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Delivering high-value orthopedic care requires optimizing value, defined as health outcomes achieved per dollar spent. Published literature is stippled with inaccurate proxies for cost, including negotiated reimbursement rates, fees paid, or listed prices. Time-driven activity-based costing (TDABC) offers a more robust and accurate approach to calculating cost, including shoulder care. In the present study, we sought to determine the drivers of total cost in arthroscopic rotator cuff repair (aRCR) using TDABC. Consecutive patients undergoing aRCR at multiple sites associated with a large urban health care system between January 2019 and September 2021 were identified. Total cost was determined using TDABC methodology. The episode of care was defined by 3 phases: preoperative, intraoperative, and postoperative care. Patient, procedure, rotator cuff tear morphology, and surgeon characteristics were collected. Bivariate analysis was performed across all characteristics between high-cost (top decile) and all other aRCRs. Multivariable linear regression was used to identify the key cost drivers. In total, 625 aRCRs performed by 24 orthopedic surgeons and 572 aRCRs performed by 13 orthopedic surgeons were included in the bivariate and multivariable linear regression analyses, respectively. By TDABC analysis, total aRCR cost varied 6-fold (5.9×) from least to most costly. Intraoperative costs accounted for 91% of average total cost, followed by preoperative costs and postoperative costs (6% and 3%, respectively). Biologic adjuncts (regression coefficient [RC] 0.54, 95% confidence interval [CI] 0.49-0.58, P <.001) and surgeon idiosyncrasy (RC of highest-cost surgeon 0.50, 95% CI 0.26-0.73, P <.001) were the major cost drivers in aRCR. Patient age, comorbidities, number of rotator cuff tendons torn, and revision surgery were not significantly associated with total cost. The amount of tendon retraction (RC 0.0012, 95% CI 0.000020-0.0024, P =.046), average Goutallier grade (RC 0.029, 95% CI 0.0086-0.049, P =.005), and the number of anchors used (RC 0.039, 95% CI 0.032-0.046, P <.001) were also significantly associated with cost, but with far smaller effect sizes. Episode of care costs vary nearly 6-fold in aRCR and are almost exclusively dictated by the intraoperative phase. Tear morphology and repair technique contribute to cost, although the largest cost drivers of aRCR are the use of biologic adjuncts and surgeon idiosyncrasy, defined as something a surgeon does or does not do that impacts total cost and is not controlled for in the current analysis. Future work should seek to better delineate what these surgeon idiosyncrasies may represent. [ABSTRACT FROM AUTHOR]

Many viruses undergo transient conformational change to surveil their environments for receptors and host factors. In Hepatitis B virus (HBV) infection, after the virus enters the cell, it is transported to the nucleus by interaction of the HBV capsid with an importin α/β complex. The interaction between virus and importins is mediated by nuclear localization signals on the capsid protein’s C-terminal domain (CTD). However, CTDs are located inside the capsid. In this study, we asked where does a CTD exit the capsid, are all quasi-equivalent CTDs created equal, and does the capsid structure deform to facilitate CTD egress from the capsid? Here, we used Impβ as a tool to trap transiently exposed CTDs and examined this complex by cryo-electron microscopy. We examined an asymmetric reconstruction of a T = 4 icosahedral capsid and a focused reconstruction of a quasi-6-fold vertex (3.8 and 4.0 Å resolution, respectively). Both approaches showed that a subset of CTDs extended through a pore in the center of the quasi-6- fold complex. CTD egress was accompanied by enlargement of the pore and subtle changes in quaternary and tertiary structure of the quasi-6-fold. When compared to molecular dynamics simulations, structural changes were within the normal range of capsid flexibility. Although pore diameter was enlarged in the Impβ-bound reconstruction, simulations indicate that CTD egress does not exclusively depend on enlarged pores. In summary, we find that HBV surveillance of its environment by transient exposure of its CTD requires only modest conformational change of the capsid [ABSTRACT FROM AUTHOR]

