Point-of-Care Ultrasound-Guided Arthrocentesis of a Pediatric Septic Ankle.

ABSTRACT: Septic arthritis is one potential cause of pediatric joint effusion and pain that may lead to significant morbidity. We present a case where point-of-care ultrasound was used to identify and aspirate a joint effusion in a pediatric patient with septic arthritis of the ankle, facilitating timely diagnosis and care. We review the technique for arthrocentesis of the ankle and literature on point-of-care ultrasound in the diagnosis of pediatric septic arthritis.

Patient and social factors related to nebulizer use in COPD patients at the transition of care: a qualitative study.

BACKGROUND: Transition from hospital to home is a vulnerable period for patients with COPD exacerbations, with a high risk for readmission and mortality. Twenty percent of patients with an initial hospitalization for a COPD exacerbation are readmitted to a hospital within 30 days, costing the health care system over $15 billion annually. While nebulizer therapy directed at some high-risk COPD patients may improve the transition from hospital to home, patient and social factors are likely to contribute to difficulties with their use. Current literature describing the COPD patient's experience with utilizing nebulizer therapy, particularly during care transitions, is limited. Therefore, the objective of this study was to explore underlying COPD patient and social factors contributing to practical difficulties with nebulizer use at the care transition from hospital to home. METHODS: This was a qualitative study conducted between September 2020 and June 2022. Patients were included if they were ≥ 40 years old, had a current diagnosis of COPD, had an inpatient admission at a hospital, and were discharged directly to home with nebulizer therapy. Semi-structured, one-on-one interviews with patients were conducted covering a broad range of patient and social factors and their relationships with nebulizer use and readmission. Interviews were recorded and transcribed verbatim. A thematic analysis was performed using a mixed inductive and deductive approach. RESULTS: Twenty-one interviews were conducted, and subjects had a mean age of 64 ± 8.4 years, 62% were female, and 76% were White. The predominant interview themes were health care system interactions and medication management. The interviews highlighted that discharge counseling methods and depth of counseling from hospitals were inconsistent and were not always patient-friendly. They also suggested that patients could appropriately identify, set up, and utilize their nebulizer treatment without difficulties, but additional patient education is required for nebulizer clean up and maintenance. CONCLUSIONS: Our interviews suggest that there is room for improvement within the health care system for providing consistent, effective discharge counseling. Also, COPD patients discharged from a hospital on nebulizer therapy can access and understand their treatment but require additional education for nebulizer clean up and maintenance.

Integrating community health workers within a pharmacy to address health-related social needs.

BACKGROUND: Community pharmacies in the United States are beginning to serve as patient care service destinations addressing both clinical and health-related social needs (HRSN). Although there is support for integrating social determinant of health (SDoH) activities into community pharmacy practice, the literature remains sparse on optimal pharmacy roles and practice models. OBJECTIVE: To assess the feasibility of a community pharmacy HRSN screening and referral program adapted from a community health worker (CHW) model and evaluate participant perceptions and attitudes toward the program. METHODS: This feasibility study was conducted from January 2022 to April 2022 at an independent pharmacy in Buffalo, NY. Collaborative relationships were developed with 3 community-based organizations including one experienced in implementing CHW programs. An HRSN screening and referral intervention was developed and implemented applying a CHW practice model. Pharmacy staff screened subjects for social needs and referred to an embedded CHW, who assessed and referred subjects to community resources with as-needed follow-up. Post intervention, subjects completed a survey regarding their program experience. Descriptive statistics were used to report demographics, screening form, and survey responses. RESULTS: Eighty-six subjects completed screening and 21 (24.4%) an intervention and referral. Most participants utilized Medicaid (57%) and lived within a ZIP Code associated with the lowest estimated quartile for median household income (66%). Eighty-seven social needs were identified among the intervention subjects, with neighborhood and built environment (31%) and economic stability challenges (30%) being the most common SDoH domains. The CHW spent an average of 33 minutes per patient from initial case review through follow-up. All respondents had a positive perception of the program, and the majority agreed that community pharmacies should help patients with their social needs (70%). CONCLUSIONS: This feasibility study demonstrated that embedding a CHW into a community pharmacy setting can successfully address HRSN and that participants have a positive perception toward these activities.

Clinical and economic effectiveness of a pharmacy and primary care collaborative transition of care program.

