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Cynthia Matossian,1 John D Stephens,2 Michelle K Rhee,3 Stephen E Smith,4 Parag A Majmudar,5 Subba Rao Gollamudi,6 Ravi H Patel,7 Maria E Rosselson,5 Aditi Bauskar,8 Alyssa Montieth,8 Fabiana Q Silva,8 Srilatha Vantipalli,8 Andrea Gibson,8 Jamie Lynne Metzinger,8 Michael H Goldstein8 1CM Associates, LLC, New Hope, PA, USA; 2Tyson Eye, Fort Myers, FL, USA; 3Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Eye Associates, Fort Myers, FL, USA; 5Chicago Cornea Consultants, Ltd., Chicago, IL, USA; 6Eye Specialty Group, Memphis, TN, USA; 7Eye Associates of Central Texas, Round Rock, TX, USA; 8Ocular Therapeutix, Inc., Bedford, MA, USACorrespondence: Srilatha Vantipalli, Ocular Therapeutix, Inc, 24 Crosby Drive, Bedford, MA, 01730, USA, Tel +1 413-230-7242, Email SVantipalli@ocutx.comPurpose: To describe the early real-world experience of physicians with an intracanalicular dexamethasone insert (DEX) in patients undergoing cataract surgery and to capture the clinical impact of adopting this therapy.Patients and Methods: 23 United States sites including Ambulatory Surgical Center Setting (ASC) and Outpatient Clinical settings. Respondents were physicians who had early experience with DEX in cataract surgery patients. This was a Phase 4 experiential cross-sectional survey study comprised of 3 sequential online physician surveys. Descriptive statistics summarized the surveys’ responses to determine the early impressions of the respondents.Results: Forty-two physicians completed surveys. On average, physicians reported feeling comfortable administering DEX after placing 3 inserts (mean 2.7; standard deviation 1.9). Most physicians (92%) were satisfied with DEX, and all physicians (100%) reported that DEX improved patient compliance. Most physicians (62.5%) indicated they would highly prefer DEX over traditional steroid eyedrops for the management of post-surgical inflammation and pain.Conclusion: The surveys exploring the early use of DEX suggest that DEX is a clinically effective treatment with a rapid initial learning curve and integrates well into clinical use. Physicians had a very positive early experience with DEX, including comfort with insertion and satisfaction. DEX shows promise as a primary treatment choice of physicians for ocular inflammation and pain following cataract surgery by offering patients a hands-free innovative therapy that delivers a preservative-free steroid to the ocular surface over approximately 30 days.Keywords: intracanalicular dexamethasone insert, phacoemulsification, hands-free therapy, ocular pain, ocular inflammation, sustained-release drug delivery

ObjectiveLarge studies of knee osteoarthritis (KOA) require well-characterized efficient methods to assess progression. We previously developed the local-area cartilage segmentation (LACS) software method, to measure cartilage volume on magnetic resonance imaging (MRI) scans. The present study further validates this method in a larger patient cohort and assesses predictive validity in a case-control study.MethodThe OA Biomarkers Consortium FNIH Project, a case-control study of KOA progression nested within the Osteoarthritis Initiative (OAI), includes 600 subjects in four subgroups based on radiographic and pain progression. Our software tool measured change in medial femoral cartilage volume in a central weight-bearing region. Different sized regions of cartilage were assessed to explore their sensitivity to change. The readings were performed on MRI scans at the baseline and 24-month visits. We used standardized response means (SRMs) for responsiveness and logistic regression for predictive validity.ResultsCartilage volume change was associated strongly with radiographic progression (odds ratios (OR) = 4.66; 95% confidence intervals (CI) = 2.85-7.62). OR were significant but of lesser magnitude for the combined radiographic and pain progression outcome (OR = 1.70; 95% CI = 1.40-2.07). For the full 600 subjects, theSRM was -0.51 for the largest segmented area. Smaller areas of cartilage segmentation were also able to predict the case-control status. The average reader time for the largest area was less than 20 min per scan. Smaller areas could be assessed with less reader time.ConclusionWe demonstrated that the LACS method is fast, responsive, and associated with radiographic and pain progression, and is appropriate for existing and future large studies of KOA.

