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Chondroitin sulfate proteoglycans (CSPGs), up-regulated in and around the lesion after traumatic spinal cord injury (SCI), are key extracellular matrix inhibitory molecules that limit axon growth and consequent recovery of function. CSPG-mediated inhibition occurs via interactions with axonal receptors, including leukocyte common antigen- related (LAR) phosphatase. We tested the effects of a novel LAR inhibitory peptide in rats after hemisection at cervical level 2, a SCI model in which bulbospinal inspiratory neural circuitry originating in the medullary rostral ventral respiratory group (rVRG) becomes disconnected from phrenic motor neuron (PhMN) targets in cervical spinal cord, resulting in persistent partial-to-complete diaphragm paralysis. LAR peptide was delivered by a soaked gelfoam, which was placed directly over the injury site immediately after C2 hemisection and replaced at 1 week post-injury. Axotomized rVRG axons originating in ipsilateral medulla or spared rVRG fibers originating in contralateral medulla were separately assessed by anterograde tracing via AAV2-mCherry injection into rVRG. At 8 weeks post-hemisection, LAR peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. LAR peptide promoted robust regeneration of ipsilateral-originating rVRG axons into and through the lesion site and into intact caudal spinal cord to reach PhMNs located at C3-C5 levels. Furthermore, regenerating rVRG axons re-established putative monosynaptic connections with their PhMNs targets. In addition, LAR peptide stimulated robust sprouting of both modulatory serotonergic axons and contralateral-originating rVRG fibers within the PhMN pool ipsilateral/caudal to the hemisection. Our study demonstrates that targeting LAR-based axon growth inhibition promotes multiple forms of respiratory neural circuit plasticity and provides a new peptide-based therapeutic strategy to ameliorate the devastating respiratory consequences of SCI.

The histories of African crops remain poorly understood despite their contemporary importance. Integration of crops from western, eastern and northern Africa probably first occurred in the Great Lakes Region of eastern Africa; however, little is known about when and how these agricultural systems coalesced. This article presents archaeobotanical analyses from an approximately 9000-year archaeological sequence at Kakapel Rockshelter in western Kenya, comprising the largest and most extensively dated archaeobotanical record from the interior of equatorial eastern Africa. Direct radiocarbon dates on carbonized seeds document the presence of the West African crop cowpea ( Vigna unguiculata (L.) Walp) approximately 2300 years ago, synchronic with the earliest date for domesticated cattle ( Bos taurus ). Peas ( Pisum sativum L. or Pisum abyssinicum A. Braun) and sorghum ( Sorghum bicolor (L.) Moench) from the northeast and eastern African finger millet ( Eleusine coracana (L.) Gaertn.) are incorporated later, by at least 1000 years ago. Combined with ancient DNA evidence from Kakapel and the surrounding region, these data support a scenario in which the use of diverse domesticated species in eastern Africa changed over time rather than arriving and being maintained as a single package. Findings highlight the importance of local heterogeneity in shaping the spread of food production in sub-Saharan Africa.

Purpose: Numerous research has reported that total knee arthroplasty (TKA) cannot reproduce axial tibial rotations of normal knees. The objective of this study was to measure the tibiofemoral articular contact motions and axial tibial rotations of TKA knees to investigate the mechanism causing the knee kinematics change of after TKAs., Methods: Eleven patients with unilateral cruciate retaining (CR) TKA were tested for measurements of knee motion during a weight-bearing flexion from 0° to 105° using an imaging technique. The tibiofemoral contact kinematics were determined using the contact points on medial and lateral surfaces of the tibia and femoral condyles. Axial tibial rotations were calculated using the differences between the medial and lateral articulation distances on the femoral condyles and tibial surfaces at each flexion interval of 15°., Results: On femoral condyles, articular contact distances are consistently longer on the medial than on the lateral sides (p < 0.05) up to 60° of flexion, corresponding to internal tibial rotations (e.g., 1.3° ± 1.0° at 15-30° interval). On tibial surfaces, the articular contact point on the medial side moved more posteriorly than on the lateral side at low flexion angles, corresponding to external tibial rotations (e.g., -1.4° ± 1.8° at 15-30° interval); and more anteriorly than on the lateral sides at mid-range flexion, corresponding to internal tibial rotations (e.g., 0.8° ± 1.7° at 45-60° interval). At higher flexion, articular motions on both femoral condyles and tibial surfaces caused minimal changes in tibial rotations., Conclusions: These results indicate that the axial tibial rotations of these TKA knees were mainly attributed to asymmetric articulations on the medial and lateral femoral condyles and tibial surfaces. The data can help understand the mechanisms causing axial tibial rotations of TKA knees and help improve implant designs for restoration of normal knee kinematics., (© 2024. The Author(s).)

