Disparities in influenza vaccination exist between Hispanic and non-Hispanic White US nursing home (NH) residents, but the geographic areas with the largest disparities remain unknown. We examined ...how these racial/ethnic disparities differ across states and hospital referral regions (HRRs).
This retrospective cohort study included >14 million short-stay and long-stay US NH resident-seasons over 7 influenza seasons from October 1, 2011, to March 31, 2018, where residents could contribute to 1 or more seasons. Residents were aged ≥65 years and enrolled in Medicare fee-for-service. We used the Medicare Beneficiary Summary File to ascertain race/ethnicity and Minimum Data Set assessments for influenza vaccination. We calculated age- and sex-standardized percentage point (pp) differences in the proportions vaccinated between non-Hispanic White and Hispanic (any race) resident-seasons. Positive pp differences were considered disparities, where the proportion of non-Hispanic White residents vaccinated was greater than the proportion of Hispanic residents vaccinated. States and HRRs with ≥100 resident-seasons per age-sex stratum per racial/ethnic group were included in analyses.
Among 7 442 241 short-stay resident-seasons (94.1% non-Hispanic White, 5.9% Hispanic), the median standardized disparities in influenza vaccination were 4.3 pp (minimum, maximum: 0.3, 19.2; n = 22 states) and 2.8 pp (minimum, maximum: -3.6, 10.3; n = 49 HRRs). Among 6 758 616 long-stay resident-seasons (93.7% non-Hispanic White, 6.5% Hispanic), the median standardized differences were -0.1 pp (minimum, maximum: -4.1, 11.4; n = 18 states) and -1.8 pp (minimum, maximum: -6.5, 7.6; n = 34 HRRs).
Wide geographic variation in influenza vaccination disparities existed across US states and HRRs. Localized interventions targeted toward areas with high disparities may be a more effective strategy to promote health equity than one-size-fits-all national interventions.
•Limited deep-sea exploration still hinders assessments of its environmental status.•We applied the Nested Environmental status Assessment Tool to deep EU waters.•24 indicators were selected, helping ...implement MSFD in the EU’s deep sea.•NEAT results were in reasonable agreement with expert judgement and literature.
The deep sea is the largest biome on Earth but the least explored. Our knowledge of it comes from scattered sources spanning different spatial and temporal scales. Implementation of marine policies like the European Union’s Marine Strategy Framework Directive (MSFD) and support for Blue Growth in the deep sea are therefore hindered by lack of data. Integrated assessments of environmental status require tools to work with different and disaggregated datasets (e.g. density of deep-sea habitat-forming species, body-size distribution of commercial fishes, intensity of bottom trawling) across spatial and temporal scales. A feasibility study was conducted as part of the four-year ATLAS project to assess the effectiveness of the open-access Nested Environmental status Assessment Tool (NEAT) to assess deep-sea environmental status. We worked at nine selected study areas in the North Atlantic focusing on five MSFD descriptors (D1-Biodiversity, D3-Commercial fish and shellfish, D4-Food webs, D6-Seafloor integrity, D10-Marine litter). The objectives of the present study were to i) explore and propose indicators that could be used in the assessment of deep-sea environmental status, ii) evaluate the performance of NEAT in the deep sea, and iii) identify challenges and opportunities for the assessment of deep-sea status. Based on data availability, data quality and expert judgement, in total 24 indicators (one for D1, one for D3, seven for D4, 13 for D6, two for D10) were used in the assessment of the nine study areas, their habitats and ecosystem components. NEAT analyses revealed differences among the study areas for their environmental status ranging from “poor” to “high”. Overall, the NEAT results were in moderate to complete agreement with expert judgement, previous assessments, scientific literature on human-pressure gradients and expected management outcomes. We suggest that the assessment of deep-sea environmental status should take place at habitat and ecosystem level (rather than at species level) and at relatively large spatial scales, in comparison to shallow-water areas. Limited knowledge across space (e.g. distribution of habitat-forming species) and the scarcity of long-term data sets limit our knowledge about natural variability and human impacts in the deep sea preventing a more systematic assessment of habitat and ecosystem components in the deep sea. However, stronger cross-sectoral collaborations, the use of novel technologies and open data-sharing platforms will be critical for establishing environmental baseline indicator values in the deep sea that will contribute to the science base supporting the implementation of marine policies and stimulating Blue Growth.
Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, ...we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
Abstract
Context
In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional ...therapy with active vitamin D and phosphate.
Objective
We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy.
