Clinical outcomes after a biopsy diagnosis of antibody-mediated rejection in pediatric heart transplant recipients.

Background: Extending survival after heart transplant (HT) is of paramount importance for childhood recipients of HT. Acute rejection is a significant event, and biopsy remains the most specific means for distinguishing between cellular (ACR) and antibody-mediated rejection (AMR).

Methods: All children in the Pediatric Heart Transplant Society Registry who underwent HT between January 2015 and June 2022 and had ≥1 rejection episode were included.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

Introduction: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.

Methods: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays.

Fostering Animal Welfare and Advancing 3Rs Principles through the Establishment of a 3Rs Advisory Group.

Based on the current state of science, the use of animals remains essential in bringing safe and effective medicines to patients. Respect for laboratory animal welfare and the application of 3Rs principles (the replacement, reduction, and refinement of animal use in research) are a priority throughout the pharmaceutical industry. Given the rapid pace of development, technological progress, and the emergence of new-approach methodologies (NAMs) in the field of biomedical research, maintaining a leading position in scientific advancements with a focus on the principles of replace, reduce, and refine (3Rs) can be quite challenging.

Postintensive Care Syndrome: Feasibly Bridging Care at a Tertiary Trauma Center.

Background: Advancements in critical care management have improved mortality rates of trauma patients; however, research has identified physical and psychological impairments that remain with patients for an extended time. Cognitive impairments, anxiety, stress, depression, and weakness in the postintensive care phase are an impetus for trauma centers to examine their ability to improve patient outcomes.

Objective: This article describes one center's efforts to intervene to address postintensive care syndrome in trauma patients.

Economic Benefits from Managing Coffee Berry Borer () in Hawaii.

Coffee berry borer (CBB) is considered the most damaging insect pest of coffee worldwide. CBB was first detected on Hawai'i Island in 2010, and quickly spread throughout the state's coffee-growing regions. With the introduction of this pest, Hawaii's small yet economically important coffee industry was changed forever with growers facing significantly higher production and labor costs, as well as decreased yield and coffee quality.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies.

Navigating Trauma Patients and Families Through Unfamiliar Territory.

Background: Trauma teams work diligently to manage the complex medical needs of trauma patients. In addition to medical care, there is also a need to assist patients and their families as they navigate the emotional and physical journey of trauma. The role of trauma nurse navigator was developed to address these holistic needs.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs.

Increased risk of infections in pediatric Fontan patients after heart transplantation.

Background: Infectious complications are a major cause of morbidity and mortality after HT. Fontan patients may be more susceptible to post-HT infections.

Methods: This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for FF physiology or DCM, who underwent induction with ATG.

Toxicologic Pathology Forum: Opinion on Not Euthanizing Control Animals in the Recovery Phase of Non-Rodent Toxicology Studies.

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups.

Fatal nocardiosis infection in a pediatric patient with an immunodeficiency after heart re-transplantation.

Background: Nocardia infections are rare opportunistic infections in SOT recipients, with few reported pediatric cases. Pediatric patients with single ventricle congenital heart defects requiring HT may be more susceptible to opportunistic infections due to a decreased T-cell repertoire from early thymectomy and potential immunodeficiencies related to their congenital heart disease. Other risk factors in SOT recipients include the use of immunosuppressive medications and the development of persistent lymphopenia, delayed count recovery and/or lymphocyte dysfunction.

Variation in Use of High-Flow Nasal Cannula and Noninvasive Ventilation Among Patients With COVID-19.

Background: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19.

Methods: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry.

Increasing the Reuse of Protein Non-Naïve Nonhuman Primates in Pharmaceutical Drug Discovery and Development: An Overview and Industry Position on the Challenges and Benefits.

The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists.

Targeting the translational machinery in gastrointestinal stromal tumors (GIST): a new therapeutic vulnerability.

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting.

Recurrent Croup.

Croup refers to airway inflammation and edema leading to obstruction of the larynx, trachea, and bronchi. Croup is the most common cause of acute airway obstruction in young children. It is characterized by the onset of low-grade fever, barky cough, stridor, hoarseness, and respiratory distress.

Pituitary Metastasis Presenting With Central Diabetes Insipidus and Panhypopituitarism.

Objective: We report a case of pituitary metastasis (PM) presenting with acute anterior and posterior pituitary dysfunction following a two-decade-long oncologic course marked by disease progression.