Purpose: To compare the anatomic and functional outcomes of half-dose photodynamic therapy (PDT) and yellow 577-nm subthreshold micropulse laser (SMLT) in treating patients with chronic central serous chorioretinopathy (CSCR)., Design: Prospective, double-masked, randomized, controlled clinical trial., Participants: Patients with chronic CSCR confirmed by clinical features and multimodal imaging., Methods: Eligible patients were randomized (1:1) to receive half-dose PDT or SMLT. The same treatment was repeated if persistent subretinal fluid (SRF) was observed. Treatment responses were evaluated 1 month after treatment and every 3 months until the end point at 12 months., Main Outcome Measures: The primary outcome measure was the complete resolution of SRF on OCT scan at month 12. Secondary outcomes included the changes in best-corrected visual acuity (BCVA), central macular thickness (CMT) as measured by OCT, retinal sensitivity as measured by microperimetry, and vision-related quality of life using the National Eye Institute 25-Item Visual Function Questionnaire., Results: Between April 2017 and October 2020, 68 patients were recruited. At 1 month after treatment, SRF resolved in 8 (24.2%) of 33 patients receiving SMLT and in 20 (58.8%) of 34 patients receiving half-dose PDT. This increased to 23 (82.1%) of 28 patients in the SMLT group and 30 (90.9%) of 33 patients in the half-dose PDT group at 12 months of follow-up. Kaplan-Meier survival curves showed significantly faster resolution of SRF in the half-dose PDT group than the SMLT group (P = 0.016). Both groups showed significant improvement in BCVA (-0.12 ± 0.21, P = 0.005 for SMLT; -0.13 ± 0.12, P < 0.001 for half-dose PDT), CMT (-154.2 ± 105.6, P < 0.001 for SMLT; -140.8 ± 94.0, P < 0.001 for half-dose PDT), and retinal sensitivity (5.70 ± 5.02, P < 0.001 for SMLT; 6.05 ± 3.83, P < 0.001 for half-dose PDT) at 12 months compared with baseline. There was no significant difference between the 2 treatment groups at each time point in all investigations except BCVA at 3 months (P = 0.03)., Conclusions: When comparing half-dose PDT to subthreshold SMLT, this study has shown both treatments to be viable options, with half-dose PDT achieving faster anatomic success and functional improvement., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aim: Preexisting anti-polyethylene glycol (PEG) antibodies (APAs) may affect the efficacy and safety of PEGylated compounds. Omontys ® and Krystexxa ® withdrawal and SARS-CoV-2 RNA vaccine anaphylaxis have all been linked to APAs. This project aimed to develop and validate a method to detect total antibodies against PEG, pre- and post-dose. Materials & methods: The repetitive, linear PEG structure prevented the use of a bridging homogenous format, hence the requirement to use a solid-phase extraction and acid dissociation assay coupled with the Meso Scale Discovery ® platform. Results & conclusion: Using singlicate analysis, the method was validated to successfully detect APA pre- and post-dose, with a crucial aspect of the method being the preparation of an appropriate negative control.

