SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors.

Purpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.

Percutaneous Drainage of Pediatric Pulmonary Abscesses: An Effective Therapy.

INTRODUCTION: Pulmonary abscess is a complication of lung infection with localized necrosis and purulent cavity formation. Pulmonary abscesses are typically managed using antibiotic therapy with anatomic surgical resection reserved as a rescue. Percutaneous drainage is considered relatively contraindicated in some centers due to perceived risk of bronchopleural fistula. However, drain placement has been frequently employed at our institution. The purpose of this study was to review and describe our longitudinal experience. METHODS: Medical records of children diagnosed with lung abscess and treated with percutaneous drainage from 2005 through 2023 were reviewed. Patient clinical parameters, follow-up imaging, and clinical outcomes were evaluated. RESULTS: Percutaneous drainage (n = 24) or aspiration alone (n = 4) under imaging guidance was performed by interventional radiologists for 28 children with lung abscesses. A single catheter (8-12 Fr) was deployed in the pulmonary abscess cavity and remained for a median of 6 days (IQR: 6-8 days). The median hospital stay was 10 days (IQR: 8.8-14.8 days). The technical success rate for percutaneous drainage or aspiration of primary pulmonary abscesses was 100% (26/26). Two children were later diagnosed with secondarily infected congenital pulmonary airway malformations that were both successfully drained and ultimately surgically resected. The abscess cavities resolved in all patients and catheters were removed upon clinical, radiographic, and laboratory improvement. Complications included the presence of two bronchopleural fistula, both of which were treated with immediate pleural drain placement. CONCLUSION: Percutaneous drainage of pulmonary abscesses is an effective therapeutic option in children and can be considered alongside antibiotics as part of the initial treatment for pulmonary abscesses. Bronchopleural fistula can occur, but at a lower frequency than previously reported. LEVEL OF EVIDENCE: Level V.

The influence of sex on activity in voluntary wheel running, forced treadmill running, and open field testing.

Introduction: Physical activity is commonly used for both measuring and treating dysfunction. While preclinical work has been historically biased towards males, the use of both male and female animals is gaining popularity after multiple NIH initiatives. With increasing inclusion of both sexes, it has become imperative to determine sex differences in common behavioral assays. The purpose of this study was to determine baseline sex differences in 3 activity assays: voluntary wheel running, forced treadmill running, and open field testing. Methods: This was a secondary analysis of sex differences in healthy mice in 3 different assays: Separate mice were used for each assay. Specifically, 16 mice underwent 28 days of voluntary wheel running, 178 mice underwent forced treadmill running, and 88 mice underwent open field testing. Differences between sex across several activity parameters were examined for each assay. Results: In voluntary wheel running, sex differences with larger effect sizes were observed in distance run, running time, and bout duration, with smaller effect size differences in speed, and no difference in total bouts. In forced treadmill running, differences were shown in time to exhaustion, but no difference in max speed attained. In open field, there were sex differences in active time but not in distance and speed in data aggregated over 30 minutes; however, distance and speed in male mice showed a downward trajectory over the final 20 minutes of testing, whereas females maintained the same trajectory. Conclusion: These data suggest that male mice demonstrate comparable activity intensity as female mice but do not match female's duration of activity, especially for volitional tasks. Researchers utilizing these assays should account for sex differences as they could potentially mask true findings in an experiment. Plain English Summary: Physical activity is a common measure to examine function in human subjects with and without disease. Animal models often use measures of physical activity to assess function, yet most of these measures have been done in males only, making interpretation and translation to females and humans difficult. Several measures have been used to measure activity in animals, including those examining voluntary running behavior, maximum capacity, and general activity levels; sex differences between these measures are unclear. We discovered sex differences throughout each of three activity tests. In voluntary running behavior there were large differences between sexes with females running a greater distance and spending more time running. There were small differences in the maximum capacity with females running for a longer period at high intensity. General activity levels showed small differences with females being less active than males. Thus, the greatest differences were found for voluntary running and small differences were found for maximum capacity and general activity levels; differences observed were dependent on the task. Researchers utilizing these assays should account for sex differences as they could potentially mask true findings in an experiment.

Antibiotic Prescribing Patterns for Urinary Tract Infections and Pneumonia by Prescriber Type and Specialty in Nursing Home Care, 2016-2018.

