The clinical and cost-effectiveness of elective primary total knee replacement with PAtellar Resurfacing compared to selective patellar resurfacing: a pragmatic multicentre randomized controlled Trial (PART).

Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon's decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing.

A Novel TGFß Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice.

As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats. Radiation persistently increases the signaling cascade of transforming growth factor ß (TGFß), leading to heightened fibrosis as characteristic of the delayed effects of radiation exposure. We investigate here a potential radiation medical countermeasure, IPW-5371, a small molecule inhibitor of TGFßRI kinase (ALK5). We found that mice exposed to sub-lethal whole-body irradiation and chronic Western diet consumption but treated with IPW-5371 had a similar body weight, food consumption, and fat mass compared to control mice exposed to radiation. The IPW-5371 treated mice maintained lower fibrosis and fat accumulation in the liver, were more responsive to insulin and had lower circulating triglycerides and better muscle endurance. Future studies are needed to verify the improvement by IPW-5371 on the structure and function of other metabolically active tissues such as adipose and skeletal muscle, but these data demonstrate that IPW-5371 protects liver and whole-body health in rodents exposed to radiation and a Western diet, and there may be promise in using IPW-5371 to prevent the development of MAFLD.

Correlation of Patient-Reported Social Determinants of Health With Census Tract Measures of Socioeconomic Disadvantage in Patients With GI Cancers in Eastern North Carolina.

PURPOSE: Investigating the impact of social determinants of health (SDOHs) on cancer care in large populations relies on census estimates. Routine clinic SDOH screening provides timely patient-level information which could inform best practices. This study evaluated the correlation between patient-reported SDOH needs and population-level census tract measures. METHODS: This was a retrospective cross-sectional study of a cohort of adult patients with GI malignancy screened for SDOHs such as financial insecurity, transportation, and food insecurity during initial outpatient evaluation at East Carolina University (formerly Vidant) Health Medical Center in Greenville, NC (November 2020-July 2021). Primary outcomes included number and severity of identified SDOH needs and area deprivation index (ADI) and census tract measures for each patient. Spearman rank correlations were calculated among patient-level needs and between patient-level needs and similar census tract measures. RESULTS: Of 112 patients screened, 58.9% self-identified as White (n = 66) and 41.1% as Black (n = 46). A total of 50.5% (n = 54) resided in a rural county. The collective median state ADI rank was 7 (IQR, 5-9). The median household income was $38,125 in US dollars (USD) (IQR, $31,436-$48,934 [USD]). Only 12.5% (n = 14) reported a moderate or severe financial need. Among reported needs, financial need moderately correlated with food insecurity (coefficient, 0.46; P < .001) and transportation (coefficient, 0.45; P < .001). Overall, census tract measures and reported needs poorly correlated. Lack of transportation correlated with percentage of households without a vehicle (coefficient, 0.18; P = .03) and limited access to healthy foods (coefficient, 0.18; P = .04). CONCLUSION: Given the poor correlation between reported and census needs, population-level measures may not accurately predict patient-reported needs. These findings highlight the importance of SDOH screening in the clinical setting to reduce health disparities and identify opportunities to improve care delivery.

Prevalence of sexual abuse and intimate partner violence in adults with spina bifida.

BACKGROUND: People with disabilities and chronic medical conditions are known to be at higher risk of sexual abuse (SA) and intimate partner violence (IPV). People with spina bifida (SB) are vulnerable, but little is known about the prevalence of abuse in this population. OBJECTIVE: To evaluate the prevalence and risk factors of SA and IPV in adults with SB. METHODS: An anonymous international cross-sectional online survey of adults with SB asked about history of SA ("sexual contact that you did not want") and IPV ("hit, slapped, kicked, punched or hurt physically by a partner"). RESULTS: Median age of the 405 participants (61% female) was 35 years. Most self-identified as heterosexual (85%) and were in a romantic relationship (66%). A total of 19% reported a history of SA (78% no SA, 3% preferred not to answer). SA was more frequently reported by women compared to men (27% vs. 5%, p < 0.001) and non-heterosexual adults compared to heterosexuals (41% vs. 15%, p < 0.001). Twelve percent reported a history of IPV (86% no IPV, 2% preferred not to answer). IPV was more frequently reported by women compared to men (14% vs. 9%, p = 0.02), non-heterosexuals compared to heterosexuals (26% vs. 10%, p = 0.002), and adults with a history of sexual activity versus those without (14% vs. 2%, p = 0.01). CONCLUSION: People with SB are subjected to SA and IPV. Women and non-heterosexuals are at higher risk of both.