This study aimed to develop and validate a novel flexion axis concept by calculating the points on femoral condyles that could maintain constant heights during knee flexion. Twenty-two knees of 22 healthy subjects were investigated when performing a weightbearing single leg lunge. The knee positions were captured using a validated dual fluoroscopic image system. The points on sagittal planes of the femoral condyles that had minimal changes in heights from the tibial plane along the flexion path were calculated. It was found that the points do formulate a medial-lateral flexion axis that was defined as the iso-height axis (IHA). The six degrees of freedom (6DOF) kinematics data calculated using the IHA were compared with those calculated using the conventional transepicondylar axis and geometrical center axis. The IHA measured minimal changes in proximal-distal translations and varus-valgus rotations along the flexion path, indicating that the IHA may have interesting clinical implications. Therefore, identifying the IHA could provide an alternative physiological reference for improvement of contemporary knee surgeries, such as ligament reconstruction and knee replacement surgeries that are aimed to reproduce normal knee kinematics and medial/lateral soft tissue tensions during knee flexion., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Purpose: The purpose of the study was to describe the cases of intraocular inflammation following COVID-19 vaccination (Comirnaty mRNA vaccine and CoronaVac vaccine) in Hong Kong., Methods: This was a retrospective case series., Results: This series includes 16 eyes among 10 female patients, with a mean age of 49.4 ± 17.4 years. Eight patients (80%) received the Pfizer-BioNTech mRNA vaccination. Anterior uveitis was the most common presentation of postvaccination uveitis (50%) observed in our series, followed by intermediate uveitis (30%) and posterior uveitis (20%), respectively. A case of retinal vasculitis in the form of frosted branch angiitis, previously only reported following COVID-19 infection, was observed following COVID-19 vaccination. The median time from vaccination to uveitis onset was 15.2 days (range: 0-6 weeks). Inflammation in 11 out 16 eyes (68.75%) was completely resolved with topical steroids., Conclusion: Anterior uveitis was the predominant presentations of uveitis flare-ups following COVID-19 in our case series, followed by intermediate uveitis. Aligning with the current global literature concerning this issue, most of the uveitis attacks presented as anterior uveitis and were completely resolved with topical steroids. Consequently, the risk of uveitis flare-ups should not deter the public from receiving COVID-19 vaccines., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine., (© 2023. The Author(s).)

In-situ Raman spectroscopy has the potential to be a powerful technique for monitoring geochemical reactions at a solid-liquid interface in real time. In this article, we present the development and testing of an in-situ Raman spectroscopic cell, which can be used for reaction systems at moderate temperatures and pressure [<1000 psi (6.89 MPa), <100 °C, relevant to subsurface geologic systems] and can hold samples large enough for chemical mapping of heterogeneous rock surfaces. The system is validated by measuring the temperature-dependent conversion of gypsum to calcite over time. Near total conversion of gypsum to calcite on the mineral surface took 29 hours at room temperature and 150 minutes at 100 °C, corresponding to an 11.6-fold increase in the conversion rate. We anticipate that this cell can be an important tool in quantifying the rates of carbon mineralization relevant to geologic carbon sequestration, particularly for the elevated rates recently observed in mafic/ultramafic rocks., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Purpose: To compare the efficacy of conventional laser and subthreshold micropulse laser (SML) in treating diabetic macular edema in terms of functional outcomes and changes in quantitative metrics for the retinal capillary and choriocapillary vascular layers., Methods: Fifty-two eyes from 52 patients with treatment-naive, clinically significant macular edema were randomly assigned to the conventional laser group or SML group in a 1:1 ratio. Best-corrected visual acuity, central macular thickness (CMT), and optical coherence tomography angiography scans were measured at baseline, 1, 3, and 6 months after treatment., Results: The SML group showed rapid visual recovery, improving from baseline of 0.320 ± 0.31 logarithm of the minimum angle of resolution (20/42 Snellen) to 0.270 ± 0.22 logarithm of the minimum angle of resolution (20/37 Snellen) at 1 month ( P = 0.038) and had significant improvements in CMT at 6-month post-treatment (353.88-301.00 µ m, P = 0.005). Statistically significant changes were detected across all optical coherence tomography angiography metrics, including vessel density, vessel length density, vessel diameter index, and fractal dimension, at 6 months for both groups in the deep capillary plexus and choriocapillary plexus., Conclusion: Subthreshold micropulse laser resulted in early visual recovery and sustained macular thickness improvement in the treatment of diabetic macular edema. Microvascular perfusion parameters, including vessel density, vessel length density, and fractal dimension, improved in the deep capillary plexus and choriocapillary plexus for both treatment groups at 6 months post-treatment.