BACKGROUND: Primary care pharmacists are uniquely positioned to improve care quality by intervening within care transitions in the postdischarge period. However, additional evidence is required to demonstrate that pharmacist-led interventions can reduce health care utilization in a cost-effective manner. The study's objective was to evaluate the clinical and economic effectiveness of a pharmacy-led transition of care (TOC) program within a primary care setting. METHODS: This cluster randomized trial was conducted between 2019 and 2021 and included three primary care practices. Eligible patients were ≥18 years of age and at high risk of readmission. The multifaceted pharmacy intervention included medication reconciliation, comprehensive medication review, and patient and provider follow-up. The primary composite endpoint included hospital readmissions and emergency department (ED) visits within 30 days of discharge. Differences in outcomes were modeled using a generalized estimated equations approach and outcomes were assumed to be distributed as a Poisson random variable. A cost-benefit analysis was embedded within the study and estimated economic outcomes from a provider group/health system perspective. Cost measures included: net benefit, benefit to cost ratio (BCR), and return on investment (ROI). RESULTS: Of 300 eligible patients, 36 were in the intervention group and 264 in the control group. The intervention significantly reduced the primary composite outcome of all-cause readmissions and ED visits within 30 days (adjusted incidence rate ratio [aIRR], 0.54; 95% CI, 0.44-0.66; P < 0.001). There were significant reductions in both 30-day all-cause readmissions (aIRR, 0.64; 95% CI, 0.60-0.67; P < 0.001) and ED visits (aIRR, 0.25; 95% CI, 0.20, 0.31; P < 0.001) between groups. The net benefit of the intervention was $9,078, with a BCR of 2.11 and a ROI of 111%. Sensitivity analyses were robust to changes in economic inputs. CONCLUSION: This care transition program had positive clinical and economic benefits, providing further support for the essential role pharmacists demonstrate in providing TOC services.

A taxonomy for community pharmacy patient care services reported in Pharmacist eCare Plans.

BACKGROUND: Pharmacies belonging to the Community Pharmacy Enhanced Service Networks (CPESN) are transforming their practices with support of the Flip the Pharmacy initiative. These pharmacies are submitting eCare plans that describe care that they have provided to patients. OBJECTIVES: The objectives of this study were (1) To develop a taxonomy for services reported by community pharmacies participating in year 1 of the Flip the Pharmacy initiative and (2) to illustrate the use of the taxonomy for hypertension-related services. METHODS: A retrospective observational study design was used. The analyzed data were extracted from eCare plans submitted by participating pharmacies during the first year of the Flip the Pharmacy initiative (October 1, 2019-September 30, 2020). Systematized Nomenclature of Medicine - Clinical Terms (SNOMED-CT) codes submitted for encounter reason and for procedures were sorted into categories based on similarity of terminology in the SNOMED-CT code labels. All SNOMED-CT codes in the encounter reasons that had blood pressure or hypertension in their labels were mapped to taxonomy categories. Descriptive statistics were calculated for all variables. RESULTS: A total of 368,297 eCare plans reporting 1,049,061 SNOMED-CT procedures were submitted for 133,210 patients by 526 pharmacies. Seven categories of community pharmacy patient care services were identified: medication synchronization, medication review, monitoring, immunizations, patient education, adherence, and recommendations. Over half of the encounter reasons (63.5%) and procedures (56.2%) were for medication synchronization. Both medication review and monitoring accounted for about 10% of the encounters, and medication review made up over 30% of procedures. A total of 18,307 encounters were related to hypertension. Of these, monitoring was the most frequent, with 11,285 encounters (61.6%) encounters, followed by patient education, with 5173 encounters (28.3%). CONCLUSION: CPESN pharmacies are delivering a wide range of patient care services. This taxonomy provides a concise way to organize and report services being delivered by community pharmacies.

Monomeric/dimeric forms of Fgf15/FGF19 show differential activity in hepatocyte proliferation and metabolic function.

