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Exercise and nutrition interventions are often recommended for frailty; however, effective strategies are required for real-world implementation. Our primary aim was to assess the feasibility and acceptability of telephone and virtual delivery of MoveStrong, an 8-week exercise and nutrition program with a 4-week follow-up for older pre-frail and frail adults. A priori criteria for success included: recruitment (≥25/12 weeks), retention at follow-up (≥80%), and adherence to exercise and nutrition sessions (≥70%). We recruited community-dwelling Ontario residents; ≥60 years, ≥1 chronic condition, ≥1 FRAIL scale score. Participants received mailed materials, a personalized exercise program, 11 remote one-on-one training sessions with an exercise physiologist and 3 online dietitian-led nutrition education sessions. We completed exploratory analyses of secondary outcomes including physical function and dietary protein intake. Semi-structured interviews supported program evaluation. In total, 30 participants were enrolled. 28 (93%) participants completed program and follow-up assessments. Adherence to exercise and nutrition sessions (CI) was 84% (77%–91%) and 82% (70%–93%) respectively. At program end and follow-up [mean change (CI)], significant improvements were measured in 30-second chair stand test [3.50 (1.12–5.86), 4.54 (1.94–7.13) chair stands] and dietary protein intake [12.9 (5.7–20.0), 9.2 (0.4–18.1) g]. Overall, participants were satisfied with program delivery. Trial registration number: NCT04663685.

BACKGROUND The significance of extracapsular extension (ECE) and adjuvant treatment paradigm in patients with surgically managed human papillomavirus-positive (HPV+) oropharyngeal cancer (OPC) is debated. METHODS National, hospital-based, retrospective cohort study of 2663 patients pN+ HPV+ OPC who underwent primary surgery. RESULTS Patients with ECE had a 1.74-times risk of death (95% confidence interval [CI]: 1.26-2.40, p = 0.001) compared to patients without ECE. Among patients with pN1, ECE-positive disease, risk of overall mortality was similar across treatment paradigms (surgery alone: ref; adjuvant radiation therapy [RT]: aHR: 0.81; 95% CI: 0.36-1.85; p = 0.62; adjuvant CRT: aHR: 0.66; 95% CI: 0.34-1.32; p = 0.24). Patients with pN2 ECE-positive disease treated with adjuvant RT alone exhibited similar risk of all-cause mortality (hazard ratio: 1.04, 95% CI: 0.24-4.47, p = 0.96) compared to adjuvant chemoradiation (CRT). In patients with advanced, ECE-positive disease (e.g., pT3-T4pN2), adjuvant CRT did not reduce the risk of overall mortality relative to adjuvant RT. CONCLUSION Although pathologic ECE negatively predicts for survival in patients with HPV+ OPC, our analyses support expansion of postoperative de-intensification clinical trial eligibility criteria in patients with ECE-positive disease.

Children undergoing cleft palate repair present challenges to postoperative management due to several factors that can complicate recovery. Utilization of multimodal analgesic protocols can improve outcomes in this population. We report experience designing and implementing an enhanced recovery after surgery (ERAS) pathway for cleft palate repair to optimize postoperative recovery.The primary aim was to implement an ERAS pathway with70% bundle adherence to achieve a 30% reduction in postoperative opioid consumption within 12 months. Our secondary aims assessed intraoperative opioid consumption, length of stay, timeliness of oral intake, and respiratory recovery.A multidisciplinary team of perioperative providers developed an ERAS pathway for cleft palate patients. Key drivers included patient and provider education, formal pathway creation and implementation, multimodal pain therapy, and target-based care. Interventions included maxillary nerve blockade and enhanced intra- and postoperative medication regimens. Outcomes were displayed as statistical process control charts.Pathway compliance was 77.0%. Patients during the intervention period (n = 39) experienced a 49% reduction in postoperative opioid consumption (p .0001) relative to our historical cohort (n = 63), with a mean difference of -0.33 ± 0.11 mg/kg (95% CI -0.55 to -0.12 mg/kg). Intraoperative opioid consumption was reduced by 36% (p = .002), with a mean difference of -0.27 ± 0.09 mg/kg (95% CI -0.45 to -0.09 mg/kg). Additionally, patients in the intervention group had a 45% reduction in time to first oral intake (p = .02) relative to our historical cohort, with a mean difference of -3.81 ± 1.56 h (95% CI -6.9 to -0.70). There was no difference in PACU or hospital length of stay, but there was a significant reduction in variance of all secondary outcomes.Opioid reduction and improved timeliness of oral intake is possible with an ERAS protocol for cleft palate repair, but our protocol did not alter PACU or hospital length of stay.