Darkness pupil diameters, light reflexes, and redilatation times have been recorded with infrared TV pupillometry in 12 consecutive patients with systemic amyloidosis associated with sensory motor and autonomic neuropathy. Nine of the patients had AL amyloidosis, two had familial amyloidosis associated with a transthyretin abnormality, and one was untyped. The pupils were abnormal in all 12 patients. On the basis of redilatation lag without pupillotonia, six patients had bilateral Horner's syndrome and in one of them amyloid deposits were found in a sympathetic ganglion and in the attached sympathetic chain obtained at necropsy. Four patients had bilateral tonic pupils with light-near dissociation and two had abnormally small pupils with reduced light reactions which could not be characterised. It seems that in patients with systemic amyloidosis generalised autonomic neuropathy is strongly associated with pupil abnormality as shown by tonic reactions with light-near dissociation, by redilatation lag, or by reduced size in darkness. [ABSTRACT FROM AUTHOR]

1. The cardiovascular effects of the proprietary cold remedies, Mu-cron and Boots Cold Relief tablets were compared with 'placebo' Boots Pain Relief tablets in a double-blind study involving 16 healthy volunteers. Measurements (impedance cardiography, forearm plethysmography) were made over 4 h after oral drug administration. 2. Two Mu-cron tablets (containing phenylpropanolamine [(1R,2S)- plus (1S,2R)-norephedrine] 50 mg) increased blood pressure (maximal effect 18 +/- 1/8 +/- 1 mm Hg (mean +/- s.e. mean), P less than 0.001), stroke volume (4.9 +/- 0.8 ml m-2, P less than 0.05), total peripheral resistance (243 +/- 27 dyn s cm-5 m2, P less than 0.001) and forearm vascular resistance (1.3 +/- 0.3 mm Hg ml-1 min, P less than 0.01) and reduced the ratio of pre- ejection period to ventricular ejection time (-0.031 +/- 0.003, P less than 0.05) and forearm blood flow (-2.6 +/- 0.5 ml min-1, P less than 0.05) but did not affect heart rate or cardiac index. 3. Two Boots Cold Relief tablets (containing phenylephrine 10 mg and caffeine 60 mg) caused a small and short-lived increase in total peripheral resistance but did not have consistent effects on other measurements. Two Boots Pain Relief tablets (containing caffeine 60 mg) did not have important cardiovascular effects. 4. The cardiovascular effects of phenylpropanolamine, including vasoconstriction and an increase in cardiac performance, are consistent with its alpha- and beta 1- adrenoceptor agonist action. While it may help the symptoms of rhinitis, its use in patients with heart disease or hypertension is hazardous.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart. [ABSTRACT FROM AUTHOR]

The influence of vagal and sympathetic efferent activity on sinus arrhythmia in man has been studied in six healthy subjects by administration of hyoscine butylbromide and/or various beta- adrenoceptor blocking drugs using a microcomputer-linked electrocardiogram system. Sinus arrhythmia was quantitated as the s.d. of the R-R interval. Sinus arrhythmia was almost abolished by hyoscine butylbromide irrespective of the absence or presence and nature of the beta-adrenoceptor blocking drug. Atenolol and metoprolol alone prolonged the mean R-R interval and increased sinus arrhythmia. Oxprenolol, a drug with modest partial agonist or intrinsic sympathomimetic activity (ISA), prolonged the mean R-R interval to a lesser extent but had no effect on sinus arrhythmia. Xamoterol, which has high ISA, shortened the mean R-R interval but had no effect on sinus arrhythmia. These data yielded a non-linear relationship between sinus arrhythmia and mean R-R interval. Exaggerated sinus arrhythmia appears to accompany beta-adrenoceptor blockade only in the absence of ISA when bradycardia ensues. These findings are consistent with the hypothesis that the exaggeration in sinus arrhythmia is due to a central vagotonic effect secondary to the action of the drugs in the periphery. Changes in R-R interval induced by the adrenoceptor blocking drugs were altered to some extent by vagal blockade. This observation is consistent with the hypothesis that changes in heart rate induced by such drugs are determined in part by a change in vagal tone. [ABSTRACT FROM AUTHOR]

