Central lines, aseptic batching services, and infection rates: A pharmacy-led initiative of intravenous tube priming within a NICU.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Central line-associated bloodstream infections (CLABSIs) are hospital-acquired, serious complications that greatly affect many vulnerable neonates throughout their hospital stay. This article describes the implementation of a unique practice in which pharmacy primes continuous infusions through medication tubing for neonatal central lines in a cleanroom at Children's Hospital Colorado - Colorado Springs (CHCO-CSH). SUMMARY: This institution is a freestanding children's hospital with a level III neonatal intensive care unit (NICU) that opened in April 2019. Since then, the pharmacy department has been priming central line tubing for continuous infusions for all patients in the NICU. Neonates are at increased risk for developing CLABSIs due to their immature immune systems and frequent need for central line placement. With that in mind, the pharmacy department decided to focus efforts on this population. Pharmacists and pharmacy technicians received training on how to properly prime tubing, document when a patient received a new central line, document if a central line was removed, and record when new tubing was due based on a department policy. CONCLUSION: This novel, pharmacy-led priming procedure resulted in a low CLABSI incidence, offering a promising strategy to reduce CLABSIs in a NICU.

High-Density Lipoprotein Particle Concentration and Size Predict Incident Coronary Artery Disease Events in a Cohort With Type 1 Diabetes.

BACKGROUND: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes. METHODS AND RESULTS: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P. CONCLUSIONS: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.

Home and School Pollutant Exposure, Respiratory Outcomes, and Influence of Historical Redlining.

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States (U.S.) during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter (PM2.5), nitrogen dioxide (NO2)) and respiratory outcomes (Composite Asthma Severity Index (CASI), lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N=240) from 9 U.S. cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of CASI and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 ppb) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (p<0.01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (p<0.005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (p>0.005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

Genetic counselors' awareness and attitudes regarding gene therapies.

There are 10 gene therapies (GTs) for hereditary conditions that are currently approved by the Food and Drug Administration (FDA). While prior research demonstrates that the majority of healthcare providers lack knowledge regarding GTs, this has not been explored within the genetic counseling profession. The authors hypothesize that the availability of GTs impacts the genetic counseling profession and that there is variable awareness on this topic among genetic counselors (GCs). We conducted a survey to assess GCs' familiarity with, comfort with, and frequency of discussing FDA-approved GTs at the time of the survey, as well as GCs' perceived impact of and educational experiences related to GT. The survey was distributed through listservs and word of mouth from January through March 2021. One hundred of the 109 responses met eligibility criteria. Respondents were more familiar with onasemnogene abeparvovec-xioi (ZOLGENSMA; Novartis Gene Therapies, Inc., Durham, NC, USA) than voretigene neparvovec-rzyl (LUXTURNA; Spark Therapeutics, Inc., Philadelphia, PA, USA; p < 0.001). Familiarity with, comfort with, and frequency of discussing both GTs varied by specialty but not by years of experience. Fifty-nine percent of respondents (58/98) reported that GTs impact their work, with differences by specialty but not by years of experience. The majority of respondents (93%; 90/97) felt that GCs should be comfortable discussing GTs with patients, and most respondents (83%; 79/95) were interested in additional GT training. Only 38% of respondents (36/95) recalled GT being included in their genetic counseling training program's curriculum, which may be skewed by recent growth of this field. Our results suggest that GCs feel that GTs impact their practice, have discrepant awareness and comfort in this area, and desire additional training on this topic. Further investigation into the actual impact and models for addressing training is warranted and will be critical as the number of approved GTs increases.

Real-World Experience With Maribavir for Treatment of Cytomegalovirus Infection in High-Risk Solid Organ Transplant Recipients.

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes.

Minimizing risk while maximizing opportunity: The infectious disease organ offer process survey.

