High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Cigarette Smoke Exposure Promotes Virulence of Pseudomonas aeruginosa and Induces Resistance to Neutrophil Killing.

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. Pseudomonas aeruginosa, a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. Pseudomonas aeruginosa colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, Pseudomonas aeruginosa exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of tpx, a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of P. aeruginosa, increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen.

Trends in Vitreoretinal Procedures for Medicare Beneficiaries, 2000 to 2014.

TOPIC: The purpose of this study was to identify changes in use for vitreoretinal procedures by measuring the number of allowed services using data from the US Medicare Part B Fee-for-Service (FFS) beneficiaries and their providers. CLINICAL RELEVANCE: To analyze vitreoretinal procedural trends, which may indicate standard of care and importance of developing methods of treatments. METHODS: Medicare Part B National Summary Data Files for calendar years 2000 to 2014 were used to identify the number of allowed services for vitreoretinal procedures and commonly used pharmacologic agents. Linear regression analysis was performed to identify trends in use. MAIN OUTCOME MEASURES: To analyze vitreoretinal procedural trends, which may indicate standard of care and importance of developing methods of treatments. RESULTS: Vitreoretinal procedures grew 6-fold from 2000 to 2014. Intravitreal injections were the primary driver of growth. A total of 2922 injections were performed in 2000, compared with 2 619 950 injections in 2014 (P < 0.01). Scleral buckling declined from 6502 procedures in 2000 to 1260 procedures in 2014 (P < 0.01), whereas vitrectomy use for retinal detachment increased from 13 814 surgeries in 2008 to 19 288 surgeries in 2014 (P < 0.01). Focal laser treatments declined from 188 351 procedures in 2002 to 83 379 procedures in 2014 (P < 0.01). Panretinal photocoagulation treatments declined from 109 840 procedures in 2004 to 81 005 procedures in 2014 (P < 0.01). CONCLUSIONS: Vitreoretinal practice patterns changed significantly from 2000 to 2014. Intravitreal injections increased by 89 563%. Intravitreal injections accounted for 0.55% of all vitreoretinal procedures in 2000 and increased to 87% in 2014. Scleral buckling sharply declined, and preference for retinal detachment repair shifted further toward vitrectomy with a distribution of 83% vitrectomy, 5% scleral buckling, and 12% pneumatic retinopexy in 2014. Use of laser photocoagulation significantly declined for treatment of macular edema and proliferative retinopathy. Cryotherapy procedures declined across all indications.

Phenol soluble modulin (PSM) variants of community-associated methicillin-resistant Staphylococcus aureus (MRSA) captured using mass spectrometry-based molecular networking.

Molecular genetic analysis indicates that the problematic human bacterial pathogen methicillin-resistant Staphylococcus aureus possesses more than 2000 open reading frames in its genome. This number of potential gene products, coupled with intrinsic mechanisms of posttranslational modification, endows methicillin-resistant Staphylococcus aureus with a highly complex biochemical repertoire. Recent proteomic and metabolomic advances have provided methodologies to better understand and characterize the biosynthetic factors released by microbial organisms. Here, the emerging tool of mass spectrometry-based molecular networking was used to visualize and map the repertoire of biosynthetic factors produced by a community-associated methicillin-resistant Staphylococcus aureus strain representative of the epidemic USA300 clone. In particular, the study focused on elucidating the complexity of the recently discovered phenol soluble modulin family of peptides when placed under various antibiotic treatment stresses. Novel PSM truncated variant peptides were captured, and the type of variants that were clustered by the molecular networks platform changed in response to the different antibiotic treatment conditions. After discovery, a group of the peptides were selected for functional analysis in vitro. The peptides displayed bioactive properties including the ability to induce proinflammatory responses in human THP-1 monocytes. Additionally, the tested peptides did not display antimicrobial activity as previously reported for other phenol soluble modulin truncated variants. Our findings reveal that the PSM family of peptides are quite structurally diverse, and suggest a single phenol soluble modulin parent peptide can functionally spawn differential bioactivities in response to various external stimuli.