The healthcare sector generates approximately 10% of the total carbon emissions in the United States. Radiology is thought to be a top contributor to the healthcare carbon footprint due to high energy-consuming devices and waste from interventional procedures. In this article, we provide a background on Radiology's environmental impact, describe why hospitals should add sustainability as a quality measure, and give a framework for radiologists to reduce the carbon footprint through quality improvement and collaboration. [ABSTRACT FROM AUTHOR]

Migration and subsequent invasion of extravillous trophoblasts into the uterus is essential for proper formation of the placenta. Disruption of these processes may result in poor pregnancy outcomes including preeclampsia, placenta accreta, fetal growth restriction, or fetal death. Currently, there are several methods for quantifying cell migration and invasion in vitro , each with limitations. Therefore, we developed a novel, high-throughput method to screen chemicals for their ability to alter human trophoblast migration. Human HTR8/SVneo trophoblast cells were cultured in Oris™ cell migration plates containing stopper barriers. After EVT cells attached and chemicals were added to media, stoppers were removed thereby creating a cell-free detection zone for migration. Entry of trophoblasts into this zone was monitored through imaging every 6 h and used to calculate a relative cell density. Chemicals known to increase (epidermal growth factor) and decrease (pertussis toxin and cadmium) trophoblast migration were used to validate this in vitro method. Next, a panel of environmental chemicals including bisphenols, mycoestrogens, and flame retardants, were screened for their ability to alter trophoblast invasion. In conclusion, a real-time method to track extravillous trophoblast migration offers potential for screening contaminants as placental toxicants. [Display omitted] • Trophoblast entry into a cell-free zone can be monitored with real-time imaging. • This migration assay can be used to screen potential human placenta toxicants. • Cadmium chloride, bisphenols, and mycoestrogens reduce trophoblast migration. • Organophosphate flame retardants increase trophoblast migration. [ABSTRACT FROM AUTHOR]

This study aimed to quantify U.S. jurisdiction-level costs related to the COVID-19 Vaccination Program by estimating the per-dose-administered cost during December 20, 2020–May 31, 2021, from a combined federal and local government perspective. Costs were limited to vaccine purchase, administration (including operations and wastage), and local redistribution by jurisdictions. Data were collected through publicly available sources, published literature, and a survey of 62 jurisdictions (38 responded). A total of 284.6 million doses of COVID-19 vaccine were distributed to jurisdictions during the study period, of which 284.2 million doses were administered, and 0.4 million doses were wasted. The estimated cost per-dose-administered among the 38 jurisdictions that responded to study survey was $57.45 and imputed cost across all jurisdictions was $63.11. The findings on jurisdiction-level cost per-dose-administered and vaccination cost during the initial period of U.S. COVID-19 Vaccination Program, when demand exceeded supply, may be considered in future pandemic preparedness planning. • The estimated cost per-dose-administered among the 38 jurisdictions that responded to study survey was $57.45. • The estimate cost per-dose-administered across all jurisdictions was $63.11. • When planning for rapid vaccine access, sufficient funding is needed for redistribution and administration. [ABSTRACT FROM AUTHOR]

Background and Purpose: To determine the efficacy of standardized definitions of degenerative change in reducing variability in interpretation of lumbar spine magnetic resonance imaging within and between groups of subspecialty-trained neuroradiologists (NR) and musculoskeletal radiologists (MSK).Materials and Methods: Six radiologists, three from both NR and MSK groups were trained on a standardized classification system of degenerative change. After an 11-month washout period, they independently re-interpreted fifty exams at the L4-L5 and L5-S1 levels. Responses were converted to a six-point ordinal scale for the assessment of neural foraminal stenosis and spinal canal stenosis (SCS), three-point scale for lateral recess stenosis, and four-point scale for facet osteoarthritis (FO). Intra-subspecialty and inter-subspecialty analysis was performed using the weighted Cohen's kappa with a binary matrix of all reader pairs.Results: Inter-subspecialty agreement improved from k=0.527 (moderate) to k=0.602 (substantial) for neural foraminal stenosis, from k=0.540 (moderate) to k=0.652 (substantial) for SCS, from k=0.0818 (slight) to k=0.337 (fair) for lateral recess stenosis, and from k=0.176 (slight) to k=0.495 (moderate) for FO. The NR group demonstrated improved intra-subspecialty agreement for the assessment of SCS, from k=0.368 (fair) to k=0.638 (substantial). The MSK group demonstrated improved intra-subspecialty agreement for the assessment of FO, from k=0.134 (slight) to k=0.413 (moderate). Intra-subspecialty agreement was similar for other parameters before and after training.Conclusions: As result of the standardized definitions training, the NR and MSK groups each improved in one of the four parameters, while inter-subspecialty variability improved in all four parameters. These definitions may be useful in clinical practice across radiology subspecialties. [ABSTRACT FROM AUTHOR]

