Statistical inference for natural language processing algorithms with a demonstration using type 2 diabetes prediction from electronic health record notes.

The pointwise mutual information statistic (PMI), which measures how often two words occur together in a document corpus, is a cornerstone of recently proposed popular natural language processing algorithms such as word2vec. PMI and word2vec reveal semantic relationships between words and can be helpful in a range of applications such as document indexing, topic analysis, or document categorization. We use probability theory to demonstrate the relationship between PMI and word2vec. We use the theoretical results to demonstrate how the PMI can be modeled and estimated in a simple and straight forward manner. We further describe how one can obtain standard error estimates that account for within-patient clustering that arises from patterns of repeated words within a patient's health record due to a unique health history. We then demonstrate the usefulness of PMI on the problem of predictive identification of disease from free text notes of electronic health records. Specifically, we use our methods to distinguish those with and without type 2 diabetes mellitus in electronic health record free text data using over 400 000 clinical notes from an academic medical center.

Phenotypic Spectrum of Pentosan Polysulfate Sodium-Associated Maculopathy: A Multicenter Study.

IMPORTANCE: A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis. OBJECTIVE: To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy. DESIGN, SETTING, AND PARTICIPANTS: In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019. MAIN OUTCOMES AND MEASURES: Drug exposure, visual acuity, and retinal imaging characteristics. RESULTS: Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (-0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes [53%]) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes [23%]; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities. CONCLUSIONS AND RELEVANCE: These findings suggest that PPS-associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium-photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.

A Quantitative Severity Scale for Retinopathy of Prematurity Using Deep Learning to Monitor Disease Regression After Treatment.

Importance: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide, but treatment failure and disease recurrence are important causes of adverse outcomes in patients with treatment-requiring ROP (TR-ROP). Objectives: To apply an automated ROP vascular severity score obtained using a deep learning algorithm and to assess its utility for objectively monitoring ROP regression after treatment. Design, Setting, and Participants: This retrospective cohort study used data from the Imaging and Informatics in ROP consortium, which comprises 9 tertiary referral centers in North America that screen high volumes of at-risk infants for ROP. Images of 5255 clinical eye examinations from 871 infants performed between July 2011 and December 2016 were assessed for eligibility in the present study. The disease course was assessed with time across the numerous examinations for patients with TR-ROP. Infants born prematurely meeting screening criteria for ROP who developed TR-ROP and who had images captured within 4 weeks before and after treatment as well as at the time of treatment were included. Main Outcomes and Measures: The primary outcome was mean (SD) ROP vascular severity score before, at time of, and after treatment. A deep learning classifier was used to assign a continuous ROP vascular severity score, which ranged from 1 (normal) to 9 (most severe), at each examination. A secondary outcome was the difference in ROP vascular severity score among eyes treated with laser or the vascular endothelial growth factor antagonist bevacizumab. Differences between groups for both outcomes were assessed using unpaired 2-tailed t tests with Bonferroni correction. Results: Of 5255 examined eyes, 91 developed TR-ROP, of which 46 eyes met the inclusion criteria based on the available images. The mean (SD) birth weight of those patients was 653 (185) g, with a mean (SD) gestational age of 24.9 (1.3) weeks. The mean (SD) ROP vascular severity scores significantly increased 2 weeks prior to treatment (4.19 [1.75]), peaked at treatment (7.43 [1.89]), and decreased for at least 2 weeks after treatment (4.00 [1.88]) (all P < .001). Eyes requiring retreatment with laser had higher ROP vascular severity scores at the time of initial treatment compared with eyes receiving a single treatment (P < .001). Conclusions and Relevance: This quantitative ROP vascular severity score appears to consistently reflect clinical disease progression and posttreatment regression in eyes with TR-ROP. These study results may have implications for the monitoring of patients with ROP for treatment failure and disease recurrence and for determining the appropriate level of disease severity for primary treatment in eyes with aggressive disease.

Monitoring Disease Progression With a Quantitative Severity Scale for Retinopathy of Prematurity Using Deep Learning.