Steinmann pin augmentation versus locking plate constructs.

BACKGROUND: Aggressive bone neoplasms, such as giant cell tumors, often affect the proximal tibia warranting bony resection via curettage leaving behind massive defects that require extensive reconstruction. Reconstruction is usually accomplished with poly(methyl methacrylate) (PMMA) packing supplemented with an internal fixation construct. The purpose of this study is to compare Steinmann pin augmentation to locking plate constructs to determine which offers the stiffer reconstruction option. MATERIALS AND METHODS: Large defects were created below the lateral condyle of fresh frozen tibias. The defects extended for an average of 35 mm beneath the lateral plateau in the frontal plane, and from the anterior to posterior cortex in the sagittal plane. Distally the defect extended for an average of 35 mm to the metadiaphyseal junction. In the Pin group, the tibias were reconstructed with three 4-mm diameter Steinmann pins placed in the medullary canal and PMMA packing. In the Plate group, the tibias were reconstructed with a 6-hole 3.5-mm LCP Proximal locking plate fixed to the proximal-lateral tibia utilizing seven 3.5-mm screws and PMMA packing. The tibias were tested for stiffness on a MTS machine by applying up to 400 N to the tibial plateau in force control at 5 N/s. Fatigue properties were tested by applying a haversine loading waveform between 200 N and 1,200 N at 3 Hz simulating walking upstairs/downstairs. RESULTS: Locking plate constructs (801.8 ± 78 N/mm) had greater (p = 0.041) stiffness than tibial constructs fixed with Steinmann pins (646.5 ± 206.3 N/mm). CONCLUSIONS: Permanent deformation was similar between the Pin and Plate group; however, two tibia from the Pin group exhibited displacements >5 mm which we considered failure. LEVEL OF EVIDENCE: n/a.

Analysis of the effects of cigarette smoke on staphylococcal virulence phenotypes.

Cigarette smoking is the leading preventable cause of death, disease, and disability worldwide. It is well established that cigarette smoke provokes inflammatory activation and impairs antimicrobial functions of human immune cells. Here we explore whether cigarette smoke likewise affects the virulence properties of an important human pathogen, Staphylococcus aureus, and in particular methicillin-resistant S. aureus (MRSA), one of the leading causes of invasive bacterial infections. MRSA colonizes the nasopharynx and is thus exposed to inhalants, including cigarette smoke. MRSA exposed to cigarette smoke extract (CSE-MRSA) was more resistant to macrophage killing (4-fold higher survival; P < 0.0001). CSE-MRSA demonstrated reduced susceptibility to cell lysis (1.78-fold; P = 0.032) and antimicrobial peptide (AMP) (LL-37) killing (MIC, 8 µM versus 4 µM). CSE modified the surface charge of MRSA in a dose-dependent fashion, impairing the binding of particles with charge similar to that of AMPs by 90% (P < 0.0001). These changes persisted for 24 h postexposure, suggesting heritable modifications. CSE exposure increased hydrophobicity by 55% (P < 0.0001), which complemented findings of increased MRSA adherence and invasion of epithelial cells. CSE induced upregulation of mprF, consistent with increased MRSA AMP resistance. S. aureus without mprF had no change in surface charge upon exposure to CSE. In vivo, CSE-MRSA pneumonia induced higher mouse mortality (40% versus 10%) and increased bacterial burden at 8 and 20 h postinfection compared to control MRSA-infected mice (P < 0.01). We conclude that cigarette smoke-induced immune resistance phenotypes in MRSA may be an additional factor contributing to susceptibility to infectious disease in cigarette smokers.

From amputation to limb salvage reconstruction: evolution and role of the endoprosthesis in musculoskeletal oncology.