Augmented reality (AR) has promise as a clinical teaching tool, particularly for remote learning. The Chariot Augmented Reality Medical (CHARM) simulator integrates real-time communication into a portable medical simulator with a holographic patient and monitor. The primary aim was to analyze feedback from medical and physician assistant students regarding acceptability and feasibility of the simulator.Using the CHARM simulator, we created an advanced cardiovascular life support (ACLS) simulation scenario. After IRB approval, preclinical medical and physician assistant students volunteered to participate from August to September 2020. We delivered augmented reality headsets (Magic Leap One) to students before the study. Prior to the simulation, via video conference, we introduced students to effective communication skills during a cardiac arrest. Participants then, individually and remotely from their homes, synchronously completed an instructor-led ACLS AR simulation in groups of three. After the simulation, students participated in a structured focus group using a qualitative interview guide. Our study team coded their responses and interpreted them using team-based thematic analysis.Eighteen medical and physician assistant students participated. We identified four domains that reflected trainee experiences: experiential satisfaction, learning engagement, technology learning curve, and opportunities for improvement. Students reported that the simulator was acceptable and enjoyable for teaching trainees communication skills; however, there were some technical difficulties associated with initial use.This study suggests that multiplayer AR is a promising and feasible approach for remote medical education of communication skills during medical crises.The online version contains supplementary material available at 10.1007/s40670-022-01598-7.

BACKGROUND: Long-term opioid use has negative healthcare consequences. Opioid-naïve adults are at risk for prolonged and persistent opioid use after surgery. While these outcomes have been examined in some adolescent and teenage populations little is known about the risk of prolonged and persistent postoperative opioid use after common surgeries compared to children who do not undergo surgery, and factors associated with these issues among pediatric surgical patients of all ages. METHODS: Using a national administrative claims database, we identified 175,878 surgical visits by opioid-naïve children aged ≤18 who underwent ≥1 of the 20 most common surgeries from each of four age groups between December 31, 2002 and December 30, 2017, and who filled a perioperative opioid prescription 30 days before to 14 days after surgery. Prolonged opioid use after surgery (filling ≥1 opioid prescription 90–180 days after surgery) was compared to a reference sample of 1,354,909 nonsurgical patients randomly assigned a false “surgery” date. Multivariable logistic regression models were used to estimate the association of surgical procedures and 22 other variables of interest with prolonged opioid use and persistent postoperative opioid use (filling ≥60 days’ supply of opioids 90–365 days after surgery) for each age group. RESULTS: Prolonged opioid use after surgery occurred in 0.77%, 0.76%, 1.0%, and 3.8% of surgical patients ages 0–

Purpose The purpose of this report is to demonstrate the successful application of virtual reality to improve physical therapy in the pediatric cardiovascular intensive care unit. Early mobilization and cognitive stimulation improve morbidity of critically ill children. However, maintaining child engagement with these therapies can be challenging, especially during extended intensive care stays. Summary of key points While virtual reality has been successfully used as an analgesic and anxiolytic in the cardiovascular intensive care unit, this report demonstrates its novel use as a tool to augment physical therapy for a child who had been debilitated after heart transplantation. Virtual reality encouraged the child to engage in physical therapy sessions, participate for greater durations, and directly address barriers to discharge. Conclusions and recommendations for clinical practice While further studies are needed to define best practice, this report demonstrates that virtual reality can be safely used for carefully selected and monitored children in critical care.