Parental decision regret after pediatric urologic surgeries compared to decisions of everyday life.

INTRODUCTION: Parents are at risk of decision regret (DR) for decisions affecting their children. The Decision Regret Scale (DRS) measures medical DR but lacks context outside of healthcare. OBJECTIVE: To compare parental DR 1) between common pediatric urologic surgeries and everyday decisions and 2) with preference to make a different choice. METHODS: We conducted a cross-sectional online survey of randomly selected parents >1year (y) after their children underwent: orchiopexy (males ≤10y), open ureteral reimplant (OUR, females 2-6y), open pyeloplasty (OP, ≤2y), or robotic pyeloplasty (RP, 5-17y) (2017-2021). Higher DRS scores indicate increased DR (none: 0, mild: 1-25, moderate: 30-50, strong: 55-75, very strong: 80-100). Parents completed DRS on four decisions: their child's surgery, most recent/current romantic relationship, most recent leased/purchased car, and most recent purchased meal. Parents reported if they would make the same choice (yes/no). Nonparametric statistics were used. RESULTS: We surveyed 191 parents (orchiopexy n = 52, OUR n = 50, OP n = 51, RP n = 38). The median parent age was 36y (mothers: 86%). Some DR was reported for all decisions, but with significant differences in DR severity. The lowest median DRS score was seen with surgery (orchiopexy 0 [IQR 0-10], OUR 0 [IQR 0-5], OP 0 [IQR 0-0], RP 0 [IQR 0-0]), with no difference between surgery groups (p = 0.78). This was followed by relationship (0, IQR 0-20), car (15, IQR 0-25), and meal (20, IQR 0-30, p < 0.001). Most parents did not report any DR regarding surgery (orchiopexy 69%, OUR 74%, OP 76%, RP 76%, with no difference between surgery groups p = 0.85, Summary Figure). Comparatively, 59% of parents did not have any regret about their relationship, 37% their car, and 28% their meal (p < 0.001). All surgical DR was mild or moderate. No parent (0%) would have chosen differently for their child's surgery versus 4-12% for non-surgical decisions (p < 0.001). Overall, increasing DR corresponded to increasing desire to have made a different choice (DRS≤10: 0%, DRS 45-50: 32%, DRS 55-60: 66%, DRS≥75: 100%, p < 0.001). CONCLUSION: Parental DR varied between urological surgical and non-surgical decisions. It was lowest after surgery. Some regret was reported after every decision, but the subset of parents with regret was smallest after surgical decisions. Positive DRS scores do not necessarily correspond to parents wishing they made a different choice.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Tissue-resident macrophages specifically express Lactotransferrin and Vegfc during ear pinna regeneration in spiny mice.

The details of how macrophages control different healing trajectories (regeneration vs. scar formation) remain poorly defined. Spiny mice (Acomys spp.) can regenerate external ear pinnae tissue, whereas lab mice (Mus musculus) form scar tissue in response to an identical injury. Here, we used this dual species system to dissect macrophage phenotypes between healing modes. We identified secreted factors from activated Acomys macrophages that induce a pro-regenerative phenotype in fibroblasts from both species. Transcriptional profiling of Acomys macrophages and subsequent in vitro tests identified VEGFC, PDGFA, and Lactotransferrin (LTF) as potential pro-regenerative modulators. Examining macrophages in vivo, we found that Acomys-resident macrophages secreted VEGFC and LTF, whereas Mus macrophages do not. Lastly, we demonstrate the requirement for VEGFC during regeneration and find that interrupting lymphangiogenesis delays blastema and new tissue formation. Together, our results demonstrate that cell-autonomous mechanisms govern how macrophages react to the same stimuli to differentially produce factors that facilitate regeneration.

Obesity Heterogeneity by Neighborhood Context in a Largely Latinx Sample.