Plasma concentrations of oxprenolol have been measured in six healthy volunteers following single-dose oral administration of the drug in conventional and Oros dosage forms in fasting and postprandial states. After the Oros system, plasma concentrations reached peaks in most subjects at 3-8 h after dosing and were approximately 25% of those achieved with the conventional tablet. Plasma concentrations were well sustained for at least 24 h. A secondary peak occurred consistently at 12 h, possibly reflecting a transient change in clearance and/or distribution of the drug following the evening meal. With each formulation, plasma drug concentration profiles following administration in the fasting state did not differ significantly from those obtained when the drug was given postprandially. Drug absorption in vivo corresponded reasonably closely with in vitro drug release from the Oros system. [ABSTRACT FROM AUTHOR]

Plasma metoprolol concentrations and haemodynamic effects have been measured in six healthy male volunteers during once daily dosing with a 19/285 Oros system and twice daily dosing with 100 mg conventional tablets, on two separate occasions. Plasma drug concentrations throughout the day varied less with the Oros than with the conventional tablet regimen. Predosing concentrations were also higher with Oros but areas under the curve, after correcting for the differences in dose, were similar for the two preparations. Inhibition of exercise tachycardia was drug concentration dependent and was smoothly controlled through the day only with the Oros preparation. Predosing effects at steady-state were also greater for the Oros regimen. The decline in mean blood pressure, however, showed the same daily pattern for both regimens, and no significant differences were detected between Oros and conventional tablet treatments. The smoothness of the plasma profiles after Oros confirmed the controlled-release performance of the system in vivo and indicates its potential in the treatment of angina, cardiac arrhythmias and wherever it is important not to jeopardize steady selective beta-adrenoceptor blockade. [ABSTRACT FROM AUTHOR]

Heart-rate responses to intravenous hyoscine butylbromide, atropine and physiological saline in cumulative dosage regimens have been recorded in six healthy subjects. Atropine sulphate induced bradycardia at low, and tachycardia at higher, dose levels whereas hyoscine butylbromide caused only tachycardia but with a flatter dose-response relationship. Exact potency ratios could not be calculated because of the differing dose-response curves. However, an approximate estimate from a comparison of equiactive doses at the upper part of the curve yielded a value less than one half that obtained from the drugs' affinity constants in guinea-pig ileum. The findings suggest that, in addition to its action as a muscarinic antagonist, hyoscine butylbromide is a ganglion blocker in man as it is in animals. [ABSTRACT FROM AUTHOR]

1 Antipyrine elimination kinetics have been determined in fifteen patients before and after 4 weeks treatment with monoamine oxidase inhibitors and in five patients after treatment only. 2 Antipyrine elimination was slightly but significantly slowed by 28 days treatment with phenelzine but the degree of slowing was uninfluenced by acetylator phenotype or dosage of phenelzine administered. 3 The findings suggest that at the dosage used phenelzine is a weak inhibitor of hepatic microsomal mixed function oxidase in man and it is concluded that this is likely to provide an important source of drug interaction in some patients. [ABSTRACT FROM AUTHOR]