In 1943, Austin Moore developed the first endoprosthesis fashioned from Vitallium, providing the first alternative to traditional amputation as primary treatment of bone tumors. The success of the Vitallium endoprosthesis has since then led to the development of new materials and designs further advancing limb salvage and reconstructive surgery. Combined with the advent of chemotherapy use and imaging advances, conservative treatment of musculoskeletal tumors has expanded greatly. As the implantable options increased with the development of the Lewis expandable adjustable prosthesis and the noninvasive Phenix Growing prosthesis, receiving the diagnosis of a bone tumor no longer equates to automatic limb loss. Our review details the history and development of endoprostheses throughout orthopedic oncology in the treatment of musculoskeletal tumors.

Time is tissue. Want to save millions in wound care? Start early: a QI project to expedite referral of high-risk wound care patients to specialised care.

INTRODUCTION: Wound care is a multibillion-dollar industry, and most research and treatment are geared towards late-stage or end-stage care. The longer a patient has a wound, the more likely it is that complications (like sepsis or vascular compromise) will occur that will both extend treatment and multiply costs. We postulated that much of the suffering and healthcare costs of chronic wounds could be avoided by early identification of high-risk patients and subsequent earlier intervention. In an established regional wound clinic, our aim was to decrease referral times by 50% within 1 year, and to demonstrate the beneficial outcomes on wound healing and total cost of care. METHODS: A prospective interventional quality improvement study was performed between June 2017 and June 2018. We determined baseline referral times to the clinic and then performed three interventions. The effects on referral time, healing time and number of home care visits to achieve wound healing were collected and displayed on annotated control charts. The cost of care and potential for cost avoidance was determined by an analysis of the medical encounters of twenty chronic wound patients. RESULTS: We achieved a 53.6% reduction in average referral times to the clinic, a 59.6% reduction in average healing times and a 66.0% reduction in the average number of home care visits required to achieve healing. Our cost analysis suggested the potential for significant cost avoidance (87.7%) compared with delayed treatment outside the clinic. CONCLUSIONS: Early identification and treatment of patients at high risk for wound chronicity and complications, followed by early referral to and treatment at a specialised wound clinic, resulted in faster healing and reduced health system costs.

Mapping Chromatin Occupancy of Ppp1r1b-lncRNA Genome-Wide Using Chromatin Isolation by RNA Purification (ChIRP)-seq.

Long non-coding RNA (lncRNA) mediated transcriptional regulation is increasingly recognized as an important gene regulatory mechanism during development and disease. LncRNAs are emerging as critical regulators of chromatin state; yet the nature and the extent of their interactions with chromatin remain to be fully revealed. We have previously identified Ppp1r1b-lncRNA as an essential epigenetic regulator of myogenic differentiation in cardiac and skeletal myocytes in mice and humans. We further demonstrated that Ppp1r1b-lncRNA function is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors, TBX5 and MyoD1. Herein, we employed an unbiased chromatin isolation by RNA purification (ChIRP) and high throughput sequencing to map the repertoire of Ppp1r1b-lncRNA chromatin occupancy genome-wide in the mouse muscle myoblast cell line. We uncovered a total of 99732 true peaks corresponding to Ppp1r1b-lncRNA binding sites at high confidence (P-value < 1e-5 and enrichment score ≥ 10). The Ppp1r1b-lncRNA-binding sites averaged 558 bp in length and were distributed widely within the coding and non-coding regions of the genome. Approximately 46% of these true peaks were mapped to gene elements, of which 1180 were mapped to experimentally validated promoter sequences. Importantly, the promoter-mapped binding sites were enriched in myogenic transcription factors and heart development while exhibiting focal interactions with known motifs of proximal promoters and transcription initiation by RNA polII, including TATA, transcription initiator, CCAAT-box, and GC-box, supporting Ppp1r1b-lncRNA role in transcription initiation of myogenic regulators. Remarkably, nearly 40% of Ppp1r1b-lncRNA-binding sites mapped to gene introns, were enriched with the Homeobox family of transcription factors, and exhibited TA-rich motif sequences, suggesting potential motif specific Ppp1r1b-lncRNA-bound introns. Lastly, more than 136521enhancer sequences were detected in Ppp1r1b-lncRNA-occupancy sites at high confidence. Among these enhancers,12% exhibited cell type/tissue-specific enrichment in fetal heart and muscles. Together, our findings provide further insights into the genome-wide Ppp1r1b-lncRNA: Chromatin interactome that may potentially dictate its function in myogenic differentiation and potentially other cellular and biological processes.

