Lamina Cribrosa Microstructure in Nonhuman Primates With Naturally Occurring Peripapillary Retinal Nerve Fiber Layer Thinning.

Purpose: The lamina cribrosa (LC) is hypothesized to be the site of initial axonal damage in glaucoma with the circumpapillary retinal nerve fiber layer thickness (RNFL-T) widely used as a standard metric for quantifying the glaucomatous damage. The purpose of this study was to determine in vivo, 3-dimensional (3D) differences in the microstructure of the LC in eyes of nonhuman primates (NHPs) with naturally occurring glaucoma. Methods: Spectral-domain optical coherence tomography (OCT) scans (Leica, Chicago, IL, USA) of the optic nerve head were acquired from a colony of 50 adult rhesus monkeys suspected of having high prevalence of glaucoma. The RNFL-T was analyzed globally and in quadrants using a semi-automated segmentation software. From a set of 100 eyes, 18 eyes with the thinnest global RNFL-T were selected as the study group and 18 eyes with RNFL-T values around the 50th percentile were used as controls. A previously described automated segmentation algorithm was used for LC microstructure analysis. Parameters included beam thickness, pore diameter and their ratio (beam-to-pore ratio [BPR]), pore area and shape parameters, beam and pore volume, and connective tissue volume fraction (CTVF; beam volume/total volume). The LC microstructure was analyzed globally and in the following volumetric sectors: quadrants, central and peripheral lamina, and three depth slabs (anterior, middle, and posterior). Results: Although no significant difference was detected between groups for age, weight, or disc size, the study group had significantly thinner RNFL than the control group (P < 0.01). The study group had significantly smaller global and sectoral pore diameter and larger BPR compared with the control group. Across eyes, the global RNFL-T was associated positively with pore diameter globally. BPR and CTVF were significantly and negatively associated with the corresponding RNFL-T in the superior quadrant. Conclusions: Global and sectoral microstructural differences were detected when comparing thin and normal RNFL-T eyes. Whether these LC differences are the cause of RNFL damage or the result of remodeling of the LC requires further investigation. Translational Relevance: Our findings indicate structural alterations in the LC of NHP exhibiting natural thinning of the RNFL, a common characteristic of glaucomatous damage.

An integrated strain-level analytic pipeline utilizing longitudinal metagenomic data.

With the development of sequencing technology and analytic tools, studying within-species variations enhances the understanding of microbial biological processes. Nevertheless, most existing methods designed for strain-level analysis lack the capability to concurrently assess both strain proportions and genome-wide single nucleotide variants (SNVs) across longitudinal metagenomic samples. In this study, we introduce LongStrain, an integrated pipeline for the analysis of large-scale metagenomic data from individuals with longitudinal or repeated samples. In LongStrain, we first utilize two efficient tools, Kraken2 and Bowtie2, for the taxonomic classification and alignment of sequencing reads, respectively. Subsequently, we propose to jointly model strain proportions and shared haplotypes across samples within individuals. This approach specifically targets tracking a primary strain and a secondary strain for each subject, providing their respective proportions and SNVs as output. With extensive simulation studies of a microbial community and single species, our results demonstrate that LongStrain is superior to two genotyping methods and two deconvolution methods across a majority of scenarios. Furthermore, we illustrate the potential applications of LongStrain in the real data analysis of The Environmental Determinants of Diabetes in the Young study and a gastric intestinal metaplasia microbiome study. In summary, the proposed analytic pipeline demonstrates marked statistical efficiency over the same type of methods and has great potential in understanding the genomic variants and dynamic changes at strain level. LongStrain and its tutorial are freely available online at https://github.com/BoyanZhou/LongStrain. IMPORTANCE: The advancement in DNA-sequencing technology has enabled the high-resolution identification of microorganisms in microbial communities. Since different microbial strains within species may contain extreme phenotypic variability (e.g., nutrition metabolism, antibiotic resistance, and pathogen virulence), investigating within-species variations holds great scientific promise in understanding the underlying mechanism of microbial biological processes. To fully utilize the shared genomic variants across longitudinal metagenomics samples collected in microbiome studies, we develop an integrated analytic pipeline (LongStrain) for longitudinal metagenomics data. It concurrently leverages the information on proportions of mapped reads for individual strains and genome-wide SNVs to enhance the efficiency and accuracy of strain identification. Our method helps to understand strains' dynamic changes and their association with genome-wide variants. Given the fast-growing longitudinal studies of microbial communities, LongStrain which streamlines analyses of large-scale raw sequencing data should be of great value in microbiome research communities.

