Implementation and outcomes of beta-lactam allergy management protocol at a comprehensive cancer center.

PURPOSE: Beta-lactam allergy (BLA) is associated with increased broad-spectrum antibiotic (Br-ABX) use and worse clinical outcomes. We evaluated our hospital-wide BLA protocol (BLA-P) that used following categories: intolerance, low-risk, and high-risk. METHODS: Hospitalized adult patients with listed BLA during 10/2021-12/2022 were eligible. Exclusions were critically ill, surgical, hospice or comfort care, or non-verbal patients. Assessment was counted each time a pharmacist evaluated BLA. Interventions were no further action (high-risk allergy, patient refusal, unstable clinical status), updated allergy label, or delabeled. Delabeling was done either based on antibiotic history (direct-delabeling), or via test-dose challenge for low-risk patients. Br-ABX usage was compared in the unique delabeled patients: the empiric antibiotic use 90 days post-delabeling versus pre-delabeling using McNemar test (SPSS). RESULTS: A total of 700 assessments in 631 patients were identified. 441 assessments in 377 patients (median 63 years-old, 41% male, 50% hematological cancer) met inclusion criteria. The assessments revealed 9% intolerance, 55% low-risk, 23% high-risk and 13% unknown reaction. Interventions resulted in no further action 7%, updated label 72%, and delabeling 21%. 65% of the delabeling was via direct-delabeling and 35% test-dose challenge. Among patients who received a test-dose challenge, 36/36(97%) had no documented allergic reactions, and 1/26(3%) developed a mild rash. The use of aztreonam (pre-delabeling 28% vs. post-delabeling 1.2%, p < 0.001) and meropenem (13% vs. 2.4%, p = 0.022) significantly decreased while cefepime (24% vs. 50%, p = 0.001) and piperacillin-tazobactam (3.7% vs. 22%, p < 0.001) increased after delabeling. CONCLUSION: BLA-P led to 21% delabeling, which resulted in increased preferred Br-ABX and decrease in aztreonam/meropenem use among delabeled patients.

Chemically informed analyses of metabolomics mass spectrometry data with Qemistree.

Untargeted mass spectrometry is employed to detect small molecules in complex biospecimens, generating data that are difficult to interpret. We developed Qemistree, a data exploration strategy based on the hierarchical organization of molecular fingerprints predicted from fragmentation spectra. Qemistree allows mass spectrometry data to be represented in the context of sample metadata and chemical ontologies. By expressing molecular relationships as a tree, we can apply ecological tools that are designed to analyze and visualize the relatedness of DNA sequences to metabolomics data. Here we demonstrate the use of tree-guided data exploration tools to compare metabolomics samples across different experimental conditions such as chromatographic shifts. Additionally, we leverage a tree representation to visualize chemical diversity in a heterogeneous collection of samples. The Qemistree software pipeline is freely available to the microbiome and metabolomics communities in the form of a QIIME2 plugin, and a global natural products social molecular networking workflow.

Coinfections of Two Strains of NDM-1- and OXA-232-Coproducing Klebsiella pneumoniae in a Kidney Transplant Patient.

We report here a fatal case of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in a renal transplant patient without a travel history in the prior year, from whom 2 genetically different CRKP (sequence type 14 [ST14] and ST2497) strains carrying the same plasmids and antimicrobial resistance genes, including blaNDM-1, blaOXA-232, blaCTX-M-15, armA, and tet(D), were isolated from blood and the abdominal cavity. The isolates were susceptible to colistin, tigecycline, eravacycline, and cefiderocol, which was used to treat the CRKP in combination with ceftazidime-avibactam and polymyxin B and resulted in bacterial clearance. Despite the aggressive treatment, the patient died of ischemic colitis and multiorgan failure.

Apolipoproteins B and A1 in Ischemic Stroke Subtypes.

