Octopus-Inspired Adhesives with Switchable Attachment to Challenging Underwater Surfaces.

Adhesives that excel in wet or underwater environments are critical for applications ranging from healthcare and underwater robotics to infrastructure repair. However, achieving strong attachment and controlled release on difficult substrates, such as those that are curved, rough, or located in diverse fluid environments, remains a major challenge. Here, an octopus-inspired adhesive with strong attachment and rapid release in challenging underwater environments is presented. Inspired by the octopus's infundibulum structure, a compliant, curved stalk, and an active deformable membrane for multi-surface adhesion are utilized. The stalk's curved shape enhances conformal contact on large-scale curvatures and increases contact stress for adaptability to small-scale roughness. These synergistic mechanisms improve contact across multiple length scales, resulting in switching ratios of over 1000 within ≈30 ms with consistent attachment strength of over 60 kPa on diverse surfaces and conditions. These adhesives are demonstrated through the robust attachment and precise manipulation of rough underwater objects.

Early Readmission and Revision After Total Joint Arthroplasty: An Analysis of Cause and Cost.

Background: Bundled payments for total joint arthroplasty (TJA) were instituted by the Centers for Medicare and Medicaid Services (CMS) to reimburse providers a lump sum for operative and 90-day postoperative costs. Gaining a better understanding of which TJA patients are at risk for early return to the operating room (OR) is critical in preoperative optimization of those with modifiable risks, which could improve bundled-payment performance. Purpose: We sought to identify the most common reason for readmissions, as well as patient characteristics and costs, associated with early return to the OR among TJA patients. Methods: This was a retrospective cohort study of Medicare patients who had undergone primary total hip or knee arthroplasty (THA or TKA) between 2013 and 2018 at a tertiary care hospital. We used the CMS research identifiable files database to identify the most common reasons for readmissions and revisions within 90 days of surgery. Total billing claims were used to determine the cost of early readmissions and revisions. Multivariate regression analysis was used to determine the characteristics associated with early readmission or revision. Results: Out of 20 166 primary TJA patients identified, we found 1349 readmissions (5.6%) and 163 (0.8%) revisions within 90 days of surgery. Dislocation was the most common indication for readmission, and periprosthetic joint infection was the most common indication for revision. Early return to the OR was associated with a mean $105,988 (standard deviation [SD] = $76,865) in CMS claims for the inpatient stay. Factors associated with a higher risk of early reoperation were female sex, THA, longer length of stay, and discharge to long-term care facility. Conclusions: This retrospective cohort study found that early return to the OR after TJA increased overall 90-day costs by 260%, suggesting that early reoperation might have a significant impact on bundled payments. Further study is warranted.

Microbial DNA extraction method for avian feces and preen oil from diverse species.

As DNA sequencing technology continues to rapidly improve, studies investigating the microbial communities of host organisms (i.e., microbiota) are becoming not only more popular but also more financially accessible. Across many taxa, microbiomes can have important impacts on organismal health and fitness. To evaluate the microbial community composition of a particular microbiome, microbial DNA must be successfully extracted. Fecal samples are often easy to collect and are a good source of gut microbial DNA. Additionally, interest in the avian preen gland microbiome is rapidly growing, due to the importance of preen oil for many aspects of avian life. Microbial DNA extractions from avian fecal and preen oil samples present multiple challenges, however. Here, we describe a modified PrepMan Ultra Sample Preparation Reagent microbial DNA extraction method that is less expensive than other commonly used methodologies and is highly effective for both fecal and preen oil samples collected from a broad range of avian species. We expect our method will facilitate microbial DNA extractions from multiple avian microbiome reservoirs, which have previously proved difficult and expensive. Our method therefore increases the feasibility of future studies of avian host microbiomes.

A multicenter, randomized, non-comparative, phase II study of nivolumab ± ipilimumab for patients with metastatic sarcoma (Alliance A091401): expansion cohorts and correlative analyses.

BACKGROUND: In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers. METHODS: Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts. RESULTS: A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes. CONCLUSIONS: This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma. TRIAL REGISTRATION NUMBER: NCT02500797.

