Intrathecal topotecan with systemic checkpoint inhibitor therapy for gastroesophageal cancer with leptomeningeal involvement: two case reports and review of the literature.

Background: Leptomeningeal metastases (LM) in gastroesophageal (GE) malignancies are exceedingly rare. Historically, treatment for LM has included steroids, radiation, chemotherapy, and intrathecal (IT) chemotherapy. However, the outcomes in GE malignancies with LM remain poor. Unfortunately, clinical trials in GE malignancies have traditionally excluded those with LM, limiting advances in therapeutic strategies. Given that LM poses potentially devastating neurologic and psychologic sequelae, there is an urgent need for more effective treatments. Case Description: Patient 1 is a 44-year-old woman with localized esophageal adenocarcinoma who undergoes neoadjuvant chemoradiation followed by esophagectomy. Seven months following surgery, she develops ataxia, weakness, and nausea/vomiting. Magnetic resonance imaging (MRI) reveals intracranial disease that is subsequently successfully resected and then treated with gamma knife (GK) radiation. Pathology confirms metastases. Three months later she is found to have LM. She receives palliative whole brain radiation therapy as well as focal radiation to the spine. Following this she transitioned to concurrent IT topotecan plus intravenous (IV) ipilumumab/nivolumab with durable response beyond 14 months. Patient 2 is a 71-year-old man with de novo metastatic esophageal adenocarcinoma with durable response to 5-fluorouracil plus irinotecan. Asymptomatic intracranial metastases are detected on surveillance scans 2 years after initial diagnosis for which he receives GK. Follow up MRI identifies new LM. As such, to treat the LM, he was transitioned to IT topotecan and IV pembrolizumab with good response for 6 months until death from a gastrointestinal bleed. Conclusions: We present two cases of LM in patients with GE adenocarcinoma who had longer survival than what has been reported. They were treated with combination IT topotecan and IV checkpoint inhibition. Further studies evaluating the central nervous system tumor immune-microenvironment can help expand our understanding of how this combination has worked well in our patients and how to care for others with similar scenarios.

The genome sequence of a heart cockle, Fragum fragum (Linnaeus, 1758).

We present a genome assembly from an individual specimen of Fragum fragum (a heart cockle; Mollusca; Bivalvia; Veneroida; Cardiidae). The genome sequence is 1,153.1 megabases in span. Most of the assembly is scaffolded into 19 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 22.36 kilobases in length. Gene annotation of this assembly on Ensembl identified 17,262 protein coding genes.

The Development of Principles for Patient and Public Involvement (PPI) in Preclinical Spinal Cord Research: A Modified Delphi Study.

INTRODUCTION: There is currently limited guidance for researchers on Patient and Public Involvement (PPI) for preclinical spinal cord research, leading to uncertainty about design and implementation. This study aimed to develop evidence-informed principles to support preclinical spinal cord researchers to incorporate PPI into their research. METHODS: This study used a modified Delphi method with the aim of establishing consensus on a set of principles for PPI in spinal cord research. Thirty-eight stakeholders including researchers, clinicians and people living with spinal cord injury took part in the expert panel. Participants were asked to rate their agreement with a series of statements relating to PPI in preclinical spinal cord research over two rounds. As part of Round 2, they were also asked to rate statements as essential or desirable. RESULTS: Thirty-eight statements were included in Round 1, after which five statements were amended and two additional statements were added. After Round 2, consensus (> 75% agreement) was reached for a total of 27 principles, with 13 rated as essential and 14 rated as desirable. The principles with highest agreement related to diversity in representation among PPI contributors, clarity of the purpose of PPI and effective communication. CONCLUSION: This research developed a previously unavailable set of evidence-informed principles to inform PPI in preclinical spinal cord research. These principles provide guidance for researchers seeking to conduct PPI in preclinical spinal cord research and may also inform PPI in other preclinical disciplines. PATIENT AND PUBLIC INVOLVEMENT STATEMENT: This study was conducted as part of a project aiming to develop PPI in preclinical spinal cord injury research associated with an ongoing research collaboration funded by the Irish Rugby Football Union Charitable Trust (IRFU CT) and the Science Foundation Ireland Centre for Advanced Materials and BioEngineering Research (SFI AMBER), with research conducted by the Tissue Engineering Research Group (TERG) at the RCSI University of Medicine and Health Sciences. The project aims to develop an advanced biomaterials platform for spinal cord repair and includes a PPI Advisory Panel comprising researchers, clinicians and seriously injured rugby players to oversee the work of the project. PPI is included in this study through the involvement of members of the PPI Advisory Panel in the conceptualisation of this research, review of findings, identification of key points for discussion and preparation of the study manuscript as co-authors.