Efficacy of topical treatments for mild-to-moderate acne: A systematic review and meta-analysis of randomized control trials.

Acne is a common skin condition, but little data exist on the comparative efficacy of topical acne therapies. We conducted a systematic review and network meta-analysis to evaluate the efficacy of topical therapies for mild-to-moderate acne. Searches in PubMed/MEDLINE, Cochrane CENTRAL via Ovid, Embase via Ovid and Web of Science were conducted on 29 November 2021. Randomized controlled trials examining ≥12 weeks of topical treatments for acne vulgaris in subjects aged 12 and older were included. Main outcomes were absolute or percent change in acne lesion count and treatment success on the Investigator's Global Assessment scale. Thirty-five randomized clinical trials with 33,472 participants comparing nine different topical agents were included. Adapalene-benzoyl peroxide (BPO), clindamycin-BPO and clindamycin-tretinoin demonstrated the greatest reduction in non-inflammatory (ratio of means [RoM] 1.76; 95% CI [1.46; 2.12], RoM 1.70; 95% CI [1.44; 2.02] and RoM 1.87; 95% CI [1.53; 2.30], respectively), inflammatory (RoM 1.56; 95% CI [1.44; 1.70], RoM 1.49; 95% CI [1.39; 1.60] and RoM 1.48; 95% CI [1.36; 1.61], respectively) and total lesion count (ROM 1.67; 95% CI [1.47; 1.90], RoM 1.59; 95% CI [1.42; 1.79] and RoM 1.64; 95% CI [1.42; 1.89], respectively) compared to placebo. All single agents outperformed placebo except tazarotene, which did not significantly outperform placebo for inflammatory and non-inflammatory lesion count reduction. Most combination agents significantly outperformed their individual components in lesion count reduction and global assessment scores, except for clindamycin-tretinoin and clindamycin-BPO, which did not significantly outperform tretinoin (RoM 1.13; 95% CI [0.94; 1.36]) and BPO (RoM = 1.15, 95% CI [0.98; 1.36]), respectively, for non-inflammatory lesion reduction. There was no significant difference amongst most single agents when evaluating lesion count reduction. Combination agents are generally most effective for mild-to-moderate acne; however for non-inflammatory acne, the addition of clindamycin in topical regimens is unnecessary and should be avoided.

Disparities in Visual Field Testing Frequency Among Subjects With Glaucoma.

Purpose: Prior evidence suggests racial disparities in the utilization of visual field testing (VFT) for the diagnosis and monitoring of glaucoma. In this study, we considered the effect of baseline glaucoma severity and socioeconomic disadvantage along with other potential confounders such as test reliability, ancillary tests, and glaucoma surgeries on racial disparity in the frequency of VFT. Methods: The records of all subjects with a diagnosis of glaucoma who received VFT at an academic, tertiary care facility from January 2018 to December 2021 were accessed. Analysis was performed to compare VFT frequency, the total number of office visits (DoS), and the ratio of VFT frequency to DoS (VFT/DoS) across self-reported races while controlling for sex, age, socioeconomic disadvantage (Area Deprivation Index), VF reliability indicators and baseline mean deviation, optical coherence tomography frequency, and glaucoma surgeries. Results: Among the 2654 subjects (1515 White, 782 Black, and 357 Asian) included in this study, Black subjects had the worst socioeconomic status and disease severity at baseline. They also experienced a 3% lower VFT/DoS ratio compared to White subjects (P = 0.031). Asian subjects had a 5% lower VFT/DoS ratio compared to White subjects (P = 0.015). Discussion: We identified racial disparity in performing VFT in subjects with glaucoma even when multiple confounders were considered. Further investigation is necessary to identify other race-associated factors to work toward reducing racial disparities in VFT. Translational Relevance: Black and Asian subjects with glaucoma receive fewer VFT per visit compared to White subjects even when considering socioeconomic disadvantage and disease severity.