The significance of extracapsular extension (ECE) and adjuvant treatment paradigm in patients with surgically managed human papillomavirus-positive (HPV+) oropharyngeal cancer (OPC) is debated.National, hospital-based, retrospective cohort study of 2663 patients pN+ HPV+ OPC who underwent primary surgery.Patients with ECE had a 1.74-times risk of death (95% confidence interval [CI]: 1.26-2.40, p = 0.001) compared to patients without ECE. Among patients with pN1, ECE-positive disease, risk of overall mortality was similar across treatment paradigms (surgery alone: ref; adjuvant radiation therapy [RT]: aHR: 0.81; 95% CI: 0.36-1.85; p = 0.62; adjuvant CRT: aHR: 0.66; 95% CI: 0.34-1.32; p = 0.24). Patients with pN2 ECE-positive disease treated with adjuvant RT alone exhibited similar risk of all-cause mortality (hazard ratio: 1.04, 95% CI: 0.24-4.47, p = 0.96) compared to adjuvant chemoradiation (CRT). In patients with advanced, ECE-positive disease (e.g., pT3-T4pN2), adjuvant CRT did not reduce the risk of overall mortality relative to adjuvant RT.Although pathologic ECE negatively predicts for survival in patients with HPV+ OPC, our analyses support expansion of postoperative de-intensification clinical trial eligibility criteria in patients with ECE-positive disease.

Background: In early 2020, COVID-19 massively hit Italy, earlier and harder than any other European country. This caused a series of strict containment measures, aimed at blocking the spread of the pandemic. Healthcare delivery was also affected when resources were diverted towards care of COVID-19 patients, including intensive care wards. Aim of the study: The aim is assessing the impact of COVID-19 on cardiac imaging in Italy, compare to the Rest of Europe (RoE) and the World (RoW). Methods: A global survey was conducted in May–June 2020 worldwide, through a questionnaire distributed online. The survey covered three periods: March and April 2020, and March 2019. Data from 52 Italian centres, a subset of the 909 participating centres from 108 countries, were analyzed. Results: In Italy, volumes decreased by 67% in March 2020, compared to March 2019, as opposed to a significantly lower decrease (p < 0.001) in RoE and RoW (41% and 40%, respectively). A further decrease from March 2020 to April 2020 summed up to 76% for the North, 77% for the Centre and 86% for the South. When compared to the RoE and RoW, this further decrease from March 2020 to April 2020 in Italy was significantly less (p = 0.005), most likely reflecting the earlier effects of the containment measures in Italy, taken earlier than anywhere else in the West. Conclusions: The COVID-19 pandemic massively hit Italy and caused a disruption of healthcare services, including cardiac imaging studies. This raises concern about the medium- and long-term consequences for the high number of patients who were denied timely diagnoses and the subsequent lifesaving therapies and procedures.

Prior studies on proning awake, non‐intubated patients with hypoxemic acute respiratory failure, as well as evolving study of similar COVID‐19 patients, coupled with experience and dramatic anecdotal evidence from the COVID‐19 pandemic, suggest the importance of proning all such patients with COVID‐19 to improve oxygenation and reduce respiratory effort. Literature and experience from healthcare teams in the midst of the pandemic suggest that any COVID‐19 patients with respiratory compromise severe enough to warrant admission should be considered for proning. We additionally suggest these patients should be considered for proning as well as ongoing patient re‐positioning (e.g. right lateral decubitus, seated, and left lateral decubitus positions). Figure 1 represents the proning and positioning instructions developed at New York City Health + Hospitals/Elmhurst, a large, inner‐city, tertiary public hospital in the epicenter of the COVID‐19 pandemic in New York City, and later adapted and utilized at facilities across the United States.

