The ICD-9 to ICD-10 transition has not improved identification of rapidly progressing stage 3 and stage 4 chronic kidney disease patients: a diagnostic test study.

BACKGROUND: The International Classification of Diseases (ICD) coding system is the industry standard tool for billing, disease classification, and epidemiology purposes. Prior research has demonstrated ICD codes to have poor accuracy, particularly in relation to rapidly progressing chronic kidney disease (CKD) patients. In 2016, the ICD system moved to revision 10. This study examines subjects in a large insurer database to determine the accuracy of ICD-10 CKD-staging codes to diagnose patients rapidly progressing towards end-stage kidney disease (ESKD). PATIENTS AND METHODS: Serial observations of outpatient serum creatinine measurements from 2016 to 2021 of 315,903 patients were transformed to estimated glomerular filtration rate (eGFR) to identify CKD stage-3 and advanced patients diagnosed clinically (eGFR-CKD). CKD-staging codes from the same time period of 59,386 patients and used to identify stage-3 and advanced patients diagnosed by ICD-code (ICD-CKD). eGFR-CKD and ICD-CKD diagnostic accuracy was compared between a total of 334,610 patients. RESULTS: 5,618 patients qualified for the progression analysis; 72 were identified as eGFR rapid progressors; 718 had multiple codes to qualify as ICD rapid progressors. Sensitivity was 5.56%, with positive predictive value (PPV) 5.6%. 34,858 patients were diagnosed as eGFR-CKD stage-3 patients; 17,549 were also diagnosed as ICD-CKD stage-3 patients, for a sensitivity of 50.34%, with PPV of 58.71%. 4,069 patients reached eGFR-CKD stage-4 with 2,750 ICD-CKD stage-4 patients, giving a sensitivity of 67.58%, PPV of 42.43%. 959 patients reached eGFR-CKD stage-5 with 566 ICD-CKD stage-5 patients, giving a sensitivity of 59.02%, PPV of 35.85%. CONCLUSION: This research shows that recent ICD revisions have not improved identification of rapid progressors in diagnostic accuracy, although marked increases in sensitivity for stage-3 (50.34% vs. 24.68%), and PPV in stage-3 (58.71% vs. 40.08%), stage-4 (42.43% vs. 18.52%), and stage-5 (35.85% vs. 4.51%) were observed. However, sensitivity in stage-5 compares poorly (59.02% vs. 91.05%).

Broad organ acceptance and equitable access to early kidney transplantation.

BACKGROUND: Broad organ acceptance can increase early kidney transplantation (KTX) within <1-year of dialysis initiation while improving access inequity. METHODS: Single-center data of adult isolated deceased-donor KTX recipients between 2013 and 2020 were stratified into three 2.5-year periods before-, early after-, and late after our center's deceased-donor organ acceptance practice change, excluding a 6-month implementation period. Outcomes were assessed within five recipient subgroups based on demographic and clinical characteristics. RESULTS: Of 704 recipients, the frequency of early KTX was 22% pre-change, 36% early post-change, and 34% late post-change. Given similar post-change frequencies of early KTX, post-change eras were combined to improve analytic power of subgroup analyses. After the organ acceptance practice change (vs. pre-change), the likelihood of early KTX increased variably within historically underserved groups, including recipients who were older (37%-39%, p = .859), Black (10%-21%, p = .136), female (21%-37%, p = .034), diabetic (13%-32%, p = .010), and BMI≥35 kg/m2 (20%-34%, p = .007). Despite the practice change, Black recipients continued to experience less early KTX compared to non-Black recipients. The likelihood of delayed graft function was significantly increased (p < .001), and 1-year creatinine was significantly higher (p < .001) post-practice change, but between-era risk-adjusted death-censored graft survival was similar. CONCLUSIONS: Transition to broader donor acceptance was associated with more early KTXs among historically underserved patient subgroups. However, the effect was non-significant among Black recipients, suggesting the need for additional strategies to impact early transplant access for this population. Studies of broad organ acceptance are needed to examine both access and outcomes.

Anterior chamber depth and angle-closure glaucoma after central retinal vein occlusion.

