Initial Clinical Testing Research Articles

How Biologics Have Changed the Drug Discovery Landscape.

Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.

Abdominal MR Multitasking for radiotherapy treatment planning: A motion-resolved and multicontrast 3D imaging approach.

Radiotherapy treatment planning (RTP) using MR has been used increasingly for the abdominal site. Multiple contrast weightings and motion-resolved imaging are desired for accurate delineation of the target and various organs-at-risk and patient-tailored planning. Current MR protocols achieve these through multiple scans with distinct contrast and variable respiratory motion management strategies and acquisition parameters, leading to a complex and inaccurate planning process. This study presents a standalone MR Multitasking (MT)-based technique to produce volumetric, motion-resolved, multicontrast images for abdominal radiotherapy treatment planning. The MT technique resolves motion and provides a wide range of contrast weightings by repeating a magnetization-prepared (saturation recovery and T2 preparations) spoiled gradient-echo readout series and adopting the MT image reconstruction framework. The performance of the technique was assessed through digital phantom simulations and in vivo studies of both healthy volunteers and patients with liver tumors. In the digital phantom study, the MT technique presented structural details and motion in excellent agreement with the digital ground truth. The in vivo studies showed that the motion range was highly correlated (R2 = 0.82) between MT and 2D cine imaging. MT allowed for a flexible contrast-weighting selection for better visualization. Initial clinical testing with interobserver analysis demonstrated acceptable target delineation quality (Dice coefficient = 0.85 ± 0.05, Hausdorff distance = 3.3 ± 0.72 mm). The developed MT-based, abdomen-dedicated technique is capable of providing motion-resolved, multicontrast volumetric images in a single scan, which may facilitate abdominal radiotherapy treatment planning.

Transbronchial cryoablation in peripheral lung parenchyma with a novel thin cryoprobe and initial clinical testing

BackgroundTransbronchial cryoablation shows potential as a local therapy for inoperable peripheral lung cancer. However, its clinical application for peripheral pulmonary lesions has not been reported yet.MethodsAn improved cryoprobe with an...

Novel Synonymous Variant in IL7R Causes Preferential Expression of the Soluble Isoform

PurposeThe interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a T−B+NK+ phenotype. The objective here was to diagnose two siblings displaying the T−B+NK+ SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes.MethodsWhole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.ResultsWe discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out.ConclusionIn this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants.

Phenotype and genotype correlation of inherited epidermolysis bullosa in Indonesia.

Inherited epidermolysis bullosa (EB) is a group of genodermatoses with considerable clinical and genetic heterogeneity. Clinical diagnosis of the EB subtypes is frequently imprecise and requires confirmation with genetic testing. There is still limited study using genetic testing to identify EB subtypes in Indonesia. This study aims to identify the pathogenic variants of inherited EB patients at the Department of Dermatology and Venereology, Universitas Padjadjaran-Dr Hasan Sadikin General Hospital in Bandung, West Java, Indonesia and to describe the correlation between the phenotype and genotype of our patients. Twelve patients clinically diagnosed with EB were included in this study. Genetic testing was performed in collaboration with KK Women's and Children's Hospital, Singapore. Pathogenic variants were identified in the COL7A1 gene in seven patients, namely Dominant Dystrophic EB (DDEB) with mutation types c.5945G>T, c.6218G>A, Recessive Dystrophic EB (RDEB) c.2005C>T, c.6081dup, c.1268C>T, c.1784C>T which are all known mutations. Novel mutations were found in the COL7A1 gene in two patients namely DDEB c.6253G>T and RDEB c.6740C>T. Two EB Simplex (EBS) patients showed mutation KRT14 gene as c.356T>C, c.373C>T which are known mutation. In addition, a novel mutation in LAMA3 gene c.2649del was found in one Junctional EB (JEB) patient. The molecular diagnoses of 12 Indonesian EB patients were identified, of which three were novel pathogenic variants. Concordance between the initial clinical diagnosis and genetic testing was only 33%. This demonstrated the importance of early genetic testing for accurate diagnosis, prognostication, management and genetic counselling.

