100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Septic Cavernous Sinus Thrombosis: Clinical Characteristics, Management, and Outcomes.

BACKGROUND: Septic cavernous sinus thrombosis (CST) is a rare condition traditionally associated with high morbidity and mortality. More recent case series report more favorable outcomes, including full functional recovery. A comprehensive assessment of the clinical characteristics and prognostic factors of visual and survival outcomes in septic CST is warranted to contemporize current understanding and help guide management. METHODS: A multicentered retrospective cohort study was conducted at 2 tertiary care centers using an electronic medical record search of the term, "thrombosis of cavernous venous sinus" between January 1, 2000, and December 31, 2021. Inclusion criteria consisted of active infection and radiographic evidence of associated CST. Demographic and clinical data extracted included age at presentation, sex, infection type and extent, and ophthalmic examination findings at presentation-best-corrected visual acuity (BCVA), presence of relative afferent pupillary defect (RAPD), intraocular pressure (IOP), and extraocular motility (EOM) limitation. Management data collected consisted of type and length of antimicrobial therapy, type and length of anticoagulation administration, and surgical intervention. Primary outcomes assessed were ophthalmic examination findings at final evaluation and same-hospitalization mortality. RESULTS: A total of 27 patients with imaging-confirmed septic CST were identified at 2 tertiary care centers. At presentation, 2 (8.7%) patients had no light perception (NLP) vision, 8 (29.6%) patients had RAPD, 17 (73.9%) patients had EOM limitation, and 13 (54.2%) had IOP >21 mm Hg. All patients received antimicrobial therapy, with vancomycin being the most common agent. Fifteen patients (55.6%) received anticoagulation, and 21 (81.5%) patients underwent surgical intervention. Same-hospitalization mortality was 3 (11.1%). Among the 21 patients with ophthalmic data at follow-up, 3 (16.7%) had NLP vision, 5 (23.8%) had a persistent RAPD, 7 (31.8%) had persistent EOM limitation, and no patients had IOP elevated above 21 mm Hg. Patients with RAPD at presentation had significantly worse BCVA at final evaluation (logMAR BCVA 1.43 higher on average, P = 0.01) and a significantly higher mortality rate (37.5% vs. 0.0%, P < 0.01) than non-RAPD patients. Demographic features, BCVA at presentation, EOM limitation at presentation, elevated IOP at presentation, and comorbid orbital cellulitis were not associated with worse visual or mortality outcomes. CONCLUSIONS: Septic CST may result in permanent ophthalmic functional deficit in almost one-third of cases and mortality in approximately 11% of patients under contemporary management. New RAPD at presentation may indicate higher risk of poor visual and survival outcomes.

Subperiosteal and Orbital Abscesses: A Comparison of Clinical Features, Management, and Outcomes.

PURPOSE: To compare the clinical features, management, and outcomes between orbital cellulitis patients with subperiosteal abscess (SPA) and those with orbital abscess (OA). METHODS: A retrospective study was conducted at a tertiary care center through medical record search to identify patients with orbital cellulitis from January 1, 2000 to December 31, 2022. Charts were screened for those with radiographic evidence of SPA or OA. Demographic data and presenting clinical features were compared between the 2 cohorts. Primary outcomes compared included rates of surgical intervention, reoperation, and readmission; and length of hospital stay and final vision. RESULTS: A total of 189 patients, 162 with SPA and 27 with OA, met the criteria. The OA group (mean 46.5 ± 18.6 years) was older than the SPA group (mean 19.1 ± 21.4 years). Comorbid sinusitis was significantly more common in the SPA cohort (95.7% SPA; 70.4% OA; p < 0.001), while OA was more likely to occur with orbital trauma (29.6% vs. 8.0%; p = 0.003), implanted hardware (11.1% vs. 0.6%; p = 0.005), and comorbid diabetes (22.2% vs. 4.3%; p = 0.001). OA patients more often presented with a relative afferent pupillary defect (21.7% vs. 3.9%; p = 0.005), vision worse than 20 of 50 (42.3% vs. 16.2%; p = 0.005), and methicillin-resistant Staphylococcus aureus infection (20.8% vs. 5.8%; p = 0.036). OA was associated with a higher reoperation rate (47.8% vs. 21.3%; p = 0.019), readmission rate (18.5% vs. 5.6%, p = 0.047), and limited extraocular motility at follow-up (4.3% vs. 25%; p = 0.013); while mean length of hospital stay and final visual acuity were similar. CONCLUSION: OA may affect an older population with a divergent risk factor profile compared with SPA. OA may cause more severe functional impairment on presentation, warranting more aggressive management to achieve visual outcomes similar to SPA.