OBJECTIVE: To identify whether differences in antibiotic prescribing practices by prescriber type and specialization in nursing home (NH) care exist for urinary tract infection (UTI) and pneumonia. DESIGN: Retrospective cohort. SETTING AND PARTICIPANTS: This national study included antibiotic dispensings to traditional Medicare beneficiaries aged ≥65 years with UTI or pneumonia infections residing long-term (≥100 days) in US NHs between 2016 and 2018. METHODS: Minimum Data Set assessment data were linked to Medicare data [Part D prescription drug, inpatient hospital (MedPAR), prescriber characteristics, and enrollment]. We compared antibiotic prescribing patterns by prescriber type [physician vs advanced practice practitioner (AP)] and NH specialization (≥90% vs <90% of all associated medication dispensings to NH residents). Antibiotic dispensing measures included the total number of dispensings and duration of therapy (median number of days supplied) by antibiotic class. RESULTS: There were 264,735 antibiotic dispensings prescribed by 32,437 prescribers for 140,360 residents in 14,035 NHs. NH specialists were less likely to prescribe fluoroquinolones for UTI (22.9% NH specialist physician, 23.9% non-NH specialist physician, 21.3% NH specialist AP, 24.2% non-NH specialist AP), but more likely to prescribe fluoroquinolones for pneumonia (38.9%, 37.8%, 38.8%, 37.3%, respectively). Over time, NH specialists reduced fluoroquinolone prescribing for pneumonia to a greater extent than non-NH specialists. The duration of therapy was similar across prescriber groups for UTI, but longer among non-NH specialist APs for several antibiotic classes for pneumonia, including tetracyclines, glycopeptides and lipoglycopeptides, and metronidazole. CONCLUSIONS AND IMPLICATIONS: There were differences in antibiotic prescribing patterns by prescriber type and specialization in NH care between 2016 and 2018. Understanding how antibiotic prescribing differs based on prescriber characteristics is essential to inform antibiotic stewardship efforts. Tailoring antibiotic stewardship efforts to prescribers by NH specialization is rational given differences in antibiotic prescribing patterns based on NH specialization.

Evaluating the Safety and Efficacy of Capromorelin in Rhesus Macaques (Macaca mulatta).

Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.

Pnictogen-Rich Heterocycles Derived from a Phosphadiazonium Cation.

Heterocycles that pair main group elements and nitrogen are extremely important within the π-conjugated heterocycles research community. Compared to the vast number of boron-nitrogen heterocycles, those that include phosphorus are less common. Furthermore, the use of phosphorus-nitrogen triple bonds of any type to prepare such compounds is unprecedented. Here, we pair pyridyl hydrazonide ligands with phosphadiazonium cations and demonstrate that the chelated Mes*NP group is directly implicated in the photophysical and redox properties observed for the resulting heterocycles. In doing so, we introduce a novel building block for the production of phosphorus-containing heterocycles that could find use in small molecule activation and catalysis or as the functional component of emerging organic electronics.

Clinicians who primarily practice in nursing homes and outcomes among residents with urinary tract infection or pneumonia.

Objective: Assess the association between clinicians who primarily practice in nursing homes (NHs) and 14-day resident outcomes following initial antibiotic dispensing for pneumonia or urinary tract infection (UTI). Design: Retrospective cohort. Setting: U.S. NHs. Participants: NH residents aged ≥65 years who were prescribed antibiotics for pneumonia or UTI between 1 January 2016 and 30 November 2018. Methods: Medicare fee-for-service claims were linked to Minimum Data Set data. Clinicians who primarily practiced in NHs prescribed ≥90% of Part D dispensings to NH residents. Outcomes included death, all-cause and infection-specific hospitalization, and subsequent antibiotic dispensing. Adjusted risk ratios were estimated using inverse-probability-of-treatment-weighted (IPTW) modified Poisson regression models adjusting for 53 covariates. Results: The study population included 28,826 resident-years who were prescribed antibiotics for pneumonia and 106,354 resident-years who were prescribed antibiotics for UTI. Among the pneumonia group, clinicians who primarily practiced in NHs were associated with a greater risk of death (RR 1.3; 95%CLs 1.0, 1.6), lower risks of all-cause (RR 0.9; 95%CLs 0.8, 0.9) and infection-specific hospitalization (RR 0.8; 95%CLs 0.7, 0.9), and similar risk of subsequent antibiotic dispensing (RR 1.0; 95%CLs 1.0, 1.1) after IPTW. No meaningful associations were observed between clinicians who primarily practiced in NHs and outcomes among the UTI group. Conclusions: Clinicians who primarily practiced in NHs were associated with a lower risk of hospitalization but greater risk of mortality for NH residents with pneumonia. Further examination is needed to better understand drivers of differences in infection-related outcomes based on clinicians' training and primary practice setting.