Development and initial clinical testing of a multiplex assay evaluating histone modifier p300 acetylation in prostate cancer circulating tumor cells.

e17020 Background: Histone modifying enzymes (HMEs) hold promise as targets for drug discovery in cancer. Histone acetyltransferases and histone deacetylases dictate the presence of acetyl marks, which regulate chromatin and transcriptional activation. We previously developed a novel ‘histone array on a chip’ to measure HME dysregulation associated with the development of castration resistant prostate cancer (CRPC) (ACS Chem Biol 2017). This approach identified decreased SIRT2 expression and increased p300 activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC xenografts. These alterations were subsequently validated in castration-resistant tissues (BMC Cancer 2017). The goal of the current study was to determine if circulating tumor cells (CTCs) could be used as a therapeutic biomarker to identify patients with altered p300 acetylation activity. Methods: Blood was collected from 11 CRPC and 3 hormone-sensitive patients with advanced PC under an IRB-approved protocol. PBMCs were isolated with Ficoll-paque PLUS, and lymphocytes were depleted using anti-CD45 magnetic beads. CTCs were then captured with EpCAM labeled coated magnetic beads. Bound cells were isolated with Exclusion-based Sample Preparation (ESP) technology. Bound cells were moved through staining and washing wells prior to imaging at 20x on a fluorescent microscope. Images were analyzed with NIS Elements software. Results: We initially optimized the staining of acetyl-p300, total p300, H3K18ac, and SIRT2 in single cell prostate cancer cell cultures. Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced levels of p300 and H3K18 acetylation confirming assay specificity. CTCs from patient samples were then captured by EpCAM antibody binding and target staining revealed clear expression of acetyl-p300, acetyl-H3K18, SIRT2, and CK (cytokeratin). No expression of CD45+ cells (lymphocyte exclusion) is noted. Acetyl-p300 displayed a strong positive correlation with its target acetylated H3k18 (Pearson’s r = 0.61), and SIRT2 expression showed robust negative correlation with H3k18 (r = -0.60). A distinct group of 6/11 (55%) of CRPC patients demonstrated altered expression. In one subject with an untreated CSPC sample and subsequent CRPC sample ( > 12mo) a loss of SIRT2 expression, increased p300 activity, and histone H3 hyperacetylation are associated with the transition from hormone-sensitive to CRPC. Conclusions: Acetyl-p300, H3K18ac, and SIRT2 increase in a subset of CTC from patients with CRPC. These biomarkers are associated with increased CBP/p300 activity. This biomarker suite could potentially be used for noninvasive monitoring of outcomes and predicting tumor responses to CBP/p300 acetylation inhibitors in clinical development.

Subacute thyroiditis-an unusual endocrine cause of pyrexia of unknown origin: Case report with review of literature

We report a case of a 58-year-old male who presented with high grade fever of 45 days duration. He had presented with a dry cough and right ear pain. His initial clinical evaluation and diagnostic tests were unremarkable. During the hospital stay, he developed palpitation for which tests for thyroid functions were done which revealed subacute thyroiditis. He recovered fully with the treatment. Subacute thyroiditis is one of the rarely mentioned causes of Pyrexia of Unknown origin. A high index of suspicion and appropriate imaging is required for early diagnosis and management.

Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications ("Sleep C.A.L.M.") in the evaluation and management of nocturia: A simple approach to a complex diagnosis.

Nocturia arises from a fundamental mismatch between nocturnal urine production, storage capacity, and sleep architecture, which may be driven by abnormalities of the genitourinary tract, but also by sleep disorders, medical diseases, patient actions/lifestyle factors, or medications. This article introduces a novel system for organizing the complex differential diagnosis for nocturia, as proposed by an international collective of practicing urologists, physician specialists, and sleep experts: "Sleep CALM"-Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications. Narrative review of current evidence regarding the relevance of each "Sleep CALM" factor to nocturia pathogenesis, evaluation, and management. Nocturia and sleep disorders are highly intertwined and often bidirectional, such that nocturnal awakenings for reasons other than a sensation of bladder fullness should not be used as grounds for exclusion from nocturia treatment, but rather leveraged to broaden therapeutic options for nocturia. Nocturia is an important potential harbinger of several serious medical conditions beyond the genitourinary tract. Urologists should have a low threshold for primary care and medical specialty referral for medical optimization, which carries the potential to significantly improve nocturnal voiding frequency in addition to overall health status. Adverse patient actions/lifestyle factors, lower urinary tract dysfunction, and medication use commonly coexist with disordered sleep and comorbid medical conditions, and may be the primary mediators of nocturia severity and treatment response, or further exacerbate nocturia severity and complicate treatment. "Sleep CALM" provides a memorable and clinically relevant means by which to structure the initial patient history, physical exam, and clinical testing in accordance with current best-practice guidelines for nocturia. Although not intended as an all-encompassing diagnostic tool, the "Sleep CALM" schema may also be useful in guiding individualized ancillary testing, identifying the need for specialty referral and multidisciplinary care, and uncovering first-line treatment targets.

