Decision Impact Analysis to Measure the Influence of Molecular Signature Response Classifier Testing on Treatment Selection in Rheumatoid Arthritis.

INTRODUCTION: Clinical guidelines offer little guidance for treatment selection following inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) was validated to predict tumor necrosis factor inhibitor (TNFi) inadequate response. The decision impact of MSRC results on biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) selection was evaluated. METHODS: This is an analysis of AIMS, a longitudinal, prospective database of patients with RA tested using the MSRC. This study assessed selection of b/tsDMARDs class after MSRC testing by surveying physicians, the rate of b/tsDMARD prescriptions aligning with MSRC results, and the percentage of physicians utilizing MSRC results for decision-making. RESULTS: Of 1018 participants, 70.7% (720/1018) had treatment selected after receiving MSRC results. In this MSRC-informed cohort, 75.6% (544/720) of patients received a b/tsDMARD aligned with MSRC results, and 84.6% (609/720) of providers reported using MSRC results to guide treatment selection. The most prevalent reason reported (8.2%, 59/720) for not aligning treatment selection with MSRC results from the total cohort was health insurance coverage issues. CONCLUSION: This study showed that rheumatologists reported using the MSRC test to guide b/tsDMARD selection for patients with RA. In most cases, MSRC test results appeared to influence clinical decision-making according to physician self-report. Wider adoption of precision medicine tools like the MSRC could support rheumatologists and patients in working together to achieve optimal outcomes for RA.

Baveno VII criteria identify varices needing treatment in patients with hepatocellular carcinoma of different Barcelona Clinic Liver Cancer stages.

BACKGROUND: Baveno VII criteria for predicting varices needing treatment (VNT) have not been tested in hepatocellular carcinoma (HCC) population. We evaluated Baveno VII consensus for VNT in HCC patients of different stages according to Barcelona Clinic Liver Cancer (BCLC) stages undergoing curative hepatectomy. METHODS: This was a prospective cohort study of patients with HCC. Patients underwent transient elastography examination before HCC treatment and received at least one upper endoscopic examination afterwards. Patients were prospectively followed for clinical events including VNT. RESULTS: Six hundred and seventy-three patients (83.1% male, median age 62 years) with HCC of BCLC stage 0 (10%), A (57%), B (17%) and C (15%) were recruited and followed for 47 months. The median (range) LSM was 10.5 (6.9-20.4) kPa; 74% had LSM ≤ 20 kPa and 58% had platelet count ≥150 × 10/L, respectively. VNT occurred in 51 (7.6%) patients. In patients who fulfilled Baveno VII criteria, that is, LSM ≤ 20 kPa and platelet count above 150 × 10/L, only 11 (1.6%) patients had VNT. In all BCLC stages of HCC, the proportion of patients with VNT was below 5%, which support the validity and applicability of Baveno VII criteria in all BCLC stages of HCC. CONCLUSIONS: The Baveno VII criteria are valid and applicable in HCC patients undergoing curative hepatectomy for selecting patients to undergo screening endoscopy for VNT. The validity was consistent across different BCLC stages of HCC.

Patient outcomes improve when a molecular signature test guides treatment decision-making in rheumatoid arthritis.

BACKGROUND: The molecular signature response classifier (MSRC) predicts tumor necrosis factor-ɑ inhibitor (TNFi) non-response in rheumatoid arthritis. This study evaluates decision-making, validity, and utility of MSRC testing. METHODS: This comparative cohort study compared an MSRC-tested arm (N = 627) from the Study to Accelerate Information of Molecular Signatures (AIMS) with an external control arm (N = 2721) from US electronic health records. Propensity score matching was applied to balance baseline characteristics. Patients initiated a biologic/targeted synthetic disease-modifying antirheumatic drug, or continued TNFi therapy. Odds ratios (ORs) for six-month response were calculated based on clinical disease activity index (CDAI) scores for low disease activity/remission (CDAI-LDA/REM), remission (CDAI-REM), and minimally important differences (CDAI-MID) . RESULTS: In MSRC-tested patients, 59% had a non-response signature and 70% received MSRC-aligned therapy . In TNFi-treated patients, the MSRC had an 88% PPV and 54% sensitivity. MSRC-guided patients were significantly (p < 0.0001) more likely to respond to b/tsDMARDs than those treated according to standard care (CDAI-LDA/REM: 36.0% vs 21.9%, OR 2.01[1.55-2.60]; CDAI-REM: 10.4% vs 3.6%, OR 3.14 [1.94-5.08]; CDAI-MID: 49.5% vs 32.8%, OR 2.01[1.58-2.55]). CONCLUSION: MSRC clinical validity supports high clinical utility: guided treatment selection resulted in significantly superior outcomes relative to standard care; nearly three times more patients reached CDAI remission.