Human Fibroblast Growth Factor 19 (FGF19) and mouse ortholog Fgf15 play similar roles in liver regeneration and metabolism via the activation of Fgfr4/b-klotho (Klb). Monomeric FGF19 and dimeric Fgf15 are both necessary for liver regeneration and proper bile acid (BA) metabolism. FGF19 elicits stronger effects than Fgf15 on glucose and fatty acid metabolism and only FGF19 induces hepatocellular carcinoma (HCC). However, inhibiting FGF19/FGFR4 signaling in HCC patients is associated with toxicity due to elevated BA levels. Here, we examine the structure/function relationship in Fgf15/FGF19 to better understand the molecular basis for their distinct functions. We demonstrate that FGF19 is a more effective activator of Fgfr4 and of downstream signaling (Erk, Plcg1) than Fgf15. Furthermore, we use site-directed mutagenesis to show that the presence or absence of an unpaired cysteine in Fgf15/19 modulates ligand structure and determines the ability of these molecules to induce hepatocyte proliferation, with monomers being more potent activators. Consistent with these findings, an engineered dimeric variant of FGF19 is less effective than wild-type FGF19 at inducing liver growth in cooperation with the Wnt-enhancer RSPO3. In contrast to effects on proliferation, monomeric and dimeric ligands equally inhibited the expression of Cyp7a1, the enzyme catalyzing the rate limiting step in BA production. Thus, structure and function of Fgf15/FGF19 are intricately linked, explaining why FGF19, but not Fgf15, induces liver tumorigenesis. Our data provide insight into FGF19/FGFR4 signaling and may inform strategies to target this pathway while limiting on-target toxicity due to dysregulation of BA production or induction of hepatocyte proliferation.

Implementation and evaluation of social determinants of health practice models within community pharmacy.

BACKGROUND: While community pharmacies are an ideal setting for social needs screening and referral programs, information on social risk assessment within pharmacy practice is limited. OBJECTIVES: Our primary objective was to describe 2 social determinant of health (SDOH) practice models implemented within community pharmacies. The secondary objective was to evaluate implementation practices utilizing the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. PRACTICE DESCRIPTION: Two pharmacy groups participated in a 3-month study, one in New York (9 pharmacies) and another in Missouri (1 pharmacy). The New York pharmacies implemented an SDOH specialist practice model, in which pharmacy staff members facilitate the program. The Missouri pharmacy implemented a community health worker (CHW) model by cross training their technicians. Each pharmacy developed their program using the Community Pharmacy Enhanced Services Network Care Model. PRACTICE INNOVATION: Both programs expanded the technician role to take on additional responsibilities. The SDOH specialist model partnered with a local independent practice association to create a social needs referral program using a technology platform for closed-loop communication. All workflow steps of the self-contained CHW program were completed within the pharmacy, placing additional responsibility on the CHW and pharmacy staff. EVALUATION METHODS: RE-AIM framework dimensions of Reach, Effectiveness, and Adoption. RESULTS: Social challenges were identified in 49 of 76 (65%) generated SDOH screenings. The most prevalent social needs reported were affordability of daily needs (33%) and health care system navigation (15%). While most pharmacy staff indicated that workflow steps were clearly defined, assessments and referral tools were identified as potential gaps. While approximately 50% of pharmacy staff were comfortable with their assigned roles and in addressing SDOH challenges, physical and mental health concerns required additional education for intervention. CONCLUSION: The successful implementation of community pharmacy SDOH programs connected patients with local resources. Community pharmacies are ideally positioned to expand their public health footprint through SDOH interactions that consequently improve patient care.

Socio-demographic and -economic factors associated with 30-day readmission for conditions targeted by the hospital readmissions reduction program: a population-based study.

BACKGROUND: Early hospital readmissions remain common in patients with conditions targeted by the CMS Hospital Readmission Reduction Program (HRRP). There is still no consensus on whether readmission measures should be adjusted based on social factors, and there are few population studies within the U.S. examining how social characteristics influence readmissions for HRRP-targeted conditions. The objective of this study was to determine if specific socio-demographic and -economic factors are associated with 30-day readmissions in HRRP-targeted conditions: acute exacerbation of chronic obstructive pulmonary disease, pneumonia, acute myocardial infarction, and heart failure. METHODS: The Nationwide Readmissions Database was used to identify patients admitted with HRRP-targeted conditions between January 1, 2010 and September 30, 2015. Stroke was included as a control condition because it is not included in the HRRP. Multivariate models were used to assess the relationship between three social and economic characteristics (gender, urban/rural hospital designation, and estimated median household income within the patient's zip code) and 30-day readmission rates using a hierarchical two-level logistic model. Age-adjusted models were used to assess relationship differences between Medicare vs. non-Medicare populations. RESULTS: There were 19,253,997 weighted index hospital admissions for all diagnoses and 3,613,488 30-day readmissions between 2010 and 2015. Patients in the lowest income quartile (≤$37,999) had an increased odds of 30-day readmission across all conditions (P < 0.0001). Female gender and rural hospital designation were associated with a decreased odds of 30-day readmission for most targeted conditions (P < 0.05). Similar findings were also seen in patients ≥65 years old. CONCLUSIONS: Socio-demographic and -economic factors are associated with 30-day readmission rates and should be incorporated into tools or interventions to improve discharge planning and mitigate against readmission.

