Structural Limits of Orbital Compliance and Treatment Options for Pathologic Orbital Pressure.

PURPOSE: The integrity of the orbit has a finite structural limit due to the compliance of its tissue. The authors investigate these limits to quantify them and inform the treatment of heightened ocular and orbital pressure. METHODS: Cadaveric study with 12 orbits being volumized before randomization of treatment for pathologic levels of ocular and orbital pressure. First-line and second-line treatment was chosen randomly (lateral cantholysis, superior septolysis, inferior septolysis). Prior to treatment, IOP, orbital compartment pressure, and axial globe projection was measured after delivery of each 1cc aliquot and surgical treatment. RESULTS: Orbital compartment pressure and IOP were well correlated (r = 0.99). The average reduction in IOP after treatment averaged a 56.2 mm Hg reduction in IOP. All treatments were statistically equivalent ( p < 0.01). Loss of compliance (P LOC ) was determined when the mean plus 1 standard deviation of change in IOP/ml volume was achieved with simultaneous change in exophthalmometry of <0.5 mm change/ml added volume, indicating an acceleration in pressure in the face of a steady volume. This criteria was met for 11 of 12 orbits. The 12th orbit missed this threshold by 1 mm Hg in IOP. P LOC occurred at an average IOP of 43.0 mm Hg (±5.8 mm Hg, 90% CI) and after an average injection of 13 ml (±1.4 mm, 90% CI). Additionally, lateral cantholysis, superior septolysis, and inferior septolysis were statistically equivalent in reducing IOP after P LOC . CONCLUSIONS: IOP and orbital compartment pressure are excellent proxies for each other in the authors' model. Orbital compliance is a mathematic phenomenon that can be quantified, as evident in this investigation. P LOC can inform timing for orbital decompressions in the presence of heightened IOP. Multiple procedures can be used to extinguish dangerously high orbital compartment pressure.

Penetrating colored pencil injury with Clostridium bifermentans pre-septal cellulitis: case report, literature review, and treatment algorithm.

The incidence of penetrating orbital injuries from writing instruments continues to rise in the pediatric population. Such injuries can cause significant visual morbidity and have a lifelong psychosocial impact. While the description of graphite pencil-related orbital trauma management is well demonstrated with over 40 reported cases, a lack of consistent management protocol for colored pencil-related injuries. Here, we report an inadvertent penetrating orbital colored pencil injury with progressive mechanical ptosis and pre-septal cellulitis necessitating urgent orbitotomy, debridement, and washout to reduce inflammatory and infectious burden. The wooden body serves as a nidus for polymicrobial infection, and the unique composition of colored pencil cores may lead to inflammatory processes that require vigilant multidisciplinary surgical and medical management reflected in our literature review.

Scope of practice of oculofacial plastic and reconstructive surgeons: a public perception survey.

PURPOSE: The purpose of this study is to determine the public's perception of the scope of practice for oculofacial plastic and reconstructive surgeons (OFPRS). METHODS: A 49-question survey was distributed by QualtricsⓇ to a panel similar to the US demographic composition. Responses collected underwent bivariate statistical analysis. RESULT: A total of 530 responses were obtained, with most respondents being white, female, over the age of 35, from the Midwest, and with at least a college education or above. Most respondents did not think ophthalmologists or optometrists were surgeons, and only 158 people (29.8%) knew the primary specialty of OFPRS was ophthalmology. Board certification was preferred by 98.87% of respondents, and 95.28% preferred ASOPRS-trained OFPRS. CONCLUSIONS: Our study highlights the gap in knowledge about OFPRS as a field, the qualifications and training required, and the scope of practice. Notably, even for OFPRS-specific procedures, PRS remained the leading subspecialist chosen for interventions such as orbital decompression (58.5% vs. 71.5%), orbital reconstruction (57.9% vs. 74.2%), enucleation/evisceration (48.1% vs. 53.4%), optic nerve-related surgery (39.8% vs. 43.4%), orbital cancer resection (42.8% vs. 46.8%), and tear duct surgery (41.9% vs. 52.5%). Additionally, most respondents did not feel that facial fillers, laser skin resurfacing, eyelid cancer removal, or cataract surgery were within the OFPRS scope of practice.