Investigating the Utility of Near-Infrared Reflectance Imaging for Diabetic Retinopathy Screening.

BACKGROUND AND OBJECTIVE: We investigated the reliability of near-infrared reflectance (NIR) imaging as a method of assessing severity of diabetic retinopathy (DR). PATIENTS AND METHODS: One hundred ninety-five NIR images were reviewed by two graders for the number of hyporeflective foci, presence or absence of vascular abnormalities, and presumptive DR stage; these were correlated to fundus photography-defined DR stage. Interrater reliability was confirmed via one-way random effects model of intraclass correlation coefficients. Analysis of variance was used in subgroup analysis, receiver operating characteristic (ROC) curves were created to validate reliability of the model, and logistic regression was used to model foci and vascular abnormalities as predictors for moderate or worse disease. RESULTS: A statistically significant difference in mean number of hyporeflective foci was found between no DR and moderate non-proliferative DR (NPDR; P < 0.0001), no DR and severe NPDR (P < 0.001), no DR and proliferative DR (PDR; P < 0.0001), mild and moderate NPDR (P = 0.008), mild and severe NPDR (P < 0.001), and mild NPDR and PDR (P < 0.001). The area under the ROC curve was 0.849 (CI: 0.792 to 0.905). The threshold for detection of moderate NPDR or worse was 4.75 foci, with a sensitivity of 79.0% and a false positive rate of 20.0%. Multivariate logistic regression model incorporating hyporeflective foci with vascular abnormalities (odds ratio [OR] = 1.592, 95% CI: 1.381 to 1.835; P < 0.001) was able to accurately predict moderate disease or worse, just moderate disease (OR = 1.045, 95% CI: 1.003 to 1.089; P = 0.035), severe disease (OR = 1.050, 95% CI: 1.006 to 1.096; P = 0.027), and proliferative disease (OR = 1.050, 95% CI: 1.008 to 1.095; P = 0.018). CONCLUSIONS: NIR imaging may be an adjunct tool in screening for DR. [Ophthalmic Surg Lasers Imaging Retina 2024;55:318-325.].

Nanoarchitectonics of Bimetallic Cu-/Co-Doped Nitrogen-Carbon Nanozyme-Functionalized Hydrogel with NIR-Responsive Phototherapy for Synergistic Mitigation of Drug-Resistant Bacterial Infections.

Superbug infections and transmission have become major challenges in the contemporary medical field. The development of novel antibacterial strategies to efficiently treat bacterial infections and conquer the problem of antimicrobial resistance (AMR) is extremely important. In this paper, a bimetallic CuCo-doped nitrogen-carbon nanozyme-functionalized hydrogel (CuCo/NC-HG) has been successfully constructed. It exhibits photoresponsive-enhanced enzymatic effects under near-infrared (NIR) irradiation (808 nm) with strong peroxidase (POD)-like and oxidase (OXD)-like activities. Upon NIR irradiation, CuCo/NC-HG possesses photodynamic activity for producing singlet oxygen(1O2), and it also has a high photothermal conversion effect, which not only facilitates the elimination of bacteria but also improves the efficiency of reactive oxygen species (ROS) production and accelerates the consumption of GSH. CuCo/NC-HG shows a lower hemolytic rate and better cytocompatibility than CuCo/NC and possesses a positive charge and macroporous skeleton for restricting negatively charged bacteria in the range of ROS destruction, strengthening the antibacterial efficiency. Comparatively, CuCo/NC and CuCo/NC-HG have stronger bactericidal ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AmprE. coli) through destroying the cell membranes with a negligible occurrence of AMR. More importantly, CuCo/NC-HG plus NIR irradiation can exhibit satisfactory bactericidal performance in the absence of H2O2, avoiding the toxicity from high-concentration H2O2. In vivo evaluation has been conducted using a mouse wound infection model and histological analyses, and the results show that CuCo/NC-HG upon NIR irradiation can efficiently suppress bacterial infections and promote wound healing, without causing inflammation and tissue adhesions.