Axial tibial rotation is a characteristic motion of the knee, but how it occurs with knee flexion is controversial. We investigated the mechanisms of tibial rotations by analyzing in vivo tibiofemoral articulations. Twenty knees of 20 living human subjects were investigated during a weightbearing flexion from full extension to maximal flexion using a dual fluoroscopic imaging system. Tibiofemoral articular contact motions on medial and lateral femoral condyles and tibial surfaces were measured at flexion intervals of 15 deg from 0 deg to 120 deg. Axial tibial rotations due to the femoral and tibial articular motions were compared. Articular contact distances were longer on femoral condyles than on tibial surfaces at all flexion intervals (p < 0.05). The articular distance on medial femoral condyle is longer than on lateral side during flexion up to 60 deg. The internal tibial rotation was 6.8 ± 4.5 deg (Mean ± SD) at the flexion interval of 0-15 deg, where 6.1 ± 2.6 deg was due to articulations on femoral condyles and 0.7 ± 5.1 deg due to articulations on tibial surfaces (p < 0.05). The axial tibial rotations due to articulations on femoral condyles are significantly larger than those on tibial surfaces until 60 deg of flexion (p < 0.05). Minimal additional axial tibial rotations were observed beyond 60 deg of flexion. The axial tibial rotations were mainly attributed to uneven articulations on medial and lateral femoral condyles. These data can provide new insights into the understanding of mechanisms of axial tibial rotations and serve as baseline knowledge for improvement of knee surgeries., (Copyright © 2023 by ASME.)

Background: Despite lower circulation of influenza virus throughout 2020-2022 during the COVID-19 pandemic, seasonal influenza vaccination has remained a primary tool to reduce influenza-associated illness and death. The relationship between the decision to receive a COVID-19 vaccine and/or an influenza vaccine is not well understood., Methods: We assessed predictors of receipt of 2021-2022 influenza vaccine in a secondary analysis of data from a case-control study enrolling individuals who received SARS-CoV-2 testing. We used mixed effects logistic regression to estimate factors associated with receipt of seasonal influenza vaccine. We also constructed multinomial adjusted marginal probability models of being vaccinated for COVID-19 only, seasonal influenza only, or both as compared with receipt of neither vaccination., Results: Among 1261 eligible participants recruited between 22 October 2021-22 June 2022, 43% (545) were vaccinated with both seasonal influenza vaccine and >1 dose of a COVID-19 vaccine, 34% (426) received >1 dose of a COVID-19 vaccine only, 4% (49) received seasonal influenza vaccine only, and 19% (241) received neither vaccine. Receipt of >1 COVID-19 vaccine dose was associated with seasonal influenza vaccination (adjusted odds ratio [aOR]: 3.72; 95% confidence interval [CI]: 2.15-6.43); this association was stronger among participants receiving >1 COVID-19 booster dose (aOR = 16.50 [10.10-26.97]). Compared with participants testing negative for SARS- CoV-2 infection, participants testing positive had lower odds of receipt of 2021-2022 seasonal influenza vaccine (aOR = 0.64 [0.50-0.82])., Conclusions: Recipients of a COVID-19 vaccine were more likely to receive seasonal influenza vaccine during the 2021-2022 season. Factors associated with individuals' likelihood of receiving COVID-19 and seasonal influenza vaccines will be important to account for in future studies of vaccine effectiveness against both conditions. Participants who tested positive for SARS-CoV-2 in our sample were less likely to have received seasonal influenza vaccine, suggesting an opportunity to offer influenza vaccination before or after a COVID-19 diagnosis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: co-author J.A.L. discloses receipt of grants and honoraria from Pfizer, Inc, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid dendritic cells (pDCs) via toll-like receptors (TLRs), contributing to disease pathogenesis by driving the secretion of inflammatory type I interferons (IFNs). Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ∼3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use, resulting in retinopathy. We hypothesized that poly(ethylene glycol)- b -poly(propylene sulfide) filamentous nanocarriers, filomicelles (FMs), could directly deliver CQ to pDCs via passive, morphology-based targeting to concentrate drug delivery to specific immune cells, improve drug activity by increased inhibition of type I IFN, and enhance efficacy per dose. Healthy human peripheral blood mononuclear cells were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN-α ELISA and MX1 gene expression using real-time reverse transcription-quantitative polymerase chain reaction. Our results showed that 50 μg CQ/mg FM decreased MX1 expression and IFN-α production after TLR activation with either synthetic nucleic acid agonists or immune complex-rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs and monocytes in vitro and in tissues frequently damaged in SLE patients (i.e., kidneys), while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

Competing Interests: The authors declare no conflict of interest.