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

When the Cost of Vaping Is an Eye: A Case of an Open Globe and Superior Orbital Roof Fracture.

The authors report a penetrating orbitocerebral vape pen injury necessitating a primary enucleation and craniotomy to remove the foreign body fragments. A 31-year-old male presented with acute right vision loss after a modifiable vape pen explosion launched multiple projectile fragments into his right eye. CT revealed a deformed globe with multiple radiodense curvilinear fragments in the superior orbital roof and intracranial space. A right frontal craniotomy and orbitotomy with removal of vape pen fragments, reconstruction of the orbital roof, primary enucleation, and eyelid repair were performed in conjunction with neurosurgery. To the best of the authors' knowledge, this is the first reported penetrating globe injury from a vape pen explosion.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

The role of ERNDIM diagnostic proficiency schemes in improving the quality of diagnostic testing for inherited metabolic diseases.

External quality assurance (EQA) is crucial to monitor and improve the quality of biochemical genetic testing. ERNDIM (www.erndim.org), established in 1994, aims at reliable and standardized procedures for diagnosis, treatment and monitoring of inherited metabolic disease (IMD) by providing EQA schemes and educational activities. Currently, ERNDIM provides 16 different EQA schemes including quantitative schemes for various metabolite groups, and interpretive schemes such as diagnostic proficiency testing (DPT). DPT schemes focus on the ability of laboratories to correctly identify and interpret abnormalities in authentic urine samples across a wide range of IMDs. In the DPT schemes, six samples each year are distributed together with clinical information. Laboratories choose and perform the tests needed to reach a diagnosis. Data were collected on 345 samples, distributed to up to 105 laboratories worldwide. Diagnostic proficiency (the % of total points possible for all participating laboratories within a scheme for analysis and interpretation) ranged widely: amino acid disorders (n = 20), range 33%-100%, mean 84%; organic acid disorders (n = 35), range 14%-100%, mean 84%; lysosomal storage disorders (n = 13), range 20%-97%, mean 73%; purine/pyrimidine disorders (n = 9), range 37%-100%, mean 70%; miscellaneous disorders (n = 8), range 17%-100%, mean 65%; no IMD, range 65%-95%, mean 85%. When a sample with the same disorder was distributed in a subsequent survey, performance improved in 75 cases with no improvement seen in 32, suggesting overall improvement of performance. ERNDIM diagnostic proficiency testing is a valuable activity which can help to assess laboratory performance, identify methodological/technical challenges, be informative during quality audits and contribute to a better clinical appreciation of diagnostic uncertainty.

Opioid Prescribing Patterns of Optometrists in the Medicare Part D Database.

SIGNIFICANCE: This study aimed to determine the prescription rates and prescribing trends of opioids by optometrists in the Centers for Medicare & Medicaid Services (CMS) part D database from 2013 to 2017 and to assess opioid prescribing patterns of U.S. optometrists in the CMS part D database. METHODS: With internal review board approval, a retrospective observational cohort study was conducted on optometrists listed in the CMS part D database who prescribed opioids from 2013 to 2017. RESULTS: There was an average of 26,477 optometrists in the CMS database from 2013 to 2017, of which 5.9% prescribed opioids. Of those prescribing opioids, optometrists wrote an average of 5.9 opioid prescriptions per year. Those writing greater than 10 opioid prescriptions averaged 24.2 annually. Overall, of opioid prescribing optometrists, opioid prescriptions comprised 7% of prescriptions written per year. CONCLUSIONS: Most optometrists do not prescribe opioids, and the vast majority of those who do write few opioid prescriptions. The total number of optometrists prescribing opioids and the total number of opioid prescriptions declined from 2013 to 2017. Further investigation into the opioid prescribing practices by optometrists will help better understand specific pain needs, as opioid prescribing patterns may differ depending on patient population.

