Colopathy Associated with Pentosan Polysulfate Use.

Introduction: We describe a novel colopathy associated with pentosan polysulfate (PPS) use and measure the strength of the drug-disease association. Methods: Two-part investigation. In the cohort study of individuals with a history of prior long-term PPS use, case histories were obtained and gastrointestinal disease course was followed with review of endoscopy records and histopathology specimens. Findings were summarized with descriptive statistics. In the cross-sectional study of individuals with interstitial cystitis, drug exposure and medical histories were obtained for patients seen at a single clinical center. Strength of association between PPS use and diagnoses of inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS) was measured with multivariate logistic regression. Results: In the cohort study of 13 participants, median PPS exposure was 2.04 kg (0.99-2.54). Eleven (84.6%) developed symptoms suggestive of IBD and/or IBS after initiation of PPS therapy. Of the 10 participants whose endoscopic and histopathologic findings we reviewed, six had abnormal-appearing colonic mucosa on endoscopy and all 10 had abnormal mucosal changes on histology. Clinical and histologic improvement was observed after PPS cessation. In the cross-sectional study of 219 subjects with interstitial cystitis, PPS use was a statistically significant predictor of both the IBD [adjusted odds ratio=3.3 (95% confidence interval, 1.2-8.8, p=0.02)] and the composite IBD+IBS [adjusted odds ratio=3.3 (95% confidence interval, 1.5-7.3, p=0.002)] outcomes. Discussion: We describe a strong association between PPS use and a clinical diagnosis of IBD and/or IBS. Histopathologic findings suggest a novel drug-associated colopathy, with some subjects requiring colectomy for dysplasia.

Outcomes of Early Versus Late Tracheostomy in Patients With COVID-19: A Multinational Cohort Study.

Timing of tracheostomy in patients with COVID-19 has attracted substantial attention. Initial guidelines recommended delaying or avoiding tracheostomy due to the potential for particle aerosolization and theoretical risk to providers. However, early tracheostomy could improve patient outcomes and alleviate resource shortages. This study compares outcomes in a diverse population of hospitalized COVID-19 patients who underwent tracheostomy either "early" (within 14 d of intubation) or "late" (more than 14 d after intubation). DESIGN: International multi-institute retrospective cohort study. SETTING: Thirteen hospitals in Bolivia, Brazil, Spain, and the United States. PATIENTS: Hospitalized patients with COVID-19 undergoing early or late tracheostomy between March 1, 2020, and March 31, 2021. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: A total of 549 patients from 13 hospitals in four countries were included in the final analysis. Multivariable regression analysis showed that early tracheostomy was associated with a 12-day decrease in time on mechanical ventilation (95% CI, -16 to -8; p < 0.001). Further, ICU and hospital lengths of stay in patients undergoing early tracheostomy were 15 days (95% CI, -23 to -9 d; p < 0.001) and 22 days (95% CI, -31 to -12 d) shorter, respectively. In contrast, early tracheostomy patients experienced lower risk-adjusted survival at 30-day post-admission (hazard ratio, 3.0; 95% CI, 1.8-5.2). Differences in 90-day post-admission survival were not identified. CONCLUSIONS: COVID-19 patients undergoing tracheostomy within 14 days of intubation have reduced ventilator dependence as well as reduced lengths of stay. However, early tracheostomy patients experienced lower 30-day survival. Future efforts should identify patients most likely to benefit from early tracheostomy while accounting for location-specific capacity.

The Impact of Diabetes and Prediabetes on Prevalence of Mycobacterium tuberculosis Infection Among Household Contacts of Active Tuberculosis Cases in Ethiopia.