Study protocol of Branch Atheromatous Disease-related stroke (BAD-study): a multicenter prospective cohort study

As a meaningful subtype of ischemic stroke in Asians, Branch atheromatous disease (BAD)-related stroke is associated with high early neurological deterioration (END) and disability, but is understudied and without recommended therapy. The mechanism of END still remains unclear. Branch atheromatous disease-related stroke study (BAD-study) therefore aims to investigate demographic, clinical and radiological features, and prognosis of BAD-related stroke in Chinese patients. BAD-study is a nationwide, multicenter, consecutive, prospective, observational cohort study enrolling patients aged 18-80years with BAD-related stroke within 72h after symptom onset. Initial clinical data, laboratory tests, and imaging data are collected via structured case report form, and follow-ups will be performed at 7days, 30days, 90days, 6months and 12months after enrollment. The primary outcome is the score on modified Rankin Scale at 90-day follow-up with single-blinded assessment. Secondary outcomes include END within 7days, and National institute of health stroke scale score, Barthel index, cerebrovascular events, major bleeding complications, and all-cause mortality during 90-day follow-up. Characteristics of penetrating and parent artery will be assessed by high-resolution magnetic resonance imaging combined with other imaging techniques. BAD-study can provide demographic, clinical, radiological, and prognostic characteristics of BAD-related stroke, and thereby potentially figure out the vascular mechanism of early neurological deterioration and optimize therapy strategy with the aid of advanced imaging technique. Baseline data and evidence will also be generated for randomized controlled trials on BAD-related stroke in the future.

Preclinical development of an EP2 antagonist for post-seizure cognitive deficits

Cognitive comorbidities can substantially reduce quality of life in people with epilepsy. Inflammation is a component of all chronic diseases including epilepsy, as well as acute events like status epilepticus (SE). Neuroinflammation is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2)-associated pathways. Activation of the EP2 receptor for prostaglandin E2 appears responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. Here we show that brief exposure of mice to TG11-77, a potent, selective, orally available and brain permeant EP2 antagonist, eliminates the profound cognitive deficit in Y-maze performance after SE and reduces delayed mortality and microgliosis, with a minimum effective i.p. dose (as free base) of 8.8 mg/kg. All in vitro studies required to submit an investigational new drug (IND) application for TG11-77 have been completed, and non-GLP dose range-finding toxicology in the rat identified no overt, organ or histopathology signs of toxicity after 7 days of oral administration at 1000 mg/kg/day. Plasma exposure in the rat was dose-linear between 15 and 1000 mg/kg dosing. TG11-77 thus appears poised to continue development towards the initial clinical test of the hypothesis that EP2 receptor modulation after SE can provide the first preventive treatment for one of the chief comorbidities of epilepsy.

CORRELATION OF CLINICAL RISK SCORES WITH ANGIOGRAPHIC EXTENT AND SEVERITY USING MODIFIED GENSINI SCORE IN PATIENTS WITH ST ELEVATED MYOCARDIAL INFARCTION

Cardiovascular diseases have emerged as a significant health burden and became a leading cause of mortality in developing countries like India.In cardiovascular diseases, acute coronary syndromes are the primary cause of morbidity and mortality, for which timely diagnosis and appropriate therapy are of foremost importance to improve clinical outcomes.Different scoring systems are now available based on initial clinical history, electrocardiographic and laboratory tests that enable early risk stratification on admission. The risk scores were created and recommended by national and international guidelines to identify patients with a higher probability of adverse events, recommending more intensive treatment and early angiography in this population.In this study, we considered evaluating clinical predictors and suitable risk scores GRACE and TIMI that correlate with the severity of angiographic extent of coronary artery disease in patients presenting with ST-elevation myocardial infarction using Modified GENSINI score.