Orbital subperiosteal abscess in adolescents and adults: predictors and outcomes of nonsurgical management and surgical approaches.

PURPOSE: The aim of this study was to assess predictors and outcomes of subperiosteal abscess (SPA) management in adolescents and adults at two tertiary care centers. METHODS: This retrospective cohort study included cases of SPA from January 1 2000 to October 9 2022 at two institutions. Patients 9 years or older were categorized into surgical and nonsurgical cohorts. Surgical subgroups included those who underwent functional endoscopic sinus surgery (FESS) alone, external (transcutaneous or transconjunctival) orbitotomy alone, or combined FESS and external surgery. The presented features were assessed as potential treatment predictors. Outcomes included length of stay (LOS), final best-corrected visual acuity (BCVA), readmission rate, and reoperation rate. RESULTS: Of the 159 SPA cases included, 127 (79.9%) underwent surgery and 32 (20.1%) were managed nonsurgically. The nonsurgical cohort was younger (p = .003) with smaller abscesses (p < .001) that were more likely to be medial (p < .001). The nonsurgical cohort had shorter LOS (p < .001); final BCVA and readmission rates were similarly favorable. Abscess location was correlated with surgical approach. Superior SPA that underwent FESS or external surgery alone had higher reoperation rates (57.1.0% and 58.3%, respectively) than combined (17.9%). External approach and FESS alone resulted in lower reoperation rates (15.4% and 15.0%, respectively) than combined (27.3%) for medial SPA. Subgroup analysis in the sinusitis cohort yielded similar results. CONCLUSIONS: A trial of nonsurgical management may be safe and effective for select patients aged 9 years and older with sinusitis-derived, medial, and small SPA. When surgery is indicated, approach should be guided by abscess location to minimize reoperation risk.

Human papillomavirus, oropharyngeal cancer, and the latest vaccine: considerations for oral healthcare providers.

Human papillomavirus (HPV) is associated with both benign and malignant disorders, such as genital warts and a variety of cancers, including oropharyngeal squamous cell carcinomas (OPSCCs). The current 9-valent HPV vaccine (Gardasil 9) protects against high-risk strains that have been shown to cause OPSCC, and widespread vaccination should reduce the rate of all HPV-associated cancers. HPV-related OPSCCs differ from non-HPV-related OPSCCs in their clinical presentations and responsiveness to treatment. To provide oral healthcare providers with a basis for effective com-munication with patients, this article will examine the evolution of the HPV vaccination schedule and the role of the HPV vaccine in the prevention of OPSCCs.

Herpes zoster: treatment, management, and prevention with the recombinant DNA vaccine.

Herpes zoster (HZ) is a reactivation of dormant varicella-zoster virus that most often erupts as painful vesicles in a unilateral dermatomal distribution. A sequela of HZ is postherpetic neuralgia (PHN), which is debilitating and may be persistent. Therefore, vaccination for the prevention of HZ and its sequelae is recommended for adults aged 50 years and older as well as immunocompromised adults. In 2017, the US Food and Drug Administration approved a recombinant DNA vaccine (Shingrix) that is safe to use in immunocompromised individuals and an improvement on the live-attenuated vaccine approved in 2006. This report discusses HZ, PHN, treatment of HZ and PHN, and prevention with vaccines.