Fatty acid composition MRI of epicardial adipose tissue: Methods and detection of proinflammatory biomarkers in ST-segment elevation myocardial infarction patients.

PURPOSE: To develop a method for quantifying the fatty acid composition (FAC) of human epicardial adipose tissue (EAT) using accelerated MRI and identify its potential for detecting proinflammatory biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A multi-echo radial gradient-echo sequence was developed for accelerated imaging during a breath hold using a locally low-rank denoising technique to reconstruct undersampled images. FAC mapping was achieved by fitting the multi-echo images to a multi-resonance complex signal model based on triglyceride characterization. Validation of the method was assessed using a phantom comprised of multiple oils. In vivo imaging was performed in STEMI patients (n = 21; 14 males/seven females). FAC was quantified in EAT, subcutaneous AT, and abdominal visceral AT. RESULTS: Phantom validation demonstrated strong correlations (r > 0.97) and statistical significance (p < 0.0001) between measured and reference proton density fat fraction and FAC values. In vivo imaging of STEMI patients revealed a distinct EAT FAC profile compared to subcutaneous AT and abdominal visceral AT. EAT FAC parameters had significant correlations with left ventricular (LV) end-diastolic volume index (p < 0.05), LV end-systolic volume index (p < 0.05), and LV mass index (p < 0.05). CONCLUSIONS: Accelerated MRI enabled accurate quantification of human EAT FAC. The relationships between the EAT FAC profile and LV structure and function in STEMI patients suggest the potential of EAT FAC MRI as a biomarker for adipose tissue quality and inflammatory status in cardiovascular disease.

Stronger color evasive racial ideologies predict lower likelihood of open adoption placement with same-sex couples.

Although the adoption rate among same-sex couples has been increasing, limited research has focused on factors influencing decision making related to placing children with such couples, particularly from the standpoint of birth mothers. Additionally, there is a gap in the literature regarding how biases may influence birth mothers' decision to place their child with a same-sex couple. This study sought to examine the association between birth mothers' racial ideologies and their decision to voluntarily place their children with same-sex couples (n = 29) or mother-father couples (n = 354) during the adoption process. Results indicated that birth mothers with stronger color evasive racial attitudes were significantly less likely to place their children with same-sex couples. The need for additional research about the intersections among various forms of bias in the adoption process and the effect of potential interactions between homophobia and racism are discussed. Suggestions for professionals wishing to minimize homophobic and racist bias are provided.

Real-Time Analysis of Neuronal Cell Cultures for CNS Drug Discovery.

The ability to screen for agents that can promote the development and/or maintenance of neuronal networks creates opportunities for the discovery of novel agents for the treatment of central nervous system (CNS) disorders. Over the past 10 years, advances in robotics, artificial intelligence, and machine learning have paved the way for the improved implementation of live-cell imaging systems for drug discovery. These instruments have revolutionized our ability to quickly and accurately acquire large standardized datasets when studying complex cellular phenomena in real-time. This is particularly useful in the field of neuroscience because real-time analysis can allow efficient monitoring of the development, maturation, and conservation of neuronal networks by measuring neurite length. Unfortunately, due to the relative infancy of this type of analysis, standard practices for data acquisition and processing are lacking, and there is no standardized format for reporting the vast quantities of data generated by live-cell imaging systems. This paper reviews the current state of live-cell imaging instruments, with a focus on the most commonly used equipment (IncuCyte systems). We provide an in-depth analysis of the experimental conditions reported in publications utilizing these systems, particularly with regard to studying neurite outgrowth. This analysis sheds light on trends and patterns that will enhance the use of live-cell imaging instruments in CNS drug discovery.

Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.

MMP-3 Knockout Induces Global Transcriptional Changes and Reduces Cerebral Infarction in Both Male and Female Models of Ischemic Stroke.

Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.

Resonance sonomanometry for noninvasive, continuous monitoring of blood pressure.