Self-assembling filomicelles (FM) are of great interest to nanomedicine due to their structural flexibility, extensive systemic circulation time, and amenability to unique "cylinder-to-sphere" morphological transitions. However, current fabrication techniques for FM self-assembly are highly variable and difficult to scale. Here, we demonstrate that tetrablock copolymers composed of poly(ethylene glycol)- b -poly(propylene sulfide) (PEG- b -PPS) diblocks linked by a pi-stacking perylene bisimide (PBI) moiety permit rapid, scalable, and facile assembly of FM via the flash nanoprecipitation (FNP) method. Co-assembling the tetrablocks and PEG- b -PPS diblocks at different molar ratios resulted in mixed PBI-containing FM (mPBI-FM) with tunable length and flexibility. The flexibility of mPBI-FM can be optimized to decrease uptake by macrophages in vivo, leading to increased circulation time versus (-)PBI-FM without PBI tetrablocks after intravenous administration in mice. While PEG- b -PPS diblocks form FM within a narrow range of hydrophilic weight fractions, incorporation of pi-stacking PBI groups expanded this range to increase favorability of FM assembly. Furthermore, the aggregation-dependent fluorescence of PBI shifted during oxidation-induced "cylinder-to-sphere" transitions of mPBI-FM into micelles, resulting in a distinct emission wavelength for filamentous versus spherical nanostructures. Thus, incorporation of pi-stacking allows for rapid, scalable assembly of FM with tunable flexibility and stability for theranostic and nanomedicine applications., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Attention and working memory (WM) have classically been considered as two separate cognitive functions, but more recent theories have conceptualized them as operating on shared representations and being distinguished primarily by whether attention is directed internally (WM) or externally (attention, traditionally defined). Supporting this idea, a recent behavioral study documented a "WM Stroop effect," showing that maintaining a color word in WM impacts perceptual color-naming performance to the same degree as presenting the color word externally in the classic Stroop task. Here, we employed ERPs to examine the neural processes underlying this WM Stroop task compared to those in the classic Stroop and in a WM-control task. Based on the assumption that holding a color word in WM would (pre-)activate the same color representation as by externally presenting that color word, we hypothesized that the neural cascade of conflict-control processes would occur more rapidly in the WM Stroop than in the classic Stroop task. Our behavioral results replicated equivalent interference behavioral effects for the WM and classic Stroop tasks. Importantly, however, the ERP signatures of conflict detection and resolution displayed substantially shorter latencies in the WM Stroop task. Moreover, delay-period conflict in the WM Stroop task, but not in the WM control task, impacted the ERP and performance measures for the WM probe stimuli. Together, these findings provide new insights into how the brain processes conflict between internal representations and external stimuli, and they support the view of shared representations between internally held WM content and attentional processing of external stimuli., (© 2021 Massachusetts Institute of Technology.)

Infection is the predominant cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, very young infants fail to respond optimally to most vaccines currently in use, especially neonates. In 2005, Stanley Plotkin proposed that new delivery systems would spur a new revolution in pediatric vaccinology, just as attenuation, inactivation, cell culture of viruses, genetic engineering, and adjuvantation had done in preceding decades. Recent advances in the field of immunoengineering, which is evolving alongside vaccinology, have begun to increasingly influence vaccine formulation design. Historically, the particulate nature of materials used in many vaccine formulations was empiric, often because of the need to stabilize antigens or reduce endotoxin levels. However, present vaccine delivery systems are rationally engineered to mimic the size, shape, and surface chemistry of pathogens, and are therefore often referred to as "pathogen-like particles". More than a decade from his original assessment, we re-assess Plotkin's prediction. In addition, we highlight how immunoengineering and advanced delivery systems may be uniquely capable of enhancing vaccine responses in vulnerable populations, such as infants. IMPACT: Immunoengineering and advanced delivery systems are leading to new developments in pediatric vaccinology. Summarizes delivery systems currently in use and development, and prospects for the future. Broad overview of immunoengineering's impact on vaccinology, catering to Pediatric Clinicians and Immunologists.