Microbiology and Antibiotic Resistance Profiles of Orbital Subperiosteal Abscesses: A Comparison of Pediatric, Adolescent, and Adult Populations.

PURPOSE: The purpose of this study was to compare the microbiology and antibiotic resistance profiles of orbital subperiosteal abscesses (SPA) among 3 age cohorts. METHODS: A retrospective study was conducted at a tertiary care center through a medical record search to identify patients with orbital cellulitis and SPA on imaging from January 1, 2000 to September 10, 2022. Patients were categorized into pediatric (<9 years old), adolescent (9-18 years old), and adult (>18 years old) cohorts. Primary outcomes included culture and antibiotic susceptibility results. Secondary outcomes included antibiotic therapy and surgical intervention. RESULTS: Of the 153 SPA patients included, 62 (40.5%) were in the pediatric cohort (4 months-8 years, mean 5.0 ± 2.7), 51 (33.3%) were adolescent (9-18 years, 12.7 ± 2.8), and 40 (26.1%) were adult (19-95, 51.8 ± 19.3). Viridians group Streptococci were the most frequent organisms isolated across groups. The anaerobic infection rate was higher in the adult compared to the pediatric group (23.0% vs, 4.0%, p = 0.017), while that of the adolescent did not differ significantly from either. Pediatric patients carried a lower rate of clindamycin resistance than adolescent and adult cohorts, who shared similar rates (0 vs. 27.0% and 28.0%, respectively; p = 0.016). There were progressive increases in duration of intravenous antibiotic therapy ( p < 0.195) and rate of surgical intervention ( p < 0.001) going from younger to older cohorts. CONCLUSION: Organisms isolated from orbital SPA from the past 2 decades demonstrate a predominance of Streptococcal species. Older age may be associated with anaerobic infection, clindamycin resistance, and more aggressive management. Adolescent infections are more similar to adult rather than pediatric counterparts but may require less aggressive management than the former.

Orbital Subperiosteal Abscess: The Role of Nonsurgical Management Among Adolescents and Adults.

PURPOSE: To investigate the role of nonsurgical management in the treatment of orbital cellulitis complicated by subperiosteal abscess (SPA) in adolescent and adult populations. METHODS: A retrospective cohort study to assess the demographic, clinical, and outcome profiles of adolescent and adult patients with orbital SPA treated nonsurgically versus those who received surgical intervention. Primary outcome measures included hospitalization length and best-corrected visual acuity (BCVA) in the final evaluation. RESULTS: The study comprised 76 patients diagnosed with SPA in the setting of orbital cellulitis. Twelve were stratified into the nonsurgical cohort, while 64 represented the surgical group. Sinusitis was the most prevalent risk factor among both populations, and the rate did not differ significantly. SPA was located medially at a significantly higher rate in the nonsurgical cohort compared with the surgical. No patients in the nonsurgical population had a relative afferent pupillary defect (RAPD) on presentation. The proportion of patients who received adjunctive systemic corticosteroid therapy was comparable in both groups. Hospitalization length was significantly higher in the surgery cohort. BCVA in the final evaluation was favourable in both groups. Sinusitis subgroup analysis including eight nonsurgical patients produced overall consistent results. CONCLUSIONS: Findings from the largest study of orbital cellulitis complicated by SPA to date demonstrate a role for nonsurgical management in adolescent and adult patients who present with a medial SPA and/or ophthalmic examination without an RAPD. Among these populations, visual prognosis is favourable whether management includes surgical debridement or not, and surgical intervention may not predict a shorter duration of hospitalization.

Breaking the mold: a case of recalcitrant eyelid subconjunctival infection by Exophilia Phaeomuriformis.