Peripapillary Atrophy Area as an Indicator of Glaucomatous Structural and Functional Progression.

Purpose: To determine whether peripapillary atrophy (PPA) area is an indicator of glaucomatous structural and functional damage and progression. Methods: In this retrospective longitudinal analysis from ongoing prospective study we qualified 71 eyes (50 subjects) with glaucoma. All subjects had a comprehensive ophthalmic examination, visual field (VF), and spectral-domain optical coherence tomography (OCT) testing in at least three visits. PPA was manually delineated on en face OCT optic nerve head scans, while observing the corresponding cross-sectional images, as the hyper-reflective area contiguous with the optic disc. Results: The mean follow-up duration was 4.4 ± 1.4 years with an average of 6.8 ± 2.2 visits. At baseline, PPA area was significantly associated only with VF's mean deviation (MD; P = 0.041), visual field index (VFI; P = 0.041), superior ganglion cell inner plexiform layer (GCIPL; P = 0.011), and disc area (P = 0.011). Longitudinally, PPA area was negatively and significantly associated with MD (P = 0.015), VFI (P = 0.035), GCIPL (P = 0.009), superior GCIPL (P = 0.034), and disc area (P = 0.007, positive association). Conclusions: Longitudinal change in PPA area is an indicator of glaucomatous structural and functional progression but PPA area at baseline cannot predict future progression. Translational Relevance: Longitudinal changes in peripapillary atrophy area measured by OCT can be an indicator of structural and functional glaucoma progression.

LIMBARE: An Advanced Linear Mixed-Effects Breakpoint Analysis With Robust Estimation Method With Applications to Longitudinal Ophthalmic Studies.

Purpose: Broken stick analysis is a widely used approach for detecting unknown breakpoints where the association between measurements is nonlinear. We propose LIMBARE, an advanced linear mixed-effects breakpoint analysis with robust estimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and over time, and it effectively addresses the presence of outliers. Methods: The model setup of LIMBARE and the computing algorithm for point and confidence interval estimates of the breakpoint were introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7 ± 1.3 years to examine the longitudinal association between structural and functional measurements. Results: In simulation studies, LIMBARE showed the smallest bias and mean squared error for estimating the breakpoint, with an empirical coverage probability of corresponding confidence interval estimates closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness and one breakpoint between MD and cup-to-disc ratio, whereas the cross-sectional analysis approach detected only one and none, respectively. Conclusions: LIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, and the cross-sectional analysis approach is not recommended for future studies. Translational Relevance: Our proposed method and companion R package provide a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships among ophthalmic variables.

Reducing Ophthalmic Health Disparities Through Transfer Learning: A Novel Application to Overcome Data Inequality.