Readmissions and costs among younger and older adults for targeted conditions during the enactment of the hospital readmission reduction program.

BACKGROUND: The Hospital Readmissions Reduction Program (HRRP) was introduced to reduce readmission rates among Medicare beneficiaries, however little is known about readmissions and costs for HRRP-targeted conditions in younger populations. The primary objective of this study was to examine readmission trends and costs for targeted conditions during policy implementation among younger and older adults in the U.S. METHODS: We analyzed the Nationwide Readmission Database from January 2010 to September 2015 in younger (18-64 years) and older (≥65 years) patients with acute myocardial infarction (AMI), heart failure (HF), pneumonia, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Pre- and post-HRRP periods were defined based on implementation of the policy for each condition. Readmission rates were evaluated using an interrupted time series with difference-in-difference analyses and hospital cost differences between early and late readmissions (≤30 vs. > 30 days) were evaluated using generalized linear models. RESULTS: Overall, this study included 16,884,612 hospitalizations with 3,337,266 readmissions among all age groups and 5,977,177 hospitalizations with 1,104,940 readmissions in those aged 18-64 years. Readmission rates decreased in all conditions. In the HRRP announcement period, readmissions declined significantly for those aged 40-64 years for AMI (p < 0.0001) and HF (p = 0.003). Readmissions decreased significantly in the post-HRRP period for those aged 40-64 years at a slower rate for AMI (p = 0.003) and HF (p = 0.05). Readmission rates among younger patients (18-64 years) varied within all four targeted conditions in HRRP announcement and post-HRRP periods. Adjusted models showed a significantly higher readmission cost in those readmitted within 30 days among younger and older populations for AMI (p < 0.0001), HF (p < 0.0001), pneumonia (p < 0.0001), and AECOPD (p < 0.0001). CONCLUSION: Readmissions for targeted conditions decreased in the U.S. during the enactment of the HRRP policy and younger age groups (< 65 years) not targeted by the policy saw a mixed effect. Healthcare expenditures in younger and older populations were significantly higher for early readmissions with all targeted conditions. Further research is necessary evaluating total healthcare utilization including emergency department visits, observation units, and hospital readmissions in order to better understand the extent of the HRRP on U.S. healthcare.

Addressing social determinants of health in community pharmacy: Innovative opportunities and practice models.

Social determinants of health (SDoH) account for up to 90% of health outcomes, whereas medical care accounts for only 10%-15%; despite this disparity, only 24% of hospitals and 16% of physician practices screen for the 5 social needs. Community-embedded and highly accessible, pharmacies are uniquely positioned to connect individuals to local community and social resources and thereby address SDoH. In this article, we explore novel community pharmacy practice models that address SDoH, provide real-world examples of these models, and discuss pathways for reimbursement and sustainability. A number of innovative community pharmacy practice models that focus on social issues are currently being explored. These include integrating community health workers (CHWs) or SDoH specialists, wherein CHWs are frontline public health workers who can effectively bridge the health care system and their community, whereas SDoH specialists are pharmacy team members trained with substantial SDoH knowledge and how to use it to connect pharmacy patients to community resources. Three community pharmacy networks have implemented pilot programs using either a CHW or SDoH specialist model. An essential component for program success in all cases has been partnership development and increased interdependence between the pharmacies, local community organizations, and the public health sector. New payment models and financial incentives will be necessary to expand and sustain these programs. A potential Approach may be the use of Z codes, a subset of ICD-10-CM codes specific to assessing SDoH. Although opportunities are developing for community pharmacies to play a major role in sustainably addressing SDoH, additional work is needed before there is a widespread acceptance of pharmacies becoming service referral destinations for patients with social needs. Evaluation of these models on a wider scale will be necessary to fully evaluate their effectiveness, costs, and implementation within different community pharmacy settings.

Deriving Large-Scale Coastal Bathymetry from Sentinel-2 Images Using an HIGH-Performance Cluster: A Case Study Covering North Africa's Coastal Zone.