Background: It is uncertain whether diabetes affects the risk of developing latent tuberculosis infection (LTBI) following exposure to Mycobacterium tuberculosis (Mtb). We assessed the relationship of diabetes or prediabetes and LTBI among close and household contacts (HHCs) of patients with active pulmonary tuberculosis (TB) disease in Addis Ababa, Ethiopia. Methods: In this cross-sectional study, we performed interferon-γ release assays, TB symptom screening, and point-of-care glycolated hemoglobin (HbA1c) testing among HHCs of active TB cases. Diabetes status was classified into diabetes (HbA1c ≥6.5% or self-reported diagnosis), prediabetes (5.7%-6.4%), and euglycemia (≤5.6%). Multivariable logistic regression was used to determine the association of diabetes with LTBI. Results: Among 597 study participants, 123 (21%) had dysglycemia including diabetes (n = 31) or prediabetes (n = 92); 423 (71%) participants were diagnosed with LTBI. Twelve of 31 (39%) HHCs with diabetes were previously undiagnosed with diabetes. The prevalence of LTBI among HHCs with diabetes, prediabetes, and euglycemia was 87% (27/31), 73% (67/92), and 69% (329/474), respectively. In multivariable analysis adjusted for age, sex, and HIV status, the odds of LTBI among HHCs with diabetes were 2.33 (95% confidence interval [CI], .76-7.08) times the odds of LTBI without diabetes. When assessing interaction with age, the association of diabetes and LTBI was robust among participants aged ≥40 years (adjusted odds ratio [aOR], 3.68 [95% CI, .77-17.6]) but not those <40 years (aOR, 1.15 [95% CI, .22-6.1]). Conclusions: HHCs with diabetes may be more likely to have LTBI than those with euglycemia. Further investigations are needed to assess mechanisms by which diabetes may increase risk of LTBI after Mtb exposure.

Anterior segment optical coherence tomography findings in the Infant Aphakia Treatment Study (IATS): a secondary analysis of a randomized clinical trial.

PURPOSE: To correlate the diagnosis of glaucoma among children in the Infant Aphakia Treatment Study (IATS) by age 10 years with anterior segment optical coherence tomography (AS-OCT) findings. METHODS: A multicenter randomized controlled trial of 114 infants with unilateral congenital cataract who were 1-6 months of age at surgery. Data on long-term glaucoma-related status and outcomes were collected when children were 10.5 years old. Participants were randomized at cataract surgery to either primary intraocular lens (IOL) or no IOL implantation (contact lens [CL]). AS-OCT findings in eyes with glaucoma were compared to eyes which did not have glaucoma and to the fellow eyes, between fellow and treated eyes, and between the IOL and CL groups. RESULTS: There were no significant differences in the mean nasal and temporal anterior chamber angle (ACA) or mean nasal and temporal angle opening distance (AOD) for nonglaucomatous, glaucomatous, and fellow eyes (P = 0.31, 0.16, 0.43, 0.08 resp.). There were also no significant differences in mean nasal and temporal ACA and AOD between fellow and treated eyes (P = 0.44, 0.67, 0.57, 0.38 resp.), or between IOL and CL groups (P = 0.36, 0.35, 0.49, 0.44, resp.). CONCLUSIONS: AS-OCT confirmed that eyes with glaucoma in IATS had predominantly open angles with similar ACA and AOD to eyes without glaucoma and to fellow eyes. Furthermore, congenital cataract surgery with or without an IOL did not result in a significant difference in ACA or AOD compared to fellow eyes in IATS.

Effective lens position and pseudophakic refraction prediction error at 10½ years of age in the Infant Aphakia Treatment Study.