Methods
Conventional therapy dose groups were defined as higher-dose phosphate greater than 40 mg/kg (HPi), lower-dose phosphate 40 mg/kg or less (LPi), higher-dose alfacalcidol greater than 60 ng/kg or calcitriol greater than 30 ng/kg (HD), and lower-dose alfacalcidol 60 ng/kg or less or calcitriol 30 ng/kg or less (LD).
Results
At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses.
Conclusion
Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D.
Hemorrhage is the leading cause of preventable posttraumatic death. Many such deaths may be potentially salvageable with remote damage-control surgical interventions. As recent innovations in ...information technology enable remote specialist support to point-of-care providers, advanced interventions, such as remote damage-control surgery, may be possible in remote settings.
An anatomically realistic perfused surgical training mannequin with intrinsic fluid loss measurements (the "Cut Suit") was used to study perihepatic packing with massive liver hemorrhage. The primary outcome was loss of simulated blood (water) during six stages, namely, incision, retraction, direction, identification, packing, and postpacking. Six fully credentialed surgeons performed the same task as 12 military medical technicians who were randomized to remotely telementored (RTM) (n = 7) or unmentored (UTM) (n=5) real-time guidance by a trauma surgeon.
There were no significant differences in fluid loss between the surgeons and the UTM group or between the UTM and RTM groups. However, when comparing the RTM group with the surgeons, there was significantly more total fluid loss (p = 0.001) and greater loss during the identification (p = 0.002), retraction (p = 0.035), direction (p = 0.014), and packing(p = 0.022) stages. There were no significant differences in fluid loss after packing between the groups despite differences in the number of sponges used; RTM group used more sponges than the surgeons and significantly more than the UTM group (p = 0.048). However, mentoring significantly increased self-assessed nonsurgeon procedural confidence (p = 0.004).
Perihepatic packing of an exsanguinating liver hemorrhage model was readily performed by military medical technicians after a focused briefing. While real-time telementoring did not improve fluid loss, it significantly increased nonsurgeon procedural confidence, which may augment the feasibility of the concept by allowing them to undertake psychologically daunting procedures.
Background. Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by ...parasites or host arginase is a proposed mechanism of arginine depletion. Methods. We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope–labeled tracers measured by quadrupole time-of-flight liquid chromatography–mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice. Results. Children with cerebral malaria and P. berghei–infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice. Conclusions. Simultaneous arginine and ornithine depletion in malaria parasite–infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance.
The PRIMARY score is a 5-category scale developed to identify clinically significant intraprostate malignancy (csPCa) on
Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT (
Ga-PSMA PET) using a ...combination of anatomic site, pattern, and intensity. Developed within the PRIMARY trial, the score requires evaluation in external datasets. This study aimed to assess the reproducibility and diagnostic accuracy of the PRIMARY score in a cohort of patients who underwent multiparametric MRI (mpMRI) and
Ga-PSMA PET before prostate biopsy for the diagnosis of prostate cancer.
In total, data from 242 men who had undergone
Ga-PSMA PET and mpMRI before transperineal prostate biopsy were available for this ethics-approved retrospective study.
Ga-PSMA PET and mpMRI data were centrally collated in a cloud-based deidentified image database. Six experienced prostate-focused nuclear medicine specialists were trained (1 h) in applying the PRIMARY score with 30 sample images. Six radiologists experienced in prostate mpMRI read images as per the Prostate Imaging-Reporting and Data System (PI-RADS), version 2.1. All images were read (with masking of clinical information) at least twice, with discordant findings sent to a masked third (or fourth) reader as necessary. Cohen κ was determined for both imaging scales as 5 categories and then collapsed to binary (negative and positive) categories (score 1 or 2 vs. 3, 4, or 5). Diagnostic performance parameters were calculated, with an International Society of Urological Pathology grade group of at least 2 (csPCa) on biopsy defined as the gold standard. Combined-imaging-positive results were defined as any PI-RADS score of 4 or 5 or as a PI-RADS score of 1-3 with a PRIMARY score of 3-5.
In total, 227 patients with histopathology,
Ga-PSMA PET, and mpMRI imaging before prostate biopsy were included; 33% had no csPCa, and 67% had csPCa. Overall interrater reliability was higher for the PRIMARY scale (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant). This was similar for all 5 categories (κ = 0.65 vs. 0.48). Diagnostic performance to detect csPCa was comparable between PSMA PET and mpMRI (sensitivity, 86% vs. 89%; specificity, 76% vs. 74%; positive predictive value, 88% vs. 88%; negative predictive value, 72% vs. 76%). Using combined imaging, sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%.
The PRIMARY score applied by first-user nuclear medicine specialists showed substantial interrater reproducibility, exceeding that of PI-RADS applied by mpMRI-experienced radiologists. Diagnostic performance was similar between the 2 modalities. The PRIMARY score should be considered when interpreting intraprostatic PSMA PET images.