Objectives: To quantify the association between dose reductions of abiraterone acetate plus prednisone (AAP) or enzalutamide and prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC). Changes in medication-taking patterns of AAP or enzalutamide may arise due to clinical (e.g. toxicity) and non-clinical (e.g. patient compliance) reasons in men with mCRPC. However, it is unclear how this affects PSA progression., Methods: Veterans Health Administration electronic health record database was used to identify Veterans diagnosed with prostate cancer who initiated AAP or enzalutamide (index) from April 2010 to December 2016. PSA progression was defined as the first rise in PSA of ≥2 ng/mL and ≥25% above nadir. The relative dose intensity (RDI) was defined as the ratio of the total dispensed dose over the last two months to the standard recommended dose and was updated monthly. Dose reduction was assessed using a threshold of RDI < 80%., Results: The cohort included 6069 Veterans aged 74.6 years on average. Mean follow-up was 12.3 months. PSA progression occurred in 62.7% of patients. About 63.6% of AAP- and 67.2% of enzalutamide-treated patients had ≥1 occurrence of RDI <80%. RDI <80% was associated with an 8.8% higher risk of PSA progression (hazard ratio [HR] = 1.088; p  = .019; 95% confidence interval [CI] [1.014; 1.166])., Conclusions: Dose reduction was observed in most patients and was associated with significantly higher risk of PSA progression in men with mCRPC. These results suggest future efforts to minimize dose reductions for non-clinical reasons are warranted and that patient adherence should be encouraged to limit the risk of PSA progression.

Objectives: The objective of this study was to evaluate the association of prostate-specific antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS), and to describe healthcare resource utilization (HRU) and costs among patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) in the Veterans Health Administration setting., Methods and Materials: Patients with nmCRPC were identified from the Veterans Health Administration electronic health record database (1/2007-8/2017). PSADT was categorized as <3 months, 3 to 9 months, 9 to 15 months, ≥15 months, and unknown. MFS and OS were assessed using multivariable Cox proportional hazards regression, including PSADT as a predictor. HRU and costs were described per-patient-per-year (PPPY)., Results: Among 12,083 patients in the study, shorter PSADT was associated with shorter MFS and OS (PSADT <3 months vs. PSADT ≥15 months hazard ratio [HR] [95% confidence interval (CI)] = 0.307 [0.281, 0.335] and 0.371 [0.335, 0.410], respectively). Patients who developed metastasis had a 3-fold higher risk of death compared to those without metastasis (HR [95% CI] = 2.933 [2.763, 3.113]). Mean HRU increased following the onset of nmCRPC and metastatic castrate-resistant prostate cancer (mCRPC); mean inpatient stays more than doubled (0.2 vs. 0.5 and 0.6 vs. 2.8 PPPY, respectively). Similar increases in healthcare costs were observed; pharmacy costs more than tripled following nmCRPC ($2,074 vs. $6,839 PPPY). From nmCRPC to mCRPC, large increases were observed for inpatient costs ($7,257-$61,691), emergency room costs ($844-$1,958), and pharmacy costs ($4,115-$26,279) PPPY., Conclusions: In Veterans with nmCRPC, shorter PSADT was significantly associated with shorter MFS and OS. Onset of nmCRPC and mCRPC was associated with substantial HRU and cost increases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG- b -PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3 + Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE -/- mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy., (Copyright © 2020 Yi, Karabin, Zhu, Bobbala, Lyu, Li, Liu, Frey, Vincent and Scott.)