Background: Behavioural marker systems are used across several healthcare disciplines to assess behavioural (non-technical) skills, but rater training is variable, and inter-rater reliability is generally poor. Inter-rater reliability provides data about the tool, but not the competence of individual raters. This study aimed to test the inter-rater reliability of a new behavioural marker system (PhaBS - pharmacists' behavioural skills) with clinically experienced faculty raters and near-peer raters. It also aimed to assess rater competence when using PhaBS after brief familiarisation, by assessing completeness, agreement with an expert rater, ability to rank performance, stringency or leniency, and avoidance of the halo effect., Methods: Clinically experienced faculty raters and near-peer raters attended a 30-min PhaBS familiarisation session. This was immediately followed by a marking session in which they rated a trainee pharmacist's behavioural skills in three scripted immersive acute care simulated scenarios, demonstrating good, mediocre, and poor performances respectively. Inter-rater reliability in each group was calculated using the two-way random, absolute agreement single-measures intra-class correlation co-efficient (ICC). Differences in individual rater competence in each domain were compared using Pearson's chi-squared test., Results: The ICC for experienced faculty raters was good at 0.60 (0.48-0.72) and for near-peer raters was poor at 0.38 (0.27-0.54). Of experienced faculty raters, 5/9 were competent in all domains versus 2/13 near-peer raters (difference not statistically significant). There was no statistically significant difference between the abilities of clinically experienced versus near-peer raters in agreement with an expert rater, ability to rank performance, stringency or leniency, or avoidance of the halo effect. The only statistically significant difference between groups was ability to compete the assessment (9/9 experienced faculty raters versus 6/13 near-peer raters, p = 0.0077)., Conclusions: Experienced faculty have acceptable inter-rater reliability when using PhaBS, consistent with other behaviour marker systems; however, not all raters are competent. Competence measures for other assessments can be helpfully applied to behavioural marker systems. When using behavioural marker systems for assessment, educators must start using such rater competence frameworks. This is important to ensure fair and accurate assessments for learners, to provide educators with information about rater training programmes, and to provide individual raters with meaningful feedback., Competing Interests: Declarations. Competing interests: Author SES is an editorial board member for Advances in Simulation., (© 2024. The Author(s).)

The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5 + intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19 + cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Doctors in training (trainees) have higher rates of burnout, anxiety and depression than other professionals. An important psychological tool to combat this crisis is promotion of a growth mindset, which increases resilience and improves mental health outcomes. How growth mindset might be promoted within the clinical learning environment is underexplored. This study aimed to explore the factors promoting a growth mindset versus fixed mindset in trainees from the perspective of the trainees., Methods: This constructivist study employed a novel method of encouraging trainees' reflections on mindset adoption in the clinical learning environment. Trainees played Mindset, a tabletop simulation board game that included challenges encountered within training. This was followed by a facilitated debriefing, focusing on factors that promoted growth or fixed mindset adoption in the clinical learning environment. Debriefing transcripts were analysed using template analysis., Results: Three groups of oncology trainees and one group of medical education fellows participated (16 participants in total). Factors promoting growth mindset adoption included passion, collaboration, diverse career and role modelling. Factors promoting fixed mindset adoption included burnout and competition. Some factors, such as grit, previous success experience and singular training location promoted a fixed mindset when too much or too little were present, and promoted a growth mindset when they were in balance (the Goldilocks principle)., Conclusions: The importance of balance versus excess of certain factors, and the ubiquitous competitive culture in medicine promoting a fixed mindset, were compelling reflections. This study may aid invested parties to reflect on what factors they can upregulate and down regulate to optimise trainees' adoption of a growth mindset., (© 2024. The Author(s).)

Objective: Radiographs are frequently obtained for patients with knee osteoarthritis (KOA), with magnetic resonance imaging (MRI) reserved for those with complex KOA. There are few data on how often subsequent MRI reveals clinically actionable but unanticipated findings. The purpose of this study is to estimate the prevalence of these findings on MRI for patients managed nonoperatively for suspected meniscal tears., Methods: The Treatment of Meniscal Problems and Osteoarthritis (TeMPO) study enrolled patients aged 45 to 85 years with knee pain, osteoarthritis (Kellgren-Lawrence [KL] grades 0-3), and suspected meniscal tear. We reviewed baseline MRI and recorded notable findings, including subchondral insufficiency fractures of the knee (SIFKs), avascular necrosis (AVN), tumors, and nonsubchondral fractures. Other baseline data included demographic characteristics, Knee Injury and Osteoarthritis Outcome Score, duration of knee symptoms, and KL grade., Results: Study-ordered MRI was performed on 760 patients, with 61 concerning findings identified (8.03%, 95% confidence interval 6.09%-9.96%). A total of 25 participants had SIFKs, 10 had nonsubchondral fractures, 4 had AVN, 8 had benign tumors, and 14 had other clinically relevant findings., Conclusion: We estimated the prevalence of clinically relevant incidental findings on MRI to be 8.03% in middle-aged adults with mild to moderate KOA and suspected meniscal tear. These data may prompt clinicians to be more aware of the range of findings that can underlie knee symptoms, some of which could change management but may require different modalities of imaging to detect. Future research is needed to pinpoint factors associated with these concerning findings so that patients who are at risk can be identified and referred for advanced imaging., (© 2024 American College of Rheumatology.)

