the fungus, Histoplasma capsulatum. A case is presented of pulmonary histoplasmosis associated with altered mental state and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). CASE REPORT A 75-year-old man with a five-day history of AML treated with allogeneic hematopoietic stem cell transplantation, presented with weakness, fatigue, and slow mentation. Computed tomography (CT) of the brain was unremarkable. Laboratory investigations showed serum albumin of 2.9 g/dL, calcium of 11.6 mg/dL, ionized calcium of 1.55 mmol/L, parathyroid hormone (PTH) <6.3 pg/mL, and 25-hydroxy vitamin D of 14.4 ng/mL. Treatment began with intravenous cefepime 1 gm bid, normal saline, and the bisphosphonate, pamidronate, administered as a single dose. Three days later, his clinical status declined. He developed a dry productive cough, his oxygen saturation (O2 Sat) was 90%, and his mental status worsened. Chest CT showed diffuse bilateral lung infiltrates with ground glass opacities. Bronchioalveolar lavage and transbronchial biopsy were negative for Pneumocystis jiroveci pneumonia (PJP). The CMV rival load was 195 IU/mL. Urinalysis for Histoplasma antigen and the Fungitell® assay were positive. Treatment commenced with intravenous voriconazole (250 mg, bid) and ganciclovir (5 mg/kg, bid). A left lower lobe transbronchial lung biopsy was positive for Histoplasma capsulatum and negative for CMV. CONCLUSIONS This case report has highlighted the need for awareness of the diagnosis of histoplasmosis in patients with allogeneic hematopoietic stem cell transplantation who present with an altered mental state in the setting of hypercalcemia.

Development and evaluation of a duplex TaqMan qPCR assay for detection and quantification of Trypanosoma cruzi infection in domestic and sylvatic reservoir hosts.

BACKGROUND: A question of epidemiological relevance in Chagas disease studies is to understand Trypanosoma cruzi transmission cycles and trace the origins of (re)emerging cases in areas under vector or disease surveillance. Conventional parasitological methods lack sensitivity whereas molecular approaches can fill in this gap, provided that an adequate sample can be collected and processed and a nucleic acid amplification method can be developed and standardized. We developed a duplex qPCR assay for accurate detection and quantification of T. cruzi satellite DNA (satDNA) sequence in samples from domestic and sylvatic mammalian reservoirs. The method incorporates amplification of the gene encoding for the interphotoreceptor retinoid-binding protein (IRBP), highly conserved among mammalian species, as endogenous internal amplification control (eIAC), allowing distinction of false negative PCR findings due to inadequate sample conditions, DNA degradation and/or PCR interfering substances. RESULTS: The novel TaqMan probe and corresponding primers employed in this study improved the analytical sensitivity of the assay to 0.01 par.eq/ml, greater than that attained by previous assays for Tc I and Tc IV strains. The assay was tested in 152 specimens, 35 from 15 different wild reservoir species and 117 from 7 domestic reservoir species, captured in endemic regions of Argentina, Colombia and Mexico and thus potentially infected with different parasite discrete typing units. The eIACs amplified in all samples from domestic reservoirs from Argentina and Mexico, such as Canis familiaris, Felis catus, Sus scrofa, Ovis aries, Equus caballus, Bos taurus and Capra hircus with quantification cycles (Cq's) between 23 and 25. Additionally, the eIACs amplified from samples obtained from wild mammals, such as small rodents Akodon toba, Galea leucoblephara, Rattus rattus, the opossums Didelphis virginiana, D. marsupialis and Marmosa murina, the bats Tadarida brasiliensis, Promops nasutus and Desmodus rotundus, as well as in Conepatus chinga, Lagostomus maximus, Leopardus geoffroyi, Lepus europaeus, Mazama gouazoubira and Lycalopex gymnocercus, rendering Cq's between 24 and 33. CONCLUSIONS: This duplex qPCR assay provides an accurate laboratory tool for screening and quantification of T. cruzi infection in a vast repertoire of domestic and wild mammalian reservoir species, contributing to improve molecular epidemiology studies of T. cruzi transmission cycles.

Native valve infective endocarditis due to Micrococcus luteus in a non-Hodgkin's lymphoma patient.

Micrococcus species are typically considered contaminants from skin and mucous membranes. However, especially in severely immunocompromised patients, a blood culture with Micrococcus could be the cause of a significant infection. We report a 65-year-old female with non-Hodgkin's lymphoma who developed native valve infective endocarditis due to Micrococcus luteus. There is no defined therapeutic regimen for infective endocarditis due to Micrococcus luteus; however, our patient was successfully treated for six weeks with vancomycin and rifampin. To our knowledge, there is only one other case report of native valve endocarditis due to Micrococcus luteus.

Ecthyma Gangrenosum of Scrotum in a Patient with Neutropenic Fever: A Case Report.