Background: Crohn disease is an inflammatory bowel disease with intermittent symptoms relating to damage to the gastrointestinal tract. Compared with adult-onset Crohn disease, the childhood-onset form is more likely to be severe. Infliximab has shown efficacy in adult patients., Objective: To examine the efficacy and safety of infliximab in pediatric Crohn disease, by means of a systematic review., Data Sources: Three databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and regulatory documents were searched from inception to December 2017. Clinical trial registries, conference abstracts, and reference lists were searched to March 2018., Study Selection and Data Extraction: Randomized controlled trials (RCTs) and prospective cohort studies that compared infliximab with active control were included in the analysis. Two reviewers independently performed screening, extracted data, and assessed risk of bias. The primary outcomes were induction and maintenance of endoscopic remission and severe adverse effects., Data Synthesis: Three eligible RCTs comparing different dose regimens, 16 prospective cohort studies comparing infliximab with other therapies (adalimumab, exclusive enteral nutrition, or standard of care), and 3 prospective cohort studies comparing different infliximab regimens were identified. Meta-analysis of the RCTs showed no significant difference between infliximab every 8 weeks compared with longer intervals for maintenance of clinical remission (risk ratio [RR] 1.76, 95% confidence interval [CI] 0.98-3.19). Meta-analyses of the prospective cohort studies showed no significant differences between infliximab and adalimumab for maintenance of endoscopic remission (RR 1.07, 95% CI 0.60-1.92), between infliximab and exclusive enteral nutrition for induction of clinical remission (RR 1.09, 95% CI 0.82-1.45), or between infliximab and standard of care for maintenance of clinical remission at 6 and 12 months (RR 1.12, 95% CI 0.58-2.17, and RR 1.24, 95% CI 0.84-1.84, respectively)., Conclusions: Current evidence suggested comparable efficacy for infliximab and other therapies; however, the available literature was limited by risk of bias and small sample size. Further prospective studies are needed to confirm the efficacy and safety of this drug in pediatric Crohn disease., Competing Interests: Competing interests: None declared.

Problems persist with the integration of hip and dental implants with host bone tissues, which may result in long-term implant failure. Previous studies have found that implants bearing irregular surfaces can facilitate osseointegration. An improvement to this approach would use implant surfaces harboring a well-defined surface microstructure to decrease variability in implant surfaces. In this study, we tested whether well-defined surfaces with arrays of microdents (each with depth approximately 3 µm) significantly affected the morphology, proliferation, and osteogenic activity of mesenchymal stem cells (MSCs). Arrays of microdents tested had diameters of 9 µm, 12 µm, and 18 µm, while spacing between arrays ranged from 8 µm to 34 µm. Effects on MSC morphology (cell spreading area) and proliferation were also quantified, with both significantly decreasing on micropatterned surfaces (p<0.05) on smaller and denser microdents. In contrast, MSCs were found to deposit more calcified matrix on smaller and denser arrays of microdents. MSCs on a pattern with arrays of microdents with a diameter of 9 µm and a spacing 8 µm deposited 3-4 times more calcified matrix than on a smooth surface (p<0.05). These findings show that well-defined surface microtopographies promote osteogenic activity, which can be used on implant surfaces to improve integration with the host bone tissue.

Stress is an important factor in the initiation and maintenance of smoking in adolescents. Women are more vulnerable to the development of addiction to smoking and have more difficulty quitting than men. Women also showe enhanced responses to stress. Despite these differences, no work has been done examining the effects of stress on the reinforcing efficacy of self-administered nicotine in adolescent rats, or if there are sex differences. Male and female adolescent Long Evans rats were trained to self-administer one of three different intravenous doses of nicotine (7.5, 15, 30 μg/kg/infusion) first on fixed ratio, and then on a progressive ratio (PR) schedule beginning on postnatal day 33. The effect of the pharmacological stressor yohimbine (0.3, 0.6 mg/kg, i.p.) on the reinforcing efficacy of nicotine was then determined using the PR schedule. Yohimbine stimulated nicotine intake and increased PR breakpoints and numbers of infusions received in both male and female adolescent rats. The infusion dose of nicotine was positively associated with yohimbine-induced increases in responding. Female rats showed significantly increased breakpoints at yohimbine doses and nicotine infusion doses at which males did not. The effects of the pharmacological stressor, yohimbine on the reinforcing efficacy of nicotine are therefore linked to sex and nicotine infusion dose. Female rats are more sensitive to stress-induced potentiation of nicotine self-administration., (© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.)