INTRODUCTION: Elevated serum apolipoprotein B and the apolipoprotein B/A1 ratio have been associated with ischemic stroke and intracranial atherosclerotic disease. We sought to assess the relationship between serum levels of apolipoprotein B, apolipoprotein A1, and the apolipoprotein B/A1 ratio with ischemic stroke subtypes and large artery atherosclerosis location. MATERIALS AND METHODS: We evaluated serum apolipoprotein B and apolipoprotein A1 levels in consecutive, statin-naïve, adult ischemic stroke patients admitted to an academic medical center in southern India. We evaluated for differences in the mean serum levels of apolipoprotein B, apolipoprotein A1, and the apolipoprotein B/A1 ratio between patients with ischemic stroke attributed to intracranial atherosclerotic disease, extracranial atherosclerotic disease, small vessel disease, and cardioembolism. In secondary analysis, we assessed for differences in these serum apolipoproteins between patients with moderate-severe intracranial atherosclerotic disease and extracranial atherosclerotic disease, irrespective of ischemic stroke subtype. RESULTS: Among the 156 ischemic stroke patients enrolled in this study, there were no significant differences in serum levels of apolipoprotein B, apolipoprotein A1, and the apolipoprotein B/A1 ratio between patients with distinct ischemic stroke subtypes. No significant differences were found in serum levels of apolipoprotein B, A1 and the apolipoprotein B/A1 ratio between patients with moderate-severe intracranial atherosclerotic disease and moderate-severe extracranial atherosclerotic disease. DISCUSSION: Serum levels of apolipoprotein B and A1 did not differ between ischemic stroke subtypes. Additional studies are needed to validate our findings and to better understand the relationship between serum apolipoproteins and stroke.

Screening of donors and recipients for infections prior to solid organ transplantation.

PURPOSE OF REVIEW: This review is a brief overview of current guidelines on screening donors and candidates for bacterial, fungal, parasitic and viral infections prior to solid organ transplantation. The pretransplant period is an important time to evaluate infection exposure risk based on social history as well as to offer vaccinations. RECENT FINDINGS: One of the major changes in the past few years has been increased utilization of increased Public Health Service risk, HIV positive, and hepatitis C-positive donors. There has also been increased attention to donor and recipient risks for geographically associated infections, such as endemic fungal infections and flaviviruses. SUMMARY: Screening for donors and candidates prior to organ transplantation can identify and address infection risks. Diagnosing infections in a timely manner can help guide treatment and additional testing. Use of necessary prophylactic treatment in organ recipients can prevent reactivation of latent infections and improve posttransplant outcomes.

Coccidioidomycosis in solid organ transplant recipients.

PURPOSE OF REVIEW: The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients. RECENT FINDINGS: In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease. SUMMARY: Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed.

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease.

High density lipoprotein (HDL)-macrophage interactions have the potential to modulate macrophage function in a beneficial way to prevent the development of lipid-loaded foam cell formation in atherosclerosis. Although HDL is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. Here, we examined the effect of dysfunctional-HDL from patients with coronary artery disease, on macrophage function in comparison to functional-HDL from controls. Exposure of macrophages to dysfunctional-HDL for 24 h resulted significant increase in cellular oxidative stress, cholesterol, and cytotoxicity. It also stimulated mitochondrial membrane depolarization, DNA damage, apoptosis, and cleavage of poly (ADP-ribose) polymerase, which are characteristics of proapoptotic pathways. In contrast, functional-HDL treatment maintained cholesterol homeostasis, essential membrane potential, DNA integrity, and cell survival. These results demonstrate that HDL from coronary artery disease (CAD) patient promotes proatherogenic effects that in turn trigger macrophage apoptosis, an important feature in atherogenesis and thereby providing new insight in our understanding of the atherogenic mechanisms.

High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling.

Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-ά and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-γ and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK-dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis.

Acquired Bartter-Like Phenotype.

We present a case of middle-aged man who presented with sudden onset of weakness of both upper and lower limbs with hypotension and polyuria without any antecedent illness. Investigations showed severe hypokalemia, hypocalcemia, hyponatremia, mild hypomagnesemia, hypercalciuria, metabolic alkalosis and increased renin and aldosterone levels in the blood suggesting Bartter syndrome. Thus a diagnosis of acquired Bartter-like phenotype was made.

Hand impairment and activity limitations in four chronic diseases.