Background and Purpose: The purpose of this study is to assess the differences in degenerative spine MRI reporting between subspecialty-trained attending neuroradiologists and musculoskeletal radiologists (MSK) at a single institution, academic medical center.Materials and Methods: Fifty consecutive outpatient noncontrast lumbar spine examinations were selected from the Picture Archiving and Communication System. Three MSK and 3 neuroradiologists (NR) independently reviewed and interpreted the exams at the L4-L5 and L5-S1 levels in the same manner as in clinical practice. The assessment of neural foraminal stenosis (NFS) and spinal canal stenosis (SCS) was converted to a 5-point ordinal scale. The assessment of lateral recess stenosis (LRS) and facet osteoarthritis (FO) was recorded as present/absent. Intersubspecialty and intrasubspecialty analysis was performed using Cohen's kappa coefficient with a binary matrix of all reader pairs.Results: There was moderate intersubspecialty agreement (k = 0.527) for NFS and SCS (k = 0.540). Intersubspecialty agreement was slight for LRS (k = 0.0818) and FO (k = 0.176). The MSK group demonstrated greater intrasubspecialty agreement in assessment of NFS and SCS compared to the NR group, with nonoverlapping confidence intervals. The NR group demonstrated greater nominal intrasubspecialty agreement in the assessment of both LRS and FO, although with nonoverlapping confidence intervals.Conclusion: There is moderate intersubspecialty agreement between MSK radiologists and neuroradiologists in reporting the severity of NFS and SCS, although MSK radiologists demonstrated greater intrasubspecialty agreement. There is slight intersubspecialty agreement for LRS and FO. The demonstration of differences in inter-reader agreement is a crucial first step to attempt to ameliorate these variabilities. [ABSTRACT FROM AUTHOR]

At our institution, skull base reconstruction using a free mucosal graft from the nasal cavity floor has been the standardized technique after pituitary adenoma resection via transsellar approach. In this study, the expected appearance of the reconstruction on postoperative magnetic resonance imaging (MRI) scans is described and its integrity and impact on the sinonasal cavity are assessed. Fifty patients were selected, and their electronic medical records were reviewed for postoperative course, Sino-Nasal Outcome Test-22 (SNOT-22) scores, and nasal endoscopy reports. A total of 116 postoperative MRI scans were available to evaluate 1) the appearance and thickness of the graft, 2) the enhancement of the graft, and 3) the T2 signal in sphenoid sinus as a potential indication for inflammatory disease. There was no significant change in the thickness of the graft over time. Except for the 7 scans that were obtained without intravenous contrast, all scans showed enhancement of the graft. About half of the patients showed persistent T2 hyperintense signal at 12 and 24 months. However, this finding was not clinically significant, because postoperative SNOT-22 scores showed minimal sinonasal impact. Postoperative MRI surveillance scans showed a stable appearance of the graft that mimics the native mucosa, with enhancement through time, reflecting its robust vascularization and integration to the skull base. Although persistent T2 hyperintense signal was detected in the sphenoid sinus, clinical evidence based on nasal endoscopy reports and SNOT-22 scores indicated minimal sinonasal morbidity. [ABSTRACT FROM AUTHOR]