Clinicians can offer rheumatoid arthritis patients many types of therapies but the response rate for each of these drugs is low. For example, within the first year of treatment, just about one-half of patients respond to the first-line drug, csDMARD. Only one-third of methotrexate-unresponsive patients will respond to the most common second-line agent, a tumor necrosis factor-α inhibitor. These low response rates present a critical challenge to treating patients. Clinicians try different cs- and b/tsDMARD and fail to quickly identify the most effective options. Then, disease will progress, irreversibly destroying patient joints, diminishing patient health-related quality of life, and increasing risks of cardiovascular disease, cancer, and death. To help clinicians quickly identify the best drugs for patients in a treat-to-target approach, a precision-medicine test was developed to identify patients unlikely to respond to tumor necrosis factor-α inhibitors. This molecular signature response classifier considers both molecular features (patient RNA-expression levels) and clinical features (e.g. body mass index, sex) to predict patient response. To evaluate the effectiveness of this test, the outcomes of patients treated with classifier-selected drugs (in a large, tested cohort) were compared with outcomes of patients treated with conventionally selected therapies (in an external cohort of electronic-health-record data). Patients treated with classifier-selected therapies were approximately three times as likely to achieve remission than were patients treated with conventionally selected drugs. These results suggest that this molecular signature response classifier is a valuable tool for more quickly identifying optimal therapies to treat rheumatoid arthritis.

Optimization of magnetic bead-based nucleic acid extraction for SARS-CoV-2 testing using readily available reagents.

The COVID-19 pandemic has highlighted the need for generic reagents and flexible systems in diagnostic testing. Magnetic bead-based nucleic acid extraction protocols using 96-well plates on open liquid handlers are readily amenable to meet this need. Here, one such approach is rigorously optimized to minimize cross-well contamination while maintaining sensitivity.

State-Level Masking Mandates and COVID-19 Outcomes in the United States: A Demonstration of the Causal Roadmap.

BACKGROUND: We sought to investigate the effect of public masking mandates in US states on COVID-19 at the national level in Fall 2020. Specifically, we aimed to evaluate how the relative growth of COVID-19 cases and deaths would have differed if all states had issued a mandate to mask in public by 1 September 2020 versus if all states had delayed issuing such a mandate. METHODS: We applied the Causal Roadmap, a formal framework for causal and statistical inference. We defined the outcome as the state-specific relative increase in cumulative cases and in cumulative deaths 21, 30, 45, and 60 days after 1 September. Despite the natural experiment occurring at the state-level, the causal effect of masking policies on COVID-19 outcomes was not identifiable. Nonetheless, we specified the target statistical parameter as the adjusted rate ratio (aRR): the expected outcome with early implementation divided by the expected outcome with delayed implementation, after adjusting for state-level confounders. To minimize strong estimation assumptions, primary analyses used targeted maximum likelihood estimation with Super Learner. RESULTS: After 60 days and at a national level, early implementation was associated with a 9% reduction in new COVID-19 cases (aRR = 0.91 [95% CI = 0.88, 0.95]) and a 16% reduction in new COVID-19 deaths (aRR = 0.84 [95% CI = 0.76, 0.93]). CONCLUSIONS: Although lack of identifiability prohibited causal interpretations, application of the Causal Roadmap facilitated estimation and inference of statistical associations, providing timely answers to pressing questions in the COVID-19 response.

Solar-Supplied Satellite Internet Access Point for the Internet of Things in Remote Areas.

As satellite communications provide ubiquitous coverage, they play a key role in providing Internet connectivity in remote or marginalized areas, so as to enable the vision of a truly global connectivity of the Internet of Things (IoT). However, these areas often lack reliable electricity supply. Thus, this paper proposes a satellite internet access point powered by solar energy, so that a stable Internet connection can be provided. The access point provides Wi-Fi coverage so that sensors, IoT, and devices can connect to the access point using the Wi-Fi, a common wireless technology. Our design took some cost-saving measures to make it affordable and selected the components that require minimal maintenance operations. The satellite access point costs about USD $500, and can provide four days of Internet connectivity without solar energy.

Application of a strain rate gradient microfluidic device to von Willebrand's disease screening.