While a rare ophthalmic pathogen, infections from Exophilia spp. are increasingly identified and have been associated with catastrophic vision loss. In this case report we present a previously undescribed manifestation of the melanin-producing fungus Exophilia Phaeomuriformis to the lower eyelid, establish an effective treatment, and review related cases. Previous cases of ophthalmic E. Phaeomuriformis were confined to the cornea and included iatrogenic tissue trauma. This case shares neither associations however includes a remote SJS history that likely led to changes in conjunctival tissue integrity. Previous cases of Exophilia spp. infecting the eyelid both included surgical source control and adjuvant antibiotic. In this case, topical therapy was deferred due to SJS-related ocular cicatricial disease. Fortunately, a full resolution was achieved with surgical resection and oral antifungal treatment.

Skin cancer, sunscreens, and prevention: discussions to have with patients.

With the incidence of skin cancer increasing in the United States, the role of dental providers in noting suspicious skin lesions as well as advising patients in proper sun-protective strategies is more important than ever. However, the public conversation about proper sun protection is often laden with misunderstandings and pervasive myths. This article reviews the most common types of skin cancer, elucidates the differences among the types of UV radiation, and offers updated recommendations for proper sunscreen use along with adjunctive sun-protective strategies.

Schistosoma Transmission in a Dynamic Seasonal Environment and its Impact on the Effectiveness of Disease Control.

BACKGROUND: A seasonal transmission environment including seasonal variation of snail population density and human-snail contact patterns can affect the dynamics of Schistosoma infection and the success of control interventions. In projecting control outcomes, conventional modeling approaches have often ignored seasonality by using simplified intermediate-host modeling, or by restricting seasonal effects through use of yearly averaging. METHODS: We used mathematical analysis and numerical simulation to estimate the impact of seasonality on disease dynamics and control outcomes, and to evaluate whether seasonal averaging or intermediate-host reduction can provide reliable predictions of control outcomes. We also examined whether seasonality could be used as leverage in creation of effective control strategies. RESULTS: We found models that used seasonal averaging could grossly overestimate infection burden and underestimate control outcomes in highly seasonal environments. We showed that proper intraseasonal timing of control measures could make marked improvement on the long-term burden reduction for Schistosoma transmission control, and we identified the optimal timing for each intervention. Seasonal snail control, implemented alone, was less effective than mass drug administration, but could provide additive impact in reaching control and elimination targets. CONCLUSIONS: Seasonal variation makes Schistosoma transmission less sustainable and easier to control than predicted by earlier modeling studies.

Severe Neonatal Opioid Withdrawal Requiring Pharmacotherapy: Impact of Region of Residence.

OBJECTIVES: Our objective was to evaluate the trend and to assess the impact of maternal region of residence in Western New York (WNY), on severe neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: Term infants' born at gestational age greater than or equal to 37 weeks with severe NOWS, defined as withdrawal resulting in the receipt of pharmacologic therapy from WNY admitted to our neonatal intensive care unit (NICU) from January 1, 2008 to December 31, 2016, were included. Severe NOWS admissions to our NICU from the following five regions were controlled with birth and insurance data: (1) Urban North, (2) Erie Coastal, (3) Niagara Frontier, (4) Southern Tier, and (5) Urban South. RESULTS: "Urban South" residence was associated with an increased risk of severe NOWS (adjusted odds ratio = 1.8, 97.5% confidence interval: 1.1-2.9). The trend in admission for severe NOWS doubled between 2008 to 2010 and 2014 to 2016 (p = 0.01). More infants born to maternal nonprescribed opioid users were placed in foster care at discharge (36.5 vs. 1.9%, p < 0.001). CONCLUSION: In WNY, neonates born to mothers from the "Urban South" were twice at risk of being admitted for severe NOWS. One-third of infants with severe NOWS after nonprescribed opioid use were placed in foster care. Implementing targeted strategies at the community level may help improve outcomes in NOWS. KEY POINTS: · Maternal region of residence is a risk factor for severe neonatal opioid withdrawal.. · Admissions for severe neonatal opioid withdrawal trended up from 2008 to 2010 to 2014 to 2016.. · One-third of the infants born to mothers on nonprescribed opioids were discharged to foster care..