Objective The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine- N -oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE −/− mice fed a high fat diet (HFD). Methods ApoE −/− mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. Results High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD-fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. Conclusions These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, TEMPOL had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. TEMPOL may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability. [ABSTRACT FROM AUTHOR]

Congenital brain malformations are a major cause of morbidity and mortality in pediatric patients who are younger than 2 years. Optimization of patient care requires accurate diagnosis, which can be challenging as congenital brain malformations include an extensive variety of anomalies. Radiologic imaging helps to identify the malformations and to guide management. Understanding radiologic findings necessitates knowledge of central nervous system embryogenesis. This review discusses the imaging of congenital brain malformations encountered in patients who are younger than 2 years in the context of brain development. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Carnosine has been shown to modulate triglyceride and glycation levels in cell and animal systems. In this study we investigated whether prolonged supplementation with carnosine inhibits atherosclerosis and markers of lesion stability in hyperglycaemic and hyperlipidaemic mice. Methods: Streptozotocin-induced diabetic apo E−/− mice were maintained for 20 weeks, post-induction of diabetes. Half of the animals received carnosine (2g/L) in their drinking water. Diabetes was confirmed by significant increases in blood glucose and glycated haemoglobin, plasma triglyceride and total cholesterol levels, brachiocephalic artery and aortic sinus plaque area; and lower body mass. Results: Prolonged carnosine supplementation resulted in a significant (∼20-fold) increase in plasma carnosine levels, and a significant (∼23%) lowering of triglyceride levels in the carnosine-supplemented groups regardless of glycaemic status. Supplementation did not affect glycaemic status, blood cholesterol levels or loss of body mass. In the diabetic mice, carnosine supplementation did not diminish measured plaque area, but reduced the area of plaque occupied by extracellular lipid (∼60%) and increased both macrophage numbers (∼70%) and plaque collagen content (∼50%). The area occupied by α-actin-positive smooth muscle cells was not significantly increased. Conclusions: These data indicate that in a well-established model of diabetes-associated atherosclerosis, prolonged carnosine supplementation enhances plasma levels, and has novel and significant effects on atherosclerotic lesion lipid, collagen and macrophage levels. These data are consistent with greater lesion stability, a key goal in treatment of existing cardiovascular disease. Carnosine supplementation may therefore be of benefit in lowering triglyceride levels and suppressing plaque instability in diabetes-associated atherosclerosis. [Copyright &y& Elsevier]

Abstract: Objective: People with diabetes have an elevated risk of atherosclerosis. The accumulation of lipid within macrophage cells in the artery wall is believed to arise via the uptake and subsequent processing of modified low-density lipoproteins (LDL) via the endo-lysosomal system. In this study the effects of prolonged exposure to elevated glucose upon macrophage lysosomal function was examined to determine whether this contributes to modulated protein catabolism. Methods: Human monocytes were isolated from white-cell concentrates and differentiated, in vitro, into monocyte-derived macrophages over 11 days in medium containing 5–30 mmol/L glucose. Murine macrophage-like J774A.1 cells were incubated similarly. Lysosomal cathepsin (B, D, L and S) and acid lipase activities were assessed using fluorogenic substrates; cathepsin protein levels were examined by Western blotting. Lysosomal numbers were examined using the lysomotropic fluorescent dye LysoTracker DND-99, measurement of aryl sulfatase activity, and quantification of lysosome-associated membrane glycoprotein-1 (LAMP-1) by Western blotting. Results: Exposure to elevated glucose, but not mannitol, resulted in a concentration-dependent decrease in the activity, and to a lesser extent protein levels, of four lysosomal cathepsins. Acid lipase activity was also significantly reduced. Arysulfatase activity, LAMP-1 levels and lysosomal numbers were also decreased at the highest glucose concentrations, though to a lesser extent. Conclusion: Long term exposure of human and murine macrophage cells to elevated glucose levels result in a depression of lysosomal proteolytic and lipase activities. This may result in decreased clearance and cellular accumulation of (lipo)proteins and contribute to the accumulation of modified proteins and lipids in diabetes-associated atherosclerosis. [Copyright &y& Elsevier]