Importance: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide, but clinical diagnosis is subjective and qualitative. Objective: To describe a quantitative ROP severity score derived using a deep learning algorithm designed to evaluate plus disease and to assess its utility for objectively monitoring ROP progression. Design, Setting, and Participants: This retrospective cohort study included images from 5255 clinical examinations of 871 premature infants who met the ROP screening criteria of the Imaging and Informatics in ROP (i-ROP) Consortium, which comprises 9 tertiary care centers in North America, from July 1, 2011, to December 31, 2016. Data analysis was performed from July 2017 to May 2018. Exposure: A deep learning algorithm was used to assign a continuous ROP vascular severity score from 1 (most normal) to 9 (most severe) at each examination based on a single posterior photograph compared with a reference standard diagnosis (RSD) simplified into 4 categories: no ROP, mild ROP, type 2 ROP or pre-plus disease, or type 1 ROP. Disease course was assessed longitudinally across multiple examinations for all patients. Main Outcomes and Measures: Mean ROP vascular severity score progression over time compared with the RSD. Results: A total of 5255 clinical examinations from 871 infants (mean [SD] gestational age, 27.0 [2.0] weeks; 493 [56.6%] male; mean [SD] birth weight, 949 [271] g) were analyzed. The median severity scores for each category were as follows: 1.1 (interquartile range [IQR], 1.0-1.5) (no ROP), 1.5 (IQR, 1.1-3.4) (mild ROP), 4.6 (IQR, 2.4-5.3) (type 2 and pre-plus), and 7.5 (IQR, 5.0-8.7) (treatment-requiring ROP) (P < .001). When the long-term differences in the median severity scores across time between the eyes progressing to treatment and those who did not eventually require treatment were compared, the median score was higher in the treatment group by 0.06 at 30 to 32 weeks, 0.75 at 32 to 34 weeks, 3.56 at 34 to 36 weeks, 3.71 at 36 to 38 weeks, and 3.24 at 38 to 40 weeks postmenstrual age (P < .001 for all comparisons). Conclusions and Relevance: The findings suggest that the proposed ROP vascular severity score is associated with category of disease at a given point in time and clinical progression of ROP in premature infants. Automated image analysis may be used to quantify clinical disease progression and identify infants at high risk for eventually developing treatment-requiring ROP. This finding has implications for quality and delivery of ROP care and for future approaches to disease classification.

Disease Control With FOLFIRI Plus Ziv-aflibercept (zFOLFIRI) Beyond FOLFIRI Plus Bevacizumab: Case Series in Metastatic Colorectal Cancer (mCRC).

Background: The prognosis of patients with metastatic colorectal cancer (mCRC) is poor, especially after failure of initial systemic therapy. The VELOUR study showed modestly prolonged overall survival (OS) with ziv-aflibercept plus 5-fluorouracil, leucovorin, and irinotecan (zFOLFIRI) vs. placebo+FOLFIRI after progression on 5-fluoruracil, leucovorin, and oxaliplatin (FOLFOX) ± bevacizumab. The utility of zFOLFIRI after bevacizumab+FOLFIRI is unknown and not recommended in NCCN guidelines. We explored whether zFOLFIRI may be active beyond progression on bevacizumab+FOLFIRI. Methods: We undertook a retrospective analysis of patients treated in routine clinical practice. A chart review was conducted for a cohort (N = 19) of advanced cancer patients (18 mCRC) who received zFOLFIRI from 2014 to 2018 at Fox Chase Cancer Center (FCCC). Analysis included time on zFOLFIRI, PFS, OS, CEA trends and adverse events. A second mCRC cohort (N = 26) from the Flatiron Health EHR-derived database treated with zFOLFIRI after prior bevacizumab+FOLFOX and bevacizumab+FOLFIRI was analyzed for time-on-treatment and overall survival. Results: Median age of mCRC cohort at zFOLFIRI treatment was 54 (FCCC; N = 18) and 62 (Flatiron Health-cohort; N = 26). Of 18 FCCC mCRC patients, 1 patient had prior bevacizumab+FOLFOX and ramucirumab+irinotecan prior to zFOLFIRI for 8.5 months. Of 17 FCCC mCRC patients with prior bevacizumab+FOLFIRI who received zFOLFIRI, 13 had mutant-KRAS, 3 WT-KRAS, and one BRAF-V600E. The patient with BRAF-V600E mutation achieved stable disease on zFOLFIRI after multiple BRAF-targeted therapies. One patient (WT-KRAS mCRC) remained on zFOLFIRI for 14 months. Of 14 patients with mutated-KRAS, 8 remained on zFOLFIRI for >5 months including 3 for >15 months. The rate-of-change in CEA measures on zFOLFIRI was significantly different (p = 0.004) between rapid progressors and those with PFS>4 months. For mCRC patients treated with zFOLFIRI in the 3rd line or greater (N = 18), median PFS was 7.1 months (214 days) and median OS was 13.8 months (416 days). Median time-on-treatment with zFOLFIRI in the Flatiron Health cohort was 4.4 months, median OS was 7.8 months, and longest time-on-treatment with zFOLFIRI was 266 days. Conclusions: In these small real-world cohorts, clinical meaningful stable disease and overall survival on zFOLFIRI beyond progression on bevacizumab+FOLFIRI was observed in patients with mCRC. Further exploration of this approach is warranted.