BACKGROUND: The refraction prediction error (PE) for infants with intraocular lens (IOL) implantation is large, possibly related to an effective lens position (ELP) that is different than in adult eyes. If these eyes still have nonadult ELPs as they age, this could result in persistently large PE. We aimed to determine whether ELP or biometry at age 10½ years correlated with PE in children enrolled in the Infant Aphakia Treatment Study (IATS). METHODS: We compared the measured refraction of eyes randomized to primary IOL implantation to the "predicted refraction" calculated by the Holladay 1 formula, based on biometry at age 10½ years. Eyes with incomplete data or IOL exchange were excluded. The PE (predicted - measured refraction) and absolute PE were calculated. Measured anterior chamber depth (ACD) was used to assess the effect of ELP on PE. Multiple regression analysis was performed on absolute PE versus axial length, corneal power, rate of refractive growth, refractive error, and best-corrected visual acuity. RESULTS: Forty-three eyes were included. The PE was 0.63 ± 1.68 D; median absolute PE, 0.85 D (IQR, 1.83 D). The median absolute PE was greater when the measured ACD was used to calculate predicted refraction instead of the standard A-constant (1.88 D [IQR, 1.72] D vs 0.85 D [IQR, 1.83], resp. [P = 0.03]). Absolute PE was not significantly correlated with any other parameter. CONCLUSIONS: Variations in ELP did not contribute significantly to PE 10 years after infant cataract surgery.

Implementation and evaluation of a large-scale postpartum family planning program in Rwanda: study protocol for a clinic-randomized controlled trial.

BACKGROUND: Though the Rwandan Ministry of Health (MOH) prioritizes the scale-up of postpartum family planning (PPFP) programs, uptake and sustainability of PPFP services in Rwanda are low. Furthermore, highly effective long-acting reversible contraceptive method use (LARC), key in effective PPFP programs, is specifically low in Rwanda. We previously pilot tested a supply-demand intervention which significantly increased the use of postpartum LARC (PPLARC) in Rwandan government clinics. In this protocol, we use an implementation science framework to test whether our intervention is adaptable to large-scale implementation, cost-effective, and sustainable. METHODS: In a type 2 effectiveness-implementation hybrid study, we will evaluate the impact of our PPFP intervention on postpartum LARC (PPLARC) uptake in a clinic-randomized trial in 12 high-volume health facilities in Kigali, Rwanda. We will evaluate this hybrid study using the RE-AIM framework. The independent effectiveness of each PPFP demand creation strategy on PPLARC uptake among antenatal clinic attendees who later deliver in a study facility will be estimated. To assess sustainability, we will assess the intervention adoption, implementation, and maintenance. Finally, we will evaluate intervention cost-effectiveness and develop a national costed implementation plan. DISCUSSION: Adaptability and sustainability within government facilities are critical aspects of our proposal, and the MOH and other local stakeholders will be engaged from the outset. We expect to deliver PPFP counseling to over 21,000 women/couples during the project period. We hypothesize that the intervention will significantly increase the number of stakeholders engaged, PPFP providers and promoters trained, couples/clients receiving information about PPFP, and PPLARC uptake comparing intervention versus standard of care. We expect PPFP client satisfaction will be high. Finally, we also hypothesize that the intervention will be cost-saving relative to the standard of care. This intervention could dramatically reduce unintended pregnancy and abortion, as well as improve maternal and newborn health. Our PPFP implementation model is designed to be replicable and expandable to other countries in the region which similarly have a high unmet need for PPFP. TRIAL REGISTRATION: ClinicalTrials.gov NCT05056545 . Registered on 31 March 2022.

Lipid Levels and Short-Term Risk of Recurrent Brain Infarcts in Symptomatic Intracranial Stenosis.