The advent of fast multislice computed tomography (CT) has ushered in a new era in the noninvasive evaluation of the heart. Cardiac structures can now be quickly evaluated with exquisite detail in a noninvasive manner. Cardiac CT is increasingly being used for the noninvasive evaluation of coronary arteries, procedural planning, and evaluating chest pain in certain clinical situations. Dual-source CT is a recent technological development that has helped improve spatial and temporal resolution for cardiac CT imaging. It is one of many “next generation” CT technologies that are now pushing image quality to new levels. The interpreting radiologist must now be familiar with detailed cardiac anatomy that is routinely imaged with these next generation units. Understanding normal cardiac anatomy, including normal variants, is key to distinguishing pathology from normal structures. [Copyright &y& Elsevier]

Abstract: Kinetoplast maxicircle DNA sequence organisation was investigated in Leishmania donovani, strain 1S LdBob. Gene arrangement in the coding (conserved) region of the maxicircle is collinear with that of most trypanosomatids, with individual genes showing 80–90% nucleotide identity to Leishmania tarentolae, strain UC. The notable exception was an integration of a full-size minicircle sequence in the ND1 gene coding region found in L. donovani. Editing patterns of the mitochondrial mRNAs investigated also followed L. tarentolae UC patterns, including productive editing of the components of respiratory complexes III–V, and ribosomal protein S12 (RPS12), as well as the lack of productive editing in five out of six pan-edited cryptogenes (ND3, ND8, ND9, G3, G4) found in these species. Several guide RNAs for the editing events were localised in minicircles and maxicircles in the locations that are conserved between the species. Mitochondrial activity, including rates of oxygen consumption, the presence and the levels of respiratory complexes and their individual subunits and the steady-state levels of several mitochondrial-encoded mRNAs were essentially the same in axenically grown amastigotes and in promastigotes of L. donovani. However, some modulation of mitochondrial activity between these developmental stages was suggested by the finding of an amastigote-specific component in complex IV, a down-regulation of mitochondrial RNA-binding proteins (MRP) and MRP-associated protein (MRP-AP) in amastigotes, and by variations in the levels of RPS12, ND3, ND9, G3 and G4 pre-edited transcripts. [Copyright &y& Elsevier]

In Afghanistan, the risk of maternal death is among the highest in the world, with wide variation across the country. One explanation may be wide geographic disparities in access and use of maternal health care services. This study describes the spatial distribution of public facilities providing maternal health care in Afghanistan, specifically emergency obstetric care (EmOC), and the differences in travel time estimates using different transportation modes from 2010 to 2015 at the national and subnational levels. We conducted mapping and spatial analyses to measure the proportion of pregnant women able to access any EmOC health facility within 2 h by foot, animal, motor vehicle and a combination of transport modes. In 2015, adequate coverage of active public health facilities within 2 h of travel time was 36.6% by foot and 71.2% by a combination of transport modes. We found an 8.3% and 63.2% increase in access to EmOC facilities within 2 h of travel time by a combination of transport modes and by foot only, respectively, by 2015. Access to a combination of transportation options such as motor vehicles and animals may benefit pregnant women in reaching health facilities efficiently. Afghanistan made impressive gains in maternal healthcare access; despite these improvements, large disparities remain in geographic access by province and overall access to facilities is still poor. [ABSTRACT FROM AUTHOR]

Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to return to the SC state requires suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism that occurs during early HFSC lineage progression. HFSC fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche. Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs. These findings highlight the importance of spatiotemporal control of SC metabolic states in organ homeostasis. • HFSC niche is hypoxic and low pO 2 promotes the stem cell state • HFSCs are metabolically flexible whereas progenitor state requires glutaminolysis • Progenitor fate reversibility requires mTORC2-driven attenuation of glutamine metabolism • mTORC2 deletion impairs niche regeneration by progenitors, triggering HFSC exhaustion Mechanisms that facilitate progenitor fate reversibility back to the stem cell state remain unknown. Kim et al. show that mTORC2-Akt signaling at the end of the anagen hair follicle growth phase is required to suppress glutamine metabolism, allowing progenitors to return to the hypoxic niche, resume the stem cell state, and regenerate the bulge for long-term hair follicle stem cell maintenance. [ABSTRACT FROM AUTHOR]