Coasts are areas of vitality because they host numerous activities worldwide. Despite their major importance, the knowledge of the main characteristics of the majority of coastal areas (e.g., coastal bathymetry) is still very limited. This is mainly due to the scarcity and lack of accurate measurements or observations, and the sparsity of coastal waters. Moreover, the high cost of performing observations with conventional methods does not allow expansion of the monitoring chain in different coastal areas. In this study, we suggest that the advent of remote sensing data (e.g., Sentinel 2A/B) and high performance computing could open a new perspective to overcome the lack of coastal observations. Indeed, previous research has shown that it is possible to derive large-scale coastal bathymetry from S-2 images. The large S-2 coverage, however, leads to a high computational cost when post-processing the images. Thus, we develop a methodology implemented on a High-Performance cluster (HPC) to derive the bathymetry from S-2 over the globe. In this paper, we describe the conceptualization and implementation of this methodology. Moreover, we will give a general overview of the generated bathymetry map for NA compared with the reference GEBCO global bathymetric product. Finally, we will highlight some hotspots by looking closely to their outputs.

Pharmacist-led transitions-of-care services in primary care settings: Opportunities, experiences, and challenges.

OBJECTIVE: To initiate a call to action for ambulatory care pharmacists to play a more active role in transitional care management within primary care settings by discussing relevant opportunities, experiences, and challenges. SUMMARY: With the shift to value-based health care, greater emphasis is being placed on improving patient care quality at the lowest cost. This represents an opportunity for pharmacist integration into primary care teams to address medication management challenges in the postdischarge period. Primary care pharmacists are uniquely positioned to close gaps in care not typically addressed by hospital-based programs. These pharmacists can provide complex transition interventions tailored toward individual patients, including comprehensive medication review, patient counseling, and direct collaboration with providers. For broad acceptance of these services, current challenges include identifying and prioritizing high-risk patients, establishing the cost-effectiveness of these strategies, and ultimately applying dissemination and implementation methodologies to increase the potential impact of these interventions. CONCLUSION: Opportunities are expanding for primary care pharmacists to play a more substantial role in transitional care management in sustainable ways. For widespread implementation of these strategies, additional research is necessary to determine their clinical effectiveness as well as cost-effectiveness and to understand better the barriers and facilitators to adopting these interventions.

Prevalence of Human Papillomavirus Genotypes and Abnormal Pap Smears Among Women in the Military Health System.

Human papillomavirus infection (HPV) is the most common sexually transmitted infection among United States Military Servicemembers, and present in the majority of cervical cancers. Many of these infections are preventable, but HPV immunization is not mandatory during military service. The objective of this study was to examine the prevalence of vaccine-preventable cervical disease among women enrolled in the San Antonio Military Health System. This is a retrospective cross-sectional study of Pap smear results and HPV genotyping data among Military Servicewomen and beneficiaries. Simple descriptive statistics and logistic regression were used to assess the association between demographics, cervical pathology and high-risk HPV (hrHPV) infection. Pap smears were obtained by 16.9% of women and cervical pathology was present in 28.8% of samples. Compared to the 25-34 year group, 35-44 year-olds were more likely to have an abnormal Pap smear (OR 1.25, CI 1.05-1.50). Of the samples tested, 10.5% were positive for hrHPV. Adjusted multivariable analysis revealed that hrHPV infection was more likely among the 23-34 year group when compared to 35-44 (OR 0.50, CI 0.38-0.67), 45-54 (0.40. CI 0.28-0.59) and 55-65 year groups (0.46, CI 0.30-0.71). Active Duty Servicewomen were more likely to test positive for hrHPV when compared to Active Duty Family Members (OR 0.59, CI 0.45-0.79) and Retiree Family Members (OR 0.59, CI 0.41-0.83). Younger women and Active Duty Servicewomen are significantly more likely to have cervical infection with hrHPV. Future studies should assess the cost-effectiveness of mandatory HPV immunization for military members.

Oxygen reduction reaction induced pH-responsive chemo-mechanical hydrogel actuators.