BACKGROUND: The purpose of this study was to report the anterior chamber (AC) depth and the attack of angle-closure glaucoma (ACG) in eyes with the recent onset of central retinal vein occlusion (CRVO). METHODS: This retrospective case series included 24 patients with recent onset of CRVO (within one month of attack) from July 2001 to December 2002. The mean follow-up period of the patients was 46 months (range: 3 to 92 months). AC depth was measured using an ultrasound biomicroscopy. Clinical data, including systemic disorders, intraocular pressure, and visual outcomes were recorded. The main outcome measures were AC depth in the diseased eye and the fellow eye of the same patient and the attack of ACG after CRVO. RESULTS: The mean AC depth in the diseased eyes was significantly shallower than in the unaffected fellow eyes (2.43 ± 0.45 mm vs. 2.55 ± 0.46 mm; p < 0.001). Four patients (17 %) developed ACG after the onset of CRVO within one month of the CRVO attack. In these four patients, the mean AC depth in the diseased eyes was 1.91 ± 0.21 mm, which was much shallower than the eyes without ACG attack (2.53 ± 0.40 mm). CONCLUSIONS: AC depth is significantly shallower following the onset of CRVO. ACG can occur in patients after the onset of CRVO.

Acute angle-closure glaucoma in retinopathy of prematurity following pupil dilation.

BACKGROUND: Pupil dilation is a known risk factor for acute angle-closure glaucoma. Regular retinal evaluation is necessary for retinopathy of prematurity (ROP) cases. An acute attack of angle-closure glaucoma following pupil dilation in regressed ROP has never been reported. CASE PRESENTATION: A five-year-old girl presented to the hospital for a routine retina check-up. The patient was born prematurely with a gestation age of 27 weeks and a body weight of 980 grams. She had a history of stage 4A ROP in the right eye and received scleral buckling. After pupil dilation with 1 % tropicamide and 10 % phenylephrine for retinal examination, acute elevation of intraocular pressure (IOP) was observed in the right eye. Her IOP remained over 50 mmHg in the right eye even under treatment with oral acetazolamide and maximal tolerated doses of topical anti-glaucoma medications. Ultrasound biomicroscopy (UBM) showed that the angle in the right eye was closed 360 degrees circumferentially. In order to lower IOP, trabeculectomy with mitomycin C (0.2 mg/cc) was performed under general anesthesia. Postoperatively, the cornea became clear, the filtering bleb functioned well, and IOP returned to normal values. In the two-year follow-up, IOP was kept around 15 mmHg without anti-glaucoma medications. Although mild lens opacity was noted, her postoperative VA remained 20/200 in the right eye. CONCLUSION: Regular retinal evaluation will be necessary for the increasing number of ROP cases to be seen in the future. Ophthalmologists should bear in mind that pupil dilation for a retina check-up could result in acute angle-closure glaucoma in ROP patients.

Epithelial phenotype in total sclerocornea.

PURPOSE: To understand whether the epithelial phenotype in total sclerocornea is corneal or conjunctival in origin. METHODS: Four cases of total sclerocornea (male:female = 1:3; mean age = 5.4 ± 4.3; 1-11 years old) who received penetrating keratoplasty (PKP) at our hospital between 2008 and 2011 were included. Corneal buttons obtained during PKP were used for transmission electron microscopy (TEM) as well as immunoconfocal microscopy for cytokeratins 3, 12, and 13, goblet cell mucin MUC5AC, connexin 43, stem cell markers p63 and ABCG2, laminin-5, and fibronectin. RESULTS: After a mean follow-up period of 38.8 ± 14.0 (12-54) months, the grafts remained clear in half of the patients. TEM examination revealed a markedly attenuated Bowman's layer in the scleralized corneas, with irregular and variably thinned collagen lamellar layers, and disorganization and random distribution of collagen fibrils, which were much larger in diameter compared with a normal cornea. Immunoconfocal microscopy showed that keratin 3 was expressed in all four patients, while p63, ABCG2, and MUC5AC were all absent. Cornea-specific keratin 12 was universally expressed in Patients 1 to 3, while mucosa (including conjunctiva)-specific keratin 13 was negative in these patients. Interestingly, keratin 12 and 13 were expressed in Patient 4 in a mutually exclusive manner. Linear expression of laminin-5 in the basement membrane zone and similar expression of fibronectin were observed. CONCLUSIONS: The epithelia in total sclerocornea are essentially corneal in phenotype, but in the event of massive corneal angiogenesis, invasion by the conjunctival epithelium is possible.