Neighborhood socioeconomic context where Latinx children live may influence body weight status. Los Angeles County and Orange County of Southern California both are on the list of the top ten counties with the largest Latinx population in the USA. This heterogeneity allowed us to estimate differential impacts of neighborhood environment on children's body mass index z-scores by race/ethnicity using novel methods and a rich data source. We geocoded pediatric electronic medical record data from a predominantly Latinx sample and characterized neighborhoods into unique residential contexts using latent profile modeling techniques. We estimated multilevel linear regression models that adjust for comorbid conditions and found that a child's place of residence independently associates with higher body mass index z-scores. Interactions further reveal that Latinx children living in Middle-Class neighborhoods have higher BMI z-scores than Asian and Other Race children residing in the most disadvantaged communities. Our findings underscore the complex relationship between community racial/ethnic composition and neighborhood socioeconomic context on body weight status during childhood.

Opportunity Strikes for Reducing Cancer Drug Waste: Bortezomib as an Example of Vial Mis-Sizing in Oncology.

Mis-sized packaging leads to millions of dollars in drug waste annually. Now is the time to act.

Long-term results and explant analysis of the ReMotion total wrist arthroplasty.

The ReMotion wrist replacement has good short- to medium-term survival with an acceptable complication profile as we previously reported in a cohort of patients with rheumatoid arthritis. We now report the long-term results of the same cohort and details of explant analysis of revisions undertaken for aseptic loosening. A total of 16 wrists were reviewed. Seven prostheses remain in situ with no obvious signs of wear or radiological loosening at a mean follow-up of 15.5 years. Three wrists had been revised: one for infection and two for aseptic loosening. Five patients (six wrists) died 2-9 years after operation from unrelated causes. Explant analysis demonstrated relatively minor wear compared with the published results of the Universal-2 prosthesis. We hypothesize that this may be explained by differences in polyethylene sterilization and prosthetic design. The ReMotion wrist replacement has favourable long-term results in patients with rheumatoid arthritis with a 16-year survival rate of 78%-86%.Level of evidence: IV.

Histone deacetylation and cytosine methylation compartmentalize heterochromatic regions in the genome organization of Neurospora crassa.

Chromosomes must correctly fold in eukaryotic nuclei for proper genome function. Eukaryotic organisms hierarchically organize their genomes, including in the fungus Neurospora crassa, where chromatin fiber loops compact into Topologically Associated Domain-like structures formed by heterochromatic region aggregation. However, insufficient data exist on how histone posttranslational modifications (PTMs), including acetylation, affect genome organization. In Neurospora, the HCHC complex [composed of the proteins HDA-1, CDP-2 (Chromodomain Protein-2), Heterochromatin Protein-1, and CHAP (CDP-2 and HDA-1 Associated Protein)] deacetylates heterochromatic nucleosomes, as loss of individual HCHC members increases centromeric acetylation, and alters the methylation of cytosines in DNA. Here, we assess whether the HCHC complex affects genome organization by performing Hi-C in strains deleted of the cdp-2 or chap genes. CDP-2 loss increases intra- and interchromosomal heterochromatic region interactions, while loss of CHAP decreases heterochromatic region compaction. Individual HCHC mutants exhibit different patterns of histone PTMs genome-wide, as CDP-2 deletion increases heterochromatic H4K16 acetylation, yet smaller heterochromatic regions lose H3K9 trimethylation and gain interheterochromatic region interactions; CHAP loss produces minimal acetylation changes but increases heterochromatic H3K9me3 enrichment. Loss of both CDP-2 and the DIM-2 DNA methyltransferase causes extensive genome disorder as heterochromatic-euchromatic contacts increase despite additional H3K9me3 enrichment. Our results highlight how the increased cytosine methylation in HCHC mutants ensures genome compartmentalization when heterochromatic regions become hyperacetylated without HDAC activity.

Enduring questions in regenerative biology and the search for answers.