Mapping Chromatin Occupancy of Ppp1r1b-lncRNA Genome-Wide Using Chromatin Isolation by RNA Purification (ChIRP)-seq.

Long non-coding RNA (lncRNA) mediated transcriptional regulation is increasingly recognized as an important gene regulatory mechanism during development and disease. LncRNAs are emerging as critical regulators of chromatin state; yet the nature and the extent of their interactions with chromatin remain to be fully revealed. We have previously identified Ppp1r1b-lncRNA as an essential epigenetic regulator of myogenic differentiation in cardiac and skeletal myocytes in mice and humans. We further demonstrated that Ppp1r1b-lncRNA function is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors, TBX5 and MyoD1. Herein, we employed unbiased chromatin isolation by RNA purification (ChIRP) and high throughput sequencing to map the repertoire of Ppp1r1b-lncRNA chromatin occupancy genome-wide in the mouse muscle myoblast cell line. We uncovered a total of 99732 true peaks corresponding to Ppp1r1b-lncRNA binding sites at high confidence (p-value < 1E-5) and enrichment score ≥ 10). The Ppp1r1b-lncRNA-binding sites averaged 558 bp in length and were distributed widely within the coding and non-coding regions of the genome. Approximately 46% of these true peaks were mapped to gene elements, of which 1180 were mapped to experimentally validated promoter sequences. Importantly, the promoter-mapped binding sites were enriched in myogenic transcription factors and heart development while exhibiting focal interactions with known motifs of proximal promoters and transcription initiation by RNA Pol-II, including TATA-box, transcription initiator motif, CCAAT-box, and GC-box, supporting Ppp1r1b-lncRNA role in transcription initiation of myogenic regulators. Remarkably, nearly 40% of Ppp1r1b-lncRNA-binding sites mapped to gene introns were enriched with the Homeobox family of transcription factors and exhibited TA-rich motif sequences, suggesting potential motif-specific Ppp1r1b-lncRNA-bound introns. Lastly, more than 136521 enhancer sequences were detected in Ppp1r1b-lncRNA-occupancy sites at high confidence. Among these enhancers, 3390 (12%) exhibited cell type/tissue-specific enrichment in fetal heart and muscles. Together, our findings provide further insights into the genome-wide Ppp1r1b-lncRNA: Chromatin interactome that may dictate its function in myogenic differentiation and potentially other cellular and biological processes.

Impact of the COVID-19 Pandemic on Orthopedic Surgery Residency Training.

This study sought to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on orthopedic surgery residency training across the United States. A 26-question online survey was created and sent to all orthopedic surgery residency programs across the United States. Areas of emphasis in the survey included the pandemic's effect on work hours, operative experience, didactics, and medical student recruitment. There were 142 respondents to the survey. One hundred seventeen (82.4%) respondents stated that their residency changed to an alternative/surge schedule during the pandemic. Regarding the degree to which the pandemic affected their training, 77 (54.2%) respondents gave a rating of 8 to 10 on a scale of 0 to 10. Similarly, 94 (66.2%) residents indicated that their operative experience had decreased significantly. Twenty-two (15.5%) residents expected that their next year clinical abilities would not be affected. One hundred thirty-seven (96.5%) residents stated their program transitioned to online didactics. Responses regarding the effectiveness of online didactics were mixed. One hundred twenty-six (88.7%) respondents stated the pandemic would negatively affect the 2021 National Residency Matching Program match. This study demonstrated that the COVID-19 pandemic greatly affected orthopedic surgery residency training in the United States. Resident operative experience decreased significantly, and most respondents indicated a switch to online didactics. Effects were also felt to extend to fourth-year scheduling and the 2021 National Residency Matching Program match. [Orthopedics. 2023;46(5):315-319.].

