Longitudinal soluble marker profiles reveal strong association between cytokine storms resulting from macrophage activation and disease severity in COVID-19 disease.

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

Description of mitochondrial oxygen tension and its variability in healthy volunteers.

OBJECTIVES: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. DESIGN: Prospective cohort study. SETTING: Measurements were performed in Leiden University Medical Center, the Netherlands. PARTICIPANTS: Healthy volunteers enrolled from July to September 2020. INTERVENTIONS: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. PRIMARY AND SECONDARY OUTCOME MEASURES: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. RESULTS: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). CONCLUSIONS: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. TRIAL REGISTRATION: ClinicalTrials.gov with trial number NCT04626661.

Leucocyte and platelet activation in cardiac surgery patients with and without lung injury: A prospective cohort study.

OBJECTIONS: Development of acute lung injury after cardiac surgery is associated with an unfavourable outcome. Acute respiratory distress syndrome in general is, besides cytokine and interleukin activation, associated with activation of platelets, monocytes and neutrophils. In relation to pulmonary outcome after cardiac surgery, leucocyte and platelet activation is described in animal studies only. Therefore, we explored the perioperative time course of platelet and leucocyte activation in cardiac surgery and related these findings to acute lung injury assessed via PaO2/FiO2 (P/F) ratio measurements. METHODS: A prospective cohort study was performed, including 80 cardiac surgery patients. At five time points, blood samples were directly assessed by flow cytometry. For time course analyses in low (< 200) versus high (≥200) P/F ratio groups, repeated measurement techniques with linear mixed models were used. RESULTS: Already before the start of the operation, platelet activatability (P = 0.003 for thrombin receptor-activator peptide and P = 0.017 for adenosine diphosphate) was higher, and the expression of neutrophil activation markers was lower (CD18/CD11; P = 0.001, CD62L; P = 0.013) in the low P/F group. After correction for these baseline differences, the peri- and postoperative thrombin receptor-activator peptide-induced thrombocyte activatability was decreased in the low P/F ratio group (P = 0.008), and a changed pattern of neutrophil activation markers was observed. CONCLUSIONS: Prior to surgery, an upregulated inflammatory state with higher platelet activatability and indications for higher neutrophil turnover were demonstrated in cardiac surgery patients who developed lung injury. It is difficult to distinguish whether these factors are mediators or are also aetiologically related to the development of lung injury after cardiac surgery. Further research is warranted. TRIAL REGISTRATION: Clinical Registration number: ICTRP: NTR 5314, 26-05-2015.

Multiomic characterization of disease progression in mice lacking dystrophin.

Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of age. Integration of RNA-seq, mass spectrometry-based metabolomic and lipidomic data obtained in muscle and blood samples by Multi-Omics Factor Analysis (MOFA) led to the identification of 8 latent factors that explained 78.8% of the variance in the multiomic dataset. Latent factors could discriminate dystrophic and healthy mice, as well as different time-points. MOFA enabled to connect the gene expression signature in dystrophic muscles, characterized by pro-fibrotic and energy metabolism alterations, to inflammation and lipid signatures in blood. Our results show that omic observations in blood can be directly related to skeletal muscle pathology in dystrophic muscle.

INCREASING EVIDENCE FOR THE SAFETY OF FOVEA-INVOLVING HALF-DOSE PHOTODYNAMIC THERAPY FOR CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: A retrospective study was performed with data from the prospective randomized controlled trials, PLACE and SPECTRA, assessing the risk of foveal atrophy and the likelihood of structural and functional improvement on optical coherence tomography, after foveal half-dose photodynamic therapy in chronic central serous chorioretinopathy. METHODS: A total of 57 chronic central serous chorioretinopathy patients received a single half-dose photodynamic therapy with a treatment spot that included the fovea. Optical coherence tomography scans and fundus autofluorescence images were analyzed for structural improvement and possible atrophy development, at baseline and at several visits after treatment. Main outcome measures were integrity of the external limiting membrane and ellipsoid zone on optical coherence tomography and hypoautofluorescence on fundus autofluorescence. RESULTS: The subfoveal external limiting membrane was graded as continuous in 21 of 57 of patients (36.8%) at baseline, and the subfoveal ellipsoid zone was graded as continuous in 5 of 57 patients (8.8%) at first visit, which improved to 50 of 51 (98.0%) and 32 out of 51 (62.7%) at the final visit at 2 years, respectively (both P < 0.001). Hypoautofluorescent changes on fundus autofluorescence were present in 25 of 55 patients (45.5%) at baseline and in 23 of 51 patients (45.1%) at the final visit ( P = 0.480). CONCLUSION: In patients with chronic central serous chorioretinopathy who received a single, foveal, half-dose photodynamic therapy, a significant improvement in structure and function was seen at the final follow-up. None of the patients developed foveal atrophy.