Culture-Proven Endophthalmitis After Intravitreal Injection: A 10-Year Analysis.

BACKGROUND AND OBJECTIVE: To report on the microbiology, management, and visual outcomes of intravitreal injection (IVI)-associated, culture-proven endophthalmitis. PATIENTS AND METHODS: All patients seen at a tertiary referral center with culture-proven endophthalmitis associated with an IVI between June 2007 and July 2017 were included in this retrospective analysis. RESULTS: Thirty-five patients with culture-positive endophthalmitis following IVI were identified. All gram-positive organisms (34 of 35) were susceptible to vancomycin. Cases due to pathogens associated with oral or respiratory flora were common (31.4%, n = 11), presented earlier (2.0 days vs. 4.6 days, P < .001), were more likely to undergo pars plana vitrectomy (81.8% vs. 25.0%, P = .002) and had worse visual acuity outcomes. CONCLUSION: IVI-associated endophthalmitis pathogens and anti-microbial susceptibilities in the Pacific Northwest are similar to those reported from other geographic locations. Bacteria associated with the oral and respiratory flora are common isolates that result in a more aggressive course and worse visual outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:33-38.].

SURGICAL OUTCOMES AFTER INVERTED INTERNAL LIMITING MEMBRANE FLAP VERSUS CONVENTIONAL PEELING FOR VERY LARGE MACULAR HOLES.

PURPOSE: To evaluate the anatomical and visual outcomes of inverted flap technique of peeling of internal limiting membrane (ILM) versus standard peeling of ILM for macular holes of basal diameter more than 800 µm. METHODS: Patients with very large idiopathic macular holes more than 800 µm in basal diameter (ranging from 243 µm to 840 µm in minimum diameter) were retrospectively included in the study. In Group A, 18 eyes of 18 patients underwent ILM peeling using the inverted flap technique. In Group B, 18 eyes of 18 patients underwent conventional ILM peeling. The primary endpoint was the rate of hole closure at 6 months after surgery. The secondary outcome measure was the change in best-corrected visual acuity at 6 months after surgery. RESULTS: There were no significant differences in ocular characteristics of the study groups at baseline except for the age distribution. Mean macular hole diameter was 1,162.8 ± 206.0 µm and 1,229.6 ± 228.1 µm in Group A and Group B, respectively. The hole closure rate was 88.9% (16/18) in Group A and 77.8% (14/18) in Group B (P = 0.66). The mean gain in best-corrected visual acuity was higher in Group A than in Group B (P = 0.12) at 6 months, but this was not statistically significant. There were no severe ocular adverse events in either group. CONCLUSION: In this multicenter series, inverted ILM flap technique did not lead to significantly higher anatomical closure rates than conventional ILM peeling in large macular holes more than 800 µm in diameter.

Manifestation of a solitary retinal astrocytic hamartoma in a patient with Best macular dystrophy.

PURPOSE: To report the case of an adolescent male with a history of Best macular dystrophy and retinal astrocytic hamartoma. OBSERVATIONS: A 15 year old male with a history of Best macular dystrophy who had been followed by ophthalmology for 9 years was noted to have progressive enlargement of a superonasal peripapillary retinal lesion. Imaging and exam are consistent with a diagnosis of retinal astrocytic hamartoma. There were no extraocular signs or symptoms that were diagnostic of a phakamatosis. Genetic testing was positive for a mutation in BEST1, but not TSC1 or TSC2. CONCLUSIONS AND IMPORTANCE: Retinal astrocytic hamartoma is an unusual association with Best macular dystrophy, and this case highlights the balanced approach needed to navigate a potentially complex work-up.

Visual Outcomes after Vitrectomy for Terson Syndrome Secondary to Traumatic Brain Injury.