Background/Objective : Intravenous fluid shortages have led to fluid-sparing measures such as intravenous push (IVP) administration of antibiotics. This study aimed to compare the safety and efficacy of IVP and intravenous piggyback (IVPB) ceftriaxone in critically ill patients. Results : Demographics were similar in IVP ( n = 201) and IVPB ( n = 200) groups. Sequential Organ Failure Assessment (SOFA) score was higher, and sepsis and septic shock were more common in the IVP group. Treatment failure occurred in 37.8% of IVP and 19.5% of IVPB groups ( p < 0.001). Hospital mortality was more common with IVP (21.4% vs. 9.5%, p < 0.001). Hospital LOS was longer with IVP while intensive care unit (ICU) LOS was similar between the groups. IVP ceftriaxone (OR 2.33, 95% CI 1.43-3.79) and the SOFA score (OR 1.18, 95% CI 1.1-1.27) were associated with treatment failure. Methods : A single-center, retrospective cohort study included adults admitted to an ICU from 2016 to 2021 who received empiric ceftriaxone for ≥72 h. The primary outcome was treatment failure, defined as a composite of inpatient mortality or escalation of antibiotics. Secondary outcomes included length of stay (LOS) and mortality. Chi-squared and independent-sample t -tests were used. Treatment failure was evaluated using multivariate logistic regression. Conclusions : Compared to IVPB, IVP ceftriaxone was associated with higher treatment failure in critically ill patients. Both safety and efficacy should be considered before implementing novel antibiotic administration strategies in practice based primarily on convenience.

Background: Healthcare professionals are a precious resource, however, if they fail to integrate into the workforce, they are likely to relocate. Refugee doctors face workforce integration challenges including differences in language and culture, educational background, reduced confidence, and sense of identity. It has been proposed that simulation programmes may have the power to influence workforce integration. This study aimed to explore how an immersive simulation programme influenced workforce integration for refugee doctors joining a new healthcare system., Methods: Doctors were referred to a six-day immersive simulation programme by a refugee doctor charity. Following the simulation programme, they were invited to participate in the study. Semi-structured interviews, based on the 'pillars' conceptual model of workforce integration, were undertaken. Data were analysed using template analysis, with the workforce integration conceptual model forming the initial coding template. Themes and sub-themes were modified according to the data, and new codes were constructed. Data were presented as an elaborated pillars model, exploring the relationship between simulation and workforce integration., Results: Fourteen doctors participated. The 'learning pillar' comprised communication, culture, clinical skills and knowledge, healthcare systems and assessment, with a new sub-theme of role expectations. The 'connecting pillar' comprised bonds and bridges, which were strengthened by the simulation programme. The 'being pillar' encompassed the reclaiming of the doctor's identity and the formation of a new social identity as an international medical graduate. Simulation opportunities sometimes provided 'building blocks' for the pillars, but at other times opportunities were missed. There was also an example of the simulation programme threatening one of the integration pillars., Conclusions: Opportunities provided within simulation programmes may help refugee doctors form social connections and aid learning in a variety of domains. Learning, social connections, and skills application in simulation may help doctors to reclaim their professional identities, and forge new identities as international medical graduates. Fundamentally, simulation experiences allow newcomers to understand what is expected of them. These processes are key to successful workforce integration. The simulation community should be curious about the potential of simulation experiences to influence integration, whilst also considering the possibility of unintentional 'othering' between faculty and participants., (© 2024. The Author(s).)