Increasing Utilization of Scrubbing Devices for Peripheral Intravenous Disinfectable Needleless Closed Connectors.

Introduction Peripheral intravenous (IV) administration sets are a source of infection that increases morbidity, mortality, and healthcare costs. In this quality improvement project, we aimed to enhance compliance with peripheral IV hub disinfection at anesthesia induction to follow the American Society of Anesthesiologists (ASA) safe medication injection guidelines. Methods This study was conducted in the main operating suite of the University of Miami's principal hospital between June and October 2023. Audits of scrubbing device utilization by the anesthesiology team and focus groups were conducted before and after two educational interventions. Educational efforts focused on increasing compliance with peripheral IV disinfection using scrubbing devices.  Results Mean use per case, inferred from the number of devices dispensed, nearly doubled from 0.44 (95% CI, 0.37 to 0.59) to 0.82 (95% CI, 0.77 to 0.88) (P < 0.0001). Implications regarding steps to further enhance compliance are discussed. Conclusions Through a simple educational program, scrubbing device utilization increased significantly from baseline.

The effect of the infusion connection point on intravenous multi-infusion drug delivery to premature neonates - Use of standard concentration infusions of critical medications.

BACKGROUND: Sick neonates with haemodynamic instability often require complex medication regimens, which may result in the connection of a catecholamine infusion distally. This increases the dead volume of the infusion system, extending the time to medication delivery. This study evaluated the effects of body weight, and infusion connection point on the delivery rate of two medications infused through a multi-infusion system at infusion rates suitable for extremely and very low birth weight (ELBW and VLBW) neonates. METHODS: An infusion system consisting of six infusions was used to investigate time to delivery, drug concentration at time to delivery and quantity of adrenaline and dopamine administered by intravenous infusions at infusion rates suitable for premature neonates. RESULTS: In an ELBW neonate model, the measured adrenaline and dopamine concentration at 12 T was higher than expected (66.7 (7.5)% (mean (SD)) and 68.0 (4.4)%, respectively, P < 0.001). At the calculated time to delivery, neither drug reached target concentration. In a VLBW neonate model, the measured adrenaline and dopamine concentration at 12 T was higher than expected (92.2 (7.1)% and 97.1 (3.1)%, respectively, P < 0.001). Adrenaline reached target concentration at 27 (11) min and dopamine at 56 (12) min, times significantly shorter than calculated. The measured quantity of adrenaline and dopamine delivered was lower (P < 0.001) than calculated in all tested combinations except adrenaline at proximal connection (97.2 (3.4)%, P = 0.097) in the VLBW neonate model CONCLUSIONS: Using the most proximal available infusion connection considerably improves drug delivery times and drug doses delivered, which is critical during the administration of short-acting cardiovascular medications.

The Role of Genetics in Managing Peripheral Arterial Disease.

INTRODUCTION: Genome wide association studies (GWAS) have allowed for a rapid increase in our understanding of the underlying genetics and biology of many diseases. By capitalizing on common genetic variation between individuals, GWAS can identify DNA variants associated with diseases of interest. A variety of statistical methods can be applied to GWAS results which allows for risk factor identification, stratification, and to identify potential treatments. Peripheral artery disease (PAD) is a common vascular disease that has been shown to have a strong genetic component. This article provides a review of the modern literature and our current understanding of the role of genetics in PAD. SUMMARY: The largest available GWAS on PAD has identified 19 genome wide significant loci, with factor V Leiden and genes responsible for circulating lipoproteins being implicated in the development of PAD. Mendelian randomization studies have identified risk factors and causal associations with smoking, diabetes, and obesity and many other traits; protein-based MR has also identified circulating lipid and clotting factor levels associated with the incidence of PAD. Polygenic risk scores may allow for improved prediction of disease incidence and allow for early identification of at-risk patients but more work needs to be done to validate this approach. CONCLUSIONS: Genetic epidemiology has allowed for an increased understanding of PAD in the past decade. Genome-wide association studies have led to improved detection of genetic contributions to PAD, and further genetic analyses have validated risk factors and may provide options for improved screening in at-risk populations. Ongoing biobank studies of CLTI patients and the increasing ancestral diversity in biobank enrollment will allow for even further exploration into the pathogenesis and progression of PAD.