Pulmonary artery diameter correlates with echocardiographic parameters of right ventricular dysfunction in patients with acute pulmonary embolism.

Introduction: Right ventricular dysfunction (RVD) is a key component in the process of risk stratification in patients with acute pulmonary embolism (PE). Echocardiography remains the gold standard for RVD assessment, however, measures of RVD may be seen on CTPA imaging, including increased pulmonary artery diameter (PAD). The aim of our study was to evaluate the association between PAD and echocardiographic parameters of RVD in patients with acute PE. Methods: Retrospective analysis of patients diagnosed with acute PE was conducted at large academic center with an established pulmonary embolism response team (PERT). Patients with available clinical, imaging, and echocardiographic data were included. PAD was compared to echocardiographic markers of RVD. Statistical analysis was performed using the Student's t test, Chi-square test, or one-way analysis of variance (ANOVA); P < 0.05 was considered statistically significant. Results: 270 patients with acute PE were identified. Patients with a PAD >30 mm measured on CTPA had higher rates of RV dilation (73.1% vs 48.7%, P < 0.005), RV systolic dysfunction (65.4% vs 43.7%, P < 0.005), and RVSP >30 mmHg (90.2% vs 68%, P = 0.004), but not TAPSE ≤1.6 cm (39.1% vs 26.1%, P = 0.086). A weak increasing linear relationship between PAD and RVSP was noted (r = 0.379, P = 0.001). Conclusions: Increased PAD in patients with acute PE was significantly associated with echocardiographic markers of RVD. Increased PAD on CTPA in acute PE can serve as a rapid prognostic tool and assist with PE risk stratification at the time of diagnosis, allowing rapid mobilization of a PERT team and appropriate resource utilization.

Outpatient Treatment Guidelines of Gunshot Wound to the Hand and Wrist Resulting in an Open Fracture: Case Report.

The incidence of non-fatal gunshot wounds has significantly increased in the past decade. The current guidelines lack clarity in treatment of bullet wounds to the hand and wrist. An 18-year-old male presented to the emergency department with a gunshot wound to the hand/wrist resulting in an open fracture. The entrance wound was clean without visible bone. No neurovascular damage was reported. The wound was irrigated with saline, and a sterile dressing and splint was applied in the emergency department. The patient was discharged the same day with oral antibiotics and an appointment with an orthopedic hand specialist. Three days after the injury, the patient was taken to surgery to treat a fracture of the radius and lunate. No internal fixation was required. The fracture and bullet fragments were removed, and the patient was discharged on the same day. The patient recovered to a full range of motion and no infection was acquired throughout treatment and healing.  The current guidelines for the treatment and management of nonfatal gunshot wounds to the hand and wrist are inconsistent resulting in unnecessary admittance to the hospital. Our paper provides a template for future cases allowing for outpatient treatment.

Hickam's dictum, Occam's razor, and Crabtree's bludgeon: a case of renal failure and a clavicular mass.

OBJECTIVES: Our discussant's thoughtful consideration of the patient's case allows for review of three maxims of medicine: Occam's razor (the simplest diagnosis is the most likely to be correct), Hickam's dictum (multiple disease entities are more likely than one), and Crabtree's bludgeon (the tendency to make data fit to an explanation we hold dear). CASE PRESENTATION: A 66-year-old woman with a history of hypertension presented to our hospital one day after arrival to the United States from Guinea with chronic daily vomiting, unintentional weight loss and progressive shoulder pain. Her labs are notable for renal failure, nephrotic range proteinuria and normocytic anemia while her shoulder X-ray shows osseous resorption in the lateral right clavicle. Multiple myeloma became the team's working diagnosis; however, a subsequent shoulder biopsy was consistent with follicular thyroid carcinoma. Imaging suggested the patient's renal failure was more likely a result of a chronic, unrelated process. CONCLUSIONS: It is tempting to bludgeon diagnostic possibilities into Occam's razor. Presumption that a patient's signs and symptoms are connected by one disease process often puts us at a cognitive advantage. However, atypical presentations, multiple disease processes, and unique populations often lend themselves more to Hickam's dictum than to Occam's razor. Diagnostic aids include performing a metacognitive checklist, engaging analytic thinking, and acknowledging the imperfections of these axioms.