Neovascular glaucoma after central retinal vein occlusion in pre-existing glaucoma.

BACKGROUND: To determine the outcome of central retinal vein occlusion (CRVO) in pre-existing glaucoma and the predisposing factors of developing neovascular glaucoma (NVG). METHODS: We retrospectively assessed a pre-existing glaucoma CRVO group and a non-glaucoma CRVO group to elucidate the demographics, clinical course and ocular parameters of these two cohorts. Among the pre-existing glaucoma cases, the predisposing factors for the development of NVG were monitored, including the retinal capillary non-perfusion status, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) at presentation. RESULTS: Of 642 CRVO patients reviewed in this 10-year cohort study, 60 (9.3%) had pre-existing glaucoma at a mean follow-up of 30.8 months, including 28 (4.4%) primary open angle glaucoma (POAG), 27 (4.2%) primary angle closure glaucoma (PACG), and 5 (0.8%) normal tension glaucoma (NTG) cases. Although the presence of glaucoma in the CRVO eyes was not significantly associated with the risk of developing NVG, the incidence of developing NVG in pre-existing glaucoma eyes was significantly higher in the group with IOP greater than 20 mmHg at CRVO presentation (P = 0.02, Chi-square test) as well as in the ischemic CRVO group compared to the non-ischemic patients (P = 0.005, Fisher's exact test). Overall, 20% of pre-existing glaucoma patients needed glaucoma surgery after a CRVO event, including 11.7% of patients who developed iris neovascularisation (INV) and 8.3% of patients who developed a high IOP without INV. CONCLUSIONS: Both the retinal non-perfusion status and uncontrolled IOP contribute to NVG in patients with pre-existing glaucoma after CRVO. Following CRVO, glaucoma surgery is necessary for pre-existing glaucoma cases with intractable elevated IOP with or without INV.

Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS: Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS: In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.

Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS: Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS: In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.

Late-onset secondary pigmentary glaucoma following foldable intraocular lenses implantation in the ciliary sulcus: a long-term follow-up study.

BACKGROUND: To review the long-term outcomes of eyes with secondary pigmentary glaucoma associated with the implantation of foldable intraocular lenses (IOL) in the ciliary sulcus. METHODS: The study retrospectively reviewed a series of cases who developed secondary pigmentary glaucoma after cataract operations. Data were collected from cases that were referred between 2002 and 2011. RESULTS: Ten eyes of 10 patients who developed secondary pigmentary glaucoma after foldable IOLs implantation in the sulcus were included in this study. CONCLUSION: Secondary pigmentary glaucoma accompanying the implantation of a foldable IOL in the ciliary sulcus may present as acute IOP elevation during the early postoperative period or, more commonly, late onset of IOP elevation accompanied by advanced glaucomatous optic nerve damage. Despite treatment, the visual prognosis for these patients can be poor. Placing a foldable IOL in the ciliary sulcus could pose a threat to the vision of the patients and long-term follow-up of IOP in these patients is necessary.

Bayesian optimization of tacrolimus exposure in stable kidney transplant patients.

