Room-temperature ferroelectric nematic liquid crystal showing a large and diverging density.

The ferroelectric nematic phase (NF) is a recently discovered phase of matter in which the orientational order of the conventional nematic liquid crystal state is augmented with polar order. Atomistic simulations suggest that the polar NF phase would be denser than conventional nematics owing to contributions from polar order. Using an oscillating U-tube densitometer, we obtain detailed temperature-dependent density values for a selection of conventional liquid crystals with excellent agreement with earlier reports. Having demonstrated the validity of our method, we then record density as a function of temperature for M5, a novel room-temperature ferroelectric nematic material. We present the first experimental density data for a NF material as well as density data for a nematic that has not previously been reported. We find that the room-temperature NF material shows a large (>1.3 g cm-3) density at all temperatures studied, notably including phases without polar order. An increase in density at phase transitions is observed. The magnitude of the increase for the intermediate-to-ferroelectric nematic (NX-NF) transition is an order of magnitude smaller than the isotropic-nematic (I-N) transition. We then probe potential consequences that may result from an elevated density through measurement of the refractive indices (no and ne). The navg of M5 is compared with 5CB and polar smectic liquid crystals. We observe how the highly polar nature of the system counteracts the effects of an increase in density. With knowledge of experimental density, we are able to derive an approximation that yields the polar order parameter, 〈P1〉, from polarisation measurements. Present results may be typical of ferroelectric nematic materials, potentially guiding material development, and is especially relevant for informing ongoing studies into this emerging class of materials.

Long-Term Follow-Up of Outer Retinal Layers in Patients with Epiretinal Membranes.

PURPOSE: This study aimed to investigate the long-term effect of observed epiretinal membranes on the outer retinal layers and visual acuity. METHODS: It is a retrospective observational study. Subjects with an epiretinal membrane and consecutive optical coherence tomography scans were followed for changes in visual acuity, central macular thickness, ellipsoid zone loss, and outer foveal thickness (OFT). RESULTS: The study consisted of 24 eyes of 22 patients, with a mean follow-up of 5 ± 1.6 years. The mean visual acuity was slightly worse at the last follow-up (0.22 ± 0.36 LogMAR [20/33] vs. 0.27 ± 0.36 LogMAR [20/36], p = 0.05). Ellipsoid zone loss was found in 37.5% of eyes. Vision loss was associated with initial size of ellipsoid disruption (p = 0.048) and age (p = 0.027). A decrease in OFT was associated with an initially larger zone of ellipsoid disruption (p = 0.006) and an initially thicker OFT (p = 0.011). An epiretinal membrane associated with vitreomacular adhesion within 1,000 µm of the foveal center at baseline was associated with ellipsoid zone loss (p = 0.012) but not with a change in visual acuity. CONCLUSIONS: Ellipsoid zone changes were common in this study and tended to enlarge over time. Epiretinal membranes associated with vitreomacular adhesion within 1,000 µm of the foveal center may be a risk factor for ellipsoid zone loss.

Lighting conditions and perceived visual function in ophthalmic conditions.

PURPOSE: To determine the influence of different lighting conditions on perceived visual function in patients of different age, gender, race, and in various ophthalmic diseases. METHODS: A prospective study. A survey given to patients seen in general ophthalmic and retina clinics. Patients were asked four questions: Is your vision better, worse, or the same in (1) bright light vs dim light, (2) indoors or outdoors, (3) beginning or end of the day, and (4) sunny or cloudy day? Parameters tested were age, race, gender, visual acuity, and a variety of ophthalmic conditions. Multivariable models for each question were fit using multinomial regression. Association was considered significant if p < 0.05. RESULTS: A total of 722 patients were enrolled in the study. Patients with lower vision (LogMAR ≥ 0.3) were more likely to indicate they either had better vision indoors or outdoors compared with better vision patients (LogMAR < 0.1). Patients with pseudophakia were also more likely to indicate they had better vision on a cloudy day (OR = 1.9). White patients had double the odds of selecting bright light compared with others. Males were less likely than females to indicate better vision indoors (OR = 0.62). There were no significant associations with age-related macular degeneration (AMD) in the multivariable model. CONCLUSIONS: Most patients did not note any difference in lighting conditions, and although there is explanatory rational for some of the findings in this study, those questions concerning lighting conditions or time of day are not useful for screening of disease. Gender and ethnicity were found to have associations with lighting preferences which needs to be further studied.