BACKGROUND Ecthyma gangrenosum is an uncommon cutaneous infection commonly caused by Pseudomonas aeruginosa affecting typically immunocompromised patients. The presence of ecthyma gangrenosum can be associated with severe systemic infection often with a fatal prognosis. Most cases of ecthyma gangrenosum occur around the axilla, buttocks, and limbs; the scrotum is rarely affected. CASE REPORT A 68-year-old male with previously diagnosed acute myeloid leukemia, presented with left scrotal pain, fever, and rigors. Physical examination showed 2 ulcerating lesions with central black eschars surrounded by erythematous halos on the superior aspect of the left scrotum. Diagnosis of ecthyma gangrenosum was confirmed as both blood and lesion cultures showed growth of P. aeruginosa. After early empiric antibiotic treatment, the lesions significantly improved, and no sign of recurrence or new lesions was noticed. CONCLUSIONS Ecthyma gangrenosum should be considered in the differential diagnosis of ulcerating lesions of the scrotum. An early diagnosis and aggressive antibiotic treatment are imperative for resolution of this infection.

Investigation of temporal and spatial heterogeneities of the immune responses to Bordetella pertussis infection in the lung and spleen of mice via analysis and modeling of dynamic microarray gene expression data.

Bordetella pertussis (B. pertussis) is the causative agent of pertussis, also referenced as whooping cough. Although pertussis has been appropriately controlled by routine immunization of infants, it has experienced a resurgence since the beginning of the 21st century. Given that elucidating the immune response to pertussis is a crucial factor to improve therapeutic and preventive treatments, we re-analyzed a time course microarray dataset of B. pertussis infection by applying a newly developed dynamic data analysis pipeline. Our results indicate that the immune response to B. pertussis is highly dynamic and heterologous across different organs during infection. Th1 and Th17 cells, which are two critical types of T helper cell populations in the immune response to B. pertussis, and follicular T helper cells (TFHs), which are also essential for generating antibodies, might be generated at different time points and distinct locations after infection. This phenomenon may indicate that different lymphoid organs may have their unique functions during infection. These findings provide a better understanding of the basic immunology of bacterial infection, which may provide valuable insights for the improvement of pertussis vaccine design in the future.

Amiloidosis cardíaca: valor del diagnóstico molecular con radiotrazadores. Reporte de caso / Cardiac amyloidosis: value of molecular diagnostic with radiotracers. Case report

Resumen: La amiloidosis cardíaca es una entidad poco frecuente y progresiva que resulta en una cardiomiopatía restrictiva produciendo síntomas de falla cardíaca, síncope, arritmias o puede ser un hallazgo de ecocardiografía como pseudohipertrofia del ventrículo izquierdo (VI). La imagen molecular a través de la medicina nuclear permite diferenciar entre los dos tipos más comunes de amiloidosis sin necesidad de biopsia endomiocárdica. Presentamos el caso de un paciente de 75 años, con disnea progresiva, en el que la resonancia magnética (RM) informa sospecha de amiloidosis cardíaca, la que se confirma mediante centellografía.

Summary: Cardiac amyloidosis is a rare and progressive entity that results in a restrictive cardiomyopathy producing symptoms of heart failure, syncope, arrhythmias or it can be a finding of echocardiography as pseudo-hypertrophy of the left ventricle. Molecular imaging with nuclear medicine allows differentiating between the two most common types of amyloidosis without the need for endomyocardial biopsy. We present the case of a 75-year-old male with progressive dyspnea, in whom magnetic resonance imaging shows suspicion of cardiac amyloidosis, which is confirmed by scintigraphy.

Antitumor Response by Endoplasmic Reticulum-Targeting DNA Vaccine Is Improved by Adding a KDEL Retention Signal.

Directing an antigen to the endoplasmic reticulum (ER) improves the antigen-specific immune response, revealing a potentially useful strategy in cancer immunotherapy using tumor-associated antigens (TAAs). This can be achieved by fusing the antigen to an ER chaperone protein, such as calreticulin (CRT). We previously reported the antitumor response by fusing the CRT signal peptide (SP) and its ER retention sequence (KDEL) to full-length human papillomavirus type 16 (HPV-16) E6 and E7 antigens, obtaining a potent antitumoral effect. In this article, we compare the antitumor response due to the use of each signal (SP and/or KDEL) fused to HPV16 E6 and E7 antigens in a DNA vaccination model. Using both SP and KDEL signals promotes higher interferon (IFN)-γ production and a faster antitumor response than using only the SP, resulting in better tumor growth restraint and higher survival, indicating that the KDEL addition to an ER-directed antigen helps by shortening the time to response. Meanwhile, antigens without signals or only the KDEL signal showed no induction of antigen-specific IFN-γ or antitumor response. Our results indicate that directing the E6E7m antigen to the ER by the SP signal is sufficient to promote an efficient antitumor response. Importantly, this effect is stronger and faster when the antigen also has an ER retention sequence, such as the KDEL signal.