STUDY OBJECTIVE: The objective was to compare tacrolimus AUC0-12 determined by Non-Compartmental Analysis (NCA) using intensive sampling to Maximum a Posteriori-Bayesian (MAP-Bayesian) estimates from robust (n = 9 samples/subject) and sparse (n = 2 samples/subject) sampling in 67 stable KTRs and a validation group of similar patients. DESIGN: This open-label, prospective, single center 12-h PK study included nine serial samples collected in KTRs to determine steady-state NCA tacrolimus AUC0-12 . SETTING: This study was conducted at a single site within a large, urban hospital in the western New York area. PATIENTS: This study described tacrolimus pharmacokinetics in stable kidney transplant recipients on maintenance tacrolimus therapy. INTERVENTION: Robust and sparse AUC0-12 estimates by a MAP-Bayesian approach were obtained using the Advanced Dosing Solutions (AdDS) and ADAPT5 freeware. Limited sampling strategies were evaluated using the original population PK model (n = 67), which was also assessed using a validation group (n = 15). AUC0-12 agreement was tested by paired t-tests with intraclass correlation coefficient (ICC) and Bland Altman analysis. MEASUREMENTS AND MAIN RESULTS: A total of 35 Black and 32 White stable KTRs (estimated glomerular filtration rate [eGFR] = 55.2 ± 15.7 mL/min/1.73m2 ) received the tacrolimus dose of 3.4 ± 1.7 mg/study with troughs of 6.8 ± 1.8 ng/mL. The NCA-AUC0-12 was 123.8 ± 33.6 µg·h/L compared to MAP-Bayesian estimates for Robust-AUC0-12 of 124.7 ± 33.3 µg·h/L and optimal 2-specimen Sparse-AUC0-12 of 119.7 ± 32.7 µg·h/L for the training group. Comparison of Robust-AUC0-12 to NCA-AUC0-12 had an ICC of 0.96 (p = 0.99) while comparison of Robust-AUC0-12 to Sparse-AUC0-12 using Pre-dose trough [C(t0h )] and 1 h [C(t1h )] resulted in an ICC of 0.93 (p = 0.014). In the validation group, 5 Black and 10 White KTRs (eGFR = 56.4 ± 16.8 mL/min/1.73m2 ) received a mean tacrolimus dose of 1.9 ± 1.2 mg/study with a trough of 6.0 ± 1.7 ng/mL. The validation group's NCA-AUC0-12 (88.4 ± 33.1 µg·h/L) was comparable to Robust-AUC0-12 (85.1 ± 33.8 µg·h/L, ICC = 0.93; p = 0.12) and Sparse-AUC0-12 determined from C(t0h ) and C(t4h ) (86.7 ± 33.9 µg·h/L, ICC = 0.91; p = 0.61). CONCLUSION: MAP-Bayesian estimation for patient-specific AUC0-12 using sparse, two-specimen sampling is comparable to NCA and may enhance tacrolimus TDM in stable KTRs.

Comparison of P-glycoprotein function in peripheral blood mononuclear cells ex vivo in stable Black and White male and female kidney transplant recipients.

Kidney allograft survival remains poorer in Black compared to White recipients due to racial differences in calcineurin inhibitor (CNI) pharmacology. P-glycoprotein (P-gp), an ABC efflux transporter expressed in peripheral blood mononuclear cells (PBMCs), modulates CNI pharmacokinetics and intracellular pharmacology. This study investigated P-gp function in PBMC ex vivo at 0 (trough), 4, 8, and 12 h in stable Black and White male and female kidney transplant recipients (n = 67) receiving tacrolimus and mycophenolic acid. Tacrolimus doses were adjusted to troughs of 4-10 ng/ml. P-gp function was quantified with flow cytometric measurement of cyclosporine (CYA; 2.5 µM)-reversible efflux of P-gp substrate, 3,3'-Diethyloxacarbocyanine iodide by determining the percentage change of mean fluorescent intensity (MFI) with CYA (% ΔMFI). The composite parameter of area under the concentration versus time (AUC)0-12h % ΔMFI estimated P-gp function. Data analysis examined race, sex, and race-sex associations to P-gp function. A secondary aim analyzed ABCB1 genotypes: 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), and P-gp function. P-gp function (% ΔMFI) was higher in White patients at troughs (p = 0.031) compared to Black counterparts with similar trends at 4 and 8 h. Reduced AUC0-12h % ΔMFI was noted in Black recipients (N = 32) compared with Whites (N = 35, p = 0.029) with notable pairwise adjusted differences between Black and White women (p = 0.021). Higher AUC0-12h % ΔMFI was associated with ABCB1 2677 TT compared to GG variants (p = 0.035). The AUC0-12h % ΔMFI was greater in White than Black subjects. P-gp function was higher at troughs in White subjects and differed between race-sex groups. P-gp function in PBMC may influence intracellular tacrolimus exposure and inter-relating pharmacodynamic responses which may support race and sex pharmacologic differences.

Leukotriene inhibitors with dexamethasone show promise in the prevention of death in COVID-19 patients with low oxygen saturations.