PURPOSE: To evaluate visual outcomes after vitrectomy for intraocular hemorrhages secondary to traumatic brain injury. DESIGN: Retrospective, observational case series. PARTICIPANTS: A total of 28 eyes in 20 patients undergoing vitrectomy for Terson syndrome secondary to traumatic brain injury between 1997 and 2015. METHODS: We reviewed the records of patients undergoing a standard 20-gauge or 23-gauge pars plana vitrectomy for intraocular hemorrhages secondary to traumatic brain injury, and the timing of vitrectomy in relation to the inciting intracranial event was recorded. MAIN OUTCOME MEASURES: The primary outcome measure was the change in the preoperative visual acuity score at postoperative month 1 and at the last noted clinic appointment. RESULTS: A total of 28 eyes in 20 patients (all male) underwent pars plana vitrectomy for intraocular hemorrhages secondary to traumatic brain injury. The mean preoperative baseline logarithm of the minimum angle of resolution (logMAR) (Snellen) best-corrected visual acuity (BCVA) was 1.81±0.56 (20/1290). At 1-month postoperative follow-up, the mean BCVA was 0.30±0.33 (20/40). At the date of the last follow-up, the mean BCVA was 0.15±0.24 (20/30) and the median BCVA was 0.00 (20/20). Although the difference between preoperative and postoperative BVCA was significantly different at 1 month and the final postoperative clinic visits (P < 0.001), there was not a correlation between preoperative visual acuity as a predictor of final postoperative visual acuity outcome (r=-0.32; P = 0.09; 95% confidence interval [CI] -0.62 - 0.06). At the date of the last follow-up, the differences in visual outcomes between the individuals undergoing vitrectomy within 3 months of the inciting event, 0.08±0.15 (20/25), were not significantly different than those undergoing surgical intervention after 3 months, 0.18±0.27 (20/30) (P = 0.28). Three cases among those undergoing vitrectomy after 3 months were complicated by retinal detachment, none of which resulted in a BCVA worse than when the patient originally presented preoperatively. CONCLUSIONS: In this retrospective series of patients without other ocular pathology, surgical intervention effectively provided rapid visual recovery in the majority of individuals with intraocular hemorrhages secondary to traumatic brain injury, irrespective of the timing of vitrectomy or of preoperative visual acuity.

Physician-Industry Interactions and Anti-Vascular Endothelial Growth Factor Use Among US Ophthalmologists.

IMPORTANCE: The publication of the US Physician Payments Sunshine Act provides insight into the financial relationship between physicians and the pharmaceutical industry. This added transparency creates new opportunities of using objective data to better understand prior research that implicates pharmaceutical promotions as an important factor in a physician's decision-making process. OBJECTIVE: To assess the association between reported industry payments and physician-prescribing habits by comparing the use of anti-vascular endothelial growth factor (VEGF) intravitreal injections by US ophthalmologists to the industry payments these same physicians received. DESIGN, SETTING, PARTICIPANTS: This study reviews data from the Centers for Medicare & Medicaid Services (CMS) 2013 Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File and the CMS-sponsored August through December 2013 Open Payments program (Physician Payments Sunshine Act). Ophthalmologists who prescribe anti-VEGF injections for all indications were analyzed. MAIN OUTCOMES AND MEASURES: Association between industry payments reportedly received and the number and type of anti-VEGF injections administered. RESULTS: A total of 3011 US ophthalmologists were reimbursed by CMS for 2.2 million anti-VEGF injections in 2013. Of these physicians, 38.0% reportedly received $1.3 million in industry payments for ranibizumab and aflibercept. Analysis revealed positive associations between increasing numbers of reported industry payments and total injection use (r = 0.24; 95% CI, 0.22-0.26; P < .001), aflibercept and ranibizumab injection use (r = 0.32; 95% CI, 0.29-0.34; P < .001), and percentage of injections per physician that were aflibercept or ranibizumab (r = 0.27; 95% CI, 0.25-0.29; P < .001). A smaller association was noted between greater number of industry payments and bevacizumab injection use (r = 0.07; 95% CI, 0.04-0.09; P < .001). Similar associations were found between the total dollars of reported industry payments received to injection use. Subgroup analysis further revealed that physicians receiving $1 to $25 in reported industry benefits were more likely than those not receiving industry payments to perform a greater percentage of their injections with aflibercept and ranibizumab. CONCLUSIONS AND RELEVANCE: Among ophthalmologists who prescribe anti-VEGF medications, there is a positive association between reported pharmaceutical payments and increased use of aflibercept and ranibizumab injections. As is inherent to the design of correlation studies, this analysis cannot determine whether the payments reported caused the increased use, are a result of the increased use, or are merely associated with some other factor that causes the increased use.

Modern Strategies to Save Sight in Diabetes.

Owing to the global epidemic of obesity, the incidence of diabetes and its complications are rapidly increasing around the world. Yet, visual impairment caused by diabetic retinopathy is paradoxically on the decline. This improvement is due to better understanding of etiologic mechanisms, increased screening, and advent of newer therapies. Here, we discuss salient developments in the comprehension of the root causes of diabetic retinopathy and the molecular mechanisms underlying current treatment approaches.