Osteoporotic Fractures: Diagnosis, Evaluation, and Significance From the International Working Group on DXA Best Practices.

Osteoporotic fractures, also known as fragility fractures, are reflective of compromised bone strength and are associated with significant morbidity and mortality. Such fractures may be clinically silent, and others may present clinically with pain and deformity at the time of the injury. Unfortunately, and even at the time of detection, most individuals sustaining fragility fractures are not identified as having underlying metabolic bone disease and are not evaluated or treated to reduce the incidence of future fractures. A multidisciplinary international working group with representation from international societies dedicated to advancing the care of patients with metabolic bone disease has developed best practice recommendations for the diagnosis and evaluation of individuals with fragility fractures. A comprehensive narrative review was conducted to identify key articles on fragility fractures and their impact on the incidence of further fractures, morbidity, and mortality. This document represents consensus among the supporting societies and harmonizes best practice recommendations consistent with advances in research. A fragility fracture in an adult is an important predictor of future fractures and requires further evaluation and treatment of the underlying osteoporosis. It is important to recognize that most fragility fractures occur in patients with bone mineral density T scores higher than -2.5, and these fractures confirm the presence of skeletal fragility even in the presence of a well-maintained bone mineral density. Fragility fractures require further evaluation with exclusion of contributing factors for osteoporosis and assessment of clinical risk factors for fracture followed by appropriate pharmacological intervention designed to reduce the risk of future fracture. Because most low-trauma vertebral fractures do not present with pain, dedicated vertebral imaging and review of past imaging is useful in identifying fractures in patients at high risk for vertebral fractures. Given the importance of fractures in confirming skeletal fragility and predicting future events, it is recommended that an established classification system be used for fracture identification and reporting.

Current status and future of genomics in fetal and maternal medicine: A scientific review commissioned by European Board and College of Obstetrics and Gynaecology (EBCOG).

This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

A µ-opioid receptor modulator that works cooperatively with naloxone.

The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.

Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy.

Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones' survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models. We developed new HDAC inhibitors (5a-p), typified by a tetrahydro-γ-carboline scaffold, characterized by high HDAC6 inhibition potency with balanced physicochemical properties for in vivo studies. Compound 5d (repistat, IC50 HDAC6 = 6.32 nM) increased the levels of acetylated α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5d promoted vision rescue in the atp6v0e1-/- zebrafish model of photoreceptor dysfunction. A single intravitreal injection of 5d in the rd10 mouse model of RP supported morphological and functional preservation of cone cells and maintenance of the retinal pigment epithelium array.

Acceptability, facilitators, and barriers to a hypothetical HIV vaccine in the pre-exposure prophylaxis era.

Little is known about the pre-implementation context for a preventive HIV vaccine. We conducted interviews of individuals in Philadelphia recruited at Penn clinics and community-based organizations serving LGBTQ-identifying persons of color who 1) were cisgender men who had sex with men, or were transgender-identified, 2) had a sexually transmitted infection in the last 12 months, or sex with multiple partners within the last two weeks. We assessed acceptability, facilitators, and barriers to a hypothetical HIV vaccine using an integrated analysis approach. We interviewed 30 individuals between 2/2023-9/2023. Participants were supportive of an HIV vaccine and reported that they would strongly consider receiving one if one became available. Participants contextualized a hypothetical vaccine with the current HIV prevention context, primarily pre-exposure prophylaxis (PrEP), indicating that they would evaluate any future vaccine in comparison to their experience within the PrEP landscape.Reported facilitators for a hypothetical HIV vaccine included vaccine access, knowledge, and understanding; their risk for HIV exposure; and perceived benefits of the vaccine. Barriers included lack of understanding of the purpose of a vaccine, stigma surrounding HIV and sexual practices that may surface towards people who seek vaccination, and potential issues with effectiveness, side effects, or lack of availability.