Introduction: COVID-19 is a major health threat around the world causing hundreds of millions of infections and millions of deaths. There is a pressing global need for effective therapies. We hypothesized that leukotriene inhibitors (LTIs), that have been shown to lower IL6 and IL8 levels, may have a protective effect in patients with COVID-19. Methods: In this retrospective controlled cohort study, we compared death rates in COVID-19 patients who were taking a LTI with those who were not taking an LTI. We used the Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) to create a cohort of COVID-19-positive patients and tracked their use of LTIs between November 1, 2019 and November 11, 2021. Results: Of the 1,677,595 cohort of patients tested for COVID-19, 189,195 patients tested positive for COVID-19. Forty thousand seven hundred one were admitted. 38,184 had an oxygen requirement and 1214 were taking an LTI. The use of dexamethasone plus a LTI in hospital showed a survival advantage of 13.5% (CI: 0.23%-26.7%; p < 0.01) in patients presenting with a minimal O2Sat of 50% or less. For patients with an O2Sat of <60 and <50% if they were on LTIs as outpatients, continuing the LTI led to a 14.4% and 22.25 survival advantage if they were continued on the medication as inpatients. Conclusions: When combined dexamethasone and LTIs provided a mortality benefit in COVID-19 patients presenting with an O2 saturations <50%. The LTI cohort had lower markers of inflammation and cytokine storm.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

STUDY OBJECTIVE: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. DESIGN AND SETTING: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC0-12 ), AUC0-4 , 12-h troughs (C12 h ), maximum concentrations (Cmax ), oral clearance (Cl), with dose-normalized AUC0-12 , troughs, and Cmax with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms. PATIENTS: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated. MEASUREMENTS AND MAIN RESULTS: Black recipients exhibited higher tacrolimus AUC0-12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0-12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0-12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%-19% of tacrolimus variability in dose (p = 0.002); AUC0-12 h * (p < 0.001), and Cl (p < 0.001). CONCLUSIONS: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0-12 h .

The validity of clinical feature profiles for cytomegaloviral anterior segment infection.

BACKGROUND: Anterior segment cytomegalovirus (CMV) infection, which can be presented as anterior uveitis and corneal endotheliitis, has recently been reported in immunocompetent patients. We would like to access the validity of two presumed characteristic clinical profiles: profile 1, non-herpes simplex virus (HSV)/varicella zoster virus (VZV) corticosteroid-recalcitrant inflammatory ocular hypertensive syndrome (IOHS), and profile 2, corneal endotheliitis with specific coin-shaped keratic precipitates (KPs), that could be helpful in identifying CMV anterior segment intraocular infection. METHODS: Patients with either profile 1 or profile 2 or both were enrolled consecutively from the uveitis service in Chang Gung Memorial Hospital, Taoyuan, between January 1, 2006 and May 31, 2010. Diagnostic anterior chamber tapping was performed and followed by real-time quantitative polymerase chain reaction (PCR) to detect herpesviridae DNA including HSV I and II, VZV, CMV, and Epstein-Barr virus. RESULTS: Thirty-one eyes of 30 patients (21 males and nine females) were enrolled in this study. CMV DNA PCR was positive in 29 eyes of 28 patients (20 males and eight females). Nineteen of 20 eyes (19 patients) in profile 1 had positive CMV PCR. Ten of 11 eyes (11 patients) in profile 2 had positive CMV PCR. The positive predictive value of profile 1 and profile 2 was 94.7% and 90.9%, respectively. The positive predictive value of combining the two profiles was 93.3%. CONCLUSIONS: Non-HSV/ZVZ corticosteroid-recalcitrant IOHS and corneal endotheliitis with specific coin-shaped KPs could be used as the screening tool for CMV anterior segment intraocular infection.

Evaluating for a correlation between osteopathic examination and ultrasonography on thoracic spine asymmetry.