A unique immune signature in blood separates therapy-refractory from therapy-responsive acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is an immune cell‒driven, potentially lethal complication of allogeneic hematopoietic stem cell transplantation affecting diverse organs, including the skin, liver, and gastrointestinal (GI) tract. We applied mass cytometry (CyTOF) to dissect circulating myeloid and lymphoid cells in children with severe (grade III-IV) aGVHD treated with immune suppressive drugs alone (first-line therapy) or in combination with mesenchymal stromal cells (MSCs; second-line therapy). These results were compared with CyTOF data generated in children who underwent transplantation with no aGVHD or age-matched healthy control participants. Onset of aGVHD was associated with the appearance of CD11b+CD163+ myeloid cells in the blood and accumulation in the skin and GI tract. Distinct T-cell populations, including TCRγδ+ cells, expressing activation markers and chemokine receptors guiding homing to the skin and GI tract were found in the same blood samples. CXCR3+ T cells released inflammation-promoting factors after overnight stimulation. These results indicate that lymphoid and myeloid compartments are triggered at aGVHD onset. Immunoglobulin M (IgM) presumably class switched, plasmablasts, and 2 distinct CD11b- dendritic cell subsets were other prominent immune populations found early during the course of aGVHD in patients refractory to both first- and second-line (MSC-based) therapy. In these nonresponding patients, effector and regulatory T cells with skin- or gut-homing receptors also remained proportionally high over time, whereas their frequencies declined in therapy responders. Our results underscore the additive value of high-dimensional immune cell profiling for clinical response evaluation, which may assist timely decision-making in the management of severe aGVHD.

Long-term follow-up of chronic central serous chorioretinopathy patients after primary treatment of oral eplerenone or half-dose photodynamic therapy and crossover treatment: SPECTRA trial report No. 3.

PURPOSE: Comparing anatomic and functional efficacy and safety of primary treatment with either half-dose photodynamic therapy (PDT) or oral eplerenone, or crossover treatment in chronic central serous chorioretinopathy patients. METHODS: After the SPECTRA trial baseline visit, patients were randomized to either half-dose PDT or eplerenone and received crossover treatment if persistent subretinal fluid (SRF) on optical coherence tomography (OCT) was present at first follow-up (at 3 months). Presence of SRF and best-corrected visual acuity (BCVA) was evaluated at 12 months. RESULTS: Out of the 90 patients evaluated at 12 months, complete SRF resolution was present on OCT in 43/48 (89.6%) of patients who were primarily randomized to half-dose PDT and in 37/42 (88.1%) who were primarily randomized to eplerenone. Out of the 42 patients that were primarily randomized to eplerenone, 35 received crossover treatment with half-dose PDT. The BCVA improved significantly more at 12 months in patients who had received primary half-dose PDT as compared to the primary eplerenone group (p = 0.030). CONCLUSIONS: Twelve months after baseline visit, most patients treated with half-dose PDT (either primary or crossover treatment) still had complete SRF resolution. The long-term BCVA in patients who receive primary half-dose PDT is better than in patients in whom PDT is delayed due to initial eplerenone treatment with persistent SRF.

Limited efficacy of repeated praziquantel treatment in Schistosoma mansoni infections as revealed by highly accurate diagnostics, PCR and UCP-LF CAA (RePST trial).

