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Antibody-drug conjugates (ADCs) combining monoclonal antibodies with cytotoxic payloads are a rapidly emerging class of immune-based therapeutics with the potential to improve the treatment of cancer, including children with relapse/refractory acute lymphoblastic leukemia (ALL). CD123, the α subunit of the interleukin-3 receptor, is overexpressed in ALL and is a potential therapeutic target. Here, we show that pivekimab sunirine (PVEK), a recently developed ADC comprising the CD123-targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient-derived xenograft (PDX) models ( n  = 39). PVEK administered once weekly for 3 weeks resulted in a median event-free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B-lineage ( n  = 65) compared with T-lineage ( n  = 25) ALL PDXs ( p  < 0.0001), and mice engrafted with B-lineage PDXs achieved significantly longer EFS than those engrafted with T-lineage PDXs ( p  < 0.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B-ALL PDXs. Notably, our results showed no direct correlation between CD123 expression and mouse EFS, indicating that CD123 is necessary but not sufficient for in vivo PVEK activity. Importantly, a PDX with very high CD123 cell surface expression but resistant to in vivo PVEK treatment, failed to internalize the G4723A antibody while remaining sensitive to the PVEK payload, DGN549, suggesting a novel mechanism of resistance. In conclusion, PVEK was highly effective against a large panel of B-ALL PDXs supporting its clinical translation for B-lineage pediatric ALL., Competing Interests: Patrick A. Zweidler‐McKay and Sribalaji Lakshmikanthan report employment at ImmunoGen, Inc. at the time of analysis and reporting. All other authors declare no conflicts of interest., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Despite a varied selection of available trauma-focused evidence-based psychotherapies (TF-EBPs) for posttraumatic stress disorder (PTSD), few veterans receive a full course of an evidence-based treatment. A better understanding of and alignment with veterans' PTSD treatment goals could be one way to improve treatment engagement and adherence, consistent with veteran-oriented care within the U.S. Department of Veterans Affairs (VA) Healthcare System. Few studies have examined veterans' specific goals or reasons for seeking treatment for PTSD. We conducted a qualitative analysis using secondary data from a randomized controlled trial (RCT) of 175 veterans who were randomized to receive a TF-EBP for PTSD. Veterans completed a self-report questionnaire at baseline and were asked to identify three distinct goals for treatment using a short-answer format. Two authors coded the data and identified themes. Three themes were identified: improvements in PTSD symptoms, personal well-being and growth, and improvements in social roles and interpersonal functioning. These findings suggest that veterans with PTSD have both symptom reduction goals and functional goals at the outset of treatment. The findings also emphasize the importance of broadening the scope of treatment outcome monitoring and assessment to better reflect patient-centered care and veterans' specific goals., (© 2025 International Society for Traumatic Stress Studies.)

In response to communities where individuals experience both disproportionate numbers of Adverse childhood experiences (ACEs) and other health inequities, narrative change has emerged as a powerful tool to change how ACEs are viewed and addressed by communities. The special issue presents a set of papers examining efforts to use narrative change to address ACEs. In this commentary, we offer reflections on the introduction and three articles of the special issue and point to future considerations for implementation and impact of community narrative initiatives. For example, we assert that to prevent and address the outcomes of ACEs such as substance use and mental health problems, communities need to include and amplify the voices of those with lived experience during decision-making about policy. We also espouse using research models of resilience in communities as a way to further uptake of narrative change strategies in the literature on ACEs and health disparities in communities. Using trauma-informed outcomes and measures are also critical to measure how narrative change can move the needle to promote health equity., (© 2024 Society for Community Research and Action.)

It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate-release and extended-release tablets) in healthy volunteers. Predicted TMR concentration-time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC 0-inf (ng.h/mL) in healthy volunteers following FTR administration of the extended-release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug-drug interactions in pregnancy., (© 2024 GlaxoSmithKline. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight-site SCD Implementation Consortium (SCDIC) registry., Methods: We conducted a cross-sectional analysis of female registry participants, aged 15-45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self-reported pregnancies and outcomes., Results: Seven hundred and thirty-eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%). Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06-4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01-5.16)., Conclusion: Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD., (© 2024 International Federation of Gynecology and Obstetrics.)

The objective of this analysis was to compare clinician-based and formally calculated risk assessments by REVEAL Lite 2 and COMPERA 2.0 and to characterize parenteral prostacyclin utilization within 90 days of baseline in high-risk patients. A multisite, double-blind, retrospective chart review of patients with pulmonary arterial hypertension (PAH) was conducted with an index period of January 2014-March 2017. Patients were categorized into the "any PAH medication" or "prostacyclin-enriched" cohort based on latest PAH medication initiated within the index period. Clinicians classified the patient's 1-year mortality risk as "low," "intermediate," or "high" based on their clinical assessment. REVEAL Lite 2 and COMPERA 2.0 scores were independently calculated. Risk assessment congruency was evaluated. Parenteral prostacyclin use was evaluated within 90 days of baseline. Thirty-two clinicians participated and abstracted data for 299 patients with PAH. At baseline, mean patient age was 52 years, 6-min walk distance was 226 m, and most patients were WHO functional class II or III. Half of the patients (53%) were classified by clinician assessment as intermediate risk, while most were classified as high risk by REVEAL Lite 2 (59%) and intermediate-high risk by COMPERA 2.0 (52%). Parenteral prostascyclins were underutilized in high-risk patients, and not initiated in a timely fashion. Clinician-assessed risk category was incongruent with tool-based risk assessments in 40%-54% of patients with PAH, suggesting an underestimation of the patient's risk category by clinician gestalt. Additionally, there was a lack of timely prostacyclin initiation for patients with PAH stratified as high-risk by either tool., Competing Interests: Amresh Raina reports no potential conflict of interest with the study. Oksana A. Shlobin has served as a consultant to and on the speaker's bureau for United Therapeutics, Bayer, Merck, and Janssen; and has served as a consultant to Gossamer, Aerami, and Aerovate. Meredith Broderick, Benjamin Wu and Margaret R. Sketch are employees of United Therapeutics Corporation., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Technology provides opportunities to enhance communication skills training for genetic counseling graduate students. We assessed the acceptability of an online communication training program. Graduate student volunteers completed five online training modules on basic communication skills with opportunities to practice the skills within three simulated/standardized patient (SP) sessions. Participants completed online questionnaires reporting on acceptability, perceived usefulness, and realism of the modules and SP sessions. They also reported on the ease of transferring skills from the modules to clinical practice. Out of the 60 students who completed the baseline session, 35 (58%) completed all five training modules. Out of these 35 students, most found the modules to be useful (94%) and agreed that they were relevant to clinical practice (97%). At least 88% of participants found the genetic counselors, patient, and case scenarios to be realistic. Twenty-eight students had participated in clinical rotations since completing the intervention. Of these, 17 (61%) reported that it was at least slightly easy to use the skills in actual clinical cases. Most students also reported being able to transfer the skills they had learned into clinical practice. While the training was well-received, the relatively low completion rate of 58% raises concern that the intervention may need formal integration into the program curriculum to succeed due to the time and effort demands on students., (© 2023 National Society of Genetic Counselors. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND., Methods: RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM., Results: Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/μl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/μL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001)., Conclusion: RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV., (© 2024 British HIV Association.)