Millions of people suffer from rheumatic diseases such as gout, fibromyalgia, osteoarthritis, and rheumatoid arthritis. These can be incapacitating and detrimental to quality of life. Diet, nutrition, and weight loss have shown promise in alleviating some of this disease burden. These lifestyle changes may give patients a feeling of control and ownership over their disease as well as a nonpharmacologic means of treatment. This article reviews the available research on the effects of diet and nutrition on rheumatoid disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: The TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas6 and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. In animal models, absence of TAM kinases is associated with lupus-like disease. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE., Methods: 107 SLE patients were recruited. Of these, 45 SLE patients were matched age, gender and ethnicity with normal controls (NC). Gas6 and free protein S were measured with sandwich enzyme linked immunosorbent assays (ELISAs)., Results: Overall, the plasma concentrations of Gas6 and free protein S were not different between 45 SLE patients and 45 NC. In SLE patients, the levels of free protein S were positively correlated with age (r = 0.2405, P = 0.0126), however those of Gas6 were not. There was no correlation between the concentrations of Gas6 and free protein S in individuals. Levels of free protein S were significantly lower in SLE patients with a history of serositis, neurologic disorder, hematologic disorder and immunologic disorder. Gas6 levels were elevated in patients with a history of neurologic disorder. The SLE patients with anti-Sm or anti-cardiolipin IgG showed lower free protein S levels. Circulating free protein S was positively correlated with complement component 3 (C3) (r = 0.3858, P < 0.0001) and complement component 4 (C4) (r = 0.4275, P < 0.0001). In the patients with active BILAG hematologic involvement, the levels of free protein S were lower and those of Gas6 were higher., Conclusions: In SLE, free protein S was decreased in patients with certain types of clinical history and disease activity. Levels of free protein S were strongly correlated with C3 and C4 levels. Gas6 levels in SLE patients differed little from levels in NC, but they were elevated in the small numbers of patients with a history of neurological disease. The correlation of decreased protein S levels with lupus disease activity is consistent with a role for the TAM receptors in scavenging apoptotic cells and controlling inflammation. Protein S appears more important functionally in SLE patients than Gas6 in this regard.

An understanding of the cytokine cascade in a rheumatoid joint has led to the development of new therapeutic options, including drugs targeting tumor necrosis factor-alpha (TNF-alpha). The safety profile of these agents in patients with hepatitis-induced liver disease, however, remains a concern because of risks associated with immune suppression. To examine the effect of three different TNF-alpha antagonists, infliximab, etanercept, and adalimumab, on serum transaminases and hepatitis viral load in patients with rheumatoid arthritis (RA) and concurrent hepatitis B (HBV) or hepatitis C (HCV). Medical records of 11 patients with diagnosis of RA and documented seropositivity for hepatitis B or hepatitis C were retrospectively reviewed for worsening of hepatic inflammation and viral proliferation as measured by a rise in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and viral load while using these agents. Three patients had RA with concurrent chronic HBV and eight patients had RA with concurrent chronic HCV. Seven patients remained on a single anti-TNF-alpha agent and four patients switched to a second anti-TNF-alpha agent due to treatment failure. Two patients showed a transient elevation in AST and/or ALT from normal, but in all 11 patients, AST and ALT levels were within one time the upper range of normal at the conclusion of the study. No significant increase in viral load was seen except one patient who showed a fourfold increase from baseline. Our case series supports results obtained from previous studies examining the safety of anti-TNF-alpha agents in patients with underlying hepatic disease. Use of these agents in patients with HBV or HCV may be associated with a transient transaminitis but appears to be safe overall. In both groups, frequent monitoring of serum transaminase levels and viral load is essential.

Rheumatoid arthritis (RA) and multiple sclerosis (MS) share similar pathophysiologic processes but coexistence of both diseases in the same patient has rarely been described. We describe the case of a 32 year old woman with rheumatoid arthritis treated with 12.5 mg of methotrexate once a week and 1 mg folic acid who developed paresthesias of her upper and lower extremities. Three years later, she acutely developed 6th nerve palsy, gait imbalance and urinary urgency and a diagnosis of multiple sclerosis was made. The use of methotrexate, though effective in controlling her rheumatoid arthritis, did not influence the development or progression of her multiple sclerosis. Although RA and MS may coexist in the same patient, treatment of one disease may have no influence on the clinical course of the other. Thus, the mechanism by which methotrexate suppresses disease activity in RA but not in MS despite both being T-cell mediated autoimmune diseases requires further investigative studies.