Effects of plyometric-based structured game active breaks on fundamental movement skills, muscular fitness, self-perception, and actual behaviour in primary school students.

This study examined the effects of plyometric-based structured game active breaks on fundamental movement skills (FMS), muscular fitness, student self-perception, and teacher's rating of actual behaviour in Grade 3 and 4 students. Primary school children aged 8-10 years old, from four classes, were cluster-randomly assigned to an intervention group (IG) (n = 54) or a control group (CG) (n = 48). The IG participated in structured plyometric-based game active breaks for 7-10 minutes daily, for six consecutive weeks. The CG resumed their regular daily school routine. FMS were assessed with the Canadian Agility Movement Skills Assessment test, and muscular fitness with the standing long jump (SLJ), countermovement jump (CMJ), and seated medicine ball chest throw tests. The Self-Perception Profile for Children and the Teacher's Rating Scale of Child's Actual Behaviour assessed student self-perception and teacher's perception of student actual behaviour, respectively. A significant (p < 0.01) interaction group by time was observed, with greater improvements in the IG compared to the CG in FMS (%diff = 13.11, ƞp2 = 0.12), SLJ (%diff = 6.67, ƞp2 = 0.02), seated medicine ball chest throw (%diff = 4.69, ƞp2 = 0.08), student social self-perception (%diff = 9.31, ƞp2 = 0.10), student scholastic self-perception (%diff = 7.27, ƞp2 = 0.10), and teacher perception of student social competence (%diff = 8.31, ƞp2 = 0.05). No difference (p > 0.05) was found in other variables. Integrating plyometric-based structured game active breaks into primary school settings evidenced improvement in FMS, muscular fitness, student self-perception, and teacher's rating of student actual behaviour.

Custom Endoprosthesis-Assisted Pediatric Microsurgical Jaw Reconstruction.

Surgical treatment of pediatric maxillary and mandibular tumors can cause significant postresection disfigurement, mastication, and speech dysfunction. The need to restore form and function without compromising growth at the recipient and donor sites poses a particular reconstructive dilemma. This study evaluates outcomes of the custom endoprosthesis (CE) compared with noncustom reconstruction (NCR) and introduces an algorithm using CE to optimize available soft tissue reconstructive options. An Institutional Review Board-approved retrospective review of all patients undergoing maxillary or mandibular reconstruction between 2016 and 2022 was completed. The independent variable of interest was CE utilization. Primary outcomes of interest included hardware failure/removal or exposure, major complications, and revision surgeries. Covariates of interest included patient demographics, medical comorbidities, tumor size, and pathologic diagnosis. Statistical analyses including independent t test, χ2 analyses, and univariate/multivariate logistic regression were performed using RStudio version 4.2.1. Fifty-one patients (37 mandible and 14 maxilla) underwent CE or NCR. Of patients, 37% (n = 19) received CE. Of patients who underwent mandibular reconstruction, there were significantly lower rates of hardware exposure (14.3% versus 47.8%, P = 0.018), failure (7.1% versus 43.5%, P = 0.048), major complications (28.6% versus 78.2%, P = 0.008), and revisions (11.1% versus 50.0%, P = 0.002) in the CE cohort compared with the NCR cohort. The rates of hardware failure, exposure, major complications, and revisions did not significantly differ in maxillary reconstructions, however, CE successfully reconstructed significantly larger defects (179.5 versus 74.6 cm3, P = 0.020) than NCRs. Deviating from NCR, the authors propose an algorithm considering anatomical location, extent of resection, and patient age for soft tissue selection. This algorithm yielded improved mandibular reconstructive outcomes and no increase in complications rate in maxillary reconstruction despite larger resection defects. Furthermore, the authors' initial findings demonstrate that CE is a safe option for pediatric maxillary and mandibular reconstruction that may, in addition, facilitate improved form and function.

Calibration curve for radiation dose estimation using FDXR gene expression biodosimetry - premises and pitfalls.