Objective: The objective of this study was to describe feeding practices and weight status in a cohort of children with congenital Zika syndrome (CZS) in northeastern Brazil., Methods: This longitudinal study of children with CZS (N = 156) included data collection on child feeding practices and weight status at five timepoints between 2018 and 2022. The average age of the children was 32.1 months at enrollment and 76.6 months at the fifth assessment. Multilevel models, with repeated observations nested within children, were used to estimate time-related differences in each outcome., Results: Use of enteral feeding, such as gastrostomy, increased from 19.2% to 33.3% over 4 years (p < .001). Among children who did not exclusively use an enteral feeding method, the percentage experiencing at least one dysphagia-associated behavior, such as coughing or gagging, increased from 73.9% to 85.3% (p = .030) while consuming liquids and from 36.2% to 73.5% (p = .001) while consuming solids. Based on weight-for-age z-scores, the percentage of children who were moderately or severely underweight increased from 42.5% to 46.1% over the 4 years but was not statistically significant. Children exclusively using an enteral feeding method had significantly decreased odds of being underweight at assessments 3, 4, and 5., Conclusions: These data highlight the ongoing and increasing challenges of feeding young children with CZS. Our findings elucidate the physiological reasons children with CZS may be underweight and point to intervention targets, such as enteral feeding, to improve their feeding practices., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

Background and Purpose: Calcitonin gene-related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP-induced relaxation of human isolated coronary arteries (HCA)., Experimental Approach: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration-response curves to human α-CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation., Results: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL-12330A, and PKA inhibitors Rp-8-Br-cAMPs and H89, did not inhibit CGRP-induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM-34 + apamin, iberiotoxin or glibenclamide, or the Gα q inhibitor YM-254890. Phosphodiesterase inhibitors induced a concentration-dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries., Conclusion: While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m 2 . The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m 2 should be reduced by ∼30%, to 170 mg/m 2 , for patients with moderate or severe HI., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Spontaneous bacterial peritonitis is a life-threatening complication of cirrhosis that can increase healthcare utilization. The impact of albumin administration timing on hospital resource utilization and its optimal timing is unclear, despite its efficacy in improving survival for cirrhosis patients with spontaneous bacterial peritonitis. A retrospective study was conducted to evaluate the influence of the timing of albumin administration on the length of stay and total hospital cost for patients with cirrhosis and spontaneous bacterial peritonitis who require fluid resuscitation. The study utilized de-identified data from Cerner Health Facts® data. Adult inpatients with a diagnosis of cirrhosis and SBP receiving ≥1 antibiotic and fluid resuscitation between January 1, 2009, and April 30, 2018, were included and stratified by albumin administration timing: ≤24 hours from hospital admission ("timely albumin") or >24 hours of admission or no albumin ("non-timely albumin"). We used a Kaplan-Meier curve with log-rank test to evaluate the association between timing of albumin administration and time to hospital discharge and a generalized linear model to examine the association between albumin timing and total hospital costs. We identified 1,308 hospitalizations, of which 301 contained valid cost data. The timely albumin group had a median time to discharge of 6.95 days compared to 7.78 days in the non-timely group ( p = 0.02). Cost model showed that receiving timely albumin incurred 16% lower costs ( p = 0.027) than patients in the non-timely albumin group. Timely albumin administration with an antibiotic regimen may shorten the length of stay and lower costs, thereby reducing hospital resource utilization in patients with cirrhosis and spontaneous bacterial peritonitis requiring fluid resuscitation., Competing Interests: Dr. Navreet Sindhwani and Dr. E. Anne Davis were employees of Grifols SSNA at the time of this study. Santosh Telang was an employee of Boston Strategic Partners, Inc. at the time of this study. Dr. Karthik Raghunathan is a paid consultant for Grifols SSNA. Further information is available at https://openpaymentsdata.cms.gov/physician/803766. Dr. Kim is a paid consultant for Grifols SSNA. Dr. Greg Martin and Dr. Kunal Lodaya have no conflicts of interest to declare., (Copyright © 2024 W. Ray Kim et al.)