OBJECTIVES: Hyperlipidemia is a strong risk factor for intracranial atherosclerotic disease (ICAD) and clinical stroke recurrence. We explored the effect of serum lipid levels on subclinical infarct recurrence in the Mechanisms of earlY Recurrence in Intracranial Atherosclerotic Disease (MYRIAD) study. MATERIALS AND METHODS: We included enrolled MYRIAD patients with lipid measurements and brain MRI at baseline and brain MRI at 6-8 weeks. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6-8 weeks compared to baseline brain MRI. We assessed the association between baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and recurrent infarct at 6-8 weeks using multivariable logistic regression. RESULTS: Among 74 patients (mean age 64.2±12.9 years, 59.5% were white, 60.8% men), 20 (27.0%) had new or recurrent infarcts. Mean HDL-C (37.2 vs. 43.9 mg/dL, P=0.037) was lower and TG (113.5 vs. 91.3 mg/dL, P=0.008) was higher while TC (199.8 vs. 174.3 mg/dL, P=0.061) and LDL-C (124.3 vs. 101.2 mg/dL, P=0.053) were nominally higher among those with recurrent infarcts than those without. LDL-C (adj. OR 1.022, 95% CI 1.004-1.040, P=0.015) and TG (adj. OR 1.009, 95% CI 1.001-1.016, P=0.021) were predictors of recurrent infarct at 6-8 weeks adjusting for other clinical and imaging factors. CONCLUSIONS: Baseline cholesterol markers can predict early infarct recurrence in patients with symptomatic ICAD. More intensive and rapid lipid lowering drugs may be required to reduce risk of early recurrence.

Risk Factors Control and Early Recurrent Cerebral Infarction in Patients with Symptomatic Intracranial Atherosclerotic Disease.

BACKGROUND: The risk of early recurrent cerebral infarction (RCI) is high in patients with symptomatic intracranial atherosclerotic disease (IAD). We sought to determine the relationship between risk factor control and early RCI risk among patients with symptomatic IAD. METHODS: We analyzed participants with symptomatic IAD in the multi-center prospective observational MYRIAD study. Risk factor control was assessed at 6-8-week follow-up. Optimal risk factor control was defined by target systolic blood pressure, being non-smoker, target physical activity, and antiplatelet and antilipidemic therapy compliance. Age-adjusted associations were calculated between risk factor control and RCI determined by MRI-evident new infarcts in the territory of the stenotic vessel at 6-8 weeks from the index event. RESULTS: Among 82 participants with clinical and brain MRI information available 6-8 weeks after the index event (mean age 63.5 ±12.5 years, 62.2% men), RCI occurred in 21 (25.6%) cases. At 6-8-week follow-up, 37.8% had target systolic blood pressure, 92.7% were non-smokers, 51.2% had target physical activity, and 98.8% and 86.6% were compliant with antiplatelet and antilipidemic therapy, respectively. Optimal risk factor control increased from 4.9% at baseline to 19.5% at 6-8-week follow-up (p=0.01). None of the participants with optimal risk factor control at follow-up had RCI (0% vs. 31.8%, p<0.01). CONCLUSIONS: Only one-fifth of MYRIAD participants had optimal risk factor control during early follow-up. Approximately half and two-thirds had physical inactivity and uncontrolled systolic blood pressure, respectively. These risk factors may represent important therapeutic targets to prevent early RCI in patients with symptomatic IAD.

Intracranial dolichoectasia in patients with symptomatic intracranial atherosclerotic disease: Results from the MYRIAD study.

BACKGROUND AND PURPOSE: It is unknown whether intracranial atherosclerotic disease (ICAD), in addition to causing stenosis, also associates with abnormal arterial enlargement, a condition known as intracranial dolichoectasia (IDE). Across symptomatic ICAD patients, we aim to determine IDE prevalence and IDE impact on cerebral hemodynamics and recurrent cerebral ischemia. METHODS: We analyzed 98 participants (mean age 63.8 ± 11.9 years, 56.1% men) of the prospective observational study MYRIAD. Participants were enrolled within 21 days of an ischemic stroke or transient ischemic attack caused by moderate-to-severe ICAD. Semi-automatic vessel segmentation was used to determine diameters, length, and tortuosity-index of proximal intracranial arteries. Either ectasia (increased diameter) or dolichosis (increased length or TI) defined IDE. We assessed IDE association with new infarcts during 12-month follow-up, and IDE correlation with cerebral hemodynamics determined by quantitative MR-angiography (QMRA), MR-perfusion weighted-imaging, and transcranial Doppler breath-holding index. RESULTS: IDE was present in 35.7% of patients and 10.2% of symptomatic arteries. Basilar stenosis was associated with higher IDE prevalence (27.8% vs. 8.8%, p = 0.04), whereas other symptomatic arteries showed no association with IDE. Symptomatic arteries with IDE had lower hypoperfusion prevalence on MR-PWI (11.1% vs. 28.4%, p = 0.03). Increased diameter (r = 0.33, p<0.01) and tortuosity-index (r = 0.29, p = 0.01) showed positive correlation with QMRA flow rate. IDE was not associated with new infarcts during follow-up. CONCLUSIONS: IDE was common among symptomatic ICAD patients. IDE was not associated with stroke recurrence. Instead, increased diameter and tortuosity correlated with improved blood flow across the stenotic artery, suggesting that IDE may originate as an adaptive mechanism in ICAD.

Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease.

BACKGROUND AND PURPOSE: While prior studies identified risk factors for recurrent stroke in patients with symptomatic intracranial atherosclerotic disease, few have assessed risk factors for early infarct recurrence. METHODS: We performed a post hoc analysis of the MYRIAD study (Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease) of intracranial atherosclerotic disease patients with recent (<21 days) stroke/transient ischemic attack, 50% to 99% stenosis and who underwent 6- to 8-week magnetic resonance imaging (MRI) per protocol. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6 to 8 weeks compared to index brain MRI. Qualifying events and clinical and imaging outcomes were centrally ascertained by 2 independent reviewers. We assessed the association between baseline clinical and imaging variables and recurrent infarct in bivariate models and multivariable logistic regression to identify independent predictors of infarct recurrence. RESULTS: Of 105 enrolled patients in MYRIAD, 89 (84.8%) were included in this analysis (mean age, 64±12 years, 54 [60.7%] were male, and 53 [59.6%] were White). The median time from qualifying event to MRI was 51+16 days, on which 22 (24.7%) patients had new or recurrent infarcts. Younger age (57.7 versus 66.0 years; P<0.01), diabetes (32.6% versus 14.6%, P=0.05), index stroke (31.3% versus 4.6%, P=0.01), anterior circulation location of stenosis (29.7% versus 12.0%, P=0.08), number of diffusion-weighted imaging lesions (>1: 40.0%, 1: 26.9% versus 0: 4.4%, P<0.01), and borderzone infarct pattern (63.6% versus 25.0%, P=0.01) on baseline MRI were associated with new or recurrent infarcts. Age (adjusted odds ratio, 0.93 [95% CI, 0.89-0.98], P<0.01) and number of diffusion-weighted imaging lesions (adjusted odds ratio, 3.24 [95% CI, 1.36-7.71], P<0.01) were independently associated with recurrent infarct adjusting for hypertension, diabetes, and stenosis location (anterior versus posterior circulation). CONCLUSIONS: An index multi-infarct pattern is associated with early recurrent infarcts, a finding that might be explained by plaque instability and artery-to-artery embolism. Further investigation of plaque vulnerability in intracranial atherosclerotic disease is needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02121028.

The Myopic Shift in Aphakic Eyes in the Infant Aphakia Treatment Study After 10 Years of Follow-up.