PURPOSE: Radiation-induced alterations in gene expression show great promise for dose reconstruction and for severity prediction of acute health effects. Among several genes explored as potential biomarkers, FDXR is widely used due to high upregulation in white blood cells following radiation exposure. Nonetheless, the absence of a standardized protocols for gene expression-based biodosimetry is a notable gap that warrants attention to enhance the accuracy, reproducibility and reliability. The objective of this study was to evaluate the sensitivity of transcriptional biodosimetry to differences in protocols used by different laboratories and establish guidelines for the calculation of calibration curve using FDXR expression data. MATERIAL AND METHODS: Two sets of irradiated blood samples generated during RENEB exercise were used. The first included samples irradiated with known doses including: 0, 0.25, 0.5, 1, 2, 3 and 4 Gy. The second set consisted of three 'blind' samples irradiated with 1.8 Gy, 0.4 Gy and a sham-irradiated sample. After irradiation, samples were incubated at 37 °C over 24 h and sent to participating laboratories, where RNA isolation and FDXR expression analysis by qPCR were performed using sets of primers/probes and reference genes specific for each laboratory. Calibration curves based on FDXR expression data were generated using non-linear and linear regression and used for dose estimation of 'blind' samples. RESULTS: Dose estimates for sham-irradiated sample (0.020-0.024 Gy) and sample irradiated with 0.4 Gy (0.369-0.381 Gy) showed remarkable consistency across all laboratories, closely approximating the true doses regardless variation in primers/probes and reference genes used. For sample irradiated with 1.8 Gy the dose estimates were less precise (1.198-2.011 Gy) but remained within an acceptable margin for triage within the context of high dose range. CONCLUSION: Methodological differences in reference genes and primers/probes used for FDXR expression measurement do not have a significant impact on the dose estimates generated, provided that all reference genes performed as expected and the primers/probes target a similar set of transcript variants. The preferred method for constructing a calibration curve based on FDXR expression data involves employing linear regression to establish a function that describes the relationship between the logarithm of absorbed dose and FDXR ΔCt values. However, one should be careful with using non-irradiated sample data as these cannot be accurately represented on a logarithmic scale. A standard curve generated using this approach can give reliable dose estimations in a dose range from 50 mGy to 4 Gy at least.

The effect of high-dose selenium on mortality and postoperative organ dysfunction in post-cardiotomy cardiogenic shock patients supported with mechanical circulatory support - A post-hoc analysis of the SUSTAIN CSX trial.

PURPOSE: Cardiac surgery, post-cardiotomy cardiogenic shock (PCCS), and temporary mechanical circulatory support (tMCS) provoke substantial inflammation. We therefore investigated whether a selenium-based, anti-inflammatory strategy would benefit PCCS patients treated with tMCS in a post-hoc analysis of the sustain CSX trial. METHODS: Post-hoc analysis of patients receiving tMCS for PCCS in the Sustain CSX trial, which investigated the effects of high-dose selenium on postoperative organ dysfunction in cardiac surgery patients. PRIMARY OUTCOME: duration of tMCS therapy. SECONDARY OUTCOMES: postoperative organ dysfunction and 30-day mortality. RESULTS: Thirty-nine patients were treated with tMCS for PCCS. There was no difference in the median duration of tMCS between the selenium and the placebo group (3 days [IQR: 1-6] vs. 2 days [IQR: 1-7], p = 0.52). Median dialysis duration was longer in the selenium group (1.5 days [0-21.8] vs. 0 days [0-1.8], p = 0.048). There was no difference in 30-day mortality (53% vs. 41%, OR 1.44, 95% CI 0.32-6.47, p = 0.62). CONCLUSION: In this explorative study, a perioperative high-dose selenium-supplementation did not show beneficial effects on organ dysfunctions and mortality rates in patients with PCCS receiving tMCS.

Factors associated with pediatric ophthalmology follow-up adherence before and during the COVID-19 pandemic.