Background Living with Inflammatory Bowel Disease (IBD) has been associated with increased psychosocial stress among pediatric IBD populations. Elevated psychological stress can exacerbate disease activity and IBD symptoms like abdominal pain, which in turn can negatively impact children’s mental health. There is an increasing need for mind-body interventions that can improve biopsychosocial processes among youth with IBD. Mindfulness-based interventions (MBIs) have been shown to be efficacious in improving emotional distress, pain, and inflammation in a range of pediatric and adult chronic illness/pain populations. Few studies have explored MBIs in pediatric IBD. Using virtual reality (VR) as the medium for an MBI in pediatric IBD has great potential given the increasing prevalence of VR in children’s hospitals, the immersive nature of the technology, and the high acceptability of VR among youth. Aims 1) Assess the feasibility and acceptability of mindfulness-based virtual reality (MBVR) among youth with IBD; 2) Assess the preliminary efficacy of MBVR on anxiety and pain. Methods Youth at an outpatient IBD clinic were offered MBVR. Our team developed a 6-minute MBVR experience, “MediMindfulness-Transitions” (Stanford University & Weightless Studios), that focused participants’ awareness on a natural environment (e.g., waterfall in meadow, northern lights) and their breath. Participants rated their level of anxiety and pain on VAS scales (0-100mm) immediately before and after the MBVR experience. Paired t-tests were used to assess changes in patient reported outcomes (SPSS 26). Patients also completed a satisfaction survey and provided qualitative feedback. Results The sample included 52 participants with IBD (M=15 yrs; 69% Crohn’s disease; 58% Male; 62% White). MBVR was easily integrated into clinic flow (offered before or after MD visit) and there was 100% treatment compliance. There were high levels of enjoyment (M=4.4, range 1–5) and relaxation (M=4.3, range 1–5) post-intervention; 50% of the sample reported MBVR was an ideal length and were extremely interested in using MBRV at home. Qualitative data revealed areas of enjoyment and suggestions for future use (Table 1). Exploratory efficacy analyses revealed MBVR decreased anxiety (16.54 ± 20.56 vs 7.10 ± 13.27, p < 0.001) and pain (9.5 ± 16.19 vs 3.04 ± 6.22, p < 0.01). One patient experienced worsening of their anxiety symptoms. Conclusion MBVR was shown to be feasible and have high acceptability among youth with IBD. The results demonstrated preliminary support for MBVR reducing acute anxiety and pain. This study suggests MBVR could be a promising mind-body therapy for youth with IBD. Future studies should explore the efficacy of MBVR during IBD procedures and treatments (e.g., blood draws, MRIs, infusions) and whether longer-term use of MBVR improves biopsychosocial outcomes.

Introduction Virtual reality (VR) is an emerging tool for anxiety and fear reduction in pediatric patients. VR use is facilitated by Certified Child Life Specialists (CCLS) at pediatric hospitals. The primary aim of this study was to retrospectively review the safety of VR by analyzing adverse events after the utilization of VR under CCLS supervision. Secondary objectives were to characterize the efficacy of VR in enhancing patient cooperation, describe the integration of VR into Child Life services, and identify interventions that accompanied VR. Methods The Stanford Chariot Program developed VR applications, customized VR interfaces, and patient head straps, and distributed these to CCLS. Chart review analyzed VR utilization through CCLS patient notes. Inclusion criteria were all patients ages 6 to 18-years-old who received a Child Life intervention. Results From June 2017 to July 2018, 31 CCLS saw 8,098 patients, 3,696 of which met age criteria with pre- and post-intervention cooperation data. Two hundred thirteen patients received VR with an accompanying intervention, while 34 patients received only VR. Adverse events were rare, and included increased anxiety (3.8%, n=8), dizziness (0.5%, n=1), and nausea (0.5%, n=1). Patients were more likely to be cooperative after receiving VR (99.5%, n=212) compared to pre-intervention (96.7%, n=206, p=0.041). VR use was most common in the perioperative setting (60%, n=128), followed by outpatient clinics (15%, n=32). Conclusion VR is safe in pediatric patients with appropriate hardware, software, and patient selection. Side effects were rare and self-limited. VR appears to be associated with improvements in cooperation.

Background The number of radiolabeled monoclonal antibodies (mAbs) used for medical imaging and cancer therapy is increasing. The required chemical modification for attaching a radioactive label and all associated treatment may lead to a damaged mAb subpopulation. This paper describes a novel method, concentration through kinetics (CTK), for rapid assessment of the concentration of immunoreactive mAb and the specific radioactivity, based on monitoring binding kinetics. Methods The interaction of radiolabeled mAb with either the antigen or a general mAb binder such as Protein A was monitored in real time using the instrument LigandTracer. As the curvature of the binding trace has a distinct shape based on the interaction kinetics and concentration of the functional mAb, the immunoreactive mAb concentration could be calculated through reverse kinetic fitting of the binding curves, using software developed for this project. The specific activity, describing the degree of radioactive labeling, was determined through the use of calibrated signal intensities. Results The performance of the CTK assay was evaluated on the basis of various mAb-based interaction systems and assay formats, and it was shown that the assay can provide accurate and repeatable results for immunoreactive concentration and specific activity, with both accuracy and relative SD values below 15%. Conclusion By applying reverse kinetics on real-time binding traces it is possible to estimate the functional concentration and specific activity of radiolabeled mAb. The CTK assay may in the future be included as a complement to current quality assessment methods of radiolabeled mAbs.