A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate.

Introduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood-brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain. Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood-brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity. Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase. Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.

A Second Career for p53 as A Broad-Spectrum Antiviral?

As the world exits the global pandemic caused by the previously unknown SARS-CoV-2, we also mark the 30th anniversary of p53 being named "molecule of the year" by Science based on its role as a tumor suppressor. Although p53 was originally discovered in association with a viral protein, studies on its role in preventing carcinogenesis have far overshadowed research related to p53's role in viral infections. Nonetheless, there is an extensive body of scientific literature demonstrating that p53 is a critical component of host immune responses to viral infections. It is striking that diverse viruses have independently developed an impressive repertoire of varied mechanisms to counter the host defenses that are mediated by and through p53. The variety of ways developed by viruses to disrupt p53 in their hosts attests to the protein's importance in combatting viral pathogens. The present perspective aims to make the case that p53 ought to be considered a virus suppressor in addition to a tumor suppressor. It is hoped that additional research aimed at more fully understanding the role of p53 in antiviral immunity will result in the world being better positioned for the next pandemic than it was when SARS-CoV-2 emerged to produce COVID-19.

Geospatial Distribution of Racial Disparities in Influenza Vaccination in Nursing Homes.

OBJECTIVES: This study aimed to assess the distribution of racial disparities in influenza vaccination between White and Black short-stay and long-stay nursing home residents among states and hospital referral regions (HRRs). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: We included short-stay and long-stay older adults residing in US nursing homes during influenza seasons between 2011 and 2018. Included residents were aged ≥65 years and enrolled in Traditional Medicare. Analyses were conducted using resident-seasons, whereby residents could contribute to one or more influenza seasons if they resided in a nursing home across multiple seasons. METHODS: Our comparison of interest was marginalized vs privileged racial group membership measured as Black vs White race. We obtained influenza vaccination documentation from resident Minimum Data Set assessments from October 1 through June 30 of a particular influenza season. Nonparametric g-formula was used to estimate age- and sex-standardized disparities in vaccination, measured as the percentage point (pp) difference in the proportions of individuals vaccinated between Black and White nursing home residents within states and HRRs. RESULTS: The study included 7,807,187 short-stay resident-seasons (89.7% White and 10.3% Black) in 14,889 nursing homes and 7,308,111 long-stay resident-seasons (86.7% White and 13.3% Black) in 14,885 nursing homes. Among states, the median age- and sex-standardized disparity between Black and White residents was 10.1 percentage points (pps) among short-stay residents and 5.3 pps among long-stay residents across seasons. Among HRRs, the median disparity was 8.6 pps among short-stay residents and 5.0 pps among long-stay residents across seasons. CONCLUSIONS AND IMPLICATIONS: Our analysis revealed that the magnitudes of vaccination disparities varied substantially across states and HRRs, from no disparity in vaccination to disparities in excess of 25 pps. Local interventions and policies should be targeted to high-disparity geographic areas to increase vaccine uptake and promote health equity.

Is There a Consensus on Air Travel Following Hip and Knee Arthroplasty?

Introduction "When can I fly after my hip or knee replacement?" is a question frequently encountered by surgeons. Both air travel and arthroplasty increase the risk of venous thromboembolism (VTE); however, few studies examine the risk of air travel following arthroplasty. This study aimed to review the advice given to patients by surgeons, airlines, and insurance providers about flying after arthroplasty. We also review the current literature and available guidelines. Materials and methods A survey was sent to consultants with a special interest in hip or knee arthroplasty at 14 hospital trusts in the United Kingdom (UK) asking how long they would advise patients to avoid flying after surgery. We contacted all UK commercial airlines asking if they imposed any limitations on flying after arthroplasty. We contacted 15 UK insurance providers to determine whether they would provide insurance coverage following arthroplasty. Results A total of 110 knee surgeons and 105 hip surgeons were contacted. The response rate was 42% for hip surgeons and 44% for knee surgeons. Advised time to avoid flying varied widely from 14 to 180 days. A total of 22 airlines were contacted, and the response rate was 63% (n=14). Five airlines would not allow passengers to fly following arthroplasty and seven airlines required certification from a doctor. Fifteen insurance providers were contacted and the response rate was 73% (n=11). Seven insurance providers had restrictions on providing cover to passengers after arthroplasty. Conclusion Advice given to patients by surgeons, airlines, and insurance providers about flying following arthroplasty varies greatly. There is an absence of evidence-based guidelines to inform such advice. Further study is required to provide the evidence on which to base such advice. Therefore, we recommend that surgeons exercise caution when providing advice to patients.