BACKGROUND: Studies describe poor follow-up among children in ophthalmology prior to the COVID-19 pandemic. Although the pandemic led to worse adherence for routine medical care in children, little information exists on pediatric ophthalmology follow-up adherence during COVID-19. The purpose of this study was to evaluate the effect of COVID-19 pandemic on follow-up adherence for children with eye disease, and identified characteristics associated with follow-up adherence. METHODS: In this single-center study, the medical records of 519 new pediatric (≤18 years of age) patients seen during January, April, August, and December 2019 and 2021 were reviewed retrospectively. Patients were classified into two groups: adherent (patients who followed up within 30 days of recommended appointment time) or less-adherent (patients who followed up >30 days after recommended follow-up or never). Main outcome measure was patient adherence status. RESULTS: Follow-up adherence was similar before and during the COVID-19 pandemic (50.4% for 2019 and 49.6% for 2021 [P = 0.40]). Patients that were less likely to be adherent in both univariate and multivariable analyses included those with public insurance (adjusted OR = 0.63 [95% CI, 0.40-1.00]; P = 0.05), and those recommended to follow-up ≥3 months (adjusted OR ≤ 0.10; P < 0.001). In addition, in univariate analysis, those who declined to self-report race (OR = 0.53 [95% CI, 0.29-0.95]; P = 0.04) and those seen by optometrists (OR = 0.42 [95% CI, 0.29-0.60]; P < 0.001) were less likely to be adherent, while patients who traveled ≥177 miles to their provider were more likely to be adherent (OR = 2.88 [95% CI, 1.17-7.55]; P = 0.02). CONCLUSIONS: Follow-up adherence for childhood eye care was low but remained relatively stable before and during the COVID-19 pandemic; >50% of children were less-adherent.

RANKL-mediated osteoclast formation is required for bone loss in a murine model of Staphylococcus aureus osteomyelitis.

Staphylococcus aureus osteomyelitis leads to extensive bone destruction. Osteoclasts are bone resorbing cells that are often increased in bone infected with S. aureus. The cytokine RANKL is essential for osteoclast formation under physiological conditions but in vitro evidence suggests that inflammatory cytokines may by-pass the requirement for RANKL. The goal of this study was to determine whether RANKL-dependent osteoclast formation is essential for the bone loss that occurs in a murine model of S. aureus osteomyelitis. To this end, humanized-RANKL mice were infected by direct inoculation of S. aureus into a unicortical defect in the femur. Mice were treated with vehicle or denosumab, a human monoclonal antibody that inhibits RANKL, both before and during a 14-day infection period. The severe cortical bone destruction caused by infection was completely prevented by denosumab administration even though the bacterial burden in the femur was not affected. Osteoclasts were abundant near the inoculation site in vehicle-treated mice but absent in denosumab-treated mice. In situ hybridization demonstrated that S. aureus infection potently stimulated RANKL expression in bone marrow stromal cells. The extensive reactive bone formation that occurs in this osteomyelitis model was also reduced by denosumab administration. Lastly, there was a notable lack of osteoblasts near the infection site suggesting that the normal coupling of bone formation to bone resorption was disrupted by S. aureus infection. These results demonstrate that RANKL-mediated osteoclast formation is required for the bone loss that occurs in S. aureus infection and suggest that disruption of the coupling of bone formation to bone resorption may also contribute to bone loss in this condition.

More Than Maintaining Competence: A Qualitative Study of How Physicians Conceptualize and Engage in Lifelong Learning.

Purpose: Physicians have a professional responsibility to engage in lifelong learning. Some of this lifelong learning is required to maintain licensure and certification. Yet, this conceptualization captures only a small portion of the content areas and learning processes that physicians need to engage with to ensure quality patient care. Additionally, purposes beyond regulatory requirements and professional obligations likely drive physicians lifelong learning, though these purposes have not been explored. Given the centrality of lifelong learning to quality patient care, our study explores how physicians conceptualize and engage in lifelong learning. Method: We conducted a qualitative interview study using an interpretivist approach. In 2019, we recruited 34 academic physicians from one institution. We analyzed our data to identify themes related to conceptualization of purposes, content areas, and processes of lifelong learning and actual lifelong learning practices. Results: We interpreted participants' descriptions and examples of lifelong learning as serving three purposes: maintaining competence, supporting personal growth and fulfillment, and engaging in professional stewardship. Much of participants' discussion of lifelong learning centered around keeping up to date with medical knowledge and clinical/procedural skills, though some also mentioned efforts to improve communication, leadership, and teamwork. Participants engaged in lifelong learning through contextual, social, and individual processes. Discussion: Academic physicians engage in lifelong learning for reasons beyond maintaining competence. Medical knowledge and clinical/procedural skills receive most attention, though other areas are recognized as important. Our findings highlight opportunities for a broader, more comprehensive approach to lifelong learning that spans all areas of medical practice.