We describe and characterize elementary designs for electrochemical micro- and macro-scale chemomechanical hydrogel actuators. The actuation of a pH-sensitive cross-linked polyacrylic acid (PAA) hydrogel is driven in the model devices through the oxygen reduction reaction (ORR) occurring at the electrodes of an embedded Au mesh micro-electrochemical array. Proton consumption by the ORR at the cathode of the embedded electrochemical cell leads to the formation of a localized pH gradient that in turn drives the strain response in the composite actuators. The dynamics result from the ionization of the carboxylic acid moieties of the PAA network in the high pH region, yielding an osmotic pressure that drives a volumetric expansion due to water imbibition. This system actuates both stably and reversibly; when the electrochemically-induced ORR is halted, the localized pH gradient dissipates due to diffusive mixing, which in turn relaxes the induced strains. Two approaches to the fabrication of hydrogel actuators were examined in this work. The first method adopted a design based on small flagella (∼0.2 mm × 1.5 mm × 60 µm, width × length × height) in which the actuating PAA structures are molded atop a set of fixed electrodes mounted on a supporting substrate. These hydrogel actuators show fast, large-amplitude, and largely reversible responses in the ORR mediated chemomechanical dynamics. We also investigated larger hydrogel actuators (∼4.5 mm × 11 mm × 1 mm, width × length × height), based on an autonomous design that embeds an open mesh stretchable micro-electrode array within the hydrogel. The significant and design-dependent impacts of mass transfer on the chemomechanical dynamics are evidenced in each case, a feature examined to elucidate more efficient mesoscopic design rules for actuators of this form.

Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor.

The vasculature of the CNS is structurally and functionally distinct from that of other organ systems and is particularly prone to developmental abnormalities and hemorrhage. Although other embryonic tissues undergo primary vascularization, the developing nervous system is unique in that it is secondarily vascularized by sprouting angiogenesis from a surrounding perineural plexus. This sprouting angiogenesis requires the TGF-ß and Wnt pathways because ablation of these pathways results in aberrant sprouting and hemorrhage. We have genetically deleted Gpr124, a member of the large family of long N-terminal group B G protein-coupled receptors, few members of which have identified ligands or well-defined biologic functions in mammals. We show that, in the developing CNS, Gpr124 is specifically expressed in the vasculature and is absolutely required for proper angiogenic sprouting into the developing neural tube. Embryos lacking Gpr124 exhibit vascular defects characterized by delayed vascular penetration, formation of pathological glomeruloid tufts within the CNS, and hemorrhage. In addition, they display defects in palate and lung development, two processes in which TGF-ß and/or Wnt pathways also play important roles. We also show that TGF-ß stimulates Gpr124 expression, and ablation of Gpr124 results in perturbed TGF-ß pathway activation, suggesting roles for Gpr124 in modulating TGF-ß signaling. These results represent a unique function attributed to a long N-terminal group B-type G protein-coupled receptor in a mammalian system.

Incidence and magnitude of bacteraemia caused by flossing and by scaling and root planing.

AIM: (1) Investigate incidence, magnitude and bacterial diversity of bacteraemia due to flossing compared with scaling and root planing (SRP) and (2) Identify any associations with clinical parameters. MATERIALS AND METHODS: Full-mouth flossing and single quadrant SRP were performed at separate visits for 30 patients with chronic periodontitis. Baseline blood samples and at 30 s and 10 min. after completion of flossing, 5 min. after initiation of SRP and 30 s and 10 min. after completion of SRP were obtained. Total bacteraemia and viridans streptococcal bacteraemia (VSB) were investigated. RESULTS: Total bacteraemia incidence was 30% for flossing and 43.3% for SRP (no significant difference; p = 0.21). Flossing and SRP caused the same incidence of VSB (26.7%). Flossing caused a higher mean magnitude of total bacteraemia than SRP (7.4 ± 16.2 CFU/ml versus 2 ± 3.4 CFU/ml), but the difference was not significant (p = 0.2). Flossing caused a higher mean magnitude of VSB than SRP (1.2 ± 1.6 CFU/ml versus 0.4 ± 0.2 CFU/ml), but the difference was not significant (p = 0.09). Viridans streptococci comprised 11.4% of flossing bacteraemia isolates and 7.6% in SRP. No correlations were found between clinical parameters and incidence or magnitude of bacteraemia following flossing. Gingival inflammation was significantly associated with incidence of total bacteraemia (p = 0.01) and VSB (p = 0.001) following SRP. No correlations were found for any parameter and magnitude of total bacteraemia or VSB following SRP. CONCLUSIONS: No differences were found between flossing and SRP in the incidence or magnitude of total bacteraemia or VSB. This finding is important in the ongoing re-evaluation of antibiotic prophylaxis to prevent infective endocarditis.