BACKGROUND: Most studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods. METHODOLOGY: A sub-analysis was performed based on a previously published trial conducted in children from Côte d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA). PRINCIPAL FINDINGS: Individuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32-59%) in the standard and 78% (95% CI 66-87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52-75%) and 88%, 95% CI 78-93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11-24%) and 18% (95% CI 12-26%), even lower than observed by POC-CCA (31%, 95% CI 17-35% and 36%, 95% CI 26-47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups. CONCLUSION/SIGNIFICANCE: The efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics (i.e. KK and PCR). Quantitative worm-based diagnostics (i.e. POC-CCA and UCP-LF CAA) revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT02868385.

Urbanization and Unfavorable Changes in Metabolic Profiles: A Prospective Cohort Study of Indonesian Young Adults.

The substantial increase in the prevalence of non-communicable diseases in Indonesia might be driven by rapid socio-economic development through urbanization. Here, we carried out a longitudinal 1-year follow-up study to evaluate the effect of urbanization, an important determinant of health, on metabolic profiles of young Indonesian adults. University freshmen/women in Jakarta, aged 16−25 years, who either had recently migrated from rural areas or originated from urban settings were studied. Anthropometry, dietary intake, and physical activity, as well as fasting blood glucose and insulin, leptin, and adiponectin were measured at baseline and repeated at one year follow-up. At baseline, 106 urban and 83 rural subjects were recruited, of which 81 urban and 66 rural were followed up. At baseline, rural subjects had better adiposity profiles, whole-body insulin resistance, and adipokine levels compared to their urban counterparts. After 1-year, rural subjects experienced an almost twice higher increase in BMI than urban subjects (estimate (95%CI): 1.23 (0.94; 1.52) and 0.69 (0.43; 0.95) for rural and urban subjects, respectively, Pint < 0.01). Fat intake served as the major dietary component, which partially mediates the differences in BMI between urban and rural group at baseline. It also contributed to the changes in BMI over time for both groups, although it does not explain the enhanced gain of BMI in rural subjects. A significantly higher increase of leptin/adiponectin ratio was also seen in rural subjects after 1-year of living in an urban area. In conclusion, urbanization was associated with less favorable changes in adiposity and adipokine profiles in a population of young Indonesian adults.

Sex Hormones in Males and Females with Active Central Serous Chorioretinopathy.

PURPOSE: The aim of the study was to assess the role of sex hormones in male and female patients with central serous chorioretinopathy (CSC), a disease with a pronounced male predilection. METHODS: A total of 206 chronic CSC patients (183 males, 23 females) and 59 healthy controls (29 males, 30 females) were enrolled. Serum testosterone, estradiol, albumin, and sex hormone-binding globulin levels were determined using immunoassays. The free fraction of testosterone and the free testosterone/estradiol ratio were calculated. RESULTS: No differences in the levels of total testosterone and estradiol were observed between CSC patients and healthy controls. Albumin levels were found to be lower in male CSC patients compared to controls (controls 47.8 g/L, patients 46.0 g/L, adj. p = 0.006). Only in females with CSC, sex hormone-binding globulin levels were found to be lower (controls 94.2 nmol/L, patients 50.4 nmol/L, adj. p = 0.001), together with a higher free testosterone/estradiol ratio (controls 0.06, patients 0.18, adj. p = 0.018). CONCLUSIONS: In this study, we did not find evidence for a disturbance in sex hormone levels in males with CSC. The lower levels of sex hormone-binding globulin in females with CSC, leading to a disturbed free testosterone/estradiol ratio, warrant further investigation into the role of androgens in females with CSC.

Sbk2, a Newly Discovered Atrium-Enriched Regulator of Sarcomere Integrity.