Background: Individuals with end-stage knee osteoarthritis (OA) walk at a lower intensity (ie, slower step cadence) contributing to worse physical function. Previous literature reports daily step counts and sedentary time, with little information regarding stepping bouts or cadence. Determining relationships between daily higher stepping cadence duration and clinical outcomes can move the field toward optimal daily stepping prescription., Objective: To quantify daily physical activity patterns of individuals with end-stage knee OA and determine the contribution of high stepping cadence to explain functional capacity variability., Design: Cross-sectional analysis., Setting: Veterans Administration medical center., Participants: U.S. military veterans (n = 104; age: 67.1 years [7.2]; mean [SD]; male [89.3%]) with end-stage knee OA were enrolled., Intervention: Not applicable., Main Outcome Measure: Functional capacity (6-Minute Walk Test [6MWT]). Physical activity (activPAL wearable sensor; cadence and time sitting, standing, and stepping), pain (Western Ontario and McMaster Universities Osteoarthritis Index-pain subscale) sociodemographic variables, and comorbidities (body mass index and Functional Comorbidity Index) are the main explanatory variables., Results: Participants' wake time was mainly sitting (11.0 h/day) in ≥60-minute bouts (29.7% ± 12.7 of sitting time). Standing (3.4 hours/day) and stepping (1.4 h/day) primarily occurred in 0-5 minute bouts (standing: 87.7% ± 14.4 of standing time, stepping: 98.7% ± 12.7 of stepping time) and stepping cadence was predominantly incidental (1-19 spm; 52.9% ± 9.6 of total stepping time). Backward elimination model results indicated shorter medium-to-brisk cadence bout duration, older age, and higher pain significantly explained shorter 6MWT distance ( Adj R 2 =0.24, p < .01)., Conclusions: Individuals with knee OA spend most of their waking hours sitting, while standing and stepping occurs in short bouts at very low stepping cadence. Decreased time in high stepping cadence is associated with lower functional capacity. Future studies should explore if increasing the daily time spent in higher step cadence can improve functional capacity in this population., (© 2023 American Academy of Physical Medicine and Rehabilitation.)

Background: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies., Objectives: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder., Results: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results., Conclusions: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: To investigate the prenatal detection rate of mosaicism by SNP microarray analysis, in which an individual has not one, but two, complete genomes (sets of DNA) in their body, a normal biparental line with a Genome Wide Uniparental Disomy (GWUPD) cell line was used., Methods: This study retrospectively examines the prenatal detection of GWUPD in a cohort of ∼90,000 prenatal specimens and ∼20,000 products of conceptions (POCs) that were studied by SNP microarray., Results: In total, 25 cases of GWUPD were detected; 16 cases were detected prenatally with GWUPD (∼0.018%) and 9 POCs revealed GWUPD (0.045%). The nine POC specimens presented with placental abnormalities. The 12 amniotic fluid specimens were ascertained because of abnormal ultrasound findings. Nine of 12 pregnancies had findings consistent with Beckwith-Wiedemann syndrome or because of abnormal placentas. However, three pregnancies were detected with GWUPD of maternal origin, with less common findings and demonstrated maternal origin. Four other pregnancies showed GWUPD in a chorionic villus sample, but normal findings in amniotic fluid and apparently normal fetal development., Conclusions: This cohort with GWUPD mosaicism expands our understanding of GWUPD and has implications for prenatal care and counseling. Additional studies are necessary to understand the rarer maternal GWUPD., (© 2024 John Wiley & Sons Ltd.)

Objective: The objective of this study was to compare the vertical (vGRF), anterior-posterior (apGRF), and medial-lateral (mlGRF) ground reaction force (GRF) profiles throughout the stance phase of gait (1) between individuals 6 to 12 months post-anterior cruciate ligament reconstruction (ACLR) and uninjured matched controls and (2) between ACLR and individuals with differing radiographic severities of knee osteoarthritis (KOA), defined as Kellgren and Lawrence (KL) grades KL2, KL3, and KL4., Methods: A total of 196 participants were included in this retrospective cross-sectional analysis. Gait biomechanics were collected from individuals 6 to 12 months post-ACLR (n = 36), uninjured controls matched to the ACLR group (n = 36), and individuals with KL2 (n = 31), KL3 (n = 67), and KL4 osteoarthritis (OA) (n = 26). Between-group differences in vGRF, apGRF, and mlGRF were assessed in reference to the ACLR group throughout each percentage of stance phase using a functional linear model., Results: The ACLR group demonstrated lower vGRF and apGRF in early and late stance compared to the uninjured controls, with large effects (Cohen's d range: 1.35-1.66). Conversely, the ACLR group exhibited greater vGRF (87%-90%; 4.88% body weight [BW]; d = 0.75) and apGRF (84%-94%; 2.41% BW; d = 0.79) than the KL2 group in a small portion of late stance. No differences in mlGRF profiles were observed between the ACLR and either the uninjured controls or the KL2 group. The magnitude of difference in GRF profiles between the ACLR and OA groups increased with OA disease severity., Conclusion: Individuals 6 to 12 months post-ACLR exhibit strikingly similar GRF profiles as individuals with KL2 KOA, suggesting both patient groups may benefit from targeted interventions to address aberrant GRF profiles., (© 2023 American College of Rheumatology.)

Complicated genetic mechanisms and unpredictable health risks associated with the FMR1 premutation can result in challenges for patient education when the diagnosis is made in a newborn. From October 15, 2018, to December 10, 2021, North Carolina parents could obtain FMR1 premutation results about their newborns through a voluntary expanded newborn screening research study. The study provided confirmatory testing, parental testing, and genetic counseling. We developed web-based educational materials to augment information about fragile X premutation conveyed by a genetic counselor. Many genetics education materials are developed for the lay population. However, relatively little research is published on how well individuals understand these materials. We conducted three rounds of iterative user testing interviews to help refine web-based educational materials that support understanding and self-paced learning. The participants included 25 parents with a 2-year college degree or less and without a child identified with fragile X syndrome, premutation, or gray-zone allele. Content analysis of interview transcripts resulted in iterative changes and ultimately saturation of findings. Across all rounds of interviews, there were two terms that were commonly misunderstood (fragile and carrier) and two terms that elicited initial misconceptions that were overcome by participants. Many also had difficulty understanding the relationship between fragile X premutation and fragile X syndrome as well as appreciating the implications of having a "fragile X gene." Website layout, formatting, and graphics also influenced comprehension. Despite iterative changes to the content, certain issues with understandability persisted. The findings support the need for user testing to identify misconceptions that may interfere with understanding and using genetic information. Here, we describe a process used to develop and refine evidence-based, understandable parental resources on fragile X premutation. Additionally, we provide recommendations to address ongoing educational challenges and discuss the potential impact of bias on the part of expert content developers., (© 2023 RTI International. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Purpose: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room., Methods: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room., Results: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses., Conclusions: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD., (© 2024 John Wiley & Sons Ltd.)