Purpose: Race disparities in the healthcare system and the resulting inequality in clinical data among different races hinder the ability to generate equitable prediction results. This study aims to reduce healthcare disparities arising from data imbalance by leveraging advanced transfer learning (TL) methods. Method: We examined the ophthalmic healthcare disparities at a population level using electronic medical records data from a study cohort (N = 785) receiving care at an academic institute. Regression-based TL models were usesd, transferring valuable information from the dominant racial group (White) to improve visual field mean deviation (MD) rate of change prediction particularly for data-disadvantaged African American (AA) and Asian racial groups. Prediction results of TL models were compared with two conventional approaches. Results: Disparities in socioeconomic status and baseline disease severity were observed among the AA and Asian racial groups. The TL approach achieved marked to comparable improvement in prediction accuracy compared to the two conventional approaches as evident by smaller mean absolute errors or mean square errors. TL identified distinct key features of visual field MD rate of change for each racial group. Conclusions: The study introduces a novel application of TL that improved reliability of the analysis in comparison with conventional methods, especially in small sample size groups. This can improve assessment of healthcare disparity and subsequent remedy approach. Translational Relevance: TL offers an equitable and efficient approach to mitigate healthcare disparities analysis by enhancing prediction performance for data-disadvantaged group.

Microplastic pollution in the groundwater under a bedrock island in the South China sea.

Groundwater is the only freshwater resource on islands. Research on microplastic pollution in groundwater on islands is scarce. This study is the first to explore microplastic pollution in the groundwater under a bedrock island (Dawanshan Island) located in the South China Sea. The influence of hydrogeological factors on the distribution, source, and ageing features of microplastics in the groundwater were investigated. Despite the small scale of industrial and agricultural activities on the island, the amount of microplastics in the groundwater ranged from 34 to 64 particles/L, with over 80% of the microplastics being polyester fibres with diameters smaller than 2 mm, which is comparable to those in coastal cities. These microplastics were originated from inland plastic usage, rather than from the surrounding sea, which was confirmed by the lack of seawater intrusion on the island. Owing to the low permeability of granite, microplastics were mainly distributed in the water of the loose layer of porous sediment, and their quantity decreased with depth. In addition, the abundance of microplastics in pore groundwater increased with an increase in the velocity of groundwater flow. The severity of microplastic pollution in the groundwater increased with an increase and decrease in the content of total dissolved solids and dissolved oxygen, respectively. The microplastics originated from plastic waste disposed of on the island, rather than from seawater intrusion. Also, through groundwater infiltration into exposed soil at recharge areas, artificial wells at residential areas, and water exchange with surface water at valley areas. Microplastics buried in the groundwater aged faster along the migration path of the groundwater. These microplastics threaten the safety of people and plants on the island through exposure resulting from the extraction of groundwater for irrigation, while they endanger marine life through submarine groundwater discharge.

In vitro and in vivo assessment of a bilayered degradable rapamycin-eluting stent for ureteral stricture caused by holmium: YAG laser lithotripsy.

Ureteral stricture caused by holmium: YAG laser lithotripsy is one of the most challenging issues for urologists. Currently, evidence for rapamycin application in reducing ureterostenosis is not sufficient. This study aimed to assess the inhibition of ureteral stricture of rapamycin-eluting stents in vitro and in vivo. A bilayered drug-eluting ureteral stent consisted of drug blending with poly (lactic-co-glycolic acid) (PU/drug stent), which was over-layered by polycaprolactone (PCL) by ultrasonic atomizing spraying. Stent morphology was observed by scanning electron microscope. A kidney-ureter-bladder model was established to simulate the stents-releasing condition, and high-performance liquid chromatography was used to measure the drug release rate. The inhibitory proliferation was detected by CCK-8. The bladder of rats was injured through electro tome, and stents were implanted for 7, 14, and 28 days. The effects of drug-eluting stents was investigated by hematoxylin-eosin staining, immunofluorescence staining, real-time quantitative polymerase chain reaction and western blot. The bilayered stents could block the burst loss of the drug and maintained a sustained delivery period because of the 5.3 µm thickness of the PCL layer. The relative growth rates of cells plotted inhibitory effect on the proliferation of human urethral scar fibroblast cells. For in vivo results of 28 days, the bilayered stent maintained structural integrity and induced less deposition of crystals, thinner and less lamina propria connective tissues were formed, and α-SMA and TGF-ß1 were downregulated. Bilayered rapamycin-eluting stent is significantly effective in alleviating fibrosis in in vitro and in vivo models. STATEMENT OF SIGNIFICANCE: The occurrence of ureteral stricture resulting from holmium: YAG laser lithotripsy presents a significant challenge for urologists. Traditional double J stents have not been proven to offer a shorter indwelling time or improved inhibition of tissue blocking. While drug-eluting stents containing rapamycin, paclitaxel, and other substances have been extensively used in treating artery stenosis, there is insufficient evidence supporting their application in reducing ureterostenosis. Consequently, a biodegradable polymer ureteric scaffold incorporating rapamycin was fabricated in this study, employing ultrasonic atomization spraying technology to optimize the bilayers composed of 75/25 poly (lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL). The efficacy of the scaffold was subsequently confirmed through in vitro and in vivo experiments.