BACKGROUND: Heart development relies on tight spatiotemporal control of cardiac gene expression. Genes involved in this intricate process have been identified using animals and pluripotent stem cell-based models of cardio(myo)genesis. Recently, the repertoire of cardiomyocyte differentiation models has been expanded with iAM-1, a monoclonal line of conditionally immortalized neonatal rat atrial myocytes (NRAMs), which allows toggling between proliferative and differentiated (ie, excitable and contractile) phenotypes in a synchronized and homogenous manner. METHODS: In this study, the unique properties of conditionally immortalized NRAMs (iAMs) were exploited to identify and characterize (lowly expressed) genes with an as-of-yet uncharacterized role in cardiomyocyte differentiation. RESULTS: Transcriptome analysis of iAM-1 cells at different stages during one cycle of differentiation and subsequent dedifferentiation identified ≈13 000 transcripts, of which the dynamic changes in expression upon cardiomyogenic differentiation mostly opposed those during dedifferentiation. Among the genes whose expression increased during differentiation and decreased during dedifferentiation were many with known (lineage-specific) functions in cardiac muscle formation. Filtering for cardiac-enriched low-abundance transcripts, identified multiple genes with an uncharacterized role during cardio(myo)genesis including Sbk2 (SH3 domain binding kinase family member 2). Sbk2 encodes an evolutionarily conserved putative serine/threonine protein kinase, whose expression is strongly up- and downregulated during iAM-1 cell differentiation and dedifferentiation, respectively. In neonatal and adult rats, the protein is muscle-specific, highly atrium-enriched, and localized around the A-band of cardiac sarcomeres. Knockdown of Sbk2 expression caused loss of sarcomeric organization in NRAMs, iAMs and their human counterparts, consistent with a decrease in sarcomeric gene expression as evinced by transcriptome and proteome analyses. Interestingly, co-immunoprecipitation using Sbk2 as bait identified possible interaction partners with diverse cellular functions (translation, intracellular trafficking, cytoskeletal organization, chromatin modification, sarcomere formation). CONCLUSIONS: iAM-1 cells are a relevant and suitable model to identify (lowly expressed) genes with a hitherto unidentified role in cardiomyocyte differentiation as exemplified by Sbk2: a regulator of atrial sarcomerogenesis.

Crossover to Half-Dose Photodynamic Therapy or Eplerenone in Chronic Central Serous Chorioretinopathy Patients.

PURPOSE: To compare the efficacy and safety of crossover treatment to half-dose photodynamic therapy (PDT) and eplerenone treatment after the failure of primary treatment in patients with chronic central serous chorioretinopathy (cCSC). DESIGN: Multicenter crossover clinical trial. SUBJECTS: At 3 months after the baseline visit of the SPECTRA (Half-Dose Photodynamic Therapy Versus Eplerenone: Treatment Trial for Chronic Central Serous Chorioretinopathy) randomized controlled trial, either half-dose PDT or eplerenone treatment was evaluated for each patient, and patients who still demonstrated subretinal fluid (SRF) were included in the current study, the SPECS (Central Serous Chorioretinopathy Treated with Half-Dose PDT or Eplerenone Crossover Study) trial. METHODS: At the baseline visits for the current SPECS trial, crossover treatment was performed for patients who still demonstrated SRF. These patients received either half-dose PDT or oral eplerenone for 12 weeks. Both anatomic and functional parameters were evaluated 3 months after crossover treatment. MAIN OUTCOME MEASURES: Complete resolution of SRF on OCT. RESULTS: Forty-nine patients were included in the SPECS trial (38 received primary eplerenone treatment; 11 received half-dose PDT). At 3 months after crossover treatment, 32 of 37 (86.5%) in the crossover to half-dose PDT group and 2 of 9 (22.2%) in the crossover to eplerenone group had complete SRF resolution (P = 0.030). The mean foveal sensitivity increased significantly more in the crossover to half-dose PDT group (mean, +3.08 dB) compared with the crossover to eplerenone group (mean, -0.27 dB; P = 0.009). CONCLUSIONS: Patients with cCSC with the persistence of SRF after primary eplerenone treatment can benefit from half-dose PDT, which can induce a relatively fast and complete SRF resolution, along with an improvement in foveal sensitivity.

Huntington Disease Gene Expression Signatures in Blood Compared to Brain of YAC128 Mice as Candidates for Monitoring of Pathology.