BACKGROUND: The purpose of this study was to understand how transplant infectious disease (TID) physicians assess a potential donor with known or suspected infection and describe posttransplant management. METHODS: We designed a survey of 10 organ offer scenarios and asked questions pertaining to organ acceptability for transplantation and management posttransplant. The survey was distributed to TID clinicians via transplant society listservs and email. Responses were recorded in REDCap, and descriptive statistics were employed. RESULTS: One hundred thirteen infectious disease physicians responded to the survey, of whom 85 completed all cases. Respondents were generally in agreement regarding organ acceptability, although some divergence was seen when evaluating lungs from donors with influenza, tuberculosis, or multidrug-resistant Acinetobacter infection. Posttransplant management showed more variation. Areas of optimization were identified: (1) Further understanding of where risk-mitigation strategies within the donor offer process may improve donor acceptability and therefore organ utilization; (2) importance of recipient considerations in assessing degree of infectious risk; and (3) gaps in evidenced-based data regarding optimal posttransplant management of recipients. CONCLUSION: Evaluation of donor offers by TID clinicians is a complex process. Although the survey does not itself serve to make recommendations regarding best practices, it highlights areas where generation of data to inform acceptance and management practices may allow for improved organ utilization and recipient management.

IsoBayes: a Bayesian approach for single-isoform proteomics inference.

Studying protein isoforms is an essential step in biomedical research; at present, the main approach for analyzing proteins is via bottom-up mass spectrometry proteomics, which return peptide identifications, that are indirectly used to infer the presence of protein isoforms. However, the detection and quantification processes are noisy; in particular, peptides may be erroneously detected, and most peptides, known as shared peptides, are associated to multiple protein isoforms. As a consequence, studying individual protein isoforms is challenging, and inferred protein results are often abstracted to the gene-level or to groups of protein isoforms. Here, we introduce IsoBayes, a novel statistical method to perform inference at the isoform level. Our method enhances the information available, by integrating mass spectrometry proteomics and transcriptomics data in a Bayesian probabilistic framework. To account for the uncertainty in the measurement process, we propose a two-layer latent variable approach: first, we sample if a peptide has been correctly detected (or, alternatively filter peptides); second, we allocate the abundance of such selected peptides across the protein(s) they are compatible with. This enables us, starting from peptide-level data, to recover protein-level data; in particular, we: i) infer the presence/absence of each protein isoform (via a posterior probability), ii) estimate its abundance (and credible interval), and iii) target isoforms where transcript and protein relative abundances significantly differ. We benchmarked our approach in simulations, and in two multi-protease real datasets: our method displays good sensitivity and specificity when detecting protein isoforms, its estimated abundances highly correlate with the ground truth, and can detect changes between protein and transcript relative abundances. IsoBayes is freely distributed as a Bioconductor R package, and is accompanied by an example usage vignette.

Clearing-enabled light sheet microscopy as a novel method for three-dimensional mapping of the sensory innervation of the mouse knee.

A major barrier that hampers our understanding of the precise anatomic distribution of pain sensing nerves in and around the joint is the limited view obtained from traditional two dimensional (D) histological approaches. Therefore, our objective was to develop a workflow that allows examination of the innervation of the intact mouse knee joint in 3D by employing clearing-enabled light sheet microscopy. We first surveyed existing clearing protocols (SUMIC, PEGASOS, and DISCO) to determine their ability to clear the whole mouse knee joint, and discovered that a DISCO protocol provided the most optimal transparency for light sheet microscopy imaging. We then modified the DISCO protocol to enhance binding and penetration of antibodies used for labeling nerves. Using the pan-neuronal PGP9.5 antibody, our protocol allowed 3D visualization of innervation in and around the mouse knee joint. We then implemented the workflow in mice intra-articularly injected with nerve growth factor (NGF) to determine whether changes in the nerve density can be observed. Both 3D and 2D analytical approaches of the light sheet microscopy images demonstrated quantifiable changes in midjoint nerve density following 4 weeks of NGF injection in the medial but not in the lateral joint compartment. We provide, for the first time, a comprehensive workflow that allows detailed and quantifiable examination of mouse knee joint innervation in 3D.

Hepatitis B transmission/reactivation associated with Hepatitis B core antibody and Hepatitis C nucleic acid testing positive organs: A report from the Organ Procurement and Transplantation Network Disease Transmission Advisory Committee.

BACKGROUND: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation. AIM: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy. METHODS: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted. RESULTS: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis. CONCLUSION: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population.

The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty.