Dyads and Triads of Boron Difluoride Formazanate and Boron Difluoride Dipyrromethene Dyes.

Dye-dye conjugates have attracted significant interest for their utility in applications such as bioimaging, theranostics, and light-harvesting. Many classes of organic dyes have been employed in this regard; however, building blocks don't typically extend beyond small chromophores. This can lead to minor changes to the optoelectronic properties of the original dye. The exploration of dye-dye structures is impeded by long synthetic routes, incompatible synthetic conditions, or a mismatch of the desired properties. Here, we present the first-of-their-kind dye-dye conjugates of boron difluoride complexes of formazanate and dipyrromethene ligands. These conjugates exhibit dual photoluminescence bands that reach the near-infrared spectral region and implicate anti-Kasha processes. Cyclic voltammetry experiments revealed the generation of polyanionic species that can reversibly tolerate the uptake of up to 6 electrons. Ultimately, we demonstrate that BF2 formazanates can serve as a synthetically accessible platform to build upon new classes of dye-dye conjugates.

Multicomponent Synthesis of Poly(α-aminophosphine chalcogenide)s and Subsequent Depolymerization.

Multicomponent reactions of primary phosphines (R-PH2), diimines (R'-N═C(H)-R-(H)C═N-R'), and chalcogens (O2, S8) generate poly(α-aminophosphine chalcogenide)s (4-7) through step-growth polymerization. Characterization of the linear polymers using 31P{1H} diffusion-ordered NMR spectroscopy (DOSY) experiments aided in determining the molecular weight (Mw) of the material. Subjecting the polyphosphine oxide or sulfide to reducing conditions in the presence of a Lewis acid resulted in complete depolymerization of the polymers, quantitatively releasing the 1° phosphine and diimine (2) starting materials, with concomitant reduction of diimine to diamine (9).

Trends in COVID-19-Related Medication Use in US Nursing Homes, 2018-2022.

OBJECTIVES: Little is known about how COVID-19 treatment patterns have evolved over time in nursing homes (NHs) despite the devastating effects of COVID-19 in this setting. The aim was to describe changes in COVID-19-related medication use over time among NH residents in the United States. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: This study used electronic health records (EHR) from 11 different US NH corporations between January 1, 2018, and March 31, 2022. METHODS: The use of medications approved for COVID-19-related conditions or known to be used off-label for COVID-19 during the study period is identified. We described trends in the use of each drug and combined use per 1000 NH residents over calendar time [quarters (Q)]. RESULTS: A total of 59,022 unique residents with the use of an eligible medication were identified. Hydroxychloroquine use sharply increased from 9.8 in 2020Q1 to 30.2 orders per 1000 individuals in 2020Q2. Dexamethasone use increased sharply from 14.8 in 2020Q2 to a peak of 121.9 orders per 1000 individuals in 2020Q4. Azithromycin use increased from 44.1 in 2019Q3 to a peak of 99.9 orders per 1000 individuals in 2020Q4, with a drop in 2020Q3 of 51.3 per 1000 individuals in 2020Q3. Concurrent use of azithromycin and hydroxychloroquine increased sharply from 0.3 in 2020Q1 to 10.6 orders per 1000 residents in 2020Q2 and then drastically decreased to 0.6 per 1000 residents in 2020Q3. Concurrent use of dexamethasone and azithromycin rose considerably from 0.7 in 2020Q2 to 28.2 orders per 1000 residents in 2020Q4. CONCLUSIONS AND IMPLICATIONS: As in other settings, COVID-19-related medication use in NHs appears to have changed in response to the shifting evidence base and availability of medications during the pandemic. Providers should continue to diligently modify their prescribing as new evidence accrues.

Geographic Variation in Racial Disparities in Receipt of High-Dose Influenza Vaccine Among US Older Adults.