While the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood representing signatures in human brain, showing biomarker potential. Since drug candidates are generally first screened in rodent models, we aimed to identify HD signatures in blood and brain of YAC128 HD mice and compare these with previously identified human signatures. RNA sequencing was performed on blood withdrawn at two time points and four brain regions from YAC128 and control mice. Weighted gene co-expression network analysis was used to identify clusters of co-expressed genes (modules) associated with the HD genotype. These HD-associated modules were annotated via text-mining to determine the biological processes they represented. Subsequently, the processes from mouse blood were compared with mouse brain, showing substantial overlap, including protein modification, cell cycle, RNA splicing, nuclear transport, and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition, we identified HD blood-specific pathology, confirming previous findings for peripheral pathology in blood. Finally, we identified hub genes for HD-associated blood modules and proposed a strategy for gene selection for development of a disease progression monitoring panel.

EFFICACY OF HALF-DOSE PHOTODYNAMIC THERAPY VERSUS HIGH-DENSITY SUBTHRESHOLD MICROPULSE LASER FOR TREATING PIGMENT EPITHELIAL DETACHMENTS IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: Comparing the effect of half-dose photodynamic therapy and high-density subthreshold micropulse laser treatment on retinal pigment epithelial detachments (PEDs) in chronic central serous chorioretinopathy. METHODS: This study included data from the PLACE trial, a prospective randomized controlled trial comparing half-dose photodynamic therapy and high-density subthreshold micropulse laser treatment in chronic central serous chorioretinopathy. Main outcome measurements were changes in both the foveal PED and the highest PED within the macula at baseline compared with first and final evaluation visit. RESULTS: At baseline, a macular PED was detected in 76.9% of patients (123/160), and a PED within 1,500 µm from the foveal center in 37.5% of patients (60/160). In the half-dose photodynamic therapy arm (61 patients), there was a significantly larger decrease in the highest macular PED compared with the high-density subthreshold micropulse laser treatment arm (62 patients) at both first and final evaluation visits (P < 0.001 and P = 0.012, respectively). The decrease of highest foveal PED was significant at first visit (P = 0.025). CONCLUSION: Half-dose photodynamic therapy is superior to high-density subthreshold micropulse laser treatment with regard to a statistically significant reduction in the height of macular PEDs in active chronic central serous chorioretinopathy. These findings may also have implications for other diseases within the pachychoroid disease spectrum that can present with PEDs.

Long Bone Fractures in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence, Natural History, and Risk Factors.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder arising along a broad spectrum. Long-bone fractures are a common, painful, and potentially disabling complication. However, fracture prevalence and risk factors have not been well-established, making it difficult to predict which patients are at risk for a severe course. Clinical and imaging data were reviewed from two large, well-phenotyped cohorts (National Institutes of Health [NIH] in the United States and the Leiden University Medical Center [LUMC] in the Netherlands) to identify long-bone fractures at FD sites. Skeletal burden score was quantified using bone scintigraphy. Multiple linear regressions were performed to identify clinical associations with fractures. A total of 419 patients were included (186 NIH, 233 LUMC); 194 (46%) had MAS endocrinopathies. Median age at last follow-up was 30.2 years (range 3.2-84.6, interquartile range [IQR] 25.5), and median skeletal burden score was 16.6 (range 0-75, IQR 33). A total of 48 (59%) patients suffered one or more lifetime fracture (median 1, range 0-70, IQR 4). Median age at first fracture was 8 years (range 1-76, IQR 10). Fracture rates peaked between 6 and 10 years of age and decreased thereafter. Lifetime fracture rate was associated with skeletal burden score (ß = 0.40, p < 0.01) and MAS hyperthyroidism (ß = 0.22, p = 0.01). Younger age at first fracture was associated with skeletal burden score (ß = -0.26, p = 0.01) and male sex (ß = -0.23, p = 0.01). Both skeletal burden score >25 and age at first fracture ≤7 years were associated with a higher total number of lifetime fractures (median 4, range 1-70, IQR 5 versus median 1, range 1-13, IQR 1) (p < 0.01). In conclusion, higher skeletal burden score and MAS hyperthyroidism are associated with long-bone fractures in FD/MAS. Both skeletal burden score ≥25 and age at first fracture ≤7 years are associated with a higher lifetime long-bone fracture risk and may predict a more severe clinical course. These results may allow clinicians to identify FD/MAS patients at risk for severe disease who may be candidates for early therapeutic interventions. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Half-Dose Photodynamic Therapy Versus Eplerenone in Chronic Central Serous Chorioretinopathy (SPECTRA): A Randomized Controlled Trial.