A critical temporal window for selectin-dependent CD4+ lymphocyte homing and initiation of late-phase inflammation in contact sensitivity.

Contact sensitivity (CS) is an inflammatory disorder characterized by early and late phases of leukocyte recruitment. We used a noninvasive intravital microscopy technique allowing for the direct visualization of leukocyte rolling and adhesion on blood vessel endothelium. By blocking specific adhesion molecules, we elucidated the molecular mechanisms mediating early leukocyte recruitment to be E- and P-selectin and demonstrated that leukocyte recruitment in the late phase had a different adhesive profile (mainly alpha(4)-integrin). Complete blockade of E- and P-selectin within the first 2 h of leukocyte-endothelial cell interactions (but not later) eliminated selectin-independent leukocyte recruitment at 24 h. Despite the predominance of neutrophils in the early phase, specific elimination of CD4(+) lymphocytes in the early phase eliminated the late response. CD4(+) lymphocytes homed to skin via E- and P-selectin within the early phase and induced the late phase response. Addition of these same CD4(+) lymphocytes 2 h after antigen challenge was too late for these cells to home to the skin and induce late phase responses. Our data clearly demonstrate that the antigen-challenged microenvironment is only accessible to CD4(+) lymphocytes for the first 2 h, and that this process is essential for the subsequent recruitment of other leukocyte populations in late phase responses.

The clinical utility of Ki-67 in assessing tumor biology and aggressiveness in patients with appendiceal carcinoids.

BACKGROUND/OBJECTIVE: To elucidate the correlation of Ki-67 with tumor biology and survival in appendiceal carcinoid tumors. METHOD: A retrospective chart review conducted on 51 patients with appendiceal carcinoid tumors who underwent surgical intervention from 1991 to 2008. MIB-1, an antibody of Ki-67, was used to determine cell proliferation and correlated with clinical and histological parameters. MIB-1 index was categorized according to the World Health Organization (WHO) classification. RESULT: Of the 51 patients, 32 had tumors <2 cm; 3 >2 cm; and 16 with unspecified tumor size. Increased MIB proliferative index did not significantly correlate with increasing tumor size (P = 0.426). Twelve patients had metastatic disease on presentation: 9 had MIB-1 index <2%, 1 had index 2-15% and 2 with index >15%. No significant correlation between MIB index and metastasis was demonstrated (P = 0.68). Median follow-up was 40 months (range 10-183 months) with a 51% follow-up rate. Seven mortalities and three recurrences presented in 26 patients. Assessment of survival demonstrated significantly decreased survival by increasing MIB index. Survival rate by MIB index was as follows: <2% was 97%, 2-15% was 85% and >15% was 67% (P = 0.02). CONCLUSION: Increased MIB index significantly correlated with decreased survival. No correlation was demonstrated by MIB index and tumor size or presentation with metastatic disease.

Fundus autofluorescence, optical coherence tomography, and electroretinogram findings in choroidal sclerosis.