Case Report: An elderly woman with a history of stage IIA invasive ductal carcinoma of the breast presented with confusion. Her laboratory evaluation was significant for panhypopituitarism and central diabetes insipidus, and magnetic resonance imaging findings were suggestive of PM.

Multiplexed Quantitative Analysis of Antibody-Drug Conjugates with Labile CBI-Dimer Payloads Using Immunoaffinity LC-MS/MS.

Quantitative analysis of antibody-drug conjugates (ADCs) involves cleavage of ADCs into smaller analytes representing different components and subsequent measurements from multiple assays for a more comprehensive pharmacokinetic (PK) assessment. Multiple PK analytes including the drug remaining conjugated to the antibody (or antibody-conjugated drug, acDrug) and total antibody can be accessed simultaneously using a multiplex assay by proteolytic digestion of an ADC, if the sites of conjugation are homogeneous for an ADC and the linker drug is stable to proteases. Herein, a multiplexed immunoaffinity liquid chromatography-mass spectrometry (LC-MS)/MS PK assay is described involving immunoaffinity enrichment, enzymatic conversion of prodrug, trypsin digestion, and LC-MS/MS as applied to next-generation ADCs constructed from linker drugs bearing dimeric cyclopropabenzindole (CBI) payloads (duocarmycin analogues).

An Anti-CD22--CBI-Dimer Antibody-Drug Conjugate (ADC) for the Treatment of Non-Hodgkin Lymphoma That Provides a Longer Duration of Response than Auristatin-Based ADCs in Preclinical Models.

We are interested in developing a second generation of antibody-drug conjugates (ADCs) for the treatment of non-Hodgkin lymphoma (NHL) that could provide a longer duration of response and be more effective in indolent NHL than the microtubule-inhibiting ADCs pinatuzumab vedotin [anti-CD22-vc-monomethyl auristatin E (MMAE)] and polatuzumab vedotin (anti-CD79b-vc-MMAE). Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor MMAE. Clinical trial data suggest that these ADCs have promising efficacy for the treatment of NHL; however, some patients do not respond or become resistant to the ADCs.

Gender Disparity in Academic Rank and Productivity Among Public Health Physician Faculty in North America.

Background The issue of gender disparity is particularly important in the domain of public health where the tone of its leadership is pivotal in bringing about impactful change to research, policies, and the wellbeing of our various populations. Our aim is to explore the gender disparity of author metrics and academic rankings of public health physician faculty through a cross-sectional study. Methods Data collection for this retrospective cross-sectional study took place during June and July of 2017.

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells.

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity.

Healthy Hearts via Live Videoconferencing: An Exercise and Diet Intervention in Pediatric Heart Transplant Recipients.

Background Pediatric heart transplant recipients have high-risk cardiovascular profiles that can affect their long-term outcomes; however, promoting exercise and healthy diet has not been a major focus in the field. The objective of this study was to test the feasibility and impact of a supervised exercise and diet intervention delivered via live videoconferencing in this population. Methods and Results Patients 8 to 19 years of age at least 1 year post heart transplantation were enrolled.

An IQ Consortium Perspective on The Scientific Committee on Health, Environmental and Emerging Risks Final Opinion on the Need for Nonhuman Primates in Biomedical Research, Production and Testing of Products and Devices (Update 2017).

The recent Scientific Committee on Health, Environmental and Emerging Risks Final Opinion on "The need for nonhuman primates in biomedical research, production and testing of products and devices" (2017 SCHEER) highlights approaches that could significantly contribute to the replacement, reduction, and refinement of nonhuman primate (NHP) studies. Initiatives that have the potential to affect NHP welfare and/or their use are expected to be appropriate, fair, and objective and publicly disseminated information focused on NHPs in biomedical research, which includes toxicologic and pathologic research and testing, should be objectively evaluated by stakeholder scientists, researchers, and veterinarians. Thus, IQ Consortium member companies convened to develop an informed and objective response, focusing on identifying areas of agreement, potential gaps, or missing information in 2017 SCHEER.

Evaluation and use of an anti-cynomolgus monkey CD79b surrogate antibody-drug conjugate to enable clinical development of polatuzumab vedotin.

Background And Purpose: Polatuzumab vedotin is an antibody-drug conjugate (ADC) being developed for non-Hodgkin's lymphoma. It contains a humanized anti-CD79b IgG1 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti-mitotic agent. Polatuzumab vedotin binds to human CD79b only.