Cardiovascular disease is the leading cause of death worldwide. Existing methods for continuous, noninvasive blood pressure (BP) monitoring suffer from poor accuracy, uncomfortable form factors, or a need for frequent calibration, limiting their adoption. We introduce a new framework for continuous BP measurement that is noninvasive and calibration-free called resonance sonomanometry. The method uses ultrasound imaging to measure both the arterial dimensions and artery wall resonances that are induced by acoustic stimulation, which offers a direct measure of BP by a fully determined physical model. The approach and model are validated in vitro using arterial mock-ups and then in multiple arteries in human subjects. This approach offers the promise of robust continuous BP measurements, providing significant benefits for early diagnosis and treatment of cardiovascular disease.

Hypoxic-Normoxic Crosstalk Activates Pro-Inflammatory Signaling in Human Cardiac Fibroblasts and Myocytes in a Post-Infarct Myocardium on a Chip.

Myocardial infarctions locally deprive myocardium of oxygenated blood and cause immediate cardiac myocyte necrosis. Irreparable myocardium is then replaced with a scar through a dynamic repair process that is an interplay between hypoxic cells of the infarct zone and normoxic cells of adjacent healthy myocardium. In many cases, unresolved inflammation or fibrosis occurs for reasons that are incompletely understood, increasing the risk of heart failure. Crosstalk between hypoxic and normoxic cardiac cells is hypothesized to regulate mechanisms of repair after a myocardial infarction. To test this hypothesis, microfluidic devices are fabricated on 3D printed templates for co-culturing hypoxic and normoxic cardiac cells. This system demonstrates that hypoxia drives human cardiac fibroblasts toward glycolysis and a pro-fibrotic phenotype, similar to the anti-inflammatory phase of wound healing. Co-culture with normoxic fibroblasts uniquely upregulates pro-inflammatory signaling in hypoxic fibroblasts, including increased secretion of tumor necrosis factor alpha (TNF-α). In co-culture with hypoxic fibroblasts, normoxic human induced pluripotent stem cell (hiPSC)-derived cardiac myocytes also increase pro-inflammatory signaling, including upregulation of interleukin 6 (IL-6) family signaling pathway and increased expression of IL-6 receptor. Together, these data suggest that crosstalk between hypoxic fibroblasts and normoxic cardiac cells uniquely activates phenotypes that resemble the initial pro-inflammatory phase of post-infarct wound healing.

Toward a Diagnostic Imaging Algorithm for Undifferentiated Pulsatile Tinnitus.

OBJECTIVE: Decisions around the diagnostic evaluation for pulsatile tinnitus (PT) remain challenging. We describe the usage patterns and diagnostic accuracy of imaging modalities and propose an evidence-based diagnostic approach for undifferentiated PT. STUDY DESIGN: Retrospective. SETTING: Single otology/neurotology clinic. SUBJECTS: Patients with PT presenting between 2009 and 2020. MAIN OUTCOME MEASURES: Sensitivity, specificity, diagnostic yield, and diagnostic accuracy. RESULTS: A total of 315 subjects met inclusion criteria (74% female, mean ± SD age = 52 ± 17 years). Subjects were divided into four cohorts based on exam findings: normal (n = 229), venous cohort (n = 34), arterial cohort (n = 16), and outer/middle ear pathology cohort (n = 40). In total, 53% of patients received a nonidiopathic diagnosis for PT. The most common identifiable cause was sigmoid sinus dehiscence (78%) in the venous cohort, carotid stenosis (36%) in the arterial cohort, and glomus tumor (56%) in the outer/middle ear pathology cohort. There was a higher diagnostic rate among patients with positive exam findings compared to those with unrevealing exams ( p = 0.04). Imaging studies with the highest diagnostic yield were computed tomography (CT) venography (44%), formal angiography (42%), and magnetic resonance venography (40%); studies with the highest specificity were formal angiography (0.82), CT angiography (0.67), and CT venography (0.67). A diagnostic algorithm is proposed. CONCLUSIONS: Reaching a diagnosis in patients with PT requires a systematic approach, taking into account both clinical and radiographic information. Physical examination is a key first step for differentiating patients into venous, arterial, and other cohorts to narrow down the likely pathology and determine which radiographic studies have the highest yield and accuracy.