Microbiome data analysis via machine learning models: Exploring vital players to optimize kitchen waste composting system.

Composting, reliant on microorganisms, effectively treats kitchen waste. However, it is difficult to precisely understand the specific role of key microorganisms in the composting process by relying solely on experimental research. This study aims to employ machine learning models to explore key microbial genera and to optimize composting systems. After introducing a novel microbiome preprocessing approach, Stacking models were constructed (R2 is about 0.8). The SHAP method (SHapley Additive exPlanations) identified Bacillus, Acinetobacter, Thermobacillus, Pseudomonas, Psychrobacter, and Thermobifida as prominent microbial genera (Shapley values ranging from 3.84 to 1.24). Additionally, microbial agents were prepared to target the identified key genera, and experiments demonstrated that the composting quality score was 76.06 for the treatment and 70.96 for the control. The exogenous agents enhanced decomposition and improved compost quality in later stages. In summary, this study opens up a new avenue to identifying key microorganisms and optimizing the biological treatment process.

Rational use of drugs to alleviate adverse outcomes caused by COVID-19 quarantine in women with intrahepatic cholestasis of pregnancy.

Purpose: This study aimed to investigate the impacts of home quarantine on pregnancy outcomes of women with intrahepatic cholestasis of pregnancy (ICP) during the COVID-19 outbreak and whether the rational use of drugs will change these impacts. Methods: This multi-center study was conducted to compare the pregnancy outcomes in women with ICP between the home quarantine group and the non-home quarantine group in southwest China. Propensity score matching was performed to confirm the pregnancy outcomes of the medication group and the non-medication group in women with ICP during the epidemic period. Results: A total of 3,161 women with ICP were enrolled in this study, including 816 in the home quarantine group and 2,345 in the non-home quarantine group. Women with ICP in the home quarantine group had worse pregnancy outcomes, such as a growing risk of gestational diabetes mellitus A1, fetal growth restriction, pre-eclampsia, preterm delivery, and even stillbirth. Drug therapy could alleviate some adverse pregnancy outcomes caused by home quarantine, including pre-eclampsia, preterm delivery, and meconium-stained amniotic fluid. Conclusion: COVID-19 quarantine would increase the incidence of ICP and lead to adverse pregnancy outcomes in women with ICP. The rational use of drugs reduced some obstetrical complications and improved partial pregnancy outcomes. Our findings suggested that the government and hospitals should enhance their management and life guidance for women with ICP and speed up developing home quarantine guidelines.

Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.

Implementation fidelity to a behavioral diabetes prevention intervention in two New York City safety net primary care practices.