PURPOSE: To compare the efficacy and safety between half-dose photodynamic therapy (PDT) and eplerenone therapy for treating chronic central serous chorioretinopathy (cCSC). DESIGN: This was a multicenter, open-label, randomized controlled trial. METHODS: This investigator-initiated trial was conducted in 3 academic medical centers in the Netherlands. Eligible patients were randomized at a 1:1 ratio to receive either indocyanine green angiography-guided half-dose PDT or oral eplerenone for 12 weeks. Both anatomical and functional outcomes were evaluated at 3 months after the start of treatment. RESULTS: A total of 107 patients were randomly assigned to receive either half-dose PDT (n = 53) or eplerenone treatment (n = 54). Thirteen patients (3 in the PDT group and 10 in the eplerenone group) did not adhere to the study protocol. At the 3-month evaluation visit, 78% of patients in the PDT group had complete resolution of subretinal fluid accumulation compared to only 17% of patients in the eplerenone group (P < .001). Mean best-corrected visual acuity in Early Treatment of Diabetic Retinopathy Study letters at the 3-month evaluation visit was 83.7 ± 10.8 and 82.8 ± 9.0 in the PDT and eplerenone groups, respectively (P = .555). In addition, mean retinal sensitivity on microperimetry was 25.4 ± 3.4 dB and 23.9 ± 4.0 dB in the PDT and eplerenone groups, respectively (P = .041). Finally, mean vision-related quality of life scores were 87.2 ± 8.5 and 83.8 ± 12.1 in the PDT and eplerenone groups, respectively (P = .094). Three patients (6%) in the PDT group experienced adverse events during the study compared to 18 patients (33%) in the eplerenone group. CONCLUSIONS: Half-dose PDT is superior to oral eplerenone for cCSC with respect to both short-term safety and efficacy outcomes.

Joint Modeling of Longitudinal Markers and Time-to-Event Outcomes: An Application and Tutorial in Patients After Surgical Repair of Transposition of the Great Arteries.

BACKGROUND: Most patients with congenital heart disease survive into adulthood; however, residual abnormalities remain and management of the patients is life-long and personalized. Patients with surgical repair of transposition of the great arteries, for example, face the risk to develop neoaortic valve regurgitation. Cardiologists update the prognosis of the patient intuitively with updated information of the cardiovascular status of the patient, for instance from echocardiographic imaging. METHODS: Usually a time-dependent version of the Cox model is used to analyze repeated measurements with a time-to-event outcome. New statistical methods have been developed with multiple advantages, of which the most prominent one being the joint model for longitudinal and time-to-event outcome. In this tutorial, the joint modeling framework is introduced and applied to patients with transposition of the great arteries after surgery with a long-term follow-up, where repeated echocardiographic values of the neoaortic root are evaluated against the risk of neoaortic valve regurgitation. RESULTS: The data are analyzed with the time-dependent Cox model as benchmark method, and the results are compared with a joint model, leading to different conclusions. The flexibility of the joint model is shown by adding the growth rate of the neoaortic root to the model and adding repeated values of body surface area to obtain a multimarker model. Lastly, it is demonstrated how the joint model can be used to obtain personalized dynamic predictions of the event. CONCLUSIONS: The joint model for longitudinal and time-to-event data is an attractive method to analyze data in follow-up studies with repeated measurements. Benefits of the method include using the estimated natural trajectory of the longitudinal outcome, great flexibility through multiple extensions, and dynamic individualized predictions.