Noninflammatory Stress-Induced Remodeling of Mandibular Bone: Impact of Age and Pregnancy.

PURPOSE: The impact of noninflammatory stress, such as aging and pregnancy, on human long bone remodeling is well-established, but little is known about the impact of these stressors on oral bones, including the mandibular bone. To begin to fill this gap in our knowledge, we utilized a mouse mandibular model to evaluate the impact of noninflammatory simple stressors, ie, aging and pregnancy, on bone mandibular architecture and bone density in the mandible using micro-CT. MATERIALS AND METHODS: For the present study, mandibles were obtained from both aged and pregnant C57BL/6 mice and analyzed using micro-CT technology. Micro-CT metrics included bone volume fraction (BVF), total volume (TV), tissue density, and apparent density in the mandible on the mandibular area of compact and trabecular bone, in which the teeth are embedded. All bone-related metrics data from aged and pregnant mice were analyzed using ANOVA analysis and visualized in boxplots. RESULTS: Age-dependent bone remodeling occurred over 4 to 18 weeks of age, ie, increases in BVF, TV, BV/TV, as well as tissue and bone density. Evaluation of bone remodeling in breeder mice (repeated pregnancy model) and virgin mice (age-matched controls) at 37 weeks of age demonstrated that breeder mice had a dramatic decline in all bone metrics measured. CONCLUSIONS: This study underscores the need for more research on noninflammatory stress-related mandibular bone remodeling (eg, age and pregnancy), which compromises bone strength and tooth anchoring. The data also underscores loss of alveolar bone height, as in periodontitis, is an important metric for a more complete assessment of bone loss. This report on mice provides essential data that can be applied for oral-maxillofacial surgeons and periodontists when planning for dental implants in patients with such stressors. Periodontitis related bone loss occurs independent of skeletal homeostasis, although osteoporosis may adversely affect alveolar bone height in humans.

Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group.

Precision medicine is a dynamic area embracing a diverse and increasing type of approaches that allow the targeting of new medicines, screening programs or preventive healthcare strategies, which include the use of biologic markers or complex tests driven by algorithms also potentially taking account of patient preferences. The International Society for Pharmacoeconomics and Outcome Research expanded its current work around precision medicine to (1) describe the evolving paradigm of precision medicine with examples of current and evolving applications, (2) describe key stakeholders perspectives on the value of precision medicine in their respective domains, and (3) define the core factors that should be considered in a value assessment framework for precision medicine. With the ultimate goal of improving health of well-defined patient groups, precision medicine will affect all stakeholders in the healthcare system at multiple levels spanning the individual perspective to the societal perspective. For an efficient, timely and practical precision medicine value assessment framework, it will be important to address these multiple perspectives through building consensus among the stakeholders for robust procedures and measures of value aspects, including performance of precision mechanism; aligned reimbursement processes of precision mechanism and subsequent treatment; transparent expectations for evidence requirements and study designs adequately matched to the intended use of the precision mechanism and to the smaller target patient populations; recognizing the potential range of value-generation such as ruling-in and ruling-out decisions.

Mapping from the International Classification of Diseases (ICD) 9th to 10th Revision for Research in Biologics and Biosimilars Using Administrative Healthcare Data.