RATIONALE: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. OBJECTIVES: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). METHODS: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates. MEASUREMENTS AND MAIN RESULTS: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables. CONCLUSIONS: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

A Lung-Expressing mRNA Delivery Platform with Tunable Activity in Hypoxic Environments.

Messenger RNA (mRNA) delivery platforms often facilitate protein expression in the liver following intravenous injection and have been optimized for use in normally oxygenated cells (21% O2 atmosphere). However, there is a growing need for mRNA therapy in diseases affecting non-liver organs, such as the lungs. Additionally, many diseases are characterized by hypoxia (<21% O2 atmosphere), a state of abnormally low oxygenation in cells and tissues that can reduce the efficacy of mRNA therapies by upwards of 80%. Here, we report a Tunable Lung-Expressing Nanoparticle Platform (TULEP) for mRNA delivery, whose properties can be readily tuned for optimal expression in hypoxic environments. Briefly, our study begins with the synthesis and characterization of a novel amino acrylate polymer that can be effectively complexed with mRNA payloads into TULEPs. We study the efficacy and mechanism of mRNA delivery using TULEP, including analysis of the cellular association, endocytosis mechanisms, endosomal escape, and protein expression in a lung cell line. We then evaluate TULEP under hypoxic conditions and address hypoxia-related deficits in efficacy by making our system tunable with adenosine triphosphate (ATP). Finally, we conclude our study with an in vivo analysis of mRNA expression, biodistribution, and tolerability of the TULEP platform in mice. In presenting these data, we hope that our work highlights the utility of TULEPs for tunable and effective mRNA delivery while more broadly highlighting the utility of considering oxygen levels when developing mRNA delivery platforms.

Accuracy of Urinalysis for UTI in Spina Bifida.

OBJECTIVES: Urinary tract infections (UTIs) are common, but overdiagnosed, in children with spina bifida. We sought to evaluate the diagnostic test characteristics of urinalysis (UA) findings for symptomatic UTI in children with spina bifida. METHODS: Retrospective cross-sectional study using data from 2 centers from January 1, 2016, to December 31, 2021. Children with myelomeningocele aged <19 years who had paired UA (and microscopy, when available) and urine culture were included. The primary outcome was symptomatic UTI. We used generalized estimating equations to control for multiple encounters per child and calculated area under the receiver operating characteristics curve, sensitivity, and specificity for positive nitrites, pyuria (≥10 white blood cells/high-powered field), and leukocyte esterase (more than trace) for a symptomatic UTI. RESULTS: We included 974 encounters from 319 unique children, of which 120 (12.3%) met our criteria for UTI. Pyuria had the highest sensitivity while nitrites were the most specific. Comparatively, nitrites were the least sensitive and pyuria was the least specific. When the cohort was limited to children with symptoms of a UTI, pyuria remained the most sensitive parameter, whereas nitrites remained the least sensitive. Nitrites continued to be the most specific, whereas pyuria was the least specific. Among all encounters, the overall area under the receiver operating characteristics curve for all components of the UA was lower in children who use clean intermittent catheterizations compared with all others. CONCLUSIONS: Individual UA findings have moderate sensitivity (leukocyte esterase or pyuria) or specificity (nitrites) but overall poor diagnostic accuracy for symptomatic UTIs in children with spina bifida.

A standardized approach to evaluation and reporting of synovial histopathology in two surgically induced murine models of osteoarthritis.

OBJECTIVE: Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA. METHODS: Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined. RESULTS: There was acceptable to very good agreement when using 3-4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain. CONCLUSIONS: To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed "synovitis" score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered.

Late surgical site infections among solid organ transplant recipients: an unrecognized clinical entity.

This study identified 26 late invasive primary surgical site infection (IP-SSI) within 4-12 months of transplantation among 2073 SOT recipients at Duke University Hospital over the period 2015-2019. Thoracic organ transplants accounted for 25 late IP-SSI. Surveillance for late IP-SSI should be maintained for at least one year following transplant.

Polyphenolic Nanoparticle Platforms (PARCELs) for In Vitro and In Vivo mRNA Delivery.