What Is the Carbon Footprint of Adult Spinal Deformity Surgery?

Background/Objectives: While the economic cost of adult spinal deformity (ASD) surgery has been studied extensively, its environmental impact is unknown. The aim of this study is to determine the carbon footprint (CF) associated with ASD surgery. Methods: ASD patients who underwent > four levels of corrective surgery between 2017 and 2021 were included. The open group included a posterior-only, single-stage technique, while the minimally invasive surgery (MIS) group was defined as the use of lateral interbody fusion and percutaneous posterior screw fixation. The two groups were propensity-score matched to adjust for baseline demographic, surgical, and radiographic characteristics. Data on all disposables and reusable instruments, anesthetic gas, and non-gas medications used during surgery were collected from medical records. The CF of transporting, using, and disposing of each product and the footprint of energy use in operating rooms were calculated. The CF produced was evaluated using the carbon dioxide equivalent (CO2e), which is relative to the amount of CO2 with an equivalent global warming potential. Results: Of the 175 eligible patients, 15 pairs (65 ± 9 years, 47% female) were properly matched and analyzed for all variables. The average CF generated per case was 147.7 ± 37.3 kg-CO2e, of which 54% was attributable to energy used to sterilize reusable instruments, followed by anesthetic gas released into the environment (17%) and operating room air conditioning (15%). Conclusions: The CF generated during ASD surgery should be reduced using a multidisciplinary approach, taking into account that different surgical procedures have different impacts on carbon emission sources.

Aging precisely: Precision medicine through the lens of an older adult.

Precision medicine presents an opportunity to use novel, data-driven strategies to improve patient care. The field of precision medicine has undergone many advancements over the past few years. It has moved beyond incorporation of individualized genetic risk into medical decision-making to include multiple other factors such as unique social, demographic, behavioral, and clinical characteristics. Geriatric medicine stands to benefit heavily from the integration of precision medicine into its standard practices. Older adults, compared with other populations, have high clinical and biological heterogeneity that can alter the risks and benefits of different approaches to patient care. These factors have not been routinely considered previously by geriatricians. Yet, geriatricians' ability to address older adults' baseline heterogeneity is increasingly recognized as a cornerstone of delivering quality care in a geriatric medical practice. Given the shared focus of individualized decision-making, precision medicine is a natural fit for geriatric medicine. This manuscript provides, via cases and discussion, examples that illustrate how precision medicine can improve the care of our older patients today. We will share specific and existing tools and evidence, and review the existing multilevel barriers to further incorporate and implement these tools into clinical practice. We propose methods to address these barriers and to help realize the full potential of precision medicine for the care of older adults. We conclude with a brief discussion of potential future directions of research of precision medicine in the care of older adults.

Isolated decompression for degenerative spondylolisthesis is less costly than fusion even with high revision rates.

BACKGROUND CONTEXT: Isolated decompression and decompression with instrumented fusion are accepted surgical treatments for lumbar spondylolisthesis. Although isolated decompression is a less costly solution with similar patient-reported outcomes, it is associated with higher rates of reoperation than primary fusion. PURPOSE: To determine the costs associated with primary decompression, primary fusion, and decompression and fusion for degenerative spondylolisthesis. We further sought to establish at what revision rate is primary decompression still a less costly surgical treatment for degenerative lumbar spondylolisthesis. STUDY DESIGN/SETTING: A retrospective database study of the Medicare Provider Analysis and Review (MEDPAR) limited data set. PATIENT SAMPLE: Patients who underwent single-level fusion or decompression for degenerative spondylolisthesis. OUTCOME MEASURES: Cost of surgical care. METHODS: All inpatient stays that underwent surgery for single-level lumbar/lumbosacral degenerative spondylolisthesis in the 2019 calendar year (n=6,653) were queried from the MEDPAR limited data set. Patients were stratified into three cohorts: primary decompression (n=300), primary fusion (n=5,757), and revision fusion (n=566). Univariate analysis was conducted to determine cost differences between these groups and results were confirmed with multivariable regression. An economic analysis was then done to determine at what revision rate would primary decompression still be a less costly treatment choice. RESULTS: on univariate analysis, the cost of primary single-level decompression for spondylolisthesis was $14,690±9,484, the cost of primary single-level fusion was $26,376±11,967, and revision fusion was $26,686±11,309 (p<0.001). on multivariate analysis, primary fusion was associated with an increased cost of $3,751, and revision fusion was associated with increased cost of $7,502 (95%ci: 2,990-4,512, p<0.001). economic analysis found that a revision rate less than or equal to 43.8% would still result in primary decompression being less costly for a practice than primary fusion for all patients. CONCLUSIONS: Isolated decompression for degenerative lumbar spondylolisthesis is a less costly treatment choice even with rates of revision fusion as high as 43.8%. This was true even with an assumed revision rate of 0% after primary fusion. This study solely looks at cost data, however, and many patients may still benefit from primary fusion when appropriately indicated.