PURPOSE: The Centers for Medicare and Medicaid Services (CMS) mandated the transition from ICD-9 to ICD-10 codes on October 1, 2015. Postmarketing surveillance of newly marketed drugs, including novel biologics and biosimilars, requires a robust approach to convert ICD-9 to ICD-10 codes for study variables. We examined three mapping methods for health conditions (HCs) of interest to the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) and compared their prevalence. METHODS: Using CMS General Equivalence Mappings, we applied forward-backward mapping (FBM) to 108 HCs and secondary mapping (SM) and tertiary mapping (TM) to seven preselected HCs. A physician reviewed the mapped ICD-10 codes. The prevalence of the 108 HCs defined by ICD-9 versus ICD-10 codes was examined in BBCIC's distributed research network (September 1, 2012 to March 31, 2018). We visually assessed prevalence trends of these HCs and applied a threshold of 20% level change in ICD-9 versus ICD-10 prevalence. RESULTS: Nearly four times more ICD-10 codes were mapped by SM and TM than FBM, but most were irrelevant or nonspecific. For conditions like myocardial infarction, SM or TM did not generate additional ICD-10 codes. Through visual inspection, one-fifth of the HCs had inconsistent ICD-9 versus ICD-10 prevalence trends. 13% of HCs had a level change greater than +/-20%. CONCLUSION: FBM is generally the most efficient way to convert ICD-9 to ICD-10 codes, yet manual review of converted ICD-10 codes is recommended even for FBM. The lack of existing guidance to compare the performance of ICD-9 with ICD-10 codes led to challenges in empirically determining the quality of conversions.

Capture of biologic and biosimilar dispensings in a consortium of U.S.-based claims databases: Utilization of national drug codes and Healthcare Common Procedure Coding System modifiers in medical claims.

PURPOSE: To assess the capture of biologics (originator and biosimilar) in the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) Distributed Research Network (DRN), with a focus on medical claim National Drug Code (NDC), a new data field, and Healthcare Common Procedure Coding System (HCPCS) modifier. METHODS: We conducted a repeated cross-sectional study among patients with medical and pharmacy benefits enrolled in insurance plans participating in the BBCIC DRN between 1 January 2013 and 30 September 2017. We calculated the proportion of medical claims with ≥1 NDC and identified select biologics using four different approaches: (a) specific HCPCS alone, (b) specific HCPCS and NDC, (c) non-specific HCPCS with NDC, and (d) HCPCS with modifiers (applicable to biosimilars). Numbers of dispensings were calculated for each biologic by approach and select patient and claim characteristics. RESULTS: More than 1.5 million eligible participants contributed approximately 4 million person-years of data, including 1.2 billion medical claims. The proportion of medical claims with ≥1 NDC increased from 1.2% in 2013 to 3.0% in 2017. Medical claim NDCs identified 39% and 28% of vedolizumab dispensed in 2014 and 2015 and 30% of Epogen/Procrit dispensed overall. Out of 26,381 filgrastim biosimilar dispensings identified, 51% had a HCPCS modifier and 12% had a medical claim NDC for Zarxio. HCPCS modifiers and medical claim NDCs were present for 38% and 3% of all infliximab biosimilars dispensed (total n = 1,244). CONCLUSIONS: Medical claim NDC and HCPCS modifier improves identification of select biologics without product-specific HCPCS code, thereby facilitating product-specific biologic research.

Methodologic considerations for noninterventional studies of switching from reference biologic to biosimilars.

PURPOSE: As more biosimilars become available in the United States, postapproval noninterventional studies describing biosimilar switching and comparing effectiveness and/or safety between switchers and nonswitchers will play a key role in generating real-world evidence to inform clinical practices and policy decisions. Ensuring sound methodology is critical for making valid inferences from these studies. METHODS: The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) convened a workgroup consisting of academic researchers, industry scientists, and practicing clinicians to establish best practice recommendations for the conduct of noninterventional studies of biosimilar and reference biologic switching. The workgroup members participated in eight teleconferences between August 2017 and February 2018 to discuss specific topics and build consensus. RESULTS: This report provides workgroup recommendations covering five main considerations relating to noninterventional studies describing reference biologic to biosimilar switching and comparing reference biologic to biosimilars for safety and effectiveness in the presence of switching at treatment initiation and during follow-up: (a) selecting appropriate data sources from a range of available options including insurance claims, electronic health records, and registries; (b) study designs; (c) outcomes of interest including health care utilization and clinical endpoints; (d) analytic approaches including propensity scores, disease risk scores, and instrumental variables; and (e) special considerations including avoiding designs that ignore history of biologic use, avoiding immortal time bias, exposure misclassification, and accounting for postindex switching. CONCLUSION: Recommendations provided in this report provide a framework that may be helpful in designing and critically evaluating postapproval noninterventional studies involving reference biologic to biosimilar switching.