BACKGROUND: Racial disparities in receipt of high-dose influenza vaccine (HDV) have been documented nationally, but whether small-area geographic variation in such disparities exists remains unknown. We assessed the distribution of disparities in HDV receipt between Black and White traditional Medicare beneficiaries vaccinated against influenza within states and hospital referral regions (HRRs). METHODS: We conducted a nationally representative retrospective cohort study of 11,768,724 community-dwelling traditional Medicare beneficiaries vaccinated against influenza during the 2015-2016 influenza season (94.3% White and 5.7% Black). Our comparison was marginalized versus privileged racial group measured as Black versus White race. Vaccination and type of vaccine were obtained from Medicare Carrier and Outpatient files. Differences in the proportions of individuals who received HDV between Black and White beneficiaries within states and HRRs were used to measure age- and sex-standardized disparities in HDV receipt. We restricted to states and HRRs with ≥ 100 beneficiaries per age-sex strata per racial group. RESULTS: We detected a national disparity in HDV receipt of 12.8 percentage points (pps). At the state level, the median standardized HDV receipt disparity was 10.7 pps (minimum, maximum: 2.9, 25.6; n = 30 states). The median standardized HDV receipt disparity among HRRs was 11.6 pps (minimum, maximum: 0.4, 24.7; n = 54 HRRs). CONCLUSION: Black beneficiaries were less likely to receive HDV compared to White beneficiaries in almost every state and HRR in our analysis. The magnitudes of disparities varied substantially across states and HRRs. Local interventions and policies are needed to target geographic areas with the largest disparities to address these inequities.

DPP4-Truncated CXCL12 Alters CXCR4/ACKR3 Signaling, Osteogenic Cell Differentiation, Migration, and Senescence.

Bone marrow skeletal stem cells (SSCs) secrete many cytokines including stromal derived factor-1 or CXCL12, which influences cell proliferation, migration, and differentiation. All CXCL12 splice variants are rapidly truncated on their N-terminus by dipeptidyl peptidase 4 (DPP4). This includes the common variant CXCL12 alpha (1-68) releasing a much less studied metabolite CXCL12(3-68). Here, we found that CXCL12(3-68) significantly inhibited SSC osteogenic differentiation and RAW-264.7 cell osteoclastogenic differentiation and induced a senescent phenotype in SSCs. Importantly, pre-incubation of SSCs with CXCL12(3-68) significantly diminished their ability to migrate toward CXCL12(1-68) in transwell migration assays. Using a high-throughput G-protein-coupled receptor (GPCR) screen (GPCRome) and bioluminescent resonance energy transfer molecular interaction assays, we revealed that CXCL12(3-68) acts via the atypical cytokine receptor 3-mediated ß-arrestin recruitment and as a competitive antagonist to CXCR4-mediated signaling. Finally, a reverse phase protein array assay revealed that DPP4-cleaved CXCL12 possesses a different downstream signaling profile from that of intact CXCL12 or controls. The data presented herein provides insights into regulation of CXCL12 signaling. Importantly, it demonstrates that DPP4 proteolysis of CXCL12 generates a metabolite with significantly different and previously overlooked bioactivity that helps explain discrepancies in the literature. This also contributes to an understanding of the molecular mechanisms of osteoporosis and bone fracture repair and could potentially significantly affect the interpretation of experimental outcomes with clinical consequences in other fields where CXCL12 is vital, including cancer biology, immunology, cardiovascular biology, neurobiology, and associated pathologies.

Geographic Variation in Influenza Vaccination Disparities Between Hispanic and Non-Hispanic White US Nursing Home Residents.

Background: 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). Methods: 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. Results: 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). Conclusions: 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.

Heterocyclic Phosphenium Cations and Their Divergent Coordination Chemistry.

While they are often encountered as reaction intermediates, phosphenium cations are not commonly incorporated into π-conjugated systems. We report the synthesis and characterization of donor-stabilized phosphenium cations supported by pyridylhydrazonide ligands. The preparation of these cations relies on precise control of ligand E-Z isomerism. The heterocycles were treated with a variety of transition metals, with [Rh(COD)Cl]2 yielding the only well-defined organometallic products. The optoelectronic properties of the phosphenium heterocycles and their transition-metal complexes were examined using UV-vis absorption spectroscopy, cyclic voltammetry, and modeling by density functional theory (DFT). Computations support the description of these compounds as phosphenium cations and corroborate our observation of a weak P-Npyridine bond, which was manifested experimentally as the Rh adducts undergo selective insertion of Rh into the P-Npyridine bond, depending on the substituent at phosphorus. The reported compounds provide a framework for further study of π-conjugated, N,N'-chelated phosphenium cations and their transition-metal adducts.