The impacts of acute arsenic exposure (i.e. vomiting, diarrhea, and renal failure) are distinct from those brought about by sustained, low level exposure from environmental sources or drinking of contaminated well water. Chronic arsenic exposure is a risk factor for the development of pulmonary diseases, including lung cancer. How arsenic exposure leads to pulmonary disease is not fully understood. Both acute versus chronic arsenic exposure increase EGFR expression, but do so via distinct molecular mechanisms. BEAS-2B cells were exposed to either acute sodium arsenite (5 μM for 24 h) or chronic sodium arsenite (100 nM for 24 weeks). Cells treated with acute arsenic exhibited a decrease in viability, changes in morphology, and increased mRNA level of BTC. In contrast, during 24 weeks of arsenic exposure, the cells had increased EGFR expression and activity, and increased mRNA and protein levels of TGFα. Further, chronic arsenic treatment caused an increase in cell migration in the absence of exogenous ligand. Elevated TGFα and EGFR expression are features of many non-small cell lung cancers. We propose that lung epithelial cells chronically exposed to low level arsenic increases EGFR signaling via TGFα production to enhance ligand-independent cell migration. • Acute and chronic arsenic in lung epithelial cells increase EGFR via distinct mechanisms. • Acute arsenic exposure changes cell morphology and decreases cell viability. • Chronic arsenic increases TGFα mRNA and protein levels and elevates EGFR activity. • TGFα and EGFR expression are frequently elevated in non-small cell lung cancers. [ABSTRACT FROM AUTHOR]

Selenoproteins (eg glutathione peroxidases, thioredoxin redoxin reductases, some methionine sulfoxide reductases) play a key role in reducing oxidative stress. Diabetes is linked with impaired wound healing, and increased infection and tissue morbidity. Hypothesis: that a novel seleno-sugar (SeTal) with antioxidant activity would reduce oxidative damage, decrease chemotactic signals and inflammatory mediators, and improve wound healing in wildtype and diabetic mice. Methods Pairs of circular incision wounds on wildtype C57/BL6 and diabetic (db - /db - ) mice (n=12) were treated with SeTal (1 mM) or vehicle, topically for 10 days. Wound closure, vascular perfusion (Doppler imaging) and tissue histology were assessed. Results Wound closure in wildtype mice treated with SeTal was 2-fold greater than controls at day 4 (32% vs 17.5%, p<0.05) and greater at day 10 (82% vs 65%, p<0.01). Diabetic mice showed significantly slower wound closure compared to wildtype in the absence of Se. With Se administration, significant improvements in wound closure were detected in the diabetic mice, with this being 3-fold faster than control diabetic mice at day 4 (32% vs 11%, p<0.001) and 2-fold better at day 10 (83% vs 45%, p<0.0001). Doppler imaging showed improved vascular perfusion (p<0.05) in diabetic, but not wild type, wounds treated with SeTal. Tissue histology showed decreased levels of MPO (p<0.001), MCP-1 (p<0.001), IL-6 (p<0.05) and vWF (p<0.01), and increased elastin levels (p<0.01) in diabetic wounds treated with Se compared to vehicle. Conclusions Enhanced wound healing occurs in the presence of the novel selenium compound. This enhancement was more marked in diabetic compared to wildtype mice. The decrease in monocyte chemotactic activity, IL-6 expression and improvements in tissue elasticity and tensile strength, suggest that this selenium compound may aid wound healing. [ABSTRACT FROM AUTHOR]

Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens. [ABSTRACT FROM AUTHOR]