5,6-Dihydroxy-1H-indazole (DHI) is able to self-polymerize through the same mussel-inspired chemistry responsible for generating poly(dopamine) (PDA), demonstrating the potential to expand this class ...of catecholamine-exclusive chemistry onto heterocyclic catechol derivatives for the preparation of functional materials. Although DHI exhibits slower polymerization kinetics compared to dopamine, the two chemical species are compatibly polymerizable under the same reaction conditions and allow the preparation of copolymer coatings in different molar ratios. Of these copolymers, the 1 : 3-copolymer (DHI-to-dopamine ratio) has demonstrated adequate structural stability as a polymer coating. While PDA performs as an intact framework, the incorporated DHI enhances the colloidal stability and provides additional coordinating functionality through the pyrazole moieties. The 1 : 3-copolymer was fabricated into polymer capsules which exhibit negligible cytotoxicity towards murine dermal fibroblasts (L929) and enhanced binding behaviour towards copper(ii). This represents a new channel for fabricating cargo carriers for biomedical applications that involve the use of transition metal-based species.
We present a computational implementation of mode I finite fracture mechanics (FFM) that allows us to explore how hole shape and size affects the strength of linear elastic perforated plates. We ...compute the FFM predicted strength of a plate with centre crack, circle, diamond, and hexagon perforations of different sizes, as well as filleted (rounded) diamond perforations. Of the studied hole shapes, the diamond has the lowest predicted failure stress. By varying the toughness and strength material parameters, we elucidate how energy (toughness) and stress (strength) considerations compete for dominance in the coupled FFM failure criterion. We find that as the perforation radius goes to zero, failure is strength-dominated, while at small non-zero perforation sizes both strength and toughness play a role in determining failure. For perforation shapes with stress singularities (diamond, hexagon, centre crack), toughness dominates at larger perforation sizes, while strength strongly dominates at larger radii for circle perforations. The filleted diamond computations indicate that failure stress increases continuously as the hole shape deforms from a diamond into a circle, and so does the balance between toughness and strength in the coupled criterion. The presented results suggest new avenues for experimental work to further validate and explore the FFM coupled failure criterion. Our FFM implementation that uses Matlab and Ansys is provided as supplementary material.
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•Strength of perforated plates studied with computational finite fracture mechanics.•Extendable finite fracture mechanics implementation uses Ansys and Matlab.•Centre crack, circle, diamond and hexagon perforations of different sizes.•Strength versus toughness investigated by varying material parameters.•Rounded diamond explores transition from toughness-dominated to strength-dominated failure.
Abstract
Cyclic peptides are poised to target historically difficult to drug intracellular protein–protein interactions, however, their general cell impermeability poses a challenge for ...characterizing function. Recent advances in microfluidics have enabled permeabilization of the cytoplasmic membrane by physical cell deformation (i.e., mechanoporation), resulting in intracellular delivery of impermeable macromolecules in vector‐ and electrophoretic‐free approaches. However, the number of payloads (e.g., peptides) and/or concentrations delivered via microfluidic mechanoporation is limited by having to pre‐mix cells and payloads, a manually intensive process. In this work, we show that cells are momentarily permeable (
t
1/2
= 1.1–2.8 min) after microfluidic vortex shedding (μVS) and that lower molecular weight macromolecules can be cytosolically delivered upon immediate exposure after cells are processed/permeabilized. To increase the ability to screen peptides, we built a system, dispensing‐microfluidic vortex shedding (DμVS), that integrates a μVS chip with inline microplate‐based dispensing. To do so, we synced an electronic pressure regulator, flow sensor, on/off dispense valve, and an x‐y motion platform in a software‐driven feedback loop. Using this system, we were able to deliver low microliter‐scale volumes of transiently mechanoporated cells to hundreds of wells on microtiter plates in just several minutes (e.g., 96‐well plate filled in <2.5 min). We validated the delivery of an impermeable peptide directed at MDM2, a negative regulator of the tumor suppressor p53, using a click chemistry‐ and NanoBRET‐based cell permeability assay in 96‐well format, with robust delivery across the full plate. Furthermore, we demonstrated that DμVS could be used to identify functional, low micromolar, cellular activity of otherwise cell‐inactive MDM2‐binding peptides using a p53 reporter cell assay in 96‐ and 384‐well format. Overall, DμVS can be combined with downstream cell assays to investigate intracellular target engagement in a high‐throughput manner, both for improving structure–activity relationship efforts and for early proof‐of‐biology of non‐optimized peptide (or potentially other macromolecular) tools.
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