Foveal vasculature changes and nonperfusion in patients with diabetes types I and II with no evidence of diabetic retinopathy.

PURPOSE: To analyze the foveal avascular zone (FAZ) in patients with diabetes and no retinopathy vs. controls using OCT angiography (OCT-A). METHODS: Prospective, observational clinical study. Type I and II diabetics with no retinopathy and healthy control patients underwent OCT-A. The FAZ size and capillary density were calculated using Image J and Adobe Photoshop CS8. Statistical analysis was performed using one-way ANOVA with Tukey's multiple comparison test and the Pearson correlation test. RESULTS: Fifty-two eyes of 28 diabetic patients and 28 eyes of 16 healthy controls were enrolled. Type I diabetes patients had a longer disease duration than type II (30.3 ± 10.3 vs. 12.3 ± 9.7 years). The mean superficial capillary plexus (SCP) of the FAZ area was 0.27 ± 0.1, 0.36 ± 0.14, and 0.27 ± 0.12 mm2, for the type I, type II, and controls (p = 0.0058) and was significantly larger in type II diabetics (p < 0.05). The mean DCP (deep capillary plexus) FAZ was significantly larger in type II diabetics vs. controls (0.67 ± 0.2 and 0.52 ± 0.16 mm2 respectively) (p < 0.05). Both type I and type II SCP capillary density were significantly lower than the controls (p < 0.05, p < 0.005), and DCP capillary density was significantly lower in type II vs. controls (p < 0.005). CONCLUSIONS: Type I patients showed fewer changes in the FAZ than the type II group, although their duration of diabetes was longer. Larger studies are needed to better analyze the differences between type I and type II diabetics.

Changes in Course of Retinopathy of Prematurity from 1986 to 2013: Comparison of Three Studies in the United States.

PURPOSE: To compare infant and retinopathy of prematurity (ROP) characteristics from 3 clinical studies conducted over a 27-year period in the United States. DESIGN: Secondary analysis of results of 3 clinical studies. PARTICIPANTS: Infants with birth weight (BW) <1251 g. METHODS: Analysis of data from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and Early Treatment for Retinopathy of Prematurity (ETROP) trials and the primary data from the Telemedicine Approaches for the Evaluation of Acute-Phase Retinopathy of Prematurity (e-ROP) study. MAIN OUTCOME MEASURES: Infant characteristics and onset, severity, and time course of ROP. RESULTS: Across the 3 studies, mean (standard deviation) BW and mean gestational age (GA) decreased over time from CRYO-ROP (954 g [185 g], 27.9 weeks [2.2 weeks]) to ETROP (907 g [205 g], 27.4 weeks [2.2 weeks]) to e-ROP (864 g [212 g], 27.0 weeks [2.2 weeks]), with an increase in the percentage of infants enrolled weighing <750 g (15.8% CRYO, 24.9% ETROP, 33.4% e-ROP; P<0.0001). The percentage of infants who developed ROP varied only minimally (65.8% CRYO, 68.0% ETROP, 63.7% e-ROP; P = 0.003). Moderately severe ROP (defined as prethreshold or referral warranted) varied (17.8% CRYO, 12.3% ETROP, 19.4% e-ROP; P<0.0001), whereas the time of onset of any ROP did not vary (34.3 weeks CRYO, 34.1 weeks ETROP, 34.8 weeks e-ROP). CONCLUSIONS: The BW and GA of infants enrolled in ROP studies in the United States have decreased over the past 27 years, whereas ROP prevalence and onset of disease are stable.

TISSUE PLASMINOGEN ACTIVATOR FOR SUBFOVEAL HEMORRHAGE DUE TO AGE-RELATED MACULAR DEGENERATION: Comparison of 3 Treatment Modalities.