To support efforts to vaccinate millions of Americans across the United States (US) against COVID-19, the US federal government (USG) launched the Pharmacy Partnership for Long-Term Care Program (PPP) in December 2020 and the Federal Retail Pharmacy Program (FRPP) in February 2021. These programs consisted of a collaborative partnership with the USG and 21 pharmacy organizations, including large retail chains, coordinating pharmacy services administrative organizations (PSAOs) representing independent retail and long-term care pharmacies, and pharmacy network administrators. These pharmacy organizations represented over 46,000 providers and created a robust channel for far-reaching COVID-19 vaccination across 56 state and local jurisdictions. PPP reported more than 8 million COVID-19 doses administered to residents and staff in long-term care facilities (LTCFs) as of June 2021. In addition, FRPP was responsible for administering more than 304 million doses, accounting for approximately 49% of all COVID-19 doses administered as of June 2023. This unprecedented public–private partnership allowed USG to rapidly adapt, expand, and aim to provide equitable access to vaccines for adults and eligible-aged children during the COVID-19 pandemic. As the largest federal COVID-19 vaccination program, the FRPP exemplifies how public–private partnerships can expand access to immunizations during a public health emergency. End-to-end informatics support helped pharmacies meet critical national public health goals and served as convenient access points for sustained health services. This manuscript describes lessons learned regarding informatics coordination with participating pharmacy partners to support the rapid and safe administration of COVID-19 vaccines across the US. The processes of onboarding to CDC's complex data network, establishing connections to state and local immunization information systems (IIS), and monitoring the quality of data pharmacy partners submitted to the CDC Data Clearinghouse (DCH) in alignment with the COVID-19 Vaccine Reporting Specifications (CVRS) are highlighted. [ABSTRACT FROM AUTHOR]

Quantification of the unbound portion of platinum (Pt) in human plasma is important for assessing the pharmacokinetics of the chemotherapeutic drug cisplatin. In this study, we sought to compare the recovery of unbound Pt using Nanosep® filters to 1) traditional filters (Centrifree®, Centrisart ® , Amicon®) or trichloroacetic acid (TCA) protein precipitation, and 2) unbound, bound, and total Pt concentrations in clinical specimens. For the tested filters, the impact of 1) molecular weight cut-offs, 2) centrifugation force, and 3) total Pt concentration on Pt binding in human plasma was evaluated. Pt was quantified using inductively coupled-plasma mass spectrometry. In human plasma spiked with 0.9 μg/mL Pt, the percent of unbound Pt increased at higher centrifugation speeds. By comparison, the percent of unbound Pt was highest (42.1%) following TCA protein precipitation. When total Pt was ≤0.9 μg/mL, unbound Pt (∼20–30%) was consistent across filters. Conversely, when plasma was spiked with Pt exceeding 0.9 μg/mL, the percent of unbound Pt increased from 36.5 to 48% using ultrafiltration, compared to 63.4% to 79% with TCA precipitation. In patients receiving cisplatin-containing chemotherapy, the fraction of unbound Pt at concentrations exceeding 0.9 μg/mL ranged between 35 and 90%. Moreover, the unbound fraction of Pt in plasma correlated with the concentration of unbound (R2 = 0.738) and total Pt (R2 = 0.335). In summary, this study demonstrates that 1) the percent of unbound Pt is influenced by total and unbound Pt levels in vitro and in clinical specimens, and 2) ultrafiltration with Nanosep® filters is a feasible method for quantifying unbound Pt concentrations in human plasma. [ABSTRACT FROM AUTHOR]

