Society for birth defects research and prevention's multidisciplinary research needs workshop 2022: A call to action.

The Society for Birth Defects Research and Prevention (BDRP) strives to understand and protect against potential hazards to developing embryos, fetuses, children, and adults by bringing together scientific knowledge from diverse fields. The theme of 62nd Annual Meeting of BDRP, "From Bench to Bedside and Back Again", represented the cutting-edge research areas of high relevance to public health and significance in the fields of birth defects research and surveillance. The multidisciplinary Research Needs Workshop (RNW) convened at the Annual Meeting continues to identify pressing knowledge gaps and encourage interdisciplinary research initiatives.

FDA and industry collaboration: Identifying opportunities to further reduce reliance on nonhuman primates for nonclinical safety evaluations.

The nonhuman primate (NHP) has always been a limited resource for pharmaceutical research with ongoing efforts to conserve. This is due to their inherent biological properties, the growth in biotherapeutics and other modalities, and their use in small molecule drug development. The SARS-CoV-2 pandemic has significantly impacted the availability of NHPs due to the immediate need for NHPs to develop COVID-19 vaccines and treatments and the China NHP export ban; thus, accelerating the need to further replace, reduce and refine (3Rs) NHP use.

Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective.

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines.

Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K) inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3K inhibitor that differs in structure from first-generation PI3K inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies.

Sensitivities to Thermal and Mechanical Stimuli: Adults With Sickle Cell Disease Compared to Healthy, Pain-Free African American Controls.

Evidence supports but is inconclusive that sensitization contributes to chronic pain in some adults with sickle cell disease (SCD). We determined the prevalence of pain sensitization among adults with SCD pain compared with pain-free healthy adults. In a cross sectional, single session study of 186 African American outpatients with SCD pain (age 18-74 years, 59% female) and 124 healthy age, gender, and race matched control subjects (age 18-69 years, 49% female), we compared responses to standard thermal (Medoc TSA II) and mechanical stimuli (von Frey filaments).

A Stepped-Wedge Randomized Controlled Trial: Effects of eHealth Interventions for Pain Control Among Adults With Cancer in Hospice.

Context: Unrelieved cancer pain at the end of life interferes with achieving patient-centered goals.

Objective: To compare effects of usual hospice care and PAINRelieveIt® on pain outcomes in patients and their lay caregivers.

Methods: In a five-step, stepped-wedge randomized, controlled study, 234 patients (49% male, 18% Hispanic, 51% racial minorities) and 231 lay caregivers (26% male, 20% Hispanic, 54% racial minorities) completed pre-pain/post-pain measures.

Thermal and mechanical quantitative sensory testing values among healthy African American adults.

Purpose: Only a few studies have reported quantitative sensory testing (QST) reference values for healthy African Americans, and those studies are limited in sample size and age of participants. The study purpose was to characterize QST values in healthy, pain-free African American adults and older adults whose prior pain experiences and psychological status were also measured. We examined the QST values for differences by sex, age, and body test site.

Keys to Recruiting and Retaining Seriously Ill African Americans With Sickle Cell Disease in Longitudinal Studies: Respectful Engagement and Persistence.

Objectives: Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges.

Design: In a repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry.

Results from oral gavage carcinogenicity studies of ruxolitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats.

Ruxolitinib is a selective and potent inhibitor of Janus kinase (JAK) 1 and JAK2. It is approved for the treatment of patients with intermediate or high-risk myelofibrosis, or those with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. To investigate its carcinogenic potential, ruxolitinib was administered by oral gavage once daily to Tg.

Implementing the PAIN RelieveIt Randomized Controlled Trial in Hospice Care: Mechanisms for Success and Meeting PCORI Methodology Standards.

This purpose of this article is to describe how we adhere to the Patient-Centered Outcomes Research Institute's (PCORI) methodology standards relevant to the design and implementation of our PCORI-funded study, the PAIN RelieveIt Trial. We present details of the PAIN RelieveIt Trial organized by the PCORI methodology standards and components that are relevant to our study. The PAIN RelieveIt Trial adheres to four PCORI standards and 21 subsumed components.

Pain Intensity and Misconceptions Among Hospice Patients With Cancer and Their Caregivers: Status After 2 Decades.

There is little evidence about barriers to pain management or their relationships with pain outcomes of hospice patients with cancer. The purpose of the study was to determine the barriers reported by hospice patients with cancer and their caregivers and the relationships with demographic characteristics and the patients' pain. In this cross-sectional study, we used selected baseline data from an ongoing randomized clinical trial of patient and lay caregiver dyads receiving home-level hospice care.

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity.

Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data.

Reproductive health choices for young adults with sickle cell disease or trait: randomized controlled trial immediate posttest effects.

Background: People with sickle cell disease (SCD) or sickle cell trait (SCT) may not have information about genetic inheritance needed for making informed reproductive health decisions. CHOICES is a Web-based, multimedia educational intervention that provides information about reproductive options and consequences to help those with SCD or SCT identify and implement an informed parenting plan. Efficacy of CHOICES compared with usual care must be evaluated.

Developmental toxicology: new directions workshop: refining testing strategies and study designs.

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics.

Overview: developmental toxicology: new directions.

Since regulatory agencies began implementing the use of standardized developmental toxicology protocols in the mid-1960s, our knowledge base of embryo-fetal development and technologies for experimentation has grown exponentially. These developmental toxicology protocols were a direct result of the thalidomide tragedy from earlier that decade, when large numbers of women were exposed to the drug and over 10,000 cases of phocomelia resulted. In preventing a recurrence of such tragedies, the testing protocols are immensely successful and the field of toxicology has been dedicated to using them to advance safety and risk assessment of chemicals and pharmaceuticals.

Paris on the Mekong: using the aid effectiveness agenda to support human resources for health in the Lao People's Democratic Republic.

Background: This study examines the potential of aid effectiveness to positively influence human resources for health in developing countries, based on research carried out in the Lao People's Democratic Republic (Lao PDR). Efforts to make aid more effective--as articulated in the 2005 Paris Declaration and recently reiterated in the 2008 Accra Agenda for Action--are becoming an increasingly prominent part of the development agenda. A common criticism, though, is that these discussions have limited impact at sector level.

Coverage and costs of a school deworming programme in 2007 targeting all primary schools in Lao PDR.

Infections with soil-transmitted helminths (STHs) are among the commonest infections in Lao PDR. Recent investigation in this country showed that intestinal helminths currently infect the majority of school-aged children. The Lao Government has addressed the problem by organizing regular anthelminthic chemotherapy with mebendazole 500mg for school and pre-school children in conjunction with health education activities incorporated into the national school curriculum.

Effects of the opioid analgesic oxymorphone hydrochloride on reproductive function in male and female rats.

Background: Endogenous opioids seem to regulate hypothalamic gonadotropin release in both males and females, as evidenced by the effects of opioid agonists and antagonists on LHRH release and reproductive hormone levels. The effects of long-term oral administration of opioid analgesics on reproductive function have not been well characterized.

Methods: The reproductive effects of oxymorphone, a potent opioid agonist, were investigated in male and female Crl:CD(SD) IGS BR rats at oral doses of 0, 5, 10, and 25 mg/kg/day (25 animals/sex/group).

Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain.

Dextromethorphan is a widely used antitussive agent, also showing increased recreational abuse. Dextromethorphan and its metabolite dextrorphan are non-competitive antagonists at the N-methyl-d-aspartate (NMDA) receptor ion channel. Single doses of some NMDA receptor antagonists produce neuropathologic changes in neurons of the retrosplenial/posterior cingulate cortices (RS/PC), characterized by vacuolation or neurodegeneration.