Anatomie und Diagnostik von Subskapularissehnenrupturen

Among lesions of the rotator cuff, subscapularis tendon tears are one of the less common injuries and mostly occur in combination with additional lesions of the posterosuperior rotator cuff and the long biceps tendon. If asubscapularis tendon rupture is suspected in the initial clinical testing, the primary diagnostics should include modern cross-sectional magnetic resonance imaging to assess the tendon lesion and to detect concomitant pathologies. Nevertheless, subscapularis tendon lesions are often initially overlooked and first correctly diagnosed during shoulder arthroscopy.

Analytical validation and initial clinical testing of quantitative microscopic evaluation for PD-L1 and HLA I expression on circulating tumor cells from patients with non-small cell lung cancer

IntroductionPD-L1 expression in non-small cell lung cancer (NSCLC) predicts response to immune checkpoint blockade, however is an imperfect biomarker given tumor heterogeneity, and the antigen presentation pathway requiring other components including HLA I expression. HLA I downregulation may contribute to resistance, warranting its evaluation in attempts to guide patient selection. In addition, earlier detection of acquired resistance could prompt earlier change in treatment and prolong patient survival. Analysis of circulating tumor cells (CTCs) captures heterogeneity across multiple sites of metastases, enables detection of changes in tumor burden that precede radiographic response, and can be obtained in serial fashion.MethodsTo quantify the expression of both PD-L1 and HLA I on CTCs, we developed exclusion-based sample preparation technology, achieving high-yield with gentle magnetic movement of antibody-labeled cells through virtual barriers of surface tension. To achieve clinical-grade quantification of rare cells, we employ high quality fluorescence microscopy image acquisition and automated image analysis together termed quantitative microscopy.ResultsIn preparation for clinical laboratory implementation, we demonstrate high precision and accuracy of these methodologies using a diverse set of control materials. Preliminary testing of CTCs isolated from patients with NSCLC demonstrate heterogeneity in PD-L1 and HLA I expression and promising clinical value in predicting PFS in response to PD-L1 targeted therapies.ConclusionsBy confirming high performance, we ensure compatibility for clinical laboratory implementation and future application to better predict and detect resistance to PD-L1 targeted therapy in patients with NSCLC.

Псевдогиперкалиемия в клинической практике. Диагностический поиск при гиперкалиемии

Hyperkalemia could be a serious diagnostic challenge to general practitioners, since it could be a life-threatening condition. The causes of hyperkalemia are diverse. These include preanalytical errors, release of potassium resulting from cell lysis, potassium shifting between intra- and extracellular spaces, decreased renal excretion, administration of medications. Diagnostic search should start with history taking. Initial clinical and laboratory tests are usually scheduled by the general practitioner at the outpatient stage. In case of excluded pseudohyperkalemia and medication effects, when hyperkalemia cannot be explained by the existing patient’s disorders, the search for undiscovered kidney, endocrine or cardiovascular diseases should be carried out.

Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact

T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia. It is a typically aggressively growing and chemotherapy-resistant malignancy with a poor prognosis. T-PLL cells resemble activated, post-thymic T-lymphocytes with memory-type effector functions. Constitutive transcriptional activation of genes of the T-cell leukemia 1 (TCL1) family based on genomic inversions/translocations is recognized as a key event in T-PLL’s pathogenesis. TCL1’s multiple effector pathways include the enhancement of T-cell receptor (TCR) signals. New molecular dependencies around responses to DNA damage, including repair and apoptosis regulation, as well as alterations of cytokine and non-TCR activation signaling were identified as perturbed hallmark pathways within the past years. We currently witness these vulnerabilities to be interrogated in first pre-clinical concepts and initial clinical testing in relapsed/refractory T-PLL patients. We summarize here the current knowledge on the molecular understanding of T-PLL’s pathobiology and critically assess the true translational progress around this to help appraisal by caregivers and patients. Overall, the contemporary concepts on T-PLL’s pathobiology are condensed in a comprehensive mechanistic disease model and promising interventional strategies derived from it are highlighted.

Practical management of hypertension in adults

Hypertension is the most powerful, independent, preventable risk factor for death and disability from cardiovascular diseases. Initial clinical assessment and diagnostic testing are essential to disclose; (a) secondary causes to avoid resistant cases that needs specific therapy, (b) co-morbid conditions that limits choice of drug-therapy, and (c) target organ damage that dictates specialized approach. In this review article; an algorithm for its management is outlined that includes also specific practical approach to those with emergencies, urgencies and co-morbid conditions.
 Keywords: adults, coronary artery disease, heart failure, hypertension, renal failure, stroke.