PURPOSE: To analyze and compare the effects of three common treatment modalities for a thick subfoveal hemorrhage due to exudative age-related macular degeneration on final visual acuity and the size of the final subretinal scar. DESIGN: Retrospective case series. SETTING: Single-site, tertiary referral center. PATIENTS: Thirty-nine patients with exudative age-related macular degeneration and acute SMH greater than 250 µm. INTERVENTION: Patients received vitrectomy with a subretinal tissue plasminogen activator (tPA) injection, pneumatic displacement (PD) with intravitreal tPA, or PD without tPA within 2 weeks of presentation. MAIN OUTCOME MEASURE: Functional outcome was determined by Snellen visual acuity. Anatomical outcome was determined as the final disciform scar size. RESULTS: Treatment groups did not differ in age, sex, initial visual acuity, the initial area of the thick subfoveal hemorrhage, follow-up duration, lens status, duration of exudative age-related macular degeneration, previous intravitreal bevacizumab injections, or time from last given injection to the acute thick subfoveal hemorrhage. Final visual acuity improved significantly in both the vitrectomy and subretinal tPA injection group (P < 0.001), and the intravitreal tPA injection group (P = 0.002) but not with PD alone. Patients treated with subretinal tPA achieved 40% ± 54% reduction in final scar area, in contrast to 27% ± 35% decrease in patients treated with intravitreal tPA (P = 0.001). CONCLUSION: Treatment with tPA improves the functional and anatomical outcomes in patients with thick subfoveal hemorrhage due to subfoveal choroidal neovascular membrane secondary to exudative age-related macular degeneration and was superior to PD without tPA. Vitrectomy with subretinal tPA injection reduced the final disciform scar compared with PD with or without intravitreal tPA.

Exploring Concordance of Patient-Reported Information on PatientsLikeMe and Medical Claims Data at the Patient Level.

BACKGROUND: With the emergence of data generated by patient-powered research networks, it is informative to characterize their correspondence with health care system-generated data. OBJECTIVES: This study explored the linking of 2 disparate sources of real-world data: patient-reported data from a patient-powered research network (PatientsLikeMe) and insurance claims. METHODS: Active patients within the PatientsLikeMe community, residing in the United States, aged 18 years or older, with a self-reported diagnosis of multiple sclerosis or Parkinson's disease (PD) were invited to participate during a 2-week period in December 2014. Patient-reported data were anonymously matched and compared to IMS Health medical and pharmacy claims data with dates of service between December 2009 and December 2014. Patient-level match (identity), diagnosis, and usage of disease-modifying therapies (DMTs) were compared between data sources. RESULTS: Among 603 consenting patients, 94% had at least 1 record in the IMS Health dataset; of these, there was 93% agreement rate for multiple sclerosis diagnosis. Concordance on the use of any treatment was 59%, and agreement on reports of specific treatment usage (within an imputed 5-year period) ranged from 73.5% to 100%. CONCLUSIONS: It is possible to match patient identities between the 2 data sources, and the high concordance at multiple levels suggests that the matching process was accurate. Likewise, the high degree of concordance suggests that these patients were able to accurately self-report their diagnosis and, to a lesser degree, their treatment usage. Further studies of linked data types are warranted to evaluate the use of enriched datasets to generate novel insights.

Correction of: Exploring Concordance of Patient-Reported Information on PatientsLikeMe and Medical Claims Data at the Patient Level.

[This corrects the article DOI: 10.2196/jmir.5130.].

Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT).