STUDY DESIGN: Retrospective cohort. INTRODUCTION: Hand involvement in osteoarthritis (OA) and rheumatoid arthritis (RA) are well known to occupational and physical therapists; however, it is not known whether the impairments and activity limitations with diabetes (DMII) and systemic sclerosis (SSc) are as severe as those observed with OA and RA. PURPOSE: To compare the hand impairments and activity limitations in the 4 diseases. METHODS: A convenience sample of 156 participants received evaluations of hand impairments: strength, joint motion, and dexterity and completed a hand activity limitations questionnaire. RESULTS: The SSc and RA participants had weaker pinch, decreased joint motion and more activity limitations than the DMII and OA groups. There were no significant differences between the groups for right hand grip strength and pegboard dexterity, and applied dexterity. CONCLUSIONS: OA and DMII groups had significantly less impairments and activity limitations than the SSc and RA groups. LEVEL OF EVIDENCE: 2C.

Primary human parvovirus B19 infection in an HIV infected patient on antiretroviral therapy.

INTRODUCTION: Persons with HIV infection frequently present with anaemia from different causes, including use of antiretroviral therapy (typically zidovudine), iron deficiency, vitamin B12 deficiency, opportunistic infections (such as mycobacterial and fungal infections), chronic disease, AIDS-associated malignancies, autoimmune haemolysis, and direct effects of HIV infection itself. Persistent infection with Parvovirus B19 (B19) is an important treatable cause of anaemia in HIV-infected patients. CASE PRESENTATION: We present a case of anaemia in HIV positive patient who did not respond to change of drug therapy and nutritional supplements. Bone marrow biopsy suggested parvo virus infection. CONCLUSIONS: Chronic anaemia due to Parvo virus B19 infection is a treatable cause. Human Parvo virus B19 infection is a diagnosis of exclusion in patients who are started on antiretroviral therapy develop anaemia and later not responding to empirical management. Chronic anaemia requiring recurrent transfusions in HIV positive patient Parvo virus infection should be suspected and evaluated.

Random embedded calibrated statistical blind steganalysis using cross validated support vector machine and support vector machine with particle swarm optimization.

The evolvement in digital media and information technology over the past decades have purveyed the internet to be an effectual medium for the exchange of data and communication. With the advent of technology, the data has become susceptible to mismanagement and exploitation. This led to the emergence of Internet Security frameworks like Information hiding and detection. Examples of domains of Information hiding and detection are Steganography and steganalysis respectively. This work focus on addressing possible security breaches using Internet security framework like Information hiding and techniques to identify the presence of a breach. The work involves the use of Blind steganalysis technique with the concept of Machine Learning incorporated into it. The work is done using the Joint Photographic Expert Group (JPEG) format because of its wide use for transmission over the Internet. Stego (embedded) images are created for evaluation by randomly embedding a text message into the image. The concept of calibration is used to retrieve an estimate of the cover (clean) image for analysis. The embedding is done with four different steganographic schemes in both spatial and transform domain namely LSB Matching and LSB Replacement, Pixel Value Differencing and F5. After the embedding of data with random percentages, the first order, the second order, the extended Discrete Cosine Transform (DCT) and Markov features are extracted for steganalysis.The above features are a combination of interblock and intra block dependencies. They had been considered in this paper to eliminate the drawback of each one of them, if considered separately. Dimensionality reduction is applied to the features using Principal Component Analysis (PCA). Block based technique had been used in the images for better accuracy of results. The technique of machine learning is added by using classifiers to differentiate the stego image from a cover image. A comparative study had been during with the classifier names Support Vector Machine and its evolutionary counterpart using Particle Swarm Optimization. The idea of cross validation had also been used in this work for better accuracy of results. Further parameters used in the process are the four different types of sampling namely linear, shuffled, stratified and automatic and the six different kernels used in classification specifically dot, multi-quadratic, epanechnikov, radial and ANOVA to identify what combination would yield a better result.

The Management of Parkinson's Disease: An Overview of the Current Advancements in Drug Delivery Systems.