Head and neck arteriovenous malformations: University of Tennessee experience, 2012-2022.

OBJECTIVE: Head and neck arteriovenous malformations (AVMs) are complex lesions that represent a subset of vascular anomalies (VAs). The authors present an analysis of their institutional experience managing these lesions as a multidisciplinary team. METHODS: A retrospective chart review was performed of head and neck AVM patients treated at the authors' institution from 2012 to 2022. Recorded data included patient demographic characteristics, details of clinical presentation, Schöbinger clinical scale and Yakes AVM classification results, and details of all endovascular and surgical treatments. The primary outcome of the study was clinical response to treatment. Angiographic occlusion and complication rates were reported. Chi-square tests were used for comparative statistics. RESULTS: Sixteen patients (9 female, 56%) with AVMs of the head and neck presented from age 3 to 77 years. The Schöbinger stage was stage II in 56% of patients (n = 9) and stage III in 44% of patients (n = 7). The Yakes AVM classification was nidus type (2a, 2b, or 4) in 7 patients (43%) and fistula type (1, 3a, or 3b) in 9 patients (57%). The majority of patients (n = 11, 69.0%) were managed with embolization as the only treatment modality, with an average of 1.5 embolizations/patient (range 1-3). Surgical resection was employed in 5 patients (4 in combination with embolization). Symptom resolution and symptom control were achieved in 69% and 31% of patients, respectively, in the entire cohort. A radiographic cure was demonstrated in 50% of patients. There were no statistical differences in clinical outcomes or radiographic cure rates between patients treated with different modalities. CONCLUSIONS: Head and neck AVMs can be treated successfully with a primarily endovascular management strategy by a multidisciplinary team with the goal of symptomatic control.

Effect of Premature Tube Extrusion for Simple Congenital Nasolacrimal Duct Obstruction: A Comparison of Monocanalicular and Bicanalicular Intubation.

ABSTRACT: The objective of this article is to compare the incidence of premature dislocation of silicone tubes and the effect on treatment success between monocanalicular (MCI) and bicanalicular (BCI) intubation in pediatric patients with simple congenital nasolacrimal duct obstruction. Retrospective comparative case series of 108 eyes of 78 pediatric patients with simple congenital nasolacrimal duct obstruction who underwent probing with either BCI (n = 38 eyes) or MCI (n = 70 eyes) from 2017 to 2020. Premature tube extrusion was defined as any tube removed prior to the 3 month postoperative appointment. Success was defined as resolution of tearing 3 months post tube removal. Ages ranged from 10 months to 5.35 years (mean, 1.95 years; Standard deviation (SD), 0.91). Premature tube extrusion occurred in 15 eyes with BCI and 29 eyes with MCI. Success rates were not significantly different regardless of intubation type between the planned tube removal (90.6%) and the premature tube extrusion cohorts (84.1%), P = 0.89. There was no significant difference in treatment success between the planned tube removal (92.7% MCI, 87% BCI) and the premature tube extrusion cohorts (86.2% MCI, 80% BCI). Complications included 2 infections (1 MCI, 1 BCI) and 2 cases of tube related keratopathy (1 MCI, 1 BCI) that all resolved with tube removal. There were 2 BCI patients that presented to the emergency department for premature tube extrusion. Silicone intubation regardless of stent type is an effective treatment for simple congenital nasolacrimal duct obstruction. There was no significant difference in treatment success between tubes that extrude prematurely, and tubes removed at term based on type of intubation.

Long-acting opioid prescribing patterns of ophthalmic plastic surgeons in the medicare Part D database.