OBJECTIVES: To report the myopic shift in the aphakic eyes of a cohort of children who underwent unilateral cataract surgery during infancy and were then followed longitudinally for 10.5 years. METHODS: One-half of the children enrolled in the Infant Aphakia Treatment Study (IATS) were randomized to aphakia and contact lens correction after unilateral cataract surgery. They then underwent ocular examinations using standardized protocols at prescribed time intervals until age 10.5 years. RESULTS: Thirty of 57 children randomized to aphakia remained aphakic at age 10.5, having undergone unilateral cataract surgery at a median age of 1.6 (IQR: 1.1-3.1) months. The median refractive error (RE) in the 57 eyes randomized to aphakia immediately after cataract surgery was 19.01 D (IQR: 16.98-20.49) compared to 10.38 D (IQR: 7.50-14.00) for the 30 eyes that remained aphakic at age 10.5 years. The mean change in RE in aphakic eyes was -2.11 D/year up to age 1.5 years, -0.68 D/year from 1.5 to 5.0 years, and -0.35 D/year from age 5 to 10.5 years. At age 10.5 years, 18 patients continued to wear a contact lens correction (silicone elastomer, n=6; gas permeable, n=6; hydrogel, n=5; and silicone hydrogel, n=1) (median RE, 12.50 D), 9 wore only spectacles (median RE, 4.00 D), and 4 wore no correction (median RE, 11.25 D) to correct their aphakic eye. CONCLUSIONS: The RE in aphakic eyes decreased by 44% from infancy to age 10.5 years. About two-thirds of children who remained aphakic at age 10.5 years continued to wear a contact lens.

Schistosoma mansoni Infection Is Associated With a Higher Probability of Tuberculosis Disease in HIV-Infected Adults in Kenya.

BACKGROUND: Helminth infections can modulate immunity to Mycobacterium tuberculosis (Mtb). However, the effect of helminths, including Schistosoma mansoni (SM), on Mtb infection outcomes is less clear. Furthermore, HIV is a known risk factor for tuberculosis (TB) disease and has been implicated in SM pathogenesis. Therefore, it is important to evaluate whether HIV modifies the association between SM and Mtb infection. SETTING: HIV-infected and HIV-uninfected adults were enrolled in Kisumu County, Kenya, between 2014 and 2017 and categorized into 3 groups based on Mtb infection status: Mtb-uninfected healthy controls, latent TB infection (LTBI), and active TB disease. Participants were subsequently evaluated for infection with SM. METHODS: We used targeted minimum loss estimation and super learning to estimate a covariate-adjusted association between SM and Mtb infection outcomes, defined as the probability of being Mtb-uninfected healthy controls, LTBI, or TB. HIV status was evaluated as an effect modifier of this association. RESULTS: SM was not associated with differences in baseline demographic or clinical features of participants in this study, nor with additional parasitic infections. Covariate-adjusted analyses indicated that infection with SM was associated with a 4% higher estimated proportion of active TB cases in HIV-uninfected individuals and a 14% higher estimated proportion of active TB cases in HIV-infected individuals. There were no differences in estimated proportions of LTBI cases. CONCLUSIONS: We provide evidence that SM infection is associated with a higher probability of active TB disease, particularly in HIV-infected individuals.

Glaucoma-Related Adverse Events at 10 Years in the Infant Aphakia Treatment Study: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Glaucoma-related adverse events constitute serious complications of cataract removal in infancy, yet long-term data on incidence and visual outcome remain lacking. Objective: To identify and characterize incident cases of glaucoma and glaucoma-related adverse events (glaucoma + glaucoma suspect) among children in the Infant Aphakia Treatment Study (IATS) by the age of 10.5 years and to determine whether these diagnoses are associated with optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) assessment. Design, Setting, and Participants: Analysis of a multicenter randomized clinical trial of 114 infants with unilateral congenital cataract who were aged 1 to 6 months at surgery. Data on long-term glaucoma-related status and outcomes were collected when children were 10.5 years old (July 14, 2015, to July 12, 2019) and analyzed from March 30, 2019, to August 6, 2019. Interventions: Participants were randomized at cataract surgery to either primary intraocular lens (IOL), or aphakia (contact lens [CL]). Standardized definitions of glaucoma and glaucoma suspect were created for IATS and applied for surveillance and diagnosis. Main Outcomes and Measures: Development of glaucoma and glaucoma + glaucoma suspect in operated-on eyes up to age 10.5 years, plus intraocular pressure, axial length, RNFL (by optical coherence tomography), and ONH photographs. Results: In Kaplan-Meier analysis, for all study eyes combined (n = 114), risk of glaucoma after cataract removal rose from 9% (95% CI, 5%-16%) at 1 year, to 17% (95% CI, 11%-25%) at 5 years, to 22% (95% CI, 16%-31%) at 10 years. The risk of glaucoma plus glaucoma suspect diagnosis after cataract removal rose from 12% (95% CI, 7%-20%) at 1 year, to 31% (95% CI, 24%-41%) at 5 years, to 40% (95% CI, 32%-50%) at 10 years. Risk of glaucoma and glaucoma plus glaucoma suspect diagnosis at 10 years was not significantly different between treatment groups. Eyes with glaucoma (compared with eyes with glaucoma suspect or neither) had longer axial length but relatively preserved RNFL and similar ONH appearance and visual acuity at age 10 years. Conclusions and Relevance: Risk of glaucoma-related adverse events continues to increase with longer follow-up of children following unilateral cataract removal in infancy and is not associated with primary IOL implantation. Development of glaucoma (or glaucoma suspect) after removal of unilateral congenital cataract was not associated with worse visual acuity outcomes at 10 years. Trial Registration: ClinicalTrials.gov Identifier: NCT00212134.