The potential for basic research to uncover the inner workings of regenerative processes and produce meaningful medical therapies has inspired scientists, clinicians, and patients for hundreds of years. Decades of studies using a handful of highly regenerative model organisms have significantly advanced our knowledge of key cell types and molecular pathways involved in regeneration. However, many questions remain about how regenerative processes unfold in regeneration-competent species, how they are curtailed in non-regenerative organisms, and how they might be induced (or restored) in humans. Recent technological advances in genomics, molecular biology, computer science, bioengineering, and stem cell research hold promise to collectively provide new experimental evidence for how different organisms accomplish the process of regeneration. In theory, this new evidence should inform the design of new clinical approaches for regenerative medicine. A deeper understanding of how tissues and organs regenerate will also undoubtedly impact many adjacent scientific fields. To best apply and adapt these new technologies in ways that break long-standing barriers and answer critical questions about regeneration, we must combine the deep knowledge of developmental and evolutionary biologists with the hard-earned expertise of scientists in mechanistic and technical fields. To this end, this perspective is based on conversations from a workshop we organized at the Banbury Center, during which a diverse cross-section of the regeneration research community and experts in various technologies discussed enduring questions in regenerative biology. Here, we share the questions this group identified as significant and unanswered, i.e., known unknowns. We also describe the obstacles limiting our progress in answering these questions and how expanding the number and diversity of organisms used in regeneration research is essential for deepening our understanding of regenerative capacity. Finally, we propose that investigating these problems collaboratively across a diverse network of researchers has the potential to advance our field and produce unexpected insights into important questions in related areas of biology and medicine.

The impact of restricted provision of publicly funded elective hip and knee joints replacement during the COVID-19 pandemic in England.

AIMS: Elective hip and knee replacement operations were suspended in April 2020 due to the COVID-19 pandemic. The impact of this suspension and continued disruption to the delivery of joint replacement surgery is still emerging. We describe the impact of the pandemic on the provision of publicly funded elective hip and knee replacement surgery at one teaching hospital in England and on which patients had surgery. METHODS: We included all elective primary and revision hip and knee replacements performed at one hospital between January 2016 and June 2021. Using data for the years 2016-2019, we estimated the expected number of operations and beds occupied per month in January 2020 to June 2021 using time series linear models (adjusting for season and trend). We compared the predictions with the real data for January 2020 to June 2021 to assess the impact of the pandemic on the provision of elective hip and knee replacements. We compared the length of stay and characteristics (age, gender, number of comorbidities, index of multiple deprivation) of patients who had surgery before the pandemic with those who had surgery during the pandemic. RESULTS: We included 6,964 elective primary and revision hip and knee replacements between January 2016 and June 2021. Between January 2020 and June 2021 primary hip replacement volume was 59% of predicted, and 47% for primary knee replacements. Revision hip replacement volume was 77% of predicted, and 42% for revision knee replacement. Median length of stay was one day shorter for primary (4 vs 3 days) and revision (6 vs 5 days) operations during the pandemic compared with before. Patients operated on during the pandemic were younger and had slightly more comorbidities than those operated on before the pandemic. CONCLUSIONS: The restricted provision of elective hip and knee replacements during the COVID-19 pandemic changed the patient casemix, but did not introduce new inequalities in access to these operations. Patients were younger, had more comorbidities, and stayed in hospital for less time than those treated before the pandemic. Approximately half the number of operations were performed during the pandemic than would have been expected and the effect was greatest for revision knee replacements.

Impact of an enhanced recovery after surgery program with a multimodal analgesia care pathway on opioid prescribing and clinical outcomes for patients undergoing colorectal surgery.

Background: Opioids are a mainstay for acute pain management, but their side effects can adversely impact patient recovery. Multimodal analgesia (MMA) is recommended for treatment of postoperative pain and has been incorporated in enhanced recovery after surgery (ERAS) protocols. The objective of this quality improvement study was to implement an MMA care pathway as part of an ERAS program for colorectal surgery and to measure the effect of this intervention on patient outcomes and costs. Methods: This pre-post study included 856 adult inpatients who underwent an elective colorectal surgery at three hospitals within an integrated healthcare system. The impact of ERAS program implementation on opioid prescribing practices, outcomes, and costs was examined after adjusting for clinical and demographic confounders. Results: Improvements were seen in MMA compliance (34.0% vs 65.5%, P < 0.0001) and ERAS compliance (50.4% vs 57.6%, P < 0.0001). Reductions in mean days on opioids (4.2 vs 3.2), daily (51.6 vs 33.4 mg) and total (228.8 vs 112.7 mg) morphine milligram equivalents given during hospitalization, and risk-adjusted length of stay (4.3 vs 3.6 days, P < 0.05) were also observed. Conclusions: Implementing ERAS programs that include MMA care pathways as standard of care may result in more judicious use of opioids and reduce patient recovery time.

Biased brain and behavioral responses towards kin in males of a communally breeding species.