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically-based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed., (© 2023 Simulations Plus Inc., PTC Therapeutics, Inc. and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Studies focusing on safety outcomes typically require large populations to comprehensively characterise the patient groups exposed to the medicines under investigation. However, there is often less information for subpopulations, such as pregnant or breastfeeding women, particularly when new medicines are considered. It is important to understand what information can be obtained from drug utilization studies (DUS) involving pregnant women in the early years postmarketing to provide supportive information for safety studies. The aims of this literature review are to (1) identify and review DUS for new medicines in pregnancy and breastfeeding and (2) list and summarise key information items to be reported in a DUS for new medicines in pregnancy., Methods: To identify postmarketing DUS of new prescription medicines or enantiomers in pregnancy, a systematic literature review was undertaken in PubMed and Embase between January 2015 and June 2022. In addition, the complete database of the ENCePP EU PAS Register was systematically searched to June 2022., Results: We identified 11 published DUS on new medicines in pregnancy from the ENCePP EU PAS Register and none from other sources. No studies on breastfeeding were identified. The 11 identified publications reported the medicine's use for the first 3 to 5 years after marketing approval. No reports assessed utilization in the first 3 years of approval. It was usual to issue interim reports annually (7 studies). All studies concerned conditions managed in ambulatory care (primary care and outpatient facilities) and included some primary care prescribing. Most ( n = 8) only had prescribing/dispensing data available at individual level for ambulatory care; outpatient prescribing was included in three of these studies Three studies held a limited amount of in-hospital prescribing data. A DUS can confirm at an early stage whether there are sufficient exposed pregnancies in available data sources to ensure a safety study is powered to detect a difference in the prevalence of adverse pregnancy or infant outcomes or if additional data from other databases are needed. A DUS may also help address methodological considerations such as selection of comparators. DUS can be performed embedded in a DUS in the general population, in a cohort of women of childbearing age, or in a cohort of pregnant women., Conclusion: This review summarises key aspects of a DUS for new medicines in pregnancy. DUS for new medicines in pregnancy should be planned before marketing, scheduled for the first 3 to 5 years after release, with annual interim/progress reports, and reported in peer-reviewed journals. By offering detailed information on data sources, exposure timing, prevalence and location, coprescribing, comorbidities, coexposures, and demographics, a DUS will offer a firm foundation for safety studies and will help to contextualize spontaneous reporting of serious adverse events., Competing Interests: S.L.L. is an employee of Novartis Pharmaceutical Company, A.G. of Janssen Biologics, J.S. of Bristol Myers Squibb, K.W. of GlaxoSmithKline, M.S. of Merck Healthcare, J.M. of Pfizer, and D.M.N. of Novo Nordisk., (Copyright © 2024 Sandra Lopez-Leon et al.)