Multi-layer structure of Inconel 625 coatings prepared by magnetron sputtering.

The coating/substrate interface and oxide layers of the Inconel 625 film may have significant impacts on its material properties, especially the corrosion behavior of the film. However, since the interface and oxide layer can be very thin and experimental toolbox to characterize them is limited, the detailed vertical structure of Inconel 625 coatings remains poorly understood. In this study, a multi-layer structure in Inconel 625 film prepared by magnetron sputtering is revealed using X-ray reflectometry (XRR) and neutron reflectometry (NR) techniques. Thickness and major composition of each layer are obtained. The results indicate that there exists a ~2 nm-thick Cr-rich Inconel sublayer underneath the main Inconel 625 film. An oxide layer mainly consisting of NiO with thickness of ~2 nm is found on the surface of the main Inconel 625 film. In addition, we identified a ~2 Å contamination layer between sapphire substrate and Inconel film even after argon ion sputtering cleaning. We also found that the thickness of the main Inconel 625 film grows linearly with the deposition time, with thicknesses of other layers remaining constant. Our findings provide insight into the multi-layered structures of Inconel 625 coatings with atomic-scale spatial resolution and give directions for future study to improve the corrosion resistance of Inconel 625 coatings.

Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement on Perioperative Smoking Cessation.

Smokers are at increased risk for surgical complications. Despite the known benefits of smoking cessation, many perioperative health care providers do not routinely provide smoking cessation interventions. The variation in delivery of perioperative smoking cessation interventions may be due to limited high-level evidence for whether smoking cessation interventions used in the general population are effective and feasible in the surgical population, as well as the challenges and barriers to implementation of interventions. Yet smoking is a potentially modifiable risk factor for improving short- and long-term patient outcomes. The purpose of the Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement on Perioperative Smoking Cessation is to present recommendations based on current scientific evidence in surgical patients. These statements address questions regarding the timing and intensity of interventions, roles of perioperative health care providers, and behavioral and pharmacological interventions. Barriers and strategies to overcome challenges surrounding implementation of interventions and future areas of research are identified. These statements are based on the current state of knowledge and its interpretation by a multidisciplinary group of experts at the time of publication.

Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of permanent blindness worldwide. The current mainstay of treatment for neovascular AMD (nAMD) is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents: aflibercept, ranibizumab, and off-label bevacizumab. Injections can be given monthly, every two or three months ('extended-fixed'), or as needed (pro re nata (PRN)). A variant of PRN is 'treat-and-extend' whereby injections are resumed if recurrence is detected and then delivered with increasing intervals. Currently, injection frequency varies among practitioners, which underscores the need to characterize an optimized approach to nAMD management. OBJECTIVES: To investigate the effects of monthly versus non-monthly intravitreous injection of an anti-VEGF agent in people with newly diagnosed nAMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers from 2004 to October 2019; checked references; handsearched conference abstracts; and contacted pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared different treatment regimens for anti-VEGF agents in people with newly diagnosed nAMD. We considered standard doses only (ranibizumab 0.5 mg, bevacizumab 1.25 mg, aflibercept 2.0 mg, or a combination of these). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for trial selection, data extraction, and analysis. MAIN RESULTS: We included 15 RCTs. The total number of participants was 7732, ranging from 37 to 2457 in each trial. The trials were conducted worldwide. Of these, six trials exclusively took place in the US, and three included centers from more than one country. Eight trials were at high risk of bias for at least one domain and all trials had at least one domain at unclear risk of bias. Seven trials (3525 participants) compared a PRN regimen with a monthly injection regimen, of which five trials delivered four to eight injections using standard PRN and three delivered nine or 10 injections using a treat-and-extend regimen in the first year. The overall mean change in best-corrected visual acuity (BCVA) at one year was +8.8 letters in the monthly injection group. Compared to the monthly injection, there was moderate-certainty evidence that the mean difference (MD) in BCVA change at one year for the standard PRN subgroup was -1.7 letters (95% confidence interval (CI) -2.8 to -0.6; 4 trials, 2299 participants), favoring monthly injections. There was low-certainty evidence of a similar BCVA change with the treat-and-extend subgroup (0.5 letters, 95% CI -3.1 to 4.2; 3 trials, 1226 participants). Compared to monthly injection, there was low-certainty evidence that fewer participants gained 15 or more lines of vision with standard PRN treatment at one year (risk ratio (RR) 0.87, 95% CI 0.76 to 0.99; 4 trials, 2299 participants) and low-certainty evidence of a similar gain with treat-and-extend versus monthly regimens (RR 1.11, 95% CI 0.91 to 1.36; 3 trials, 1169 participants). The mean change in central retinal thickness was a decrease of -166 µm in the monthly injection group; the MD compared with standard PRN was 21 µm (95% CI 6 to 32; 4 trials, 2215 participants; moderate-certainty evidence) and with treat-and extend was 22 µm (95% CI 37 to -81 µm; 2 trials, 635 participants; low-certainty evidence), in favor of monthly injection. Only one trial (498 participants) measured quality of life and reported no evidence of a difference between regimens, but data could not be extracted (low-certainty evidence). Both PRN regimens (standard and 'treat-and-extend') used fewer injections than monthly regimens (standard PRN: MD -4.6 injections, 95% CI -5.4 to -3.8; 4 trials, 2336 participants; treat-and-extend: -2.4 injections, 95% CI -2.7 to -2.1 injections; moderate-certainty evidence for both comparisons). Two trials provided cost data (1105 participants, trials conducted in the US and the UK). They found that cost differences between regimens were reduced if bevacizumab rather than aflibercept or ranibizumab were used, since bevacizumab was less costly (low-certainty evidence). PRN regimens were associated with a reduced risk of endophthalmitis compared with monthly injections (Peto odds ratio (OR) 0.13, 95% CI 0.04 to 0.46; 6 RCTs, 3175 participants; moderate-certainty evidence). Using data from all trials included in this review, we estimated the risk of endophthalmitis with monthly injections to be 8 in every 1000 people per year. The corresponding risk for people receiving PRN regimens was 1 in every 1000 people per year (95% CI 0 to 4). Three trials (1439 participants) compared an extended-fixed regimen (number of injections reported in only one large trial: 7.5 in one year) with monthly injections. There was moderate-certainty evidence that BCVA at one year was similar for extended-fixed and monthly injections (MD in BCVA change compared to extended-fixed group: -1.3 letters, 95% CI -3.9 to 1.3; RR of gaining 15 letters or more: 0.94, 95% CI 0.80 to 1.10). The change in central retinal thickness was a decrease of 137 µm in the monthly group; the MD with the extended-fixed group was 8 µm (95% CI -11 to 27; low-certainty evidence). The frequency of endophthalmitis was lower in the extended-fixed regimen compared to the monthly group, but this estimate was imprecise (RR 0.19, 95% CI 0.03 to 1.11; low-certainty evidence). If we assumed a risk of 8 cases of endophthalmitis in 1000 people receiving monthly injections over one year, then the corresponding risk with extended-fixed regimen was 2 in 1000 people (95% CI 0 to 9). Other evidence comparing different extended-fixed or PRN regimens yielded inconclusive results. AUTHORS' CONCLUSIONS: We found that, at one year, monthly regimens are probably more effective than PRN regimens using seven or eight injections in the first year, but the difference is small and clinically insignificant. Endophthalmitis is probably more common with monthly injections and differences in costs between regimens are higher if aflibercept or ranibizumab are used compared to bevacizumab. This evidence only applies to settings in which regimens are implemented as described in the trials, whereas undertreatment is likely to be common in real-world settings. There are no data from RCTs on long-term effects of different treatment regimens.

Pulmonary Adenocarcinoma Metastatic to Periocular Skin and Orbital Tissue Presenting as Orbital Cellulitis.