Rising temperature extremes during critical reproductive periods threaten the yield of major grain and fruit crops. Flowering plant reproduction depends on development of sufficient numbers of pollen grains and on their ability to generate a cellular extension, the pollen tube, which elongates through the pistil to deliver sperm cells to female gametes for double fertilization. These critical phases of the life cycle are sensitive to temperature and limit productivity under high temperature (HT). Previous studies have investigated the effects of HT on pollen development, but little is known about how HT applied during the pollen tube growth phase affects fertility. Here, we used tomato as a model fruit crop to determine how HT affects the pollen tube growth phase, taking advantage of cultivars noted for fruit production in exceptionally hot growing seasons. We found that exposure to HT solely during the pollen tube growth phase limits fruit biomass and seed set more significantly in thermosensitive cultivars than in thermotolerant cultivars. Importantly, we found that pollen tubes from the thermotolerant Tamaulipas cultivar have enhanced growth in vivo and in vitro under HT. Analysis of the pollen tube transcriptome's response to HT allowed us to develop hypotheses for the molecular basis of cellular thermotolerance in the pollen tube and we define two response modes (enhanced induction of stress responses, and higher basal levels of growth pathways repressed by heat stress) associated with reproductive thermotolerance. Importantly, we define key components of the pollen tube stress response identifying enhanced ROS homeostasis and pollen tube callose synthesis and deposition as important components of reproductive thermotolerance in Tamaulipas. Our work identifies the pollen tube growth phase as a viable target to enhance reproductive thermotolerance and delineates key pathways that are altered in crop varieties capable of fruiting under HT conditions., Competing Interests: Declaration of interests: R.P. is the Editor-in-Chief of Plant Reproduction. All other authors declare no competing interests.

Previous studies of hematopoietic stem cells (HSCs) primarily focused on single cell-based niche models, yielding fruitful but conflicting findings 1-5 . Here we report our investigation on the fetal liver (FL) as the primary fetal hematopoietic site using spatial transcriptomics. Our study reveals two distinct niches: the portal-vessel (PV) niche and the sinusoidal niche. The PV niche, composing N-cadherin (N-cad) Hi Pdgfrα + mesenchymal stromal cells (MSCs), endothelial cells (ECs), and N-cad Lo Albumin + hepatoblasts, maintains quiescent and multipotential FL-HSCs. Conversely, the sinusoidal niche, comprising ECs, hepatoblasts and hepatocytes, as well as potential macrophages and megakaryocytes, supports proliferative FL-HSCs biased towards myeloid lineages. Unlike prior reports on the role of Cxcl12, with its depletion from vessel-associated stromal cells leading to 80% of HSCs' reduction in the adult bone marrow (BM) 6,7 , depletion of Cxcl12 via Cdh2 CreERT (encoding N-cad) induces altered localization of HSCs from the PV to the sinusoidal niches, resulting in an increase of HSC number but with myeloid-bias. Similarly, we discovered that adult BM encompasses two niches within different zones, each composed of multi-cellular components: trabecular bone area (TBA, or metaphysis) supporting deep-quiescent HSCs, and central marrow (CM, or diaphysis) fostering heterogenous proliferative HSCs. This study transforms our understanding of niches by shifting from single cell-based to multicellular components within distinct zones, illuminating the intricate regulation of HSCs tailored to their different cycling states.

Abstract: Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab, and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue vs induction followed by nonmyeloablative, infusional etoposide plus cytarabine. The primary end point was progression-free survival (PFS). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs 11%; P = .05). Thirty-six patients received autologous stem cell transplant, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs nonmyeloablative arm (73% vs 51%; P = .02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs 71%; P = .21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. This trial was registered at www.clininicals.gov as #NCT01511562., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Pilar cysts are common benign cysts of follicular origin that typically arise in areas of skin containing dense hair follicles such as the scalp. Here we describe a unique case of a young woman who was found to have a pilar cyst on the dorsum of her hand, a rather atypical location given the relative lack of pilosebaceous units. This case illustrates the variability in pilar cyst presentation and the importance of considering a pilar cyst in the differential diagnosis of a patient presenting with a tumor of the dorsal hand., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ladd et al.)