Lymphatic vessel transit seeds cytotoxic resident memory T cells in skin draining lymph nodes.

Lymphatic transport shapes the homeostatic immune repertoire of lymph nodes (LNs). LN-resident memory T cells (TRMs) play an important role in site-specific immune memory, yet how LN TRMs form de novo after viral infection remains unclear. Here, we tracked the anatomical distribution of antiviral CD8+ T cells as they seeded skin and LN TRMs using a model of vaccinia virus-induced skin infection. LN TRMs localized to the draining LNs (dLNs) of infected skin, and their formation depended on the lymphatic egress of effector CD8+ T cells from the skin, already poised for residence. Effector CD8+ T cell transit through skin was required to populate LN TRMs in dLNs, a process reinforced by antigen encounter in skin. Furthermore, LN TRMs were protective against viral rechallenge in the absence of circulating memory T cells. These data suggest that a subset of tissue-infiltrating CD8+ T cells egress from tissues during viral clearance and establish a layer of regional protection in the dLN basin.

Lower vascular conductance responses to handgrip exercise are improved following acute antioxidant supplementation in young individuals with post-traumatic stress disorder.

Young individuals with post-traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23 ± 3 years), and 13 age- and sex-matched controls (CTRL) participated in the study. Exercise-induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6 kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P = 0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6 kg: P < 0.01) by blunting elevated exercise-induced MAP responses (3 kg: P = 0.01; 6 kg: P < 0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise-induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance.

Prevalence and determinants of moderate-to-severe anaemia in the third trimester of pregnancy: a multicenter cross-sectional study in Lagos, Nigeria.

The high burden of anaemia during pregnancy underscores the urgent need to gain a comprehensive understanding of the factors contributing to its widespread occurrence. Our study assessed the prevalence and the trends of moderate-to-severe anaemia (MSA) in late pregnancy (28 to 36 weeks) and then investigated the key determinants driving this prevalence among women in Lagos, Nigeria. We conducted a secondary data analysis involving 1216 women enrolled in the Predict-PPH study between January and March 2023. We employed a multivariate binary logistic regression model with a backward stepwise selection approach to identify significant predictors of MSA. The study revealed a 14.5% prevalence of MSA during pregnancy. Independent predictors of MSA included having given birth to two or more children (adjusted odds ratio = 1.46, 95% confidence interval: 1.03-2.07), having a maternal body mass index (BMI) of 28 kg/m2 or higher (adjusted odds ratio = 1.84, 95% confidence interval: 1.29-2.61), having less than tertiary education (adjusted odds ratio = 1.51, 95% confidence interval: 1.08-2.11), and being unemployed (adjusted odds ratio = 1.97, 95% confidence interval: 1.19-3.26). It is crucial for pregnant women, particularly those with higher parities and elevated BMI, to be monitored regularly for anaemia and its consequences during their antenatal care. Additionally, addressing the link between low education, unemployment, and anaemia necessitates comprehensive strategies that empower women in terms of education and economic status to enhance the overall well-being of individuals and communities, ultimately reducing the prevalence of anaemia and associated health issues in pregnancy.

Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.