CONTEXT: The thoracic spine is a common area of focus in osteopathic manipulative medicine (OMM) for a variety of conditions. Thoracic spine somatic dysfunction diagnosis is achieved by palpating for asymmetry at the tips of the transverse processes (TPs). Previous studies reveal that instead of following the rule of threes, the TPs of a given thoracic vertebra generally align with the spinous process (SP) of the vertebra above. Ultrasonography has been widely utilized as a diagnostic tool to monitor musculoskeletal conditions; it does not utilize ionizing radiation, and it has comparable results to gold-standard modalities. In the case of thoracic somatic dysfunction, ultrasound (US) can be utilized to determine the location of each vertebral TP and its relationship with the SP. Previous studies have investigated the correlation between OMM and ultrasonography of the cervical, lumbar, and sacral regions. However, there has been no study yet that has compared osteopathic structural examination with ultrasonographic examination of the thoracic vertebral region. OBJECTIVES: To examine the relationship between osteopathic palpation and ultrasonographic measurements of the thoracic spine by creating a study design that utilizes interexaminer agreement and correlation. METHODS: The ClinicalTrials.gov study identifier is NCT04823637. Subjects were student volunteers recruited from the Midwestern University (MWU)-Glendale campus. A nontoxic, nonpermanent marker was utilized to mark bony landmarks on the skin. Two neuromusculoskeletal board-certified physicians (OMM1, OMM2) separately performed structural exams by palpating T2-T5 TPs to determine vertebral rotation. Two sonographers (US1, US2) separately scanned and measured the distance from the tip of the SP to the adjacent TPs of the vertebral segment below. Demographic variables were summarized with mean and standard deviation. Interexaminer agreement was assessed with percent agreement, Cohen's Kappa, and Fleiss' Kappa. Correlation was measured by Spearman's rank correlation coefficient. Recruitment and protocols were approved by the MWU Institutional Review Board (IRB). RESULTS: US had fair interexaminer agreement for the overall most prominent segmental rotation of the T3-T5 thoracic spine, with Cohen's Kappa at 0.27 (0.09, 0.45), and a total agreement percentage at 51.5%. Osteopathic palpation revealed low interexaminer agreement for the overall most prominent vertebral rotation, with Cohen's Kappa at 0.05 (0.0, 0.27), and 31.8%. Segment-specific vertebral analysis revealed slight agreement between US examiners, with a correlation coefficient of 0.23, whereas all other pairwise comparisons showed low agreement and correlation. At T4, US had slight interexaminer agreement with 0.24 correlation coefficient, and osteopathic palpation showed low interexaminer (OMM1 vs. OMM2) agreement (0.17 correlation coefficient). At T5, there was moderate agreement between the two sonographers with 0.44 (0.27, 0.60) and 63.6%, with a correlation coefficient of 0.57, and slight agreement between OMM1 and OMM2 with 0.12 (0.0, 0.28) and 42.4%, with 0.23 correlation coefficient. CONCLUSIONS: This preliminary study of an asymptomatic population revealed that there is a low-to-moderate interexaminer reliability between sonographers, low-to-slight interexaminer reliability between osteopathic physicians, and low interexaminer reliability between OMM palpatory examination and ultrasonographic evaluation of the thoracic spine.

Insight Into Disorder, Stress and Strain of Radiation Damaged Pyrochlores: A Possible Mechanism for the Appearance of Defect Fluorite.

We have examined the irradiation response of a titanate and zirconate pyrochlore-both of which are well studied in the literature individually-in an attempt to define the appearance of defect fluorite in zirconate pyrochlores. To our knowledge this study is unique in that it attempts to discover the mechanism of formation by a comparison of the different systems exposed to the same conditions and then examined via a range of techniques that cover a wide length scale. The conditions of approximately 1 displacement per atom via He2+ ions were used to simulate long term waste storage conditions as outlined by previous results from Ewing in a large enough sample volume to allow for neutron diffraction, as not attempted previously. The titanate sample, used as a baseline comparison since it readily becomes amorphous under these conditions behaved as expected. In contrast, the zirconate sample accumulates tensile stress in the absence of detectable strain. We propose this is analogous to the lanthanide zirconate pyrochlores examined by Simeone et al. where they reported the appearance of defect fluorite diffraction patterns due to a reduction in grain size. Radiation damage and stress results in the grains breaking into even smaller crystallites, thus creating even smaller coherent diffraction domains. An (ErNd)2(ZrTi)2O7 pyrochlore was synthesized to examine which mechanism might dominate, amorphization or stress/strain build up. Although strain was detected in the pristine sample via Synchrotron X-ray diffraction it was not of sufficient quality to perform a full analysis on.

Intravitreal loading injection of ganciclovir with or without adjunctive oral valganciclovir for cytomegalovirus anterior uveitis.