Refractive growth variability in the Infant Aphakia Treatment Study.

PURPOSE: Prediction of refraction after cataract surgery in children is limited by the variance in rate of refractive growth (RRG3). This study compared RRG3 in aphakic and pseudophakic eyes with their fellow, normal eyes in the Infant Aphakia Treatment Study. SETTING: Twelve clinical sites in the United States. DESIGN: Randomized clinical trial. METHODS: Infants randomized to unilateral cataract extraction had RRG3 calculated based on biometric data (axial length and keratometry) at cataract surgery and at 10 years of age, for both the normal and cataract eyes. Subjects were included if complete biometric data from both eyes were available both at surgery and at 10 years. Variance in RRG3 was compared between the groups with Pitman test for equality of variance between correlated samples. RESULTS: Longitudinal biometric data were available for 103 of the 114 patients enrolled. RRG3 was -15.00 diopters (D) (3.00 D) for normal eyes (reported as mean [SD]), -17.70 D (6.20 D) for aphakic eyes, and -16.70 D (6.20 D) for pseudophakic eyes (P < .0001 for comparison of variances in RRG3 between normal and all operated eyes). Further analysis found differences in the variance in axial length growth (P < .0001) between operated and normal eyes; the variance in keratometry measurement change did not reach significance. CONCLUSIONS: The standard deviation in the RRG3 of normal eyes in our study was half of that found in eyes that underwent cataract surgery.

Outcomes of secondary intraocular lens implantation in the Infant Aphakia Treatment Study.

PURPOSE: To report outcomes of secondary intraocular lens (IOL) implantation in the Infant Aphakia Treatment Study (IATS). SETTING: Multicenter clinical practice. DESIGN: Secondary analysis of patients enrolled in a randomized clinical trial. METHODS: Details regarding all secondary IOL surgeries conducted in children enrolled in the IATS were compiled. Visual outcomes, refractive outcomes, and adverse events at the age of 10½ years were evaluated. Comparisons were made with eyes that remained aphakic and with eyes randomized to primary IOL placement. RESULTS: The study included 114 infants, 57 in the aphakic group and 57 in the primary IOL group; 55 of 57 patients randomized to aphakia with contact lens correction were seen for the 10½-year study visit; 24 (44%) of 55 eyes had secondary IOL surgery. Median age at IOL surgery was 5.4 years (range 1.7 to 10.3 years). Mean absolute prediction error was 1.00 ± 0.70 diopters (D). At age 10½ years, the median logarithm of the minimum angle of resolution visual acuity (VA) was 0.9 (range 0.2 to 1.7), similar to VA in the 31 eyes still aphakic (0.8, range 0.1 to 2.9); the number of eyes with stable or improved VA scores between the 4½-year and 10½-year study visits was also similar (78% secondary IOL eyes; 84% aphakic eyes). For eyes undergoing IOL implantation after the 4½-year study visit (n = 22), the mean refraction at age 10½ years was -3.20 ± 2.70 D (range -9.90 to 1.10 D), compared with -5.50 ± 6.60 D (n = 53, range -26.50 to 3.00 D) in eyes with primary IOL (P = .03). CONCLUSIONS: Delayed IOL implantation allows a more predictable refractive outcome at age 10½ years, although the range of refractive error is still large.