Correlation between scores and outcome in Acute Coronary Syndrome patients

A proper analysis for the connection between baseline characteristics and the incidence of death and death-plus-myocardial (re)infarction at 30 days was done by [1]. The most important baseline features associated with death in analysis were age, heart rate, systolic blood pressure, ST-segment depression, signs of pump failure, and elevated levels of biomarkers. A risk estimation score was developed from this analysis [1].Over the last 10 years, multiple methods of risk stratification for ACS patients have been developed. Different scores are now available based on initial clinical history, ECG, and laboratory tests that enable early risk stratification on admission. Even among patients with ST-elevation myocardial infarction (STEMI), for whom initial therapeutic options are well defined, patient risk characteristics impact short and long term medical decision making [2].The TIMI risk score [3] is validated predictor of short term mortality.so we aimed to Correlate between TIMI score and in hospital outcomes in Acute Coronary Syndrome patients and concluded that the higher the TIMI score the higher adverse in hospital clinical cardiovascular outcomes.

Hemechip: An Automated Portable Microchip Electrophoresis Platform for Point-of-Care Sickle Cell Disease Screening

Sickle Cell Disease (SCD) affects more than 14 million people globally, primarily in economically disadvantaged populations. Its management requires early diagnosis, monitoring, and treatment throughout the lifespan of the patient. Early diagnosis of SCD remains a challenge in the developing world due to requirements for sophisticated lab equipment and skilled personnel. American Society of Hematology with other organizations launched the Sickle Cell Disease Coalition, calling for improved patient care. In low-income countries, notably those in Sub-Saharan Africa, the mortality rate for children <5 years with SCD is 50-80%, without early diagnosis and basic care. Access to testing is lacking in these areas since existing SCD screening methods are expensive and resource intensive. The situation calls for an accurate and affordable diagnostic tool designed for point-of-care (POC). To address this need, we developed HemeChip, an accurate, affordable, and rapid “microchip electrophoresis” test, packaged in a small, easy-to-use, and low-cost mass-producible platform. HemeChip identifies SCD and other critical hemoglobinopathies as well as provides relative percentages of hemoglobin types. HemeChip is the first paper-based microchip electrophoresis platform that performs both qualitative and quantitative analysis of hemoglobins. Here, we build on our previous work (Blood 2015 126:3379) by presenting an initial clinical performance analysis of HemeChip's results, compared with High Performance Liquid Chromatography (HPLC), the clinical gold standard.The compact single-use microchip of the HemeChip platform encompasses cellulose acetate paper, in which the hemoglobin separation takes place, as well as integrated stainless-steel electrodes (Fig. 1A). The HemeChip test is performed in four steps: (i) finger/heel prick equivalent amount of whole blood (diluted and lysed) is applied to the microchip (Fig. 1A); (ii) microchip is placed inside the HemeChip reader (Fig. 1B); (iii) real time images of the hemoglobin electrophoresis are captured during the test by the portable reader; and (iv) custom built-in software automatically analyses the results real-time, extracts relevant peak positions, and performs quantitative analysis (Fig. 1C) similar to HPLC. Total procedure takes less than 10 minutes.HemeChip reliably detects hemoglobin types and categorizes patient samples as normal (Hb AA), sickle cell trait (Hb SA), sickle cell anemia (Hb SS), and sickle-hemoglobin C disease (Hb SC) (Table 1). All 77 blood samples tested were obtained under Institutional Review Board (IRB) approval. Tests were performed by both experienced and minimally-trained personnel. Test results for both categories did not introduce discrepancy or variation in accuracy. The HemeChip tests correctly categorized patient samples as Hb AA, Hb SA, Hb SS, and Hb SC with 96.6%-100% accuracy compared with HPLC (Table 1).HemeChip provides high accuracy for hemoglobin phenotype detection and excellent compliance with the clinical gold standard for quantification of the results, which suggests that the HemeChip platform could address the unmet need for screening in regions where SCD is prevalent. Field-testing of HemeChip for SCD screening is ongoing in sub-Saharan Africa.Acknowledgments: This work was supported by: Case-Coulter Translational Research Partnership, Clinical and Translational Science Collaborative of Cleveland (National Center for Advancing Translational Sciences), NIH Center for Accelerated Innovation at Cleveland Clinic, and Center for Integration of Medicine & Innovative Technology.Figure 1: HemeChip overview and initial clinical testing results. (A) Illustration of hemoglobin separation during a HemeChip test. (i) initial, (ii) intermediate, and (iii) final phase of the separation in HemeChip. (B) (i) Portable HemeChip Reader with custom built-in analysis software, (ii) Ssingle use HemeChip cartridge microchip after a test. (C) HemeChip image analysis showing identification and quantification for an Hb SA blood sample. (i) Captured image of hemoglobin separation. (ii) Averaged pixel plot along the HemeChip length reveals intensity peaks and hemoglobin types. (iii) Baseline corrected area under curve determines the relative percentage of hemoglobins compared with HPLC. [Display omitted] DisclosuresLittle:Hemex Health: Equity Ownership. Gurkan:Hemex Health: Employment, Equity Ownership.