BACKGROUND: A pilot study was conducted to evaluate the therapeutic results of intravitreal ganciclovir injection as a loading dose with or without the following oral valganciclovir for the treatment of cytomegalovirus (CMV) anterior uveitis in immunocompetent patients. METHODS: Six consecutive patients in whom active CMV anterior uveitis was detected by polymerase chain reaction assay of the aqueous humor were enrolled between January 2006 and December 2008. These patients received an intravitreal injection of ganciclovir (2 mg/0.05 ml) as a loading dose. Subsequent use of oral valganciclovir (900 mg twice a day) was determined according to the severity of the post-injection aqueous inflammation. Immune status and anterior chamber reaction of individual patients, visual acuity, intraocular pressure (IOP) at study entry, and follow-up intervals were examined. RESULTS: The mean patient-month follow-up period after intravitreal injection was 14.7 months (range, 12-22 months). Two patients received only the intravitreal ganciclovir injection once and four patients had received the following oral valganciclovir for average 2.3 months (range, 1-4 months). With this treatment strategy, the best-corrected visual acuity of the patients improved or stabilized; the IOP and the inflammation of anterior chamber of the patients were well controlled at all time points and there were no treatment-associated complications by the end of follow-up. CONCLUSIONS: In patients with CMV anterior uveitis, intravitreal ganciclovir injection as a loading dose with or without the following oral valganciclovir can control the inflammation and IOP well.

Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P < 0.001) with 50% lower AUC∗ (P < 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.

Correlation between structural progression in glaucoma and obstructive sleep apnea.

BACKGROUND/OBJECTIVES: To investigate the correlation between obstructive sleep apnea (OSA) severity and the structural and functional progression in patients with glaucoma. SUBJECTS/METHODS: This retrospective comparative cohort study included subjects from the polysomnography database in Chang Gung Memorial Hospital between June 1, 2009, and June 1, 2017, by identifying patients who had received diagnoses of primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), or glaucoma suspect. Patients with follow-up time of <3 years and/or <3 consecutive reliable optical coherence tomography (OCT) or visual field (VF) tests were excluded. Progression of overall peripapillary retinal nerve fiber layer (RNFL) thickness on OCT scans and VF mean deviation (MD) or VF index (VFI) were determined through linear regression trend analysis. RESULTS: Thirty-two patients were included. There was a trend to higher percentage of progression on RNFL thickness and VF in higher OSAS severity. After stratifying patients to no OSA/mild OSA (group 1) and moderate/severe OSA (group 2), group 2 exhibited a significantly higher percentage of RNFL thickness progression than did group 1 (64.7% vs 26.7%, P = 0.042). Multivariate Cox regression analysis showed that severe OSA had an 8.448-fold higher risk of RNFL thickness progression after age, sex, diabetes mellitus, hypertension, hyperlipidemia, and body mass index adjustment (95% confidence interval, 1.464-48.752, P = 0.017). CONCLUSIONS: Severe OSA is significantly correlated with a higher risk of structural deterioration in patients with glaucoma.

Glaucoma is associated with peripheral vascular endothelial dysfunction.

PURPOSE: To evaluate peripheral vascular endothelial function in patients with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) using noninvasive endothelium-dependent flow-mediated vasodilation (FMD). DESIGN: Case-control study. PARTICIPANTS: Thirty patients with NTG, 30 with POAG, and 30 healthy age- and gender-matched controls. METHODS: Participants underwent measurement of FMD and endothelium-independent nitroglycerin-mediated vasodilation (NMD) via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. All patients also underwent blood sampling for biochemistry, lipid profile, and high sensitivity C-reactive protein analysis. MAIN OUTCOME MEASURES: The association of FMD with NTG and POAG. RESULTS: The FMD values differed significantly between the patients with NTG, those with POAG, and controls: NTG, 2.70+/-2.25%; POAG, 5.33+/-2.81%; controls, 7.21+/-2.36%; P<0.001. In comparison with the POAG group and normal controls, the NTG group demonstrated markedly impaired FMD. The POAG group exhibited higher intermediate FMD than the NTG group (P<0.001) but significantly lower FMD than normal controls (P = 0.012). Multivariate analysis indicated that independent predictors for impaired FMD were presence of NTG, presence of POAG, and advanced age. Additionally, FMD values were significantly lower in glaucoma patients than in controls (4.02+/-2.85% vs. 7.21+/-2.36%; P<0.001). CONCLUSIONS: Patients with glaucoma have impaired FMD. Additionally, patients with NTG have lower FMD than those with POAG.