Pulmonary hypertension (PH) due to interstitial lung disease (ILD), a commonly encountered complication of fibrotic ILDs, is associated with significant morbidity and mortality. Until recently, the studies of pulmonary vasodilator therapy in PH-ILD have been largely disappointing, with some even demonstrating the potential for harm. This paper is part of a series of Consensus Statements from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative for Group 3 Pulmonary Hypertension, with prior publications covering pathogenesis, prevalence, clinical features, phenotyping, clinical trials, and impact of PH-ILD. It offers a comprehensive review of and a holistic approach to treatment of PH-ILD, including the management of underlying interstitial lung diseases, importance of treating the comorbidities, emphasis on importance of exercise and palliation of dyspnea, and review of the most up-to-date guidelines for referral for potential lung transplant work up. It also summarizes the prior, ongoing, and possibly future studies in treatment of the vascular derangement of this morbid condition., Competing Interests: Dr. Oksana A. Shlobin has consulted for United Therapeutics, Bayer, Altavant, Aerovate, Jenssen&Jenssen and Merck, and is on the speaker bureau for UT, Bayer, and J&J. Mr. Eric Shen is an employee of United Therapeutics Corporation and owns stocks/shares in the company. Dr. Lucilla Piccari has received research funding from and served as a speaker for Janssen and Ferrer, advised Janssen, Ferrer, and United Therapeutics as well as received support for attending congresses from Janssen, MSD, and Ferrer, all of which not related to this manuscript. Dr. John A. Scandurra is an employee of Aria CV Inc. and owns stocks/shares in the company. Dr. Paul M. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work. Dr. Stephen J. Wort received honoraria from Janssen, MSD, Bayer, and Acceleron for advisory boards, received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen and Bayer, and travel grants, conference registration and accommodation from Actelion and GSK. Dr. Sylvia M. Nikkho is an employee of Bayer AG. Dr. Steven D. Nathan a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck, and Daewoong., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community., Competing Interests: Boucly reports consulting fees from AOP Orphan; payment, honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AOP Orphan, MSD, and Janssen; and support for attending meetings/travel from MSD and Janssen. Moles reports grants or contracts from Acceleron Pharma, Janssen, and CVS Caremark; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Gossamer Bio. Elwing reports grants or contracts from United Therapeutics Corporation, Gossamer Bio, Bayer, Acceleron/Merck, Altavant, Aerovate, Tenax, Pharmosa, Actelion/Janssen, Arena, Lung, Liquidia, and Phase Bio; consulting fees for United Therapeutics Corporation; support for attending meetings and/or travel for United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Liquida, Acceleron/Merck, Janssen/Actelion, and Insmed; and other financial or nonfinancial interests from Bayer as a grant reviewer. Jose reports grants or contracts from Team Phenomenal Hope Charity, Francis Family Foundation, United Therapeutics, and Janssen/Johnson & Johnson. Alves Jr. reports payment or honoraria from Bayer and Janssen; and support for attending meetings and/or travel from Janssen. Minty reports consulting fees from Janssen Pharmaceuticals and Orpyx Medical Technologies; and stock or stock options from Orpyx Medical Technologies. Weatherald reports grants or contracts from Janssen, Bayer, Merck, Canadian Institutes for Health Research, and the Heart & Stroke Foundation of Canada; consulting fees from Janssen and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen and Merck; payment for expert testimony from Sprigings Intellectual Property Law; support for attending meetings and/or travel from Janssen; participation on a data safety monitoring board or advisory board from Janssen, Acceleron, and Université Laval; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from the Pulmonary Hypertension Association of Canada. Mathai reports grants or contracts from NIH/NHLBI (HL125175) and DOD (W81XWH‐20‐1‐0768); consulting fees from Actelion/Janssen, Aerovate, Merck, United Therapeutics Corporation, and Theravance; and participation on a data safety monitoring board or advisory board from Bayer. Sahay reports grants or contracts from United Therapeutics Corporation, Janssen, Bayer, Merck, Liquidia, and Gossamer; consulting fees from Merck, Liquidia, and Gossamer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics Corporation (received by hospital rather than self); patents planned, issued, or pending with Janssen; and participation on a data safety monitoring board or advisory board with GSK, Bayer, United Therapeutics, and Janssen. Pulido reports grants or contracts from Janssen, MSD, and United Therapeutics; consulting fees from Janssen, Bayer, Gossamer, and MSD; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Janssen, and Pfizer. Badagliacca reports grants or contracts from United Therapeutics Corporation, Ferrer, and Janssen; consulting fees from MSD, United Therapeutics Corporation, Ferrer, Janssen, and AOP; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, United Therapeutics Corporation, Ferrer, Janssen, and AOP; and support for attending meetings and/or travel from MSD, United Therapeutics Corporation, Ferrer, Janssen, and AOP. Cirulis reports grants or contracts from Entelligence (now ATS); and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, with ATS Web Committee Co‐Director and ATS Program Committee. Gerges reports grants or contracts from AOP Health; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AOP Health, Actelion/Janssen, and Ferrer; and support for attending meetings and/or travel from AOP Health, Actelion/Janssen, Ferrer, Daiichi Sankyo, and MSD. Gillmeyer reports grants or contracts from Parker B. Francis Fellowship Award, Doris Duke Charitable Foundation Award, and National Center for Advancing Translational Sciences, National Institutes of Health (BU‐CTSI Grant Number 1UL1TR001430); and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for the American Thoracic Society Program Committee (unpaid). Hobohm reports consulting fees for Janssen, Boston Consulting, and MSD. Lau reports grants or contracts from Janssen and GSK; consulting fees for Janssen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen. Morland reports grants or contracts from United Therapeutics Corporation; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from the PVRI Innovative Drug Development Initiative (unpaid); and stock or stock options from United Therapeutics Corporation. Nikkho reports grants or contracts from Bayer AG; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from the PVRI Innovative Drug Development Initiative (unpaid). The remaining authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response., Methods: DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL)., Results: This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment., Conclusions: This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile., (© 2023 GSK and The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Opioid overdose has claimed the lives of over 340,000 Americans in the last decade. Over that same period, policymakers have taken steps to increase the availability of naloxone-an opioid antagonist used to rescue overdose victims-to people in the community. Previous studies, most of which have examined the effects of state laws designed to facilitate access to naloxone, have reached mixed conclusions about the effects of naloxone access on fatal and non-fatal overdoses. This paper exploits a unique policy experiment provided by two naloxone giveaways intended to increase naloxone possession among the general public in Pennsylvania to estimate the causal impact of naloxone distribution on fatal overdoses and opioid-related emergency department (ED) visits. Using a difference-in-differences design, I find evidence that opioid overdose deaths fell immediately following the first giveaway but increased following the second giveaway and discuss these apparently contradictory findings in the context of the changing composition of the opioid supply. I also find some evidence of a decline in opioid overdose-related ED visits following the giveaways. This study is the first to examine the effects of untargeted naloxone distribution and has implications for other novel, naloxone distribution efforts currently underway., (© 2023 The Authors. Health Economics published by John Wiley & Sons Ltd.)

We conducted qualitative research with family planning clients, potential clients, and service providers on barriers and opportunities for improving the quality of family planning services in the Philippines. The family planning service providers included the primary, secondary, and tertiary levels of the health system. Our goal was to aid in developing more effective family planning quality improvement (QI) programs. Our methods included focus groups, key informant interviews and thematic content analysis of the qualitative data. We found four themes: the components of quality of family planning care; factors influencing quality; challenges for improving quality; and provider bias in the types of family planning services offered to clients. We identified five implications for QI, including: reduce provider bias; level off the understanding of QI concepts and roles among the different family planning service providers; involve men more actively; design new digital communication strategies for reaching clients and potential clients; and explore collaborations with private sector pharmacies. The findings from this study can guide the development of a pilot family planning QI programme in the Philippines. The findings provide themes and practical insights for an intervention-focused theory of change on how to improve current programs, design new programs, be more responsive to the needs and concerns of clients and potential clients and be well-accepted and sustained by providers. This can lay the groundwork for improving family planning outcomes and reducing teenage pregnancy rates and the unmet need for family planning throughout the Philippines., (© 2023 The Authors. The International Journal of Health Planning and Management published by John Wiley & Sons Ltd.)