Von Willebrand's disease (VWD) is the most common inherited bleeding disorder caused by either quantitative or qualitative defects of von Willebrand factor (VWF). Current tests for VWD require relatively large blood volumes, have low throughput, are time-consuming, and do not incorporate the physiologically relevant effects of haemodynamic forces. We developed a microfluidic device incorporating micro-contractions that harnesses well-defined haemodynamic strain gradients to initiate platelet aggregation in citrated whole blood. The microchannel architecture has been specifically designed to allow for continuous real-time imaging of platelet aggregation dynamics. Subjects aged ≥18 years with previously diagnosed VWD or who presented for evaluation of a bleeding disorder, where the possible diagnosis included VWD, were tested. Samples were obtained for device characterization as well as for pathology-based testing. Platelet aggregation in the microfluidic device is independent of platelet amplification loops but dependent on low-level platelet activation, GPIb/IX/V and integrin αIIbß3 engagement. Microfluidic output directly correlates with VWF antigen levels and is able to sensitively detect aggregation defects associated with VWD subtypes. Testing demonstrated a strong correlation with standard clinical laboratory-based tests. Head-to-head comparison with PFA100® demonstrated equivalent, if not improved, sensitivity for screening aggregation defects associated with VWD. This strain rate gradient microfluidic prototype has the potential to be a clinically useful, rapid and high throughput-screening tool for VWD as well as other strain-dependent platelet disorders. In addition, the microfluidic device represents a novel approach to examine the effects of high magnitude/short duration (ms) strain rate gradients on platelet function.

Cement Augmentation in Sacroiliac Screw Fixation Offers Modest Biomechanical Advantages in a Cadaver Model.

BACKGROUND: Sacroiliac screw fixation in elderly patients with pelvic fractures is prone to failure owing to impaired bone quality. Cement augmentation has been proposed as a possible solution, because in other anatomic areas this has been shown to reduce screw loosening. However, to our knowledge, this has not been evaluated for sacroiliac screws. QUESTIONS/PURPOSES: We investigated the potential biomechanical benefit of cement augmentation of sacroiliac screw fixation in a cadaver model of osteoporotic bone, specifically with respect to screw loosening, construct survival, and fracture-site motion. METHODS: Standardized complete sacral ala fractures with intact posterior ligaments in combination with ipsilateral upper and lower pubic rami fractures were created in osteoporotic cadaver pelves and stabilized by three fixation techniques: sacroiliac (n = 5) with sacroiliac screws in S1 and S2, cemented (n = 5) with addition of cement augmentation, and transsacral (n = 5) with a single transsacral screw in S1. A cyclic loading protocol was applied with torque (1.5 Nm) and increasing axial force (250-750 N). Screw loosening, construct survival, and sacral fracture-site motion were measured by optoelectric motion tracking. A sample-size calculation revealed five samples per group to be required to achieve a power of 0.80 to detect 50% reduction in screw loosening. RESULTS: Screw motion in relation to the sacrum during loading with 250 N/1.5 Nm was not different among the three groups (sacroiliac: 1.2 mm, range, 0.6-1.9; cemented: 0.7 mm, range, 0.5-1.3; transsacral: 1.1 mm, range, 0.6-2.3) (p = 0.940). Screw subsidence was less in the cemented group (3.0 mm, range, 1.2-3.7) compared with the sacroiliac (5.7 mm, range, 4.7-10.4) or transsacral group (5.6 mm, range, 3.8-10.5) (p = 0.031). There was no difference with the numbers available in the median number of cycles needed until failure; this was 2921 cycles (range, 2586-5450) in the cemented group, 2570 cycles (range, 2500-5107) for the sacroiliac specimens, and 2578 cycles (range, 2540-2623) in the transsacral group (p = 0.153). The cemented group absorbed more energy before failure (8.2 × 105 N*cycles; range, 6.6 × 105-22.6 × 105) compared with the transsacral group (6.5 × 105 N*cycles; range, 6.4 × 105-6.7 × 105) (p = 0.016). There was no difference with the numbers available in terms of fracture site motion (sacroiliac: 2.9 mm, range, 0.7-5.4; cemented: 1.2 mm, range, 0.6-1.9; transsacral: 2.1 mm, range, 1.2-4.8). Probability values for all between-group comparisons were greater than 0.05. CONCLUSIONS: The addition of cement to standard sacroiliac screw fixation seemed to change the mode and dynamics of failure in this cadaveric mechanical model. Although no advantages to cement were observed in terms of screw motion or cycles to failure among the different constructs, a cemented, two-screw sacroiliac screw construct resulted in less screw subsidence and greater energy absorbed to failure than an uncemented single transsacral screw. CLINICAL RELEVANCE: In osteoporotic bone, the addition of cement to sacroiliac screw fixation might improve screw anchorage. However, larger mechanical studies using these findings as pilot data should be performed before applying these preliminary findings clinically.

Platelet biology: the role of shear.