Psychrophilic alkaline phosphatase (AP) from the Antarctic strain TAB5 was subjected to directed evolution in order to identify the key residues steering the enzyme's cold-adapted activity and stability. A round of random mutagenesis and further recombination yielded three thermostable and six thermolabile variants of the TAB5 AP. All of the isolated variants were characterised by their residual activity after heat treatment, Michaelis-Menten kinetics, activation energy and microcalorimetric parameters of unfolding. In addition, they were modelled into the structure of the TAB5 AP. Mutations which affected the cold-adapted properties of the enzyme were all located close to the active site. The destabilised variants H135E and H135E/G149D had 2- and 3-fold higher kcat, respectively, than the wild-type enzyme. Wild-type AP has a complex heat-induced unfolding pattern while the mutated enzymes loose local unfolding transitions and have large shifts of the Tm values. Comparison of the wild-type and mutated TAB5 APs demonstrates that there is a delicate balance between the enzyme activity and stability and that it is possible to improve the activity and thermostability simultaneously as demonstrated in the case of the H135E/G149D variant compared to H135E.

Alkaline phosphatases (APs) are non-specific phosphohydrolases that are widely used in molecular biology and diagnostics. We describe the structure of the cold active alkaline phosphatase from the Antarctic bacterium TAB5 (TAP). The fold and the active site geometry are conserved with the other AP structures, where the monomer has a large central beta-sheet enclosed by alpha-helices. The dimer interface of TAP is relatively small, and only a single loop from each monomer replaces the typical crown domain. The structure also has typical cold-adapted features; lack of disulfide bridges, low number of salt-bridges, and a loose dimer interface that completely lacks charged interactions. The dimer interface is more hydrophobic than that of the Escherichia coli AP and the interactions have tendency to pair with backbone atoms, which we propose to result from the cold adaptation of TAP. The structure contains two additional magnesium ions outside of the active site, which we believe to be involved in substrate binding as well as contributing to the local stability. The M4 site stabilises an interaction that anchors the substrate-coordinating R148. The M5 metal-binding site is in a region that stabilises metal coordination in the active site. In other APs the M5 binding area is supported by extensive salt-bridge stabilisation, as well as positively charged patches around the active site. We propose that these charges, and the TAP M5 binding, influence the release of the product phosphate and thus might influence the rate-determining step of the enzyme.

Introduction: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. Methods:Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1 = 220 (or 240) ms immediately followed by 30 test-beats at S2 = 200 ms. This S1–S2 protocol was repeated for S2 = 190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. Results:Physiologically relevant inhibition (IC20) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (Ceff). At the highest achievable levels, fluoxetine (20-fold Ceff) and citalopram (28-fold Ceff) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold Ceff, but did not increase electrical alternans at the highest achievable dose (3.1-fold Ceff). Discussion:These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine the effects of acupuncture for individuals with neck pain. SUMMARY OF BACKGROUND DATA: Neck pain is one of the 3 most frequently reported complaints of the musculoskeletal system. Treatments for neck pain are varied, as are the perceptions of benefits. METHODS.: We searched CENTRAL (2006, issue 1) and MEDLINE, EMBASE, MANTIS, Cumulative Index to Nursing and Allied Health Literature from their beginning to February 2006. We searched reference lists and the acupuncture database TCMLARS in China. Any published trials using randomized (RCT) or quasi-randomized (quasi-RCT) assignment to the intervention groups, either in full text or abstract form, were included. RESULTS: We found 10 trials that examined acupuncture treatments for chronic neck pain. Overall, methodologic quality had a mean of 2.3 of 5 on the Jadad scale. For chronic mechanical neck disorders, there was moderate evidence that acupuncture was more effective for pain relief than some types of sham controls, measured immediately posttreatment. There was moderate evidence that acupuncture was more effective than inactive, sham treatments measured immediately posttreatment, and at short-term follow-up (pooled standardized mean difference, -0.37; 95% confidence interval, -0.61 to -0.12). There was limited evidence that acupuncture was more effective than massage at short-term follow-up. For chronic neck disorders with radicular symptoms, there was moderate evidence that acupuncture was more effective than a wait-list control at short-term follow-up. CONCLUSIONS: There is moderate evidence that acupuncture relieves pain better than some sham treatments, measured at the end of the treatment. There is moderate evidence that those who received acupuncture reported less pain at short-term follow-up than those on a waiting list. There is also moderate evidence that acupuncture is more effective than inactive treatments for relieving pain posttreatment, and this is maintained at short-term follow-up.