PURPOSE: The purpose of this study was to describe fundus autofluorescence (FAF), optical coherence tomography, and electroretinogram findings in choroidal sclerosis. METHODS: This is a retrospective case series. Eight eyes of four patients with choroidal sclerosis were evaluated with FAF, optical coherence tomography, and electroretinogram testing. RESULTS: In all eight eyes, FAF imaging showed hypofluorescent placoid lesions corresponding to areas of chorioretinal atrophy seen on stereo biomicroscopy. Prominent hyperfluorescent linear markings underlying regions of atrophic disease were observed in all eyes, likely representative of normal choroidal vessel autofluorescence. In two eyes, FAF showed punctate hypofluorescent lesions in the fovea that were not visualized on biomicroscopy. In one eye, FAF identified a central island of preserved retinal pigment epithelium that was not realized on ophthalmoscopic examination. Optical coherence imaging was significant for loss of choroidal fine tubular structures, retinal pigment epithelium, and outer nuclear layer in regions of chorioretinal atrophy. Full-field electroretinogram testing showed generalized rod-cone dysfunction in all patients with a lower B- to A-wave ratio in two patients. CONCLUSION: Fundus autofluorescence and optical coherence tomography are nonin-vasive diagnostic adjuncts that can aid in the diagnosis of choroidal sclerosis. Fundus autofluorescence may be a more sensitive marker of disease extent and progression than clinical examination alone. Electroretinogram testing can result in an electronegative maximal response.

Fundus autofluorescence and optical coherence tomography of congenital grouped albinotic spots.

PURPOSE: The purpose of this study was to describe the findings of fundus autofluores-cence (FAF) and optical coherence tomography in a series of patients with congenital grouped albinotic spots. METHODS: Three eyes of three patients with congenital grouped albinotic spots were evaluated with FAF and optical coherence tomography imaging to evaluate the nature of the albinotic spots. RESULTS: In all three eyes with congenital grouped albinotic spots, FAF imaging showed autofluorescent spots corresponding to the albinotic spots seen on stereo biomicroscopy. One eye also had additional spots detected on FAF imaging that were not visible on stereo biomicroscopy or color fundus photographs. Fundus autofluorescence imaging of the spots showed decreased general autofluorescence and decreased peripheral autofluorescence surrounding central areas of retained or increased autofluorescence. Optical coherence tomography showed a disruption in signal from the hyperreflective layer corresponding to the inner and outer segment junction and increased signal backscattering from the choroid in the area of the spots. Fluorescein angiography showed early and stable hyperfluorescence of the spots without leakage. CONCLUSION: In this case series, FAF showed decreased autofluorescence of the spots consistent with focal retinal pigment epithelium atrophy or abnormal material blocking normal autofluorescence and areas of increased autofluorescence suggesting retinal pigment epithelium dysfunction. The findings of optical coherence tomography and fluorescein angiography suggest photoreceptor and retinal pigment epithelium layer abnormalities. Fundus autofluorescence and optical coherence tomography are useful noninvasive diagnostic adjuncts that can aid in the diagnosis of congenital grouped albinotic spots, help determine extent of disease, and contribute to our understanding of its pathophysiology.

Acute orbitocranial inflammation following radioimmunotherapy for non-Hodgkin lymphoma.

Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan may result in hemorrhagic tumor necrosis with acute orbital and intracranial inflammation.

Virtual Reality and Augmented Reality-Translating Surgical Training into Surgical Technique.

PURPOSE OF REVIEW: As immersive learning outside of the operating room is increasingly recognized as a valuable method of surgical training, virtual reality (VR) and augmented reality (AR) are increasingly utilized in orthopedic surgical training. This article reviews the evolving nature of these training tools and provides examples of their use and efficacy. The practical and ethical implications of incorporating this technology and its impact on both orthopedic surgeons and their patients are also discussed. RECENT FINDINGS: Head-mounted displays (HMDs) represent a possible adjunct to surgical accuracy and education. While the hardware is advanced, there is still much work to be done in developing software that allows for seamless, reliable, useful integration into clinical practice and training. Surgical training is changing: AR and VR will become mainstays of future training efforts. More evidence is needed to determine which training technology translates to improved clinical performance. Volatility within the HMD industry will likely delay advances in surgical training.