OBJECTIVE: To describe the incidence and outcomes of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and to assess the effect of prophylactic topical antimicrobials on incidence. DESIGN: Cohort study within a randomized clinical trial. PARTICIPANTS: Patients enrolled in CATT. METHODS: Patients with neovascular age-related macular degeneration received intravitreal injections of ranibizumab or bevacizumab under 1 of 3 dosing regimens. The study protocol specified preinjection preparation to include use of a sterile lid speculum and povidone iodine (5%). Use of preinjection and postinjection antibiotics was at the discretion of the treating ophthalmologist. Patients were followed up monthly for 2 years. MAIN OUTCOME MEASURES: Development of endophthalmitis and visual acuity. RESULTS: Endophthalmitis developed after 11 of 18 509 injections (1 per 1700 [0.06%]; 95% confidence interval, 0.03%-0.11%), and in 11 of 1185 patients (0.93%; 95% confidence interval, 0.52-1.66). Incidence of endophthalmitis was 0.15% among injections with no antibiotic use, 0.08% among injections with preinjection antibiotics only, 0.06% among injections with postinjection antibiotics only, and 0.04% among injections with preinjection and postinjection antibiotics (P = 0.20). All eyes were treated with intravitreal antibiotics and 4 underwent vitrectomy. Among the 11 affected eyes, the final study visual acuity was 20/40 or better in 4 eyes (36%), 20/50 to 20/80 in 2 eyes (18%), 20/100 to 20/160 in 3 eyes (27%), and worse than 20/800 in 2 eyes (18%). The final visual acuity was within 2 lines of the visual acuity before endophthalmitis in 5 eyes (45%). CONCLUSIONS: Rates of endophthalmitis were low and similar to those in other large-scale studies. Use of topical antibiotics either before or after injection does not seem to reduce the risk for endophthalmitis.

Characteristics and temporal trends in patient registries: focus on the life sciences industry, 1981-2012.

PURPOSE: Patient registries are used to monitor safety, examine real-world effectiveness, and may potentially contribute to comparative effectiveness research. To our knowledge, life sciences industry (LSI)-sponsored registries have not been systematically categorized. This study represents a first step toward understanding such registries over time. METHODS: Studies described as registries were identified in the ClinicalTrials.gov database. Characteristics from these registry records were abstracted and analyzed. RESULTS: Of 1202 registries identified, approximately 47% reported LSI sponsorship. These 562 LSI registries varied in focus: medical devices (n = 193, 34%), specific drugs (n = 173, 31%), procedures (n = 29, 5%), or particular diseases (n = 139, 25%). Thirty-three registries (<6%) evaluated pregnancy outcomes. The most common therapeutic area was cardiovascular (n = 234, 42%); others included endocrinology, immunology, oncology, musculoskeletal disorders, and neurology. The two most often measured outcomes were clinical effectiveness and safety, each of which appeared in 363/562 (65%) of LSI registries. Other outcomes included real-world clinical practice patterns (n = 122, 22%), patient-reported outcomes (n = 106, 19%), disease epidemiology/natural history (n = 69, 12%), and economic outcomes (n = 30, 5%). The number of LSI registries and their geographic diversity has increased over time. CONCLUSIONS: The LSI registries represent a substantial proportion of all patient registries documented in ClinicalTrials.gov. These prospective studies are growing in number and encompass diverse therapeutic areas and geographic regions. Most registries measure multiple outcomes and capture real-world data that may be unavailable through other study designs. This classification of LSI registries documents their use for studying heterogeneity of diseases, examining treatment patterns, measuring patient-reported outcomes, examining economic outcomes, and performing comparative effectiveness research.

Unilateral, Sectoral Retinal Metastasis of Small-Cell Lung Cancer Mimicking Viral Retinitis.

PURPOSE: To report a case of unilateral, sectoral retinal metastasis of small-cell lung cancer (SCLC) that mimicked cytomegalovirus (CMV) retinitis. METHOD: Case report. RESULTS: A 48-year-old woman presented with a four-week history of a visual field loss in her right eye. She had a past medical history of extensive-stage SCLC with brain metastasis, stable on maintenance atezolizumab for two years. On initial presentation, she was diagnosed with CMV retinitis. No improvement was observed with 4 weeks of oral valganciclovir. Upon referral for a second opinion, her fundus exam appeared compatible with CMV retinitis, and anterior chamber tap for polymerase chain reaction for viral etiologies was performed followed by intravitreal and intravenous ganciclovir without improvement. She was referred for a third opinion, where diagnostic vitrectomy with vitreous and retinal biopsies were consistent with SCLC metastatic to the retina. The patient underwent enucleation of the right eye for definitive pathologic analysis and subsequently was started on additional systemic chemotherapy. CONCLUSION: Retinal metastases are exceedingly rare, particularly retinal metastasis of SCLC. Retinal metastasis should be considered in patients initially diagnosed with viral retinitis who fail to improve despite antiviral therapy, particularly if they have a known history of malignancy. Furthermore, retinal metastasis of SCLC potentially could be misdiagnosed histopathologically as retinoblastoma if the patient's history is unknown and appropriate immunohistochemical stains are not performed.