In complex social environments, individuals may interact with not only novel and familiar conspecifics but also kin and non-kin. The ability to distinguish between conspecific identities is crucial for most animals, yet how the brain processes conspecific type and how animals may alter behavior accordingly is not well known. We examined whether the communally breeding spiny mouse (Acomys cahirinus) responds differently to conspecifics that vary in novelty and kinship. In a group interaction test, we found that males can distinguish novel kin from novel non-kin, and preferentially spend time with novel kin over familiar kin and novel non-kin. To determine whether kinship and novelty status are differentially represented in the brain, we conducted immediate early gene tests, which revealed the dorsal, but not ventral, lateral septum differentially processes kinship. Neither region differentially processes social novelty. Further, males did not exhibit differences in prosocial behavior toward novel and familiar conspecifics but exhibited more prosocial behavior with novel kin than novel non-kin. These results suggest that communally breeding species may have evolved specialized neural circuitry to facilitate a bias to be more affiliative with kin, regardless of whether they are novel or familiar, potentially to promote prosocial behaviors, thereby facilitating group cohesion.

Neural crest cells give rise to non-myogenic mesenchymal tissue in the adult murid ear pinna.

Despite being a major target of reconstructive surgery, development of the external ear pinna remains poorly studied. As a craniofacial organ highly accessible to manipulation and highly conserved among mammals, the ear pinna represents a valuable model for the study of appendage development and wound healing in the craniofacial complex. Here we provide a cellular characterization of late gestational and postnatal ear pinna development in Mus musculus and Acomys cahirinus and demonstrate that ear pinna development is largely conserved between these species. Using Wnt1-cre;ROSAmT/mG mice we find that connective tissue fibroblasts, elastic cartilage, dermal papilla cells, dermal sheath cells, vasculature, and adipocytes in the adult pinna are derived from cranial crest. In contrast, we find that skeletal muscle and hair follicles are not derived from neural crest cells. Cellular analysis using the naturally occurring short ear mouse mutant shows that elastic cartilage does not develop properly in distal pinna due to impaired chondroprogenitor proliferation. Interestingly, while chondroprogenitors develop in a mostly continuous sheet, the boundaries of cartilage loss in the short ear mutant strongly correlate with locations of vasculature-conveying foramen. Concomitant with loss of elastic cartilage we report increased numbers of adipocytes, but this seems to be a state acquired in adulthood rather than a developmental abnormality. In addition, chondrogenesis remains impaired in the adult mid-distal ear pinna of these mutants. Together these data establish a developmental basis for the study of the ear pinna with intriguing insights into the development of elastic cartilage.

A Mixed-Methods Study to Evaluate the Feasibility and Acceptability of Implementing an Electronic Health Record Social Determinants of Health Screening Instrument into Routine Clinical Oncology Practice.

BACKGROUND: Routine screening for social determinants of health (SDOH) in the outpatient oncology setting is uncommon. The primary goal of this study was to prospectively evaluate the feasibility and acceptability of implementing an electronic health record (EHR) SDOH screening instrument into routine, clinical, oncology practice. METHODS: Adult patients with newly diagnosed gastrointestinal cancer presenting to a regional cancer center (November 2020 to July 2021) were eligible. Based on the consolidated framework for implementation research, feasibility measures included screening completion, median clinic visit time, and acceptability by the inter-professional care team and patients as measured by semistructured, qualitative interviews and surveys. Secondary outcomes included SDOH needs identified. RESULTS: Of 137 eligible patients, 112 (81.8%) were screened for SDOH. Demographics of the cohort included: 41.1% black (n = 46), 48.2% rural (n = 54), 4.5% uninsured (n = 5), and 6.3% Medicaid-insured (n = 7) patients. Median visit time was 97 min (95% CI 70-107 min) before and 100 min after implementation (95% CI 75-119 min; p = 0.95). In total, 95.5% (n = 107) reported at least one SDOH need. Clinicians (7/10) reported that SDOH screening was not disruptive and were supportive of ongoing use. Patients (10/10) found the screening acceptable. Screening staff (5/5) reported workflow barriers. Patients and staff also recommended revision of specific instrument questions. CONCLUSIONS: Routine collection of SDOH in an outpatient oncology setting using an EHR instrument is feasible and does not result in increased visit time for patients or clinicians. However, staff perceptions of clinic workflow disruption were reported. Further investigation to determine whether standardized SDOH assessment can improve cancer care delivery and outcomes is ongoing.