Felids play an important role in structuring the prey community, and thus in the dynamics of the plant community in tropical forests. The diets of three species of small cats, Leopardus pardalis (ocelot), L. wiedii (margay), and L. tigrinus (oncilla) were investigated by analysis of scats and regurgitations during a one-year study at Parque Estadual Serra do Mar, Nucleo Santa Virginia, southeastern Brazil. Small non-volant mammals were the most frequent prey in all the diets. The diets of the three cats were similar but although they consumed the same prey items, they showed differential use of them. Ocelots consumed more reptiles than the other species, oncillas preyed on birds and arboreal marsupials, whereas margays were generalists.

The Fur protein regulates the expression of a wide variety of iron-responsive genes; however, the interaction of this repressor with its cognate metal ion remains controversial. The iron-bound form of Fur has proved difficult to obtain, and conflicting results have been published using Mn(II) as a probe for in vitro DNA-binding studies. We report here that the purified protein contains tightly bound zinc and propose that Zn(II) is bound to the protein in vivo. Upon purification, Fur retains ca. 2.1 mol of Zn(II)/mol of Fur monomer (Zn2Fur). One zinc is easily removed by treatment of Zn2Fur with zinc chelating agents, resulting in Zn1Fur with ca. 0.9 mol of Zn(II)/mol of protein. The remaining zinc in Zn1Fur can only be removed under denaturing conditions to yield apo-Fur with ca. 0.1 mol of Zn(II)/mol of protein. Our results suggest that many literature descriptions of purified Fur protein do not correspond to the apo-protein, but to Zn1Fur or Zn2Fur. Dissociation constants (Kd) of protein-DNA complexes are ca. 20 nM for both Zn2Fur and Zn1Fur as determined by electrophoretic mobility shift assays and DNase I footprinting assays. The two metalated forms, however, show qualitative differences in the footprinting assays while apo-Fur does not bind specifically to the operator. The existence of these Zn(II) binding sites in Fur may resolve some discrepancies in the literature and have implications concerning Zur, a Fur homologue in E. coli that regulates zinc-responsive genes.

The intent of this study was to visualize changes in the density and location of fibrinogen-related antigen (FRA) depositions within the murine vitreous space during the formation of a chronic mycobacterial-induced uveitis (CMIU) granuloma. Concurrent changes in cellular morphology of the granuloma were also examined. Fibrinogen derivatives within the exudates of granulomatous cell-mediated inflammations may induce physical induration and numerous other phlogistic effects. However, technical limitations of conventional FRA staining methods have tended to underestimate the extent of their presence within this category of inflammatory lesions. Conventional H and E sections of the CMIU granuloma confirmed the classic progression-early PMN influx, monocyte maturation and final macrophage and epithelioid cell dominance-described for such lesions. Avidin-biotin-complex staining utilizing a polyclonal mouse antifibrinogen then revealed a progressive increase in amorphous extracellular fibrinogen-FRA-positive staining material as the granuloma evolved. Thus, on day one the PMN influx showed no evidence of fibrinogen-FRA staining; at one week heavy staining was evident in the anterior chamber and in consolidated (i.e. macrophage) regions of the granuloma; at one month a heavy uniform staining appeared throughout the indurated granuloma where macrophages and epithelioid cells predominated. Patterns of heavy deposition on macrophage surfaces were suggested. The likelihood that bulky accumulations of FRA in mature granulomas are not solely fibrin, and may account for granulomatous induration and persistence, is discussed.