Retrospective studies have shown improvement in migraines after patent foramen ovale (PFO) closure. To date, no study has evaluated whether the completeness of closure affects headache status; therefore, the objective of this study was to evaluate the impact of residual right-to-left shunt (RLS) on migraine symptoms after transcatheter PFO closure in migraineurs with and without aura. This was a small-series, single-center, retrospective analysis of late follow-up data on 77 patients with presumed paradoxical embolism and migraine who underwent PFO closure for secondary stroke prevention. Power M-mode transcranial Doppler was used to assess RLS at baseline and 6 and 12 months after closure. A standardized migraine questionnaire was administered at baseline and 6, 12, and 24 months after closure. Fifty-five (71%) patients had migraine with aura. Final closure and migraine status were available for 67 patients; 23 (34%) had incomplete PFO closure, defined as 30 embolic tracks detected at final power M-mode transcranial Doppler examination (median 366 days, 95% confidence interval 332 to 474). Migraine relief (≥50% reduction in frequency) was independent of closure status (77% complete closure vs 83% incomplete closure, p = 0.76) at late follow-up (540 days, 95% confidence interval 537 to 711). Migraineurs with aura were 4.5 times more likely to experience migraine relief than migraineurs without aura. In conclusion, migraine relief may occur despite residual RLS after transcatheter PFO closure, which may suggest a reduction in RLS burden below a neuronal threshold that triggers migraine; however, this warrants further investigation. Migraine with aura may be an independent predictor of relief after PFO closure. [Copyright &y& Elsevier]

Percutaneous tissue sampling in spondylodiscitis is frequently performed but with highly variable yield in literature and unclear clinical impact. Factors that influence the culture success rate are not well established. To determine target specific yield and clinical impact of percutaneous biopsy in clinically and imaging diagnosed spinal infection and factors that may influence the yield rate. Institutional review board approved single center retrospective chart review from 2015 to 2019 analyzing imaging findings, clinical notes, procedural reports, and laboratory results on cases of concurrent imaging and clinically diagnosed spondylodiscitis that underwent percutaneous tissue sampling. A total of 111 patients and 189 specimens were analyzed. The overall culture yield in spondylodiscitis was approximately 27%, 9% affecting management. Abscess/fluid and septic arthritis aspirations had higher yield rates compared to soft tissue/phlegmon aspirations. Core sampling of the bone and disc yielded positive culture 12% of the time, 2% resulted in change in management. Upper thoracic spine biopsies were more frequently positive and associated with change in management. Positive culture elsewhere in the body represented the major reason underlying lack of clinical impact. Lack of prior antibiotic treatment and diabetes mellitus demonstrated a trend toward higher culture positivity, although a larger sample size is needed to confirm these findings. No repeat biopsy yielded positive culture. Staphylococcus spp. accounted for approximately half of the microorganisms cultured. In positive biopsies where infection was also found elsewhere in the body, the organism was nearly always congruent (96%). • Percutaneous spinal infection biopsy in the absence of abscess, phlegmon, or septic arthritis is associated with low yield. • Only 1/3 of the positive biopsies change management, most commonly due to positive culture from elsewhere in the body. • Possible mildly higher yield is seen in patients with diabetes and no prior antibiotic treatment, warranting further study. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) mediate cell-cell crosstalk by carrying bioactive molecules derived from cells. Recently, immune cell-derived EVs have been reported to regulate key biological functions such as tumor progression. CD4+ T cells orchestrate overall immunity; however, the biological role of their EVs is unclear. This study reveals that EVs derived from CD4+ T cells increase the antitumor response of CD8+ T cells by enhancing their proliferation and activity without affecting regulatory T cells (Tregs). Moreover, EVs derived from interleukin-2 (IL2)-stimulated CD4+ T cells induce a more enhanced antitumor response of CD8+ T cells compared with that of IL2-unstimulated CD4+ T cell-derived EVs. Mechanistically, miR-25-3p, miR-155-5p, miR-215-5p, and miR-375 within CD4+ T cell-derived EVs are responsible for the induction of CD8+ T cell-mediated antitumor responses. In a melanoma mouse model, the EVs potently suppress tumor growth through CD8+ T cell activation. This study demonstrates that the EVs, in addition to IL2, are important mediators between CD4+ and CD8+ T cells. Furthermore, unlike IL2, clinically used as an antitumor agent, CD4+ T cell-derived EVs stimulate CD8+ T cells without activating Tregs. Therefore, CD4+ T cell-derived EVs may provide a novel direction for cancer immunotherapy by inducing a CD8+ T cell-mediated antitumor response. [ABSTRACT FROM AUTHOR]

Summary Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 ( TET2 ) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4 + T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2 −/− RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation. [ABSTRACT FROM AUTHOR]