Algorithm to guide re-exposure to penicillin in allergic pregnant women with syphilis: Efficacy and safety

BackgroundGestational syphilis is underdiagnosed and undertreated, leading to stillbirth, prematurity, low birthweight, neonatal death, and congenital syphilis. Most patients who label as allergic to penicillin are misdiagnosed. ObjectiveTo assess the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and reporting allergy to the antibiotic. MethodsWe performed a prospective study assessing pregnant women with syphilis and labeled as allergic to penicillin. Based on clinical history, patients were divided in two groups: high-risk and low-risk to penicillin allergy. Low-risk patients with negative skin testing and negative serum specific IgE to penicillin underwent drug provocation test. The remaining patients underwent desensitization. ResultsNinety-one patients were enrolled. Allergy to penicillin was confirmed in 7.69% of pregnant women with syphilis and clinical history of allergy to penicillin; in all cases the diagnosis was made through intradermal testing, which predicted 100% of the breakthrough reactions observed during rapid drug desensitization (p < 0.001). Risk stratification based on the initial clinical reaction and skin testing to guide penicillin re-introduction through drug challenge or desensitization was safe (97.8%) and effective (97.8%). ConclusionWe developed and showed the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and labeled as allergic to this drug. Intradermal test is an excellent biomarker in the diagnosis of immediate hypersensitivity reaction to penicillin and to predict breakthrough reaction during rapid drug desensitization. Further studies may confirm the greater safety of the intravenous protocol compared to the oral protocol.

A Novel Fenestrating Device: Quick Fenestrater for Reconstructing Supra-aortic Arteries In Situ During Thoracic Endovascular Aortic Repair

BackgroundIn situ fenestration (ISF) is an effective approach for reconstructing supra-aortic branches during thoracic endovascular aortic repair (TEVAR). A dedicated device is needed for ISF. MethodsThe Quick Fenestrater (QF) underwent in vitro, animal-based, and initial clinical testing. In vitro, the polytetrafluoroethylene and Dacron aortic endografts were fenestrated using the QF, and the structure of the graft, fenestration hole, and shed particulate material were evaluated. Eight white swine had QF-aided ISF combined with TEVAR and bridge-stent implantation. The outcomes were assessed using intraoperative angiography and biopsy. Finally, 13 patients were treated with QF-assisted ISF combined with TEVAR, and the success rate, technical details, and intra- and postoperative complications were recorded. ResultsThe endograft structure was not damaged during in vitro testing. The fenestration hole was clean, and no particulate material was detected. In animal studies, all animals survived, the supra-aortic arteries were patent, and the endografts and bridge stents had normal morphology. In clinical studies, the technical success rate was 100%, and no fenestration-related neurologic complications or death occurred. One patient had a local access-related hematoma perioperatively and recovered after conservative treatment. Three patients had type III endoleaks, which resolved with no additional treatment. During a mean follow-up of 22.1 ± 6 months, no thoracic complications were identified, and the bridge stents were patent with no endoleaks. No adverse cerebrovascular events, cardiovascular events, or death occurred. ConclusionsQF-assisted ISF is a safe and effective method for the reconstruction of supra-aortic branches during TEVAR. Intermediate-term follow-up results validate the application of the novel fenestration device.