RESPONSE OF CHOROIDAL ABNORMALITIES TO PHOTODYNAMIC THERAPY VERSUS MICROPULSE LASER IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY: Place Trial Report No. 4.

PURPOSE: To compare the effects of half-dose photodynamic therapy (PDT) and high-density subthreshold micropulse laser on choroidal dysfunction evaluated by degree and extent of hyperfluorescence on indocyanine green angiography (ICGA) in chronic central serous chorioretinopathy. METHODS: Data from the multicenter, randomized, controlled PLACE trial were used in this study. Hyperfluorescent and hypofluorescent areas on ICGA, their association with subretinal fluid and visual function were assessed. RESULTS: In total, 146 patients were included (72 in the PDT and 74 in the high-density subthreshold micropulse laser treatment arm). A significantly greater decrease in the size of hyperfluorescent areas on ICGA at first visit after treatment was seen after PDT compared with high-density subthreshold micropulse laser (mean, -1.41 ± 2.40 mm2 vs. -0.04 ± 0.73 mm2, respectively; P < 0.001). A reduction in the degree of hyperfluorescence on ICGA decreased the odds of having persistent subretinal fluid on optical coherence tomography at first visit after treatment (B = 0.295; P = 0.019). There were no significant differences in best-corrected visual acuity and retinal sensitivity between the subgroup with novel hypofluorescence (n = 20, 28%) on ICGA at first visit post PDT, compared with the subgroup without novel hypofluorescence on ICGA after PDT. CONCLUSION: Choroidal abnormalities in chronic central serous chorioretinopathy can be effectively treated by ICGA-guided half-dose PDT but not with high-density subthreshold micropulse laser application.

Penalized regression calibration: A method for the prediction of survival outcomes using complex longitudinal and high-dimensional data.

Longitudinal and high-dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high-dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject-specific summaries of the longitudinal trajectories are derived from the fitted mixed models. Third, the time to event outcome is predicted using the subject-specific summaries as covariates in a penalized Cox model. To ensure a proper internal validation of the fitted PRC models, we furthermore develop a cluster bootstrap optimism correction procedure that allows to correct for the optimistic bias of apparent measures of predictiveness. PRC and the CBOCP are implemented in the R package pencal, available from CRAN. After studying the behavior of PRC via simulations, we conclude by illustrating an application of PRC to data from an observational study that involved patients affected by Duchenne muscular dystrophy, where the goal is predict time to loss of ambulation using longitudinal blood biomarkers.

Long-term effect of α1-antitrypsin augmentation therapy on the decline of FEV1 in deficient patients: an analysis of the AIR database.

BACKGROUND: Patients with ZZ (Glu342Lys) α-1-antitrypsin deficiency (ZZ-AATD) who received augmentation therapy with α-1-antitrypsin (AAT) in randomised controlled trials over 2-3 years failed to show a significant reduction of the annual decline of forced expiratory volume in 1 s (FEV1). METHODS: To compare the trajectory of FEV1 change during 4 or more years in ZZ-AATD patients with emphysema receiving or not receiving intravenous augmentation therapy, a retrospective analysis of FEV1 values entered in the Alpha-1 International Registry (AIR) of ZZ-AATD patients from five different European countries (Germany, UK, Spain, Italy and the Netherlands) was performed. The post-bronchodilator FEV1 % predicted values for baseline and follow-up over time from patients were analysed using linear mixed effects models. RESULTS: Data of 374 patients were analysed: 246 untreated and 128 treated with intravenous AAT augmentation therapy. The mean±sd follow-up duration of the untreated group was 8.60±3.34 years and 8.59±2.62 years for the treated group. The mixed effects model analysis showed a mean FEV1 decline of -0.931% predicted per year (95% CI -1.144 to -0.718) in the untreated group and a decline of -1.016% predicted per year (95% CI -1.319 to -0.7145) in the treated group. The likelihood ratio test showed no difference between the two groups (p=0.71). CONCLUSION: In our study population, we could not detect a significant difference in the annual decline of FEV1 by AAT augmentation treatment over a mean period of 8.6 years. Other approaches are needed to validate any benefit of augmentation therapy.