PURPOSE: To assess extended release/long acting (ER/LA) opioid prescribing patterns among ophthalmic plastic surgeons in the Centers for Medicare and Medicaid Services (CMS) Part D database. METHODS: A retrospective observational cohort study was conducted on oculoplastic surgeons in the CMS Part D database who prescribed ER/LA opioids from 2013 to 2017. American Society of Ophthalmic Plastics and Reconstructive Surgery (ASOPRS) and non-ASOPRS surgeons were analyzed as groups. Prescribers were also analyzed based on gender and practice experience. RESULTS: Oculoplastic surgeons (64 ASOPRS and 78 non-ASOPRS) were responsible for 1,177 ER/LA opioid prescriptions from 2013 to 2017. ASOPRS members accounted for 4.6% and non-ASOPRS members accounted for 7.5% of all ER/LA opioids prescribed by ophthalmologists over the study period (p= .02). The total number of ASOPRS and non-ASOPRS members prescribing ER/LA opioids decreased by 52% (p= .10) and 58% (p= .07) from 2013 to 2017 respectively. CONCLUSION: ER/LA opioids are indicated for treatment of chronic pain and may be appropriately prescribed by the oculoplastic surgeon in certain circumstances, however due to the higher risk of overdose injury, those circumstances must be defined and justified. While a relatively small number of oculoplastic surgeons (10.6% ASOPRS and 19.6% non-ASOPRS) prescribed ER/LA opioids from 2013 to 2017, non-ASOPRS oculoplastic surgeons wrote 23.5% more ER/LA opioid prescriptions over the study period. Over the 5-year study period there was a general decline in the prescribing of ER/LA opioids by oculoplastic surgeons. Reviewing the prescribing practices of oculoplastic specialists, regardless of professional affiliation, is necessary to understand the role of ER/LA opioids for all of ophthalmology.

Teprotumumab in Clinical Practice: Recommendations and Considerations From the OPTIC Trial Investigators.

BACKGROUND: Thyroid eye disease (TED) is a vision-threatening and debilitating condition that until very recently had no Food and Drug Administration (FDA)-approved medical therapies. Teprotumumab has recently been approved to treat TED. We aim to provide guidance for its use, based on the input of the US investigators who participated in Phase 2 and Phase 3 clinical trials. METHODS: An expert panel was convened on October 11th and November 16th of 2019. All panel members had extensive experience as investigators in the Phase 2 and/or Phase 3 clinical trials of teprotumumab. Consensus among those investigators was reached to determine patient characteristics most appropriate for teprotumumab treatment. Safety guidelines were also reviewed and agreed on. RESULTS: The authors recommend that teprotumumab be considered first-line therapy for patients with clinically significant ophthalmopathy, including those with disease duration exceeding 9 months. The clinical activity score (CAS) may be useful for longitudinal monitoring but should not be used to determine treatment eligibility. Criteria will likely be expanded after more experience with the drug. Using teprotumumab for patients with TED with substantial signs, symptoms, or morbidity without a CAS score of >4 (e.g., progressive proptosis, diplopia, and early compressive optic neuropathy) or more, could be considered. Diabetes mellitus and inflammatory bowel disease comorbidities should not be exclusionary, but stringent monitoring in these patients is recommended. Drug dosing, administration interval, and duration should adhere to the study protocol: 8 infusions, separated by 3 weeks. Patients with more severe disease may benefit from additional doses. Corticosteroids can be used before or during teprotumumab therapy. Clinical and laboratory monitoring should be consistent with good clinical practice for patients receiving teprotumumab. CONCLUSIONS: Confirming the efficacy of teprotumumab usage outside the narrow parameters of the completed clinical trials will require rigorous scientific validation. As a step in that direction, we believe its on-label usage is appropriately applied to all patients with TED with substantial symptoms or morbidity, as judged by their physician.

Postoperative Clinical Outcomes Using Standard Variables Following Levator-Mullerectomy Advancement Blepharoptosis Surgery.