A case of recurrent bilateral uveitis independently associated with dabrafenib and pembrolizumab therapy.

PURPOSE: To report the case of an adult female who presented on different occasions with recurrent uveitis provoked by initiating therapy of two recently approved agents, dabrafenib and pembrolizumab, for treatment of metastatic melanoma. OBSERVATIONS: A 61 year old female presented with bilateral anterior uveitis after initiating therapy with dabrafenib for advanced metastatic melanoma. Her symptoms resolved and exam improved with oral and topical steroid therapy. Months later, she was started on pembrolizumab and transitioned off dabrafenib. Within days of starting pembrolizumab, she developed recurrent bilateral uveitis. This responded to escalating doses of topical and oral corticosteroid therapy and resolved following discontinuation of pembrolizumab. Nine months later, our patient received her third dose of pembrolizumab due to further progression of melanoma and within three days developed blurry vision, photophobia and subsequent ophthalmologic exam demonstrated bilateral panuveitis. CONCLUSIONS AND IMPORTANCE: Dabrafenib and pembrolizumab therapy have both previously been associated with uveitis. Here, we document a case of a woman who developed acute uveitis in response to beginning therapy with dabrafenib and then later developed acute uveitis soon after initiating pembrolizumab. To our knowledge, this is the first time this uncommon side-effect has been reported in the same patient after receiving sequential targeted agents and checkpoint inhibitors.

Clinical manifestations and treatment of idiopathic and Wegener granulomatosis-associated subglottic stenosis.

OBJECTIVE: To compare and contrast the manifestations and surgical management of subglottic stenosis in patients with airway obstruction attributed to granulomatosis with polyangiitis (GPA), previously known as Wegener granulomatosis, and those with idiopathic subglottic stenosis (iSGS). DESIGN: Retrospective medical chart review. Review of subglottic stenosis cases seen in the otolaryngology department of an academic medical center from 2005 through 2010. Data were obtained on disease presentation, operative management. and findings. SETTING: Tertiary referral center. PARTICIPANTS: A total of 24 patients with iSGS and 15 patients with GPA-associated subglottic stenosis (GPA-SGS). RESULTS: All individuals with iSGS were female, and 40% of patients with GPA-SGS were male (P < .01). Patients with iSGS tended to have a higher Myer-Cotton stenosis grade at the time of dilation than those with GPA-SGS (P = .02). Individuals with GPA-SGS were more likely to undergo tracheotomy as a result of disease-related complications than individuals with iSGS (P < .01). No patients with an open airway reconstruction in the iSGS group required follow-up mechanical dilation. In contrast, all patients with open airway reconstructions in the GPA-SGS group underwent more than 1 subsequent airway dilation (P < .01). CONCLUSIONS: While surgical utilization is the mainstay of treatment in iSGS and GPA-SGS, iSGS occurs almost exclusively in females and presents with a greater degree of stenosis at the time of endoscopic dilation. In contrast, GPA-SGS is associated with greater rates of tracheotomy. Open airway reconstruction may be used in the treatment of iSGS and GPA-SGS but is much more effective in iSGS.

Progression and management of Wegener's granulomatosis in the head and neck.

OBJECTIVES/HYPOTHESIS: To describe the otolaryngologic presentation and natural history of granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, and to compare otolaryngologic outcomes of patients with systemic GPA to those with a limited form of GPA confined to the head and neck. STUDY DESIGN: Retrospective chart review. METHODS: Review of GPA cases (identified by serology, biopsy, or clinical presentation) seen in the otolaryngology department of an academic medical center. RESULTS: A total of 24 patients were identified; each patient was followed for an average 6.8 years. Sinusitis and subglottic stenosis were the most commonly observed head and neck manifestations at diagnosis, seen in 64% and 36%, respectively. Over time, disease spread to additional sites in more than half the cohort (n = 14), but only two of 13 patients with disease initially limited to the head and neck developed pulmonary disease, and none developed renal disease. Cumulatively, otitis media was more likely to be observed in patients with systemic disease (P = .04). Patients with localized (n = 12) and systemic (n = 12) GPA did not have significantly different rates of surgical interventions (0.55 vs. 0.72 surgical interventions/patient-year of follow-up, respectively, P = .19). CONCLUSIONS: GPA has a variety of head and neck manifestations, most commonly sinusitis, nasal disease, subglottic stenosis, and otitis media. GPA commonly progresses to involve additional sites, regardless of the extent of disease. These patients require frequent surgical intervention, and the clinician should remain vigilant for progression of disease.