BACKGROUND: It is critical to assess implementation fidelity of evidence-based interventions and factors moderating fidelity, to understand the reasons for their success or failure. However, fidelity and fidelity moderators are seldom systematically reported. The study objective was to conduct a concurrent implementation fidelity evaluation and examine fidelity moderators of CHORD (Community Health Outreach to Reduce Diabetes), a pragmatic, cluster-randomized, controlled trial to test the impact of a Community Health Workers (CHW)-led health coaching intervention to prevent incident type 2 Diabetes Mellitus in New York (NY). METHODS: We applied the Conceptual Framework for Implementation Fidelity to assess implementation fidelity and factors moderating it across the four core intervention components: patient goal setting, education topic coaching, primary care (PC) visits, and referrals to address social determinants of health (SDH), using descriptive statistics and regression models. PC patients with prediabetes receiving care from safety-net patient-centered medical homes (PCMHs) at either, VA NY Harbor or at Bellevue Hospital (BH) were eligible to be randomized into the CHW-led CHORD intervention or usual care. Among 559 patients randomized and enrolled in the intervention group, 79.4% completed the intake survey and were included in the analytic sample for fidelity assessment. Fidelity was measured as coverage, content adherence and frequency of each core component, and the moderators assessed were implementation site and patient activation measure. RESULTS: Content adherence was high for three components with nearly 80.0% of patients setting ≥ 1 goal, having ≥ 1 PC visit and receiving ≥ 1 education session. Only 45.0% patients received ≥ 1 SDH referral. After adjusting for patient gender, language, race, ethnicity, and age, the implementation site moderated adherence to goal setting (77.4% BH vs. 87.7% VA), educational coaching (78.9% BH vs. 88.3% VA), number of successful CHW-patient encounters (6 BH vs 4 VA) and percent of patients receiving all four components (41.1% BH vs. 25.7% VA). CONCLUSIONS: The fidelity to the four CHORD intervention components differed between the two implementation sites, demonstrating the challenges in implementing complex evidence-based interventions in different settings. Our findings underscore the importance of measuring implementation fidelity in contextualizing the outcomes of randomized trials of complex multi-site behavioral interventions. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov on 30/12/2016 and the registration number is NCT03006666 .

Long amplicon HiFi sequencing for mitochondrial DNA genomes.

Long-read sequencing technology is a powerful approach with application in various genetic and genomic research. Herein, we developed the pipeline for long amplicon high-fidelity (HiFi) sequencing and then applied it for sequencing mitochondrial DNA (mtDNA) genomes from pools of 79 Tibetan Mastiffs. We amplified the mtDNA genome with long-range PCR using two pairs of primers. Two rounds of circular consensus sequencing (CCS) were conducted and their accuracy was evaluated. The results indicate that the second round of CCS can improve the accuracy of HiFi reads. In addition, the analysis of 79 high-quality mtDNA genomes shows the Tibetan Mastiffs from outside of the Tibetan Plateau experienced hybridization with other dogs. The high quality reads generator (HQGR) software is provided to facilitate data analyses, which is publicly accessible on GitHub (https://github.com/Caizf-script/HQGR). Our long amplicon HiFi sequencing pipeline can also be applied in various target enrichment strategies for small genomes and candidate genes.

LIMBARE: an Advanced Linear Mixed-effects Breakpoint Analysis with Robust Estimation Method with Applications to Longitudinal Ophthalmic Studies.

Purpose: Broken stick analysis is a widely used approach for detecting unknown breakpoints where association between measurements is non-linear. We propose LIMBARE, an advanced li near m ixed-effects b reakpoint a nalysis with r obust e stimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and overtime, and effectively address the presence of outliers. Methods: The model setup of LIMBARE and computing algorithm for point and confidence interval estimates of the breakpoint was introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7±1.3 years to examine the longitudinal association between structural and functional measurements. Results: In simulation studies, LIMBARE showed the smallest bias and mean squared error (MSE) for estimating the breakpoint, with empirical coverage probability of corresponding CI estimate closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness (RNFL) and one breakpoint between MD and cup to disc ratio (CDR), while the cross-sectional analysis approach only detected one and none, respectively. Conclusions: LIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, while cross-sectional analysis approach is not recommended for future studies. Translational Relevance: Our proposed method and companion software R package provides a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships between ophthalmic variables.

Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo controlled multicentre trial.

INTRODUCTION: Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS: The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION: Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER: NCT05004727.