Parkinson's disease (PD) has significantly affected a large proportion of the elderly population worldwide. According to the World Health Organization, approximately 8.5 million people worldwide are living with PD. In the United States, an estimated one million people are living with PD, with approximately 60,000 new cases diagnosed every year. Conventional therapies available for Parkinson's disease are associated with limitations such as the wearing-off effect, on-off period, episodes of motor freezing, and dyskinesia. In this review, a comprehensive overview of the latest advances in DDSs used to reduce the limitations of current therapies will be presented, and both their promising features and drawbacks will be discussed. We are also particularly interested in the technical properties, mechanism, and release patterns of incorporated drugs, as well as nanoscale delivery strategies to overcome the blood-brain barrier.

Stimulation of Potent Humoral and Cellular Immunity via Synthetic Dual-Antigen MVA-Based COVID-19 Vaccine COH04S1 in Cancer Patients Post Hematopoietic Cell Transplantation and Cellular Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell patients are immunocompromised, remain at high risk following SARS-CoV-2 infection, and are less likely than immunocompetent individuals to respond to vaccination. As part of the safety lead-in portion of a phase 2 clinical trial in patients post HCT/CAR-T for hematological malignancies (HM), we tested the immunogenicity of the synthetic modified vaccinia Ankara-based COVID-19 vaccine COH04S1 co-expressing spike (S) and nucleocapsid (N) antigens. Thirteen patients were vaccinated 3-12 months post HCT/CAR-T with two to four doses of COH04S1. SARS-CoV-2 antigen-specific humoral and cellular immune responses, including neutralizing antibodies to ancestral virus and variants of concern (VOC), were measured up to six months post vaccination and compared to immune responses in historical cohorts of naïve healthy volunteers (HV) vaccinated with COH04S1 and naïve healthcare workers (HCW) vaccinated with the FDA-approved mRNA vaccine Comirnaty® (Pfizer, New York, NY, USA). After one or two COH04S1 vaccine doses, HCT/CAR-T recipients showed a significant increase in S- and N-specific binding antibody titers and neutralizing antibodies with potent activity against SARS-CoV-2 ancestral virus and VOC, including the highly immune evasive Omicron XBB.1.5 variant. Furthermore, vaccination with COH04S1 resulted in a significant increase in S- and N-specific T cells, predominantly CD4+ T lymphocytes. Elevated S- and N-specific immune responses continued to persist at six months post vaccination. Furthermore, both humoral and cellular immune responses in COH04S1-vaccinated HCT/CAR-T patients were superior or comparable to those measured in COH04S1-vaccinated HV or Comirnaty®-vaccinated HCW. These results demonstrate robust stimulation of SARS-CoV-2 S- and N-specific immune responses including cross-reactive neutralizing antibodies by COH04S1 in HM patients post HCT/CAR-T, supporting further testing of COH04S1 in immunocompromised populations.

Oesophageal and pulmonary invasive aspergillosis in a patient with multiple myeloma.

Invasive aspergillosis (IA) is a serious fungal infection that primarily affects patients with prolonged and profound neutropenia, and compromised cell-mediated immunity. Aspergillosis of the oesophagus and gastrointestinal tract is uncommon but seen in advanced cases of disseminated IA. However, it is difficult to diagnose antemortem due to the poor specificity of the symptoms and the absence of characteristic imaging findings. Therefore, the reported cases of gastrointestinal aspergillosis have been associated with high morbidity and mortality, and frequently diagnosed postmortem. Here we present a successful outcome in a patient with relapsed and refractory multiple myeloma who had presented with febrile neutropenia, cough and dysphagia, and was diagnosed with disseminated IA comprising of pulmonary and oesophageal involvement. This case highlights the need for a high index of suspicion and the importance of invasive procedures for histopathology and molecular diagnostics to ensure an early diagnosis and therapeutic intervention.

Safety and immunogenicity of a synthetic multiantigen modified vaccinia virus Ankara-based COVID-19 vaccine (COH04S1): an open-label and randomised, phase 1 trial.

Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults. Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m2 or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months. In the open-label cohort, 1·0 × 107 plaque-forming units (PFU; low dose), 1·0 × 108 PFU (medium dose), and 2·5 × 108 PFU (high dose) of COH04S1 were administered by intramuscular injection on day 0 and 28 to sentinel participants using a queue-based statistical design to limit risk. In a randomised dose expansion cohort, additional participants were randomly assigned (3:3:1), using block size of seven, to receive two placebo vaccines (placebo group), one low-dose COH04S1 and one placebo vaccine (low-dose COH04S1 plus placebo group), or two low-dose COH04S1 vaccines (low-dose COH04S1 group). The primary outcome was safety and tolerability, with secondary objectives assessing vaccine-specific immunogenicity. The primary immunological outcome was a four times increase (seroconversion) from baseline in spike-specific or nucleocapsid-specific IgG titres within 28 days of the last injection, and seroconversion rates were compared with participants who received placebo using Fisher's exact test. Additional secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ClinicalTrials.gov, NCT046339466. Findings: Between Dec 13, 2020, and May 24, 2021, 56 participants initiated vaccination. On day 0 and 28, 17 participants received low-dose COH04S1, eight received medium-dose COH04S1, nine received high-dose COH04S1, five received placebo, 13 received low-dose COH04S1 followed by placebo, and four discontinued early. Grade 3 fever was observed in one participant who received low-dose COH04S1 and placebo, and grade 2 anxiety or fatigue was seen in one participant who received medium-dose COH04S1. No severe adverse events were reported. Seroconversion was observed in all 34 participants for spike protein and 32 (94%) for nucleocapsid protein (p<0·0001 vs placebo for each comparison). Four times or more increase in SARS-CoV-2 neutralising antibodies within 56 days was measured in nine of 17 participants in the low-dose COH04S1 group, all eight participants in the medium-dose COH04S1 group, and eight of nine participants in the high-dose COH04S1 group (p=0·0035 combined dose levels vs placebo). Post-prime and post-boost four times increase in spike-specific or nucleocapsid-specific T cells secreting interferon-γ was measured in 48 (98%; 95% CI 89-100) of 49 participants who received at least one dose of COH04S1 and provided a sample for immunological analysis. Interpretation: COH04S1 was well tolerated and induced spike-specific and nucleocapsid-specific antibody and T-cell responses. Future evaluation of this COVID-19 vaccine candidate as a primary or boost vaccination is warranted. Funding: The Carol Moss Foundation and City of Hope Integrated Drug Development Venture programme.

Synergies between centralized and federated approaches to data quality: a report from the national COVID cohort collaborative.

OBJECTIVE: In response to COVID-19, the informatics community united to aggregate as much clinical data as possible to characterize this new disease and reduce its impact through collaborative analytics. The National COVID Cohort Collaborative (N3C) is now the largest publicly available HIPAA limited dataset in US history with over 6.4 million patients and is a testament to a partnership of over 100 organizations. MATERIALS AND METHODS: We developed a pipeline for ingesting, harmonizing, and centralizing data from 56 contributing data partners using 4 federated Common Data Models. N3C data quality (DQ) review involves both automated and manual procedures. In the process, several DQ heuristics were discovered in our centralized context, both within the pipeline and during downstream project-based analysis. Feedback to the sites led to many local and centralized DQ improvements. RESULTS: Beyond well-recognized DQ findings, we discovered 15 heuristics relating to source Common Data Model conformance, demographics, COVID tests, conditions, encounters, measurements, observations, coding completeness, and fitness for use. Of 56 sites, 37 sites (66%) demonstrated issues through these heuristics. These 37 sites demonstrated improvement after receiving feedback. DISCUSSION: We encountered site-to-site differences in DQ which would have been challenging to discover using federated checks alone. We have demonstrated that centralized DQ benchmarking reveals unique opportunities for DQ improvement that will support improved research analytics locally and in aggregate. CONCLUSION: By combining rapid, continual assessment of DQ with a large volume of multisite data, it is possible to support more nuanced scientific questions with the scale and rigor that they require.

Dermatology elective curriculum: Birdwatching list and travel guide.

Primary care physicians often see patients with dermatologic complaints, but do not perform as well as dermatologists in the diagnoses of common dermatologic conditions. This article describes a dermatology curriculum that aims to close the clinical practice gap by providing an efficient and effective way to teach dermatology to medical students and non-dermatology residents in the setting of a busy, outpatient dermatology practice.