A causal roadmap for generating high-quality real-world evidence.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

"An Unusual Case of Primary Vitreoretinal Lymphoma: A Transformed Lymphoma".

PURPOSE: To report a case of primary vitreoretinal lymphoma (VRL) presenting as diffuse large b-cell lymphoma (DLBCL) 19 years after initial systemic follicular lymphoma. METHOD: A case report. RESULTS: An 81-year-old male patient presented with a 1-month history of floaters and blurry vision in the left eye. He had a history of follicular non-Hodgkin lymphoma treated with systemic chemotherapy in 2002 and prostate cancer treated surgically in 2004. Ophthalmic examination revealed vitritis, retinal whitening, perivascular sheathing, and a vascularized cream-colored retinal mass in the superonasal periphery of the left eye. Diagnostic vitrectomy with retina and vitreous biopsies demonstrated DLBCL. Positron emission tomography/computed tomography confirmed the isolated lesion in the left eye without systemic involvement. Treatment with systemic and intraocular chemotherapy was planned. CONCLUSION: To the best of our knowledge, this is the first reported case of primary VRL of DLBCL transformed from follicular lymphoma. Intravitreal and systemic chemotherapy, including rituximab, should be consideered in the management of patients with transformed VRL.

Primary retinal detachment repair: comparison of 1-year outcomes of four surgical techniques.

PURPOSE: To compare functional and anatomical outcomes of modern methods of repair of primary retinal detachment. MATERIALS AND METHODS: Retrospective interventional comparative case series. A total of 1,226 patients with primary retinal detachment were included in the study. All patients completed 1-year follow-up and were divided into 4 groups: 322 patients underwent scleral buckling surgery, 442 patients underwent pars plana vitrectomy surgery, 316 patients underwent a combination of scleral buckling and vitrectomy surgery, and 56 patients underwent pneumatic retinopexy surgery for the primary repair of retinal detachment. Reattachment success rates, pre- and postoperative visual acuity, complications, and change in refractive error were reviewed. RESULTS: Initial success rate for retinal reattachment was 86% for scleral buckling only, 90% for vitrectomy only, 94% for the combination of scleral buckling and vitrectomy, and 63% for pneumatic retinopexy surgery. Although patients undergoing pneumatic retinopexy had a lower initial success rate, there was no statistically significant difference in initial reattachment rates between the other three groups. There was no statistically significant difference in final visual acuity between the four groups. Complication rates varied among the techniques used. CONCLUSION: Postoperative visual acuity at 1 year did not differ among the various techniques used to repair primary rhegmatogenous retinal detachments. However, scleral buckling, vitrectomy, or a combination of both resulted in an initially better anatomical success rate and fewer operative procedures than pneumatic retinopexy.

Bilateral neuroretinits and exudative retinal detachment with multifocal subretinal deposits secondary to Bartonella henselae infection.

PURPOSE: to describe a case of bilateral neuroretinitis with bullous retinal detachment and multiple subretinal lesions, in a 10-year-old immunocompetent girl. OBSERVATIONS: A broad workup for infectious, inflammatory and masquerade etiologies was done for the patient, resulting in positive IgM and IgG for Bartonella henselae. The patient demonstrated improvement in the visual acuity, and rapid resolution of the retinal detachment and subretinal lesions in both eyes in response to systemic rifampin, doxycycline and corticosteroids. CONCLUSIONS AND IMPORTANCE: Bartonella henselae neuroretinitis may present as an acute form of bullous retinal detachment with multiple subretinal lesions and markedly reduced vision. Significant visual improvement may occur with prompt treatment with a combination of systemic antibiotics and corticosteroids.