Background: Immunization is one of the most significant health initiatives of recent times. Despite this, vaccine hesitancy is increasing and was listed as one of the top 10 threats to global health by the World Health Organization in 2019. A major factor associated with vaccine hesitancy is thought to be the viral spread of misinformation by a small but active anti-vaccination movement., Objectives: The purpose of this study was to explore the influences of social media on vaccine decision-making in parents., Design: This study is part of a larger body of research that explored vaccine decision-making in parents. Other methods included were an online survey and semi-structured interviews. This study investigated the influence of cyberculture on parents in an online environment., Method: This study employed netnography, a form of qualitative inquiry with its roots in ethnography as methodology and a purpose-designed Facebook page as the means of exploring a purpose-designed online community with a particular focus on the culture, belief systems and influences present. Both manual and computer-assisted thematic analyses were used to analyse the data obtained., Results: Three key themes were identified in this study. These included vaccine safety concerns, the emotional debate and COVID-19-specific issues. The results indicated the presence of strong anti-vaccination sentiment combined with an 'infodemic' of conspiracy theories, misinformation and vitriol with the potential to negatively impact parents seeking immunization information., Conclusion: Given the popularity and accessibility of social media and the ready access to misinformation present online, it is evident that parental vaccine decision-making may be impacted adversely. Therefore, it is important that healthcare professionals are aware of this and provide adequate and timely education prior to parents seeking information on social media., (© The Author(s), 2024.)

Objective: Common data models provide a standard means of describing data for artificial intelligence (AI) applications, but this process has never been undertaken for medications used in the intensive care unit (ICU). We sought to develop a common data model (CDM) for ICU medications to standardize the medication features needed to support future ICU AI efforts., Materials and Methods: A 9-member, multi-professional team of ICU clinicians and AI experts conducted a 5-round modified Delphi process employing conference calls, web-based communication, and electronic surveys to define the most important medication features for AI efforts. Candidate ICU medication features were generated through group discussion and then independently scored by each team member based on relevance to ICU clinical decision-making and feasibility for collection and coding. A key consideration was to ensure the final ontology both distinguished unique medications and met Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles., Results: Using a list of 889 ICU medications, the team initially generated 106 different medication features, and 71 were ranked as being core features for the CDM. Through this process, 106 medication features were assigned to 2 key feature domains: drug product-related (n = 43) and clinical practice-related (n = 63). Each feature included a standardized definition and suggested response values housed in the electronic data library. This CDM for ICU medications is available online., Conclusion: The CDM for ICU medications represents an important first step for the research community focused on exploring how AI can improve patient outcomes and will require ongoing engagement and refinement., Competing Interests: The authors have no competing interests to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Belonging is critical for the development and wellbeing of medical students. Belonging, particularly within a 'relational being' paradigm, presents a significant challenge for students, especially within clinical learning environments. Co-creation is a learning relationship in which students are actively involved in the education process. It is inherently relational and promotes belonging within higher education environments. Little is known about utilising co-creation in the curriculum, within medical education. The aim of this study was to explore medical students' experience of co-creation of learning resources within the clinical learning environment., Methods: Following ethical approval, medical students were invited to become co-creators of a learning bulletin resource, within the paediatric acute receiving unit, at a paediatric teaching hospital. Interpretative phenomenological analysis (IPA) was used to enable an in-depth exploration of how medical students experienced co-creation within the clinical learning environment. Medical students participated in semi-structured interviews about their experience, which were transcribed verbatim and analysed using IPA. The analysis integrated individual lived experiences into an analytic summary., Results: Nine medical students participated. Three group experiential themes were identified: identity maturation; learning community and workplace integration. The support found within this co-created learning community, along with maturation of their identity, allowed the participants to experience a challenge to their existing worldview. This shift in perspective resulted in them responding and behaving in the workplace in new ways, which enabled them to belong as themselves in the clinical learning environment. These findings were situated within the developmental concept of self-authorship, as well as contributing to a new understanding of how co-creation promoted social integration., Conclusions: Co-creation enabled students to learn in a meaningful way. The relational power of co-creation, can be harnessed to deliver participatory learning experiences, within our increasingly complex healthcare environment, to support the learning, development and integration of doctors of the future., (© 2024. The Author(s).)