Preclinical Study of a Biparatopic METxMET Antibody-Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC.

PURPOSE: MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody-drug conjugate targeting MET in MET-driven patient-derived models. EXPERIMENTAL DESIGN: Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114. RESULTS: REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment. CONCLUSIONS: Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

Generic versus disease-specific adverse event reporting: a comparison of the NSQIP and SAVES databases for the identification of acute care adverse events in adult spine surgery.

OBJECTIVE: The accurate identification and reporting of adverse events (AEs) is crucial for quality improvement. A myriad of AE systems are utilized. There is a lack of understanding of the differences between prospective versus retrospective, disease-specific versus generic, and point-of-care versus chart-abstracted systems. The objective of this study was to compare the benefits and limitations between the prospective, disease-specific, point-of-care Spine Adverse Events Severity System (SAVES) and the retrospective, generic, and chart-abstracted National Surgical Quality Improvement Program (NSQIP) for the identification and reporting of AEs in adult patients undergoing spinal surgery. METHODS: The authors conducted an observational ambidirectional cohort study of adult patients undergoing spine surgery other than for trauma between 2011 and 2019 in a quaternary spine center. Patients were identified using Current Procedural Terminology codes in the NSQIP database and matched using unique medical record numbers to their corresponding record in SAVES. The incidence of AEs and per-patient AEs as recorded in NSQIP and SAVES was the primary outcome of interest. Comparable AEs were identified by matching NSQIP AEs to equivalent ones in SAVES. Chi-square tests were used to test for significant differences in the incidence of overall and comparable AEs between the databases. RESULTS: There were 2198 patients identified in NSQIP, of whom 2033 also had complete records in SAVES. SAVES identified 5342 individual AEs in 1484 patients (73%) compared with 1291 individual AEs in 807 patients (39.7%) with the NSQIP database (p < 0.001). SAVES identified 250 intraoperative and 422 postoperative spine-specific AEs that NSQIP did not record. NSQIP captured a greater number of AEs beyond 30 days, including prolonged length of stay > 30 days, unplanned readmission, unplanned reoperation, and death later than 30 days after surgery compared with SAVES. CONCLUSIONS: SAVES captures a greater incidence of peri- and intraoperative spine-specific AEs than NSQIP, while NSQIP identifies a greater number of AEs beyond 30 days. While a prospective, disease-specific, point-of-care AE system such as SAVES is specific for guiding quality improvement in spine surgery, it incurs greater time and financial costs. Conversely, a retrospective, generic, and chart-abstracted system such as NSQIP provides equivocal cross-institutional comparability with reduced time and financial costs. Specific contextual and aim-specific needs should guide the choice and implementation of an AE system.

A Bispecific METxMET Antibody-Drug Conjugate with Cleavable Linker Is Processed in Recycling and Late Endosomes.

Most antibody-drug conjugates (ADC) approved for the treatment of cancer contain protease-cleavable linkers. ADCs that traffic to lysosomes traverse highly acidic late endosomes, while ADCs that recycle to the plasma membrane traffic through mildly acidic sorting and recycling endosomes. Although endosomes have been proposed to process cleavable ADCs, the precise identity of the relevant compartments and their relative contributions to ADC processing remain undefined. Here we show that a METxMET biparatopic antibody internalizes into sorting endosomes, rapidly traffics to recycling endosomes, and slowly reaches late endosomes. In agreement with the current model of ADC trafficking, late endosomes are the primary processing site of MET, EGFR, and prolactin receptor ADCs. Interestingly, recycling endosomes contribute up to 35% processing of the MET and EGFR ADCs in different cancer cells, mediated by cathepsin-L, which localizes to this compartment. Taken together, our findings provide insight into the relationship between transendosomal trafficking and ADC processing and suggest that receptors that traffic through recycling endosomes might be suitable targets for cleavable ADCs.

IL-6-GP130 signaling protects human hepatocytes against lipid droplet accumulation in humanized liver models.

Liver steatosis is an increasing health issue with few therapeutic options, partly because of a paucity of experimental models. In humanized liver rodent models, abnormal lipid accumulation in transplanted human hepatocytes occurs spontaneously. Here, we demonstrate that this abnormality is associated with compromised interleukin-6 (IL-6)-glycoprotein 130 (GP130) signaling in human hepatocytes because of