ABSTRACT: The Muller muscle-conjunctival resection is a common technique used to treat blepharoptosis, but there is variability with the target surgical resection and expected postoperative outcomes measured by marginal reflex distance-1 (MRD1). A Levator-Mullerectomy is a novel surgical approach described by Morris et al to incorporate the levator palpebrae superioris in the same incision as the classic Muller muscle-conjunctival resection in the treatment of blepharoptosis. This a retrospective study of patients who underwent Levator-Mullerectomy for ptosis repair showing the clinical outcomes based on MRD1. Statistical analysis was performed using analysis of variance and a nonparametric Kruskal-Wallis test. One hundred-twelve eyes of 83 patients (29 bilateral cases) with a mean age 64.6 years (7-92 years) were included. The types and prevalence of blepharoptosis were involutional (83%), neurogenic (8.0%), traumatic (3.6%), apraxia (2.7%), and congenital (2.7%). There was no significant difference in clinical outcome based on type of blepharoptosis (P = 0.7). Target resection lengths of 8 mm, 10 mm, and 12 mm were compared with postoperative MRD1 change. The mean change in MRD 1 between 8 mm and 10 mm was found to be statistically significant (P = 0.001 for both) but was not statistically significant for the 12 mm resection (P = 0.8). In patients with blepharoptosis and a positive response to 2.5% phenylephrine can benefit from Levator-Mullerectomy with either an 8 mm or 10 mm resection. This novel surgical approach allows surgeons to produce a more predictable and consistent clinical outcome.

The relationship of the Phantom® Lapidus Intramedullary Nail System to neurologic and tendinous structures in the foot: An anatomic study.

BACKGROUND: The purpose of our cadaveric study was to determine the proximity of nail insertion and interlocking mechanisms in the Phantom® Lapidus Intramedullary Nail System to neurologic and tendinous structures in the foot. METHODS: We used 10 fresh-frozen human lower-extremity specimen cadavers. For each specimen, the Nail System was inserted as described in the published technique guide. We then performed dissection on the tibialis anterior tendon, extensor hallucis longus tendon, and medial dorsal cutaneous branch of the superficial peroneal nerve and we measured and averaged the distances from each of these structures from the nail. RESULTS: The tibialis anterior tendon was in closest proximity to the insertion of the proximal medial interlock K-wire with an average distance of 0.4mm from the tendon. The extensor hallucis longus tendon was in closest proximity to nail insertion with an average distance of 1.2mm. The medial dorsal cutaneous branch of the superficial peroneal nerve was in closest proximity to the distal interlock K-wire with an average distance of 7.5mm. CONCLUSIONS: The tibialis anterior tendon, extensor hallucis longus tendon, and the medial dorsal cutaneous branch of the superficial peroneal nerve are at risk with the insertion of the nail system. Blunt dissection should be performed using this system with a path to bone before instrumentation to reduce the risk of nerve and tendon injury in the foot.

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

Single-cell RNA-seq reveals dynamic paracrine control of cellular variation.

High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript's level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a 'core' module of antiviral genes is expressed very early by a few 'precocious' cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced 'peaked' inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.

Essential skin shrinkage: cicatricial ectropion, a histopathologic evaluation and clinical analysis.

Purpose: To describe common risk factors in patients with Essential Skin Shrinkage (ESS) and identify corresponding histopathologic changes in lower eyelids.Methods: A case-control study was performed after an Internal Review Board approval was obtained. Consecutive patients who underwent surgical repair for ectropion with ESS of the lower eyelid were enrolled along with 10 control patients. Informed consent was obtained on all patients. Fitzpatrick skin type, history of sun exposure and non-melanoma skin cancer was obtained along with relevant physical exam findings. Skin samples obtained during surgical repair were evaluated by light microscopy for the extent of dermal actinic change. Statistical analysis was performed.Results: Sixteen study subjects and 10 control patients were enrolled. Subjects were found to be predominantly male, older than controls (p = 0.0011) and have Fitzpatrick skin type (FST) I or II while controls had type I, II or III (p = 0.0221). Hours of sun exposure reported by subjects ranged from 23,165 to greater than 125,000 h, versus 1,459 to 46,890 h in controls (p = 0.0002). Nine of 16 (56%) subjects had a history of skin cancer compared to only 3/10 controls (30%) (p = 0.2475). Histopathologic evaluation using the Fritschi scale for dermal actinic damage identified an average grade of 3.6 for subjects and 2.4 for controls (p = 0.0095).Conclusions: ESS is predominantly seen in male individuals with FST I or II and a history of extensive sun exposure. Histopathologic evaluation shows moderate to severe actinic damage. These individuals frequently have concomitant non-melanoma skin cancer.