Infarct Recurrence in Intracranial Atherosclerosis: Results from the MyRIAD Study.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism. METHODS: This prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks. RESULTS: Amongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes. CONCLUSIONS: Despite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02121028.

Tryptophan catabolism reflects disease activity in human tuberculosis.

There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.

Imaging Patterns of Recurrent Infarction in the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) Study.

Introduction: While much is known about recurrent clinical events in patients with intracranial atherosclerotic disease (ICAD), there is limited data on characteristics of recurrent infarcts. Methods: The NIH-funded MyRIAD prospective, observational study was designed to identify mechanisms of ischemia and predictors of recurrence in ICAD. Recurrent infarction was assessed on MRI at 6-8 weeks. We reviewed the DWI/ADC and FLAIR sequences in patients with recurrent stroke and characterized the number of infarcts, infarct location, size, and patterns based on whether they were borderzone (BZ), perforator (SC/P), cortical or territorial (C/T), and mixed. Temporal characteristics were delineated by ADC/FLAIR correlation. Results: Of the 89 patients with 6-8 weeks MRI, 22 (24.7%) had recurrent infarcts in the territory of the symptomatic artery. Recurrent infarcts were evident on DWI in 63.6% and single infarcts in 54.5%. The median recurrent infarct volume was 2.0 cm3 compared to median index infarct volumes of 2.5 cm3. A mixed infarct pattern was most common (40.9%), followed by borderzone (22.7%), cortical or territorial (27.3%), while only 9.1% were in a perforator artery distribution. Amongst those with a mixed pattern, 8/9 had a borderzone distribution infarct as part of their mixed infarct pattern. Conclusion: These findings provide novel data on the characteristics of early recurrent infarcts in patients with symptomatic ICAD.

Impact of Baseline Features and Risk Factor Control on Cognitive Function in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial.

BACKGROUND: Cerebrovascular disease is an important cause of cognitive impairment. The aim of this study is to report the relationship between cognitive function and risk factors at baseline and during follow-up in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: Subjects in the SAMMPRIS trial were included in this study. In order to have an assessment of cognitive function independent of stroke, patients with a stroke as a qualifying event whose deficits included aphasia or neglect were excluded from these analyses as were those with a cerebrovascular event during follow-up. The Montreal Cognitive Assessment (MoCA) score was used to assess cognitive impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA < 26. A multivariate analysis was performed to determine what risk factors were independent predictors of cognitive function at baseline, 12 months and closeout. Among patients randomized to aggressive medical management only, the percentage of patients with cognitive impairment was compared between patients in versus out of target for each risk factor at 12 months and closeout. RESULTS: Of the 451 patients in SAMMPRIS, 371 patients met the inclusion criteria. MoCA < 26 was present in 55% at baseline. Older age and physical inactivity were associated with cognitive impairment at baseline. Older age, non-white race, lower baseline body mass index, and baseline cognitive impairment were associated with cognitive impairment at 12 months. In the aggressive medical management group, at 12 months, physical inactivity during follow-up was the strongest risk factor associated with cognitive impairment. CONCLUSION: Cognitive impairment is common in patients with severe symptomatic intracranial atherosclerosis. Physical inactivity at baseline and during follow-up is a strong predictor of cognitive impairment.