Despite their successful implementation in the COVID-19 vaccines, lipid nanoparticles (LNPs) still face a central limitation in the delivery of mRNA payloads: endosomal trapping. Improving upon this inefficiency could afford improved drug delivery systems, paving the way toward safer and more effective mRNA-based medicines. Here, we present polyphenolic nanoparticle platforms (PARCELs) as effective mRNA delivery systems. In brief, our investigation begins with a computationally guided structural analysis of 1825 discrete polyphenolic structural data points across 73 diverse small molecule polyphenols and 25 molecular parameters. We then generate structurally diverse PARCELs, evaluating their in vitro mechanism and activity, ultimately highlighting the superior endosomal escape properties of PARCELs relative to analogous LNPs. Finally, we examine the in vivo biodistribution, protein expression, and therapeutic efficacy of PARCELs in mice. In undertaking this approach, the goal of this study is to establish PARCELs as viable delivery platforms for safe and effective mRNA delivery.

Standard Opiate Prescribing in Pediatric and Adolescent Gynecologic Surgery to Reduce Opiate Use: Brief Report.

STUDY OBJECTIVE: The aim of this quality improvement (QI) project was to assess postoperative narcotic use after pediatric gynecologic surgeries and establish standard postoperative opioid dosing. Through standard dosing, we hoped to decrease variability in postoperative opioid prescriptions and decrease excess opioid doses in the community. METHODS: This quality improvement project was approved by the Children's Minnesota institutional review board. Counseling on postoperative pain management was provided pre- and postoperatively. At the 2-week postoperative visit, patients were asked about the number of opioid doses used and pain control satisfaction. Baseline data were collected for 6 months, with surgeons prescribing the number of opioid doses on the basis of their personal preference. After reviewing the prescribing practices and number of doses used, standard opioid doses were established, and data collection was repeated. RESULTS: Complete data were recorded for 30 cases before implementation of standard doses and for 29 cases after implementation. Standardized opioid dosing resulted in a 30% decrease in total opioid doses in circulation (252 to 176 doses; P = .014) and a 15% reduction in excess doses in circulation (162 to 137 doses). Forty-three percent of patients did not use any opioid doses. There was no significant difference (P = .8818) in patient pain control satisfaction rating. CONCLUSION: Standard opioid dose prescribing is feasible for common pediatric gynecologic surgeries without affecting patient pain control satisfaction. Opioid dose standardization may decrease opioid circulation within the community. Approximately 2 of every 5 patients used 0 opioid doses, which suggests that a further reduction in the standard dose prescriptions is possible.

Reduced Capsaicin-Induced Mechanical Allodynia and Neuronal Responses in the DRG in the Presence of Ptpn6 Overexpression.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region 2 domain-containing phosphatase-1 (SHP-1, encoded by Ptpn6) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Ptpn6 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Ptpn6 (Shp1-Tg) and their wild type (WT) littermates were used. Ptpn6 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Ptpn6 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Ptpn6 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Maternity healthcare professionals' experiences of supporting women in decision-making for labour and birth: a qualitative study.

OBJECTIVES: To explore and characterise maternity healthcare professionals' (MHCPs) experience and practice of shared decision-making (SDM), to inform policy, research and practice development. DESIGN: Qualitative focus group study. SETTING: Large Maternity Unit in the Southwest of England. PARTICIPANTS: MHCPs who give information relating to clinical procedures and pregnancy care relating to labour and birth and are directly involved in decision-making conversations were purposively sampled to ensure representation across MHCP groups. DATA COLLECTION: A semistructured topic guide was used. DATA ANALYSIS: Reflexive thematic analysis was undertaken. RESULTS: Seven focus groups were conducted, comprising a total of 24 participants (3-5 per group). Two themes were developed: contextualising decision-making and controversies in current decision-making. Contextual factors that influenced decision-making practices included lack of time and challenges faced in intrapartum care. MHCPs reported variation in how they approach decision-making conversations and asked for more training on how to consistently achieve SDM. There were communication challenges with women who did not speak English. Three controversies were explored: the role of prior clinical experience, the validity of informed consent when women were in pain and during life-threatening emergencies and instances where women declined medical advice. CONCLUSIONS: We found that MHCPs are committed to SDM but need better support to deliver it. Structured processes including Core Information Sets, communication skills training and decision support aids may help to consistently deliver SDM in maternity care.