Objectives: Substance use disorders and borderline personality disorders (BPD) often co-occur and may be concurrently treated by Dialectical Behavior Therapy (DBT). However, there is limited information on how drug use and suicidal ideation may interact in the daily lives of individuals receiving DBT treatment., Methods: This study examined the DBT diary cards of 47 individuals in a community mental health center's partial hospital and intensive outpatient program. Multilevel modeling techniques were used to examine the moderating effects of BPD symptom severity on the relationship between same day, 1-, 2-, and 3-day lagged drug use and suicidal ideation., Results: Results indicated a significant relationship between same-day, 1-day lagged, 2-day lagged drug use and suicidal ideation. BPD was a moderator for the relationship between 1-day lagged drug use and suicidal ideation., Conclusion: Limitations of the study include the measure for BPD symptom severity was only collected pretreatment and the results are likely limited to the effects of cannabis use on suicidal ideation. Clinicians may need to consider the prolonged effects of drug use on suicidal ideation when conducting chain analyses on suicidal behaviors., (© 2023 Wiley Periodicals LLC.)

Objective: Transcript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and juvenile DM patients receiving immunosuppressive therapies., Methods: Expression data from 14 DM and 12 juvenile DM patients were compared to matched healthy controls. Regulatory effects at the transcript and protein level were analyzed by multi-enrichment analysis for assessment of affected pathways within DM and juvenile DM., Results: Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or juvenile DM, with 70 genes shared. A subset of interferon-stimulated genes was elevated, including CXCL10, ISG15, OAS1, CLEC4A, and STAT1. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and juvenile DM, including BPI, CTSG, ELANE, LTF, MPO, and MMP8. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and juvenile DM. Up-regulated components shared by DM and juvenile DM included cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR, several Bcl-2 components, and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling., Conclusion: The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of up- and down-regulated pathways among active DM and juvenile DM patients. These pathways, particularly those which feed into PI3K/AKT and MAPK signaling and neutrophil degranulation, may be potential therapeutic targets., (© 2023 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16179. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Purpose: We aimed to describe the distribution of gestational age at birth (GAB) to inform the estimation of GAB when clinical or obstetric estimates are not available for perinatal pharmacoepidemiology studies., Methods: We estimated GAB (median, mode, mean, and standard deviation) and percentage born at each gestational week in groups based on plurality and other variables for live births in CDC's U.S. birth data., Results: In 2020, 3 617 213 newborns had birth certificates with nonmissing GAB. Among singletons (3 501 693), median and mode GAB were both 39 weeks. Births with lower median GAB were from women with eclampsia (37 weeks) or receiving intensive care (37 weeks); newborns receiving intensive care (37 weeks); newborns with birth weight <2500 g (35 weeks), <1500 g (28 weeks), or <1000 g (25 weeks); and newborns not discharged alive (23 weeks). Among twins (112 633), median GAB was 36 weeks (mode, 37 weeks). Additional noteworthy groups were women with 0-6 prenatal visits (median, 34 weeks) or 7-8 prenatal visits (median, 35 weeks) or aged 15-19 years (median, 35 weeks)., Conclusions: Some maternal and infant groups had distinct GAB distributions in the United States. This information can be useful in estimating GAB when individual-level clinical estimates are not available, such as in database studies of medication use during pregnancy., (© 2023 John Wiley & Sons Ltd.)

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil., Competing Interests: J. F. Kingrey is part of the speaker bureau for United Therapeutics, Bayer pharmaceuticals, and Janssen Pharmaceuticals, attends advisory boards for United Therapeutics, Bayer, and Janssen, consults for United Therapeutics, Bayer, Janssen, and conducts research for United Therapeutics, Janssen, Acceleron, Gossamer Bio. C. E. Miller is part of the speaker bureau for United Therapeutics, Janssen, and Bayer, attends advisory boards for United Therapeutics and Janssen, consults for United Therapeutics, and conducts clinical research for United Therapeutics, Janssen, Bayer, and Insmed. J. S. Smith serves as a speaker for and has received research funds from Bayer and United Therapeutics. V. Franco has served on advisory boards for United Therapeutics and has supported research for United Therapeutics, Merck, Acceleron, Johnson and Johnson, Respira, Aerovate, Cereno, and Abbott. R. Zolty has received payments for consulting on behalf of United Therapeutics, Bayer, and Janssen/Johnson and Johnson. R. J. Oudiz has received grants from Acceleron/Merck, Gossamer Bio, Insmed, Janssen, and United Therapeutics and honoraria/speaker fees from Merck, Janssen, and United Therapeutics. J. M. Elwing consults for United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Liquida, and Merck and has received research support and grants from Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron, Altavant, Aerovate, Tenax, and Pharmosa. J. H. Huston has conducted clinical trials for Acceleron, CardiolRx, and Aadi Bioscience. L. Melendres‐Groves has received honoraria and/or fees for consultancy and advisory committees for United Therapeutics Corporation outside of submitted works. A. Ravichandran reports personal fees from United Therapeutics, Bayer, and Actelion outside the submitted work. V. Balasubramanian serves as a consultant for United Therapeutics. B. Wu, S. Hwang, S. Seaman, and M. Broderick are paid employees of United Therapeutics. F. F. Rahaghi has consulted for United Therapeutics, Janssen PH, Merck, and Altavant; served as a speaker for United Therapeutics, Janssen PH, and Bayer; and received research funding from Janssen, Bayer, Merck, Gossamer, and Bellerophon., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Competing Interests: JSH receives consultancy fees from Global Blood Therapeutics, CVS Health and Forma Therapeutics during the conduct of this study. JSP received consultancy fees from Forma Therapeutics and funding from the National Heart Lung and Blood Institute K01 HL125495 during the conduct of this study. All the other authors have no conflicts of interest to disclose.

Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8-1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified., (© 2023 GSK. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non-randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome., Methods: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid-lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims-based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses., Results: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses., Conclusions: Given the increasing use of non-randomized designs for regulatory decision-making, the application of NCO methods will strengthen study design, analysis, and interpretation of real-world data and the credibility of the resulting real-world evidence., (© 2023 John Wiley & Sons Ltd.)

For the commercial-scale isolation of phytochemicals, a suitable plant biomass source (including species, origin, growing season, etc.) must be identified, and frequent analytical verification is required to ensure that the phytochemicals are present at predefined minimum threshold concentrations. While the latter are typically assessed in the laboratory, a more efficient and less resource-intensive approach would involve non-destructive and environmentally friendly measurements in situ. Reverse iontophoretic (RI) sampling offers a potential solution to this challenge., Objective: We aimed to demonstrate the non-destructive, RI sampling of phytochemicals of interest from biomass from four different sources., Materials and Methods: RI experiments were performed in side-by-side diffusion cells using a current density of 0.5 mA/cm 2 , for a predetermined time in a defined pH environment, using (1) fresh leaves from Mangifera indica and Centella asiatica and (2) isolated peel from Punica granatum and Citrus sinensis., Results: Mangiferin, madecassoside, punicalagin, ellagic acid, and hesperidin were extracted from the different biomasses by RI. The amounts extracted ranged from 0.03 mg/100 mg of biomass for the cathodal extraction of madecassoside to 0.63 mg/100 mg of biomass for the anodal extraction of punicalagin. A linear relationship (r 2  = 0.73) between the RI-extracted quantities of punicalagin and those determined using conventional methods was demonstrated., Conclusion: The non-destructive, in situ measurement of phytochemical levels by RI represents a feasible approach for timing the harvesting process., (© 2023 L’Oreal R&I and The Authors. Phytochemical Analysis published by John Wiley & Sons Ltd.)

Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Since 1959, the Russian Farm-Fox study has bred foxes to be either tame or, more recently, aggressive, and scientists have used them to gain insight into the brain structures associated with these behavioral features. In mice, hippocampal area CA2 has emerged as one of the essential regulators of social aggression, and so to eventually determine whether we could identify differences in CA2 between tame and aggressive foxes, we first sought to identify CA2 in foxes (Vulpes vulpes). As no clearly defined area of CA2 has been described in species such as cats, dogs, or pigs, it was not at all clear whether CA2 could be identified in foxes. In this study, we cut sections of temporal lobes from male and female red foxes, perpendicular to the long axis of the hippocampus, and stained them with markers of CA2 pyramidal cells commonly used in tissue from rats and mice. We observed that antibodies against Purkinje cell protein 4 best stained the pyramidal cells in the area spanning the end of the mossy fibers and the beginning of the pyramidal cells lacking mossy fibers, resembling the pattern seen in rats and mice. Our findings indicate that foxes do have a "molecularly defined" CA2, and further, they suggest that other carnivores like dogs and cats might as well. With this being the case, these foxes could be useful in future studies looking at CA2 as it relates to aggression., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)-positive and human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC)., Methods: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2- MBC from 2015 to 2017 who initiated first-line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results-Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan-Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated., Results: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan-Meier analysis, OS rate at 3 years after first-line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log-rank p < .0001). In Cox regression analysis, first-line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423-0.823)., Conclusions: The findings of this real-world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2- MBC, largely consistent with the evidence from clinical trials., (© 2023 American Cancer Society.)