Platelets are anucleated fragments produced by megakaryocytes that circulate in the blood. Platelets are involved in the initial cellular response to damaged endothelium and migrate to this area to prevent excessive bleeding. What is becoming more acknowledged over the last few decades is that blood flow (hemodynamics) plays a critical role in platelet function. The purpose of this review is to summarize the current understanding of platelet biology with particular focus on the role of hemodynamics. The emerging concept of shear microgradients, which are challenging the traditional model of platelet function, will also be introduced in the review.

Confocal microscopy of posterior polymorphous endothelial dystrophy.

PURPOSE: To report the in vivo confocal microscopic findings of posterior polymorphous endothelial dystrophy (PPED). METHODS: Four patients with PPED from 2 unrelated families and 2 asymptomatic children of an index patient were included in this observational case series. The eyes of the 6 subjects were examined by confocal light microscopy. RESULTS: Confocal microscopy demonstrated craters, streaks, and cracks over the corneal endothelium surface. Pleomorphism and polymegathism were present in eyes with PPED. Guttae and clusters of abnormal endothelial cells were also identified in corneas of these PPED patients. These findings were absent in eyes without clinical manifestations of PPED. CONCLUSIONS: In vivo confocal microscopy is potentially useful for excluding suspected cases of subclinical PPED. Abnormalities in the Descemet membrane and endothelium were observed.

In vivo confocal microscopy of Thygeson's superficial punctate keratitis.

A 56-year-old Chinese man diagnosed with Thygeson's keratitis by clinical biomicroscopy was examined using a tandem scanning confocal microscope. Among normal superficial epithelial cells, clumps of markedly enlarged epithelial cells were identified. Multiple highly reflective filamentary structures were observed in the deeper layers. Most of these lesions were linear; some demonstrated curled ends and others demonstrated branching lesions with 'sprouts'. No inflammatory cells were evident in the areas of corneal stroma sampled. In vivo confocal microscopy may be helpful in the diagnosis of Thygeson's superficial keratitis. To the best of our knowledge, we report the first in vivo confocal images of focal desquamation of epithelium and intraepithelial hyper-reflective linear lesions in English literature.

Orthokeratology lens-related corneal ulcers in children: a case series.

OBJECTIVE: Orthokeratology is a process by which the corneal curvature is flattened by sequentially fitting rigid gas permeable contact lenses of decreasing central curvature. There has been a resurgence of interest with the recent introduction of reverse geometry lenses. Although promising results have been described in reducing the myopic refractive error, the use of these lenses can be associated with corneal problems, as reported in this case series. DESIGN: Observational case series. PARTICIPANTS: Six children with orthokeratology-related corneal ulcers. METHODS: Consecutive cases of orthokeratology lens (OKL)-related corneal ulcers in children presented to a tertiary referral center (March 1999-June 2001) were reviewed. MAIN OUTCOME MEASURES: Preinfection and postinfection visual acuity, refraction, any organisms identified. RESULTS: Six children between the ages of 9 and 14 years (mean = 12.1) were treated. The male:female ratio was 1:5. All cases were unilateral, with equal numbers of left and right eyes. All children wore the OKL at night for a duration of 8 to 12 hours, with the onset of infection between 3 and 36 months (mean = 16.6) of OKL wear. All of the patients suffered a resultant best-corrected visual acuity loss. Five of the 6 cases were culture positive for Pseudomonas aeruginosa. CONCLUSIONS: In view of the temporary benefits of orthokeratology, together with a known increased risk of infection associated with overnight lens wear, parents of children considering orthokeratology must be informed and warned of the potential for permanent loss of vision. The ophthalmic community should have a heightened awareness of the associated complications.

Orthokeratology lens-related Pseudomonas aeruginosa infectious keratitis.

PURPOSE: To report a case of orthokeratology lens-related Pseudomonas corneal ulcer in an adult. METHODS: Case report. RESULTS: A 37-year-old man presented with a 1-day history of painful red eye. He was a soft contact lens wearer before he started on nocturnal orthokeratology lens wear of 8 to 10 hours per night 9 months ago. Corneal scraping sent for culture revealed a heavy growth of Pseudomonas aeruginosa. The patient was treated with intensive topical fortified tobramycin and ceftazidime drops. The ulcer healed with a residual paraxial corneal scar. Although his best-corrected visual acuity (BCVA) recovered from finger counting (8/200) at presentation to 20/30, he suffered visual loss from a premorbid BSCVA of 20/15. His contrast sensitivity (Vector Vision CSV 1000 test) performance was also worse than his fellow eye. CONCLUSION: Nocturnal orthokeratology lens wear may be associated with an increased risk of infection.