Background: Avoidable patient harm in hospitals is common, and doctors in training can provide underused but crucial insights into the influencers of patient safety as those working 'on the ground' within the system. This study aimed to explore the factors that influence safe care from the perspective of medical registrars, to identify targets for safety-related improvements., Methods: This study used enhanced critical incident technique (CIT), a qualitative methodology that results in a focused understanding of significant factors influencing an activity, to identify practical solutions. We interviewed 12 out of 17 consenting medical registrars in Scotland, asking them to recount their observations during clinical experiences where something happened that positively or negatively impacted on patient safety. Data were analysed manually using a modified content analysis with credibility checks as per enhanced CIT, with data exhaustiveness reached after six registrars., Results: A total of 221 critical incidents impacting patient safety were identified. These were inductively placed into 24 categories within 4 overarching categories: Individual skills , encompassing individual behavioural and technical skills; Collaboration , regarding how communication, trust, support and flexibility shape interprofessional collaboration; Organisation , concerning organisational systems and staffing and Training environment , relating to culture, civility, having a voice and learning at work. Practical targets for safety-related interventions were identified, such as clear policies for patient care ownership or educational interventions to foster civility., Conclusions: This study provides a rigorous and focused understanding of the factors influencing patient safety in hospitals, using the 'insider' perspective of the medical registrar. Safety goes beyond the individual and is reliant on safe system design, interprofessional collaboration and a culture of support, learning and respect. Organisations should also promote flexibility within clinical practice when patient needs do not conform to standardised care pathways. We suggest targeted interventions within educational and organisational priorities to improve safety in hospitals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The centromere components cohesin, CENP-A, and centromeric DNA are essential for biorientation of sister chromatids on the mitotic spindle and accurate sister chromatid segregation. Insight into the 3D organization of centromere components would help resolve how centromeres function on the mitotic spindle. We use ChIP-seq and super-resolution microscopy with single particle averaging to examine the geometry of essential centromeric components on human chromosomes. Both modalities suggest cohesin is enriched at pericentromeric DNA. CENP-A localizes to a subset of the α-satellite DNA, with clusters separated by ~562 nm and a perpendicular intervening ~190 nM wide axis of cohesin in metaphase chromosomes. Differently sized α-satellite arrays achieve a similar core structure. Here we present a working model for a common core configuration of essential centromeric components that includes CENP-A nucleosomes, α-satellite DNA and pericentromeric cohesion. This configuration helps reconcile how centromeres function and serves as a foundation to add components of the chromosome segregation machinery., (© 2023. The Author(s).)

Introduction: Patient care depends on collaborative practice. Debate remains as to the best approach to providing education for collaboration, with educational interventions often far removed from the realities of the clinical workplace. Understanding the approaches used for collaboration in clinical practice could inform practical strategies for training. For internal medicine trainees, this involves collaboration with other professions but also with other specialties. This study aimed to explore the approaches that internal medicine trainees use for interprofessional collaboration and the ways that these approaches vary when internal medicine trainees interact with different healthcare provider groups., Methods: Following ethical approval and participant consent, interprofessional communication workshops between August 2020 and March 2021 were audio recorded and transcribed verbatim. Workshops involved groups of internal medicine trainees discussing collaboration challenges and the approaches they use in clinical practice. This framework analysis study used the interprofessional collaboration framework described by Bainbridge and Regehr (building social capital, perspective taking and negotiating priorities and resources), and cross-referenced the categorised data with the healthcare groups that trainees collaborate with, to look for patterns in the data., Results: Seventeen workshops, involving 100 trainees, were included. Trainees described relationship building, perspective taking and negotiating priorities and resources. Relationship building was a modification to the original framework domain of building social capital. Themes of power and civility transcended domains with evidence of using hierarchy as leverage when negotiating and employing civility as a tactical approach throughout., Discussion: This bi-dimensional analysis highlights patterns of perspective taking when collaborating with other specialties and professions, and the approaches to negotiation of courting favour and coercion when interacting with other specialties. This study provides evidence of the strategies currently utilised by internal medicine trainees, with different healthcare groups, and presents a modified framework which could inform the development of training for collaboration.