Background: Screening mammography can detect breast cancer at an early stage. Supporters of adding ultrasonography to the screening regimen consider it a safe and inexpensive approach to reduce false-negative rates during screening. However, those opposed to it argue that performing supplemental ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments., Objectives: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography alone for breast cancer screening for women at average risk of breast cancer., Search Methods: We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov up until 3 May 2021., Selection Criteria: For efficacy and harms, we considered randomised controlled trials (RCTs) and controlled non-randomised studies enrolling at least 500 women at average risk for breast cancer between the ages of 40 and 75. We also included studies where 80% of the population met our age and breast cancer risk inclusion criteria., Data Collection and Analysis: Two review authors screened abstracts and full texts, assessed risk of bias, and applied the GRADE approach. We calculated the risk ratio (RR) with 95% confidence intervals (CI) based on available event rates. We conducted a random-effects meta-analysis., Main Results: We included eight studies: one RCT, two prospective cohort studies, and five retrospective cohort studies, enrolling 209,207 women with a follow-up duration from one to three years. The proportion of women with dense breasts ranged from 48% to 100%. Five studies used digital mammography; one study used breast tomosynthesis; and two studies used automated breast ultrasonography (ABUS) in addition to mammography screening. One study used digital mammography alone or in combination with breast tomosynthesis and ABUS or handheld ultrasonography. Six of the eight studies evaluated the rate of cancer cases detected after one screening round, whilst two studies screened women once, twice, or more. None of the studies assessed whether mammography screening in combination with ultrasonography led to lower mortality from breast cancer or all-cause mortality. High certainty evidence from one trial showed that screening with a combination of mammography and ultrasonography detects more breast cancer than mammography alone. The J-START (Japan Strategic Anti-cancer Randomised Trial), enrolling 72,717 asymptomatic women, had a low risk of bias and found that two additional breast cancers per 1000 women were detected over two years with one additional ultrasonography than with mammography alone (5 versus 3 per 1000; RR 1.54, 95% CI 1.22 to 1.94). Low certainty evidence showed that the percentage of invasive tumours was similar, with no statistically significant difference between the two groups (69.6% (128 of 184) versus 73.5% (86 of 117); RR 0.95, 95% CI 0.82 to 1.09). However, positive lymph node status was detected less frequently in women with invasive cancer who underwent mammography screening in combination with ultrasonography than in women who underwent mammography alone (18% (23 of 128) versus 34% (29 of 86); RR 0.53, 95% CI 0.33 to 0.86; moderate certainty evidence). Further, interval carcinomas occurred less frequently in the group screened by mammography and ultrasonography compared with mammography alone (5 versus 10 in 10,000 women; RR 0.50, 95% CI 0.29 to 0.89; 72,717 participants; high certainty evidence). False-negative results were less common when ultrasonography was used in addition to mammography than with mammography alone: 9% (18 of 202) versus 23% (35 of 152; RR 0.39, 95% CI 0.23 to 0.66; moderate certainty evidence). However, the number of false-positive results and necessary biopsies were higher in the group with additional ultrasonography screening. Amongst 1000 women who do not have cancer, 37 more received a false-positive result when they participated in screening with a combination of mammography and ultrasonography than with mammography alone (RR 1.43, 95% CI 1.37 to 1.50; high certainty evidence). Compared to mammography alone, for every 1000 women participating in screening with a combination of mammography and ultrasonography, 27 more women will have a biopsy (RR 2.49, 95% CI 2.28 to 2.72; high certainty evidence). Results from cohort studies with methodological limitations confirmed these findings. A secondary analysis of the J-START provided results from 19,213 women with dense and non-dense breasts. In women with dense breasts, the combination of mammography and ultrasonography detected three more cancer cases (0 fewer to 7 more) per 1000 women screened than mammography alone (RR 1.65, 95% CI 1.0 to 2.72; 11,390 participants; high certainty evidence). A meta-analysis of three cohort studies with data from 50,327 women with dense breasts supported this finding, showing that mammography and ultrasonography combined led to statistically significantly more diagnosed cancer cases compared to mammography alone (RR 1.78, 95% CI 1.23 to 2.56; 50,327 participants; moderate certainty evidence). For women with non-dense breasts, the secondary analysis of the J-START study demonstrated that more cancer cases were detected when adding ultrasound to mammography screening compared to mammography alone (RR 1.93, 95% CI 1.01 to 3.68; 7823 participants; moderate certainty evidence), whilst two cohort studies with data from 40,636 women found no statistically significant difference between the two screening methods (RR 1.13, 95% CI 0.85 to 1.49; low certainty evidence)., Authors' Conclusions: Based on one study in women at average risk of breast cancer, ultrasonography in addition to mammography leads to more screening-detected breast cancer cases. For women with dense breasts, cohort studies more in line with real-life clinical practice confirmed this finding, whilst cohort studies for women with non-dense breasts showed no statistically significant difference between the two screening interventions. However, the number of false-positive results and biopsy rates were higher in women receiving additional ultrasonography for breast cancer screening. None of the included studies analysed whether the higher number of screen-detected cancers in the intervention group resulted in a lower mortality rate compared to mammography alone. Randomised controlled trials or prospective cohort studies with a longer observation period are needed to assess the effects of the two screening interventions on morbidity and mortality., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To better understand maternal morbidity, using quality data from low- and middle-income countries (LMICs), including out-of-hospital deliveries. Additionally, to compare to the WHO estimate that maternal morbidity occurs in 15% of pregnancies, which is based largely on hospital-level data., Methods: The Global Network for Women's and Children's Health Research Maternal Newborn Health Registry collected data on all pregnancies from seven sites in six LMICs between 2015 and 2020. Rates of maternal mortality and morbidity and the differences in morbidity across delivery location and birth attendant type were evaluated., Results: Among the 280 584 deliveries included in the present analysis, the overall maternal mortality ratio was 138 per 100 000, while 11.7% of women experienced at least one morbidity. Rates of morbidity were generally higher for deliveries occurring within hospitals (19.8%) and by physicians (23.6%). The lowest rates of morbidity were noted among women delivering in non-hospital healthcare facilities (5.6%) or with non-physician clinicians (e.g. nurses, midwives [5.4%])., Conclusion: The present study shows important differences in reported maternal morbidity across delivery sites, with a trend towards lower morbidity in non-hospital healthcare facilities and among non-physician clinicians., (© 2022 International Federation of Gynecology and Obstetrics.)

Hippocampal area CA2 is a molecularly and functionally distinct region of the hippocampus that has classically been defined as the area with large pyramidal neurons lacking input from the dentate gyrus and the thorny excrescences (TEs) characteristic of CA3 neurons. A modern definition of CA2, however, makes use of the expression of several molecular markers that distinguish it from neighboring CA3 and CA1. Using immunohistochemistry, we sought to characterize the staining patterns of commonly used CA2 markers along the dorsal-ventral hippocampal axis and determine how these markers align along the proximodistal axis. We used a region of CA2 that stained for both Regulator of G-protein Signaling 14 (RGS14) and Purkinje Cell Protein 4 (PCP4; "double-labeled zone" [DLZ]) as a reference. Here, we report that certain commonly used CA2 molecular markers may be better suited for drawing distinct boundaries between CA2/3 and CA2/1. For example, RGS14+ and STEP+ neurons showed minimal to no extension into area CA1 while areas stained with VGluT2 and Wisteria Floribunda agglutinin were consistently smaller than the DLZ/CA2 borders by ~100 μ on the CA1 or CA3 sides respectively. In addition, these patterns are dependent on position along the dorsal-ventral hippocampal axis such that PCP4 labeling often extended beyond the distal border of the DLZ into CA1. Finally, we found that, consistent with previous findings, mossy fibers innervate a subset of RGS14 positive neurons (~65%-70%) and that mossy fiber bouton number and relative size in CA2 are less than that of boutons in CA3. Unexpectedly, we did find evidence of some complex spines on apical dendrites in CA2, though much fewer in number than in CA3. Our results indicate that certain molecular markers may be better suited than others when defining the proximal and distal borders of area CA2 and that the presence or absence of complex spines alone may not be suitable as a distinguishing feature differentiating CA3 from CA2 neurons., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Hippocampus published by Wiley Periodicals LLC.)