A 56-year-old man presented with a periorbital subcutaneous mass and ipsilateral visually significant orbital inflammation that was refractory to broad-spectrum antibiotics. Orbitotomy with biopsy revealed the diagnosis of metastatic lung cancer, and the patient was initiated on systemic chemotherapy and adjuvant radiation. This is the first report of pulmonary adenocarcinoma metastatic simultaneously to the periocular cutaneous and intraorbital soft tissues. Atypical periorbital and orbital inflammation may be the initial presentation of occult malignancy and require a high index of suspicion and tissue biopsy for diagnosis and life-saving management.

Nasolacrimal Lymphangioma Presenting With Hemolacria.

A 22-year-old male presented with spontaneous unilateral hemolacria and was found to have complete opacification of the ipsilateral nasolacrimal sac and duct. Endoscopic biopsy with histopathologic analysis revealed the diagnosis of nasolacrimal lymphangioma. Additional management included nasolacrimal stenting, and there was no hemolacria recurrence or epiphora. This is the first report of a nasolacrimal lymphangioma and describes the vascular malformation as a potential cause of bloody tearing.

Metastatic Renal Cell Carcinoma Masquerading as a Sphenoid Wing Meningioma.

A 47-year-old man who presented with subacute binocular diplopia and a left head turn was found to have a right sixth nerve palsy and right optic disc edema. Radiologic imaging revealed a non-lytic right greater sphenoid wing mass with a dural tail, suggestive of a sphenoid wing meningioma. The patient underwent an orbitotomy with lesion biopsy; histopathologic analysis and subsequent imaging revealed the diagnosis of metastatic clear cell renal cell carcinoma. He developed new metastases despite systemic immunotherapy, and prognosis was guarded at last follow up 3 months after diagnosis. The authors present the first reported case of renal cell carcinoma metastatic to the sphenoid wing without sinus involvement, describing an atypical presentation of an aggressive malignancy that necessitates timely diagnosis for possible survival.

Structure-function analyses reveal key features in Staphylococcus aureus IsdB-associated unfolding of the heme-binding pocket of human hemoglobin.

IsdB is a receptor on the surface of the bacterial pathogen Staphylococcus aureus that extracts heme from hemoglobin (Hb) to enable growth on Hb as a sole iron source. IsdB is critically important both for in vitro growth on Hb and in infection models and is also highly up-regulated in blood, serum, and tissue infection models, indicating a key role of this receptor in bacterial virulence. However, structural information for IsdB is limited. We present here a crystal structure of a complex between human Hb and IsdB. In this complex, the α subunits of Hb are refolded with the heme displaced to the interface with IsdB. We also observe that atypical residues of Hb, His58 and His89 of αHb, coordinate to the heme iron, which is poised for transfer into the heme-binding pocket of IsdB. Moreover, the porphyrin ring interacts with IsdB residues Tyr440 and Tyr444 Previously, Tyr440 was observed to coordinate heme iron in an IsdB·heme complex structure. A Y440F/Y444F IsdB variant we produced was defective in heme transfer yet formed a stable complex with Hb (Kd = 6 ± 2 µm) in solution with spectroscopic features of the bis-His species observed in the crystal structure. Haptoglobin binds to a distinct site on Hb to inhibit heme transfer to IsdB and growth of S. aureus, and a ternary complex of IsdB·Hb·Hp was observed. We propose a model for IsdB heme transfer from Hb that involves unfolding of Hb and heme iron ligand exchange.

Acute Sterile Canaliculitis: A Case Report and Review of the Literature.

A 53-year-old male developed secondary canaliculitis after undergoing nasolacrimal intubation with a silicone stent. Negative cultures, symptoms refractory to antibiotics, and rapid resolution after stent removal suggest an immune reaction as the mechanism of canaliculitis. This case raises awareness of noninfectious hypersensitivity or hypersensitivity-like reactions as a potential acute or subacute complication of nasolacrimal stenting.