Variation of the minimally invasive CDCR technique.

Purpose: Traditional (tCDCR) and endoscopic conjunctivodacryocystorhinostomy (eCDCR) are challenging surgical techniques requiring general anesthesia, a facial incision, and a large osteotomy and mucosal flap. Minimally invasive CDCR (miCDCR) techniques eliminate the need for some of the steps in t/eCDCR. Introduced here is a variation of the miCDCR technique using a Naugle-Fleming knurled dilator (NKD) to create the osteotomy and instruments within a central line catheter kit to help easily place or replace a Jones' tube into position within a bony conduit.Methods: This IRB-approved retrospective chart review examined all patients who underwent this miCDCR technique performed by two oculoplastic surgeons at Hamilton Eye Institute at the University of Tennessee Health Sciences Center from 2014 to 2016. Inclusion criteria: need for CDCR (either primary or repeat). Exclusion criteria: loss to follow up prior to six months. Primary endpoints: operative time, incidence of tube migration and complications, and cessation of epiphora.Results: Sixteen patients (nine men, seven women) were reviewed, with three undergoing bilateral procedure, totaling 19 cases. Age range: 47.0 to 84.0 years, average of 66.6 years (SD = 11.1). Ten patients had surgery under local/MAC augmented with IV sedation, and six had general anesthesia (38%). Average operative time was 17.4 min (SD = 10.9). One patient (5%) required revision in the six-month immediate post-operative period because of tube migration. All patients had cessation of epiphora.Conclusions: This procedure can be done safely and quickly without general anesthesia, resulting in a satisfactorily lower rate of tube migration and cessation of epiphora rates.

A Measles Outbreak in an Underimmunized Amish Community in Ohio.

BACKGROUND: Although measles was eliminated in the United States in 2000, importations of the virus continue to cause outbreaks. We describe the epidemiologic features of an outbreak of measles that originated from two unvaccinated Amish men in whom measles was incubating at the time of their return to the United States from the Philippines and explore the effect of public health responses on limiting the spread of measles. METHODS: We performed descriptive analyses of data on demographic characteristics, clinical and laboratory evaluations, and vaccination coverage. RESULTS: From March 24, 2014, through July 23, 2014, a total of 383 outbreak-related cases of measles were reported in nine counties in Ohio. The median age of case patients was 15 years (range, <1 to 53); a total of 178 of the case patients (46%) were female, and 340 (89%) were unvaccinated. Transmission took place primarily within households (68% of cases). The virus strain was genotype D9, which was circulating in the Philippines at the time of the reporting period. Measles-mumps-rubella (MMR) vaccination coverage with at least a single dose was estimated to be 14% in affected Amish households and more than 88% in the general (non-Amish) Ohio community. Containment efforts included isolation of case patients, quarantine of susceptible persons, and administration of the MMR vaccine to more than 10,000 persons. The spread of measles was limited almost exclusively to the Amish community (accounting for 99% of case patients) and affected only approximately 1% of the estimated 32,630 Amish persons in the settlement. CONCLUSIONS: The key epidemiologic features of a measles outbreak in the Amish community in Ohio were transmission primarily within households, the small proportion of Amish people affected, and the large number of people in the Amish community who sought vaccination. As a result of targeted containment efforts, and high baseline coverage in the general community, there was limited spread beyond the Amish community. (Funded by the Ohio Department of Health and the Centers for Disease Control and Prevention.).

Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.

Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase. Methylmalonyl-CoA mutase is required for the catabolism of certain (branched-chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl-Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl-Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S-adenosylmethionine, the most important cellular methyl-donor. Disruption of methionine synthase has wide-ranging implications for all methylation-dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5-methyltetrahydrofolate as a one-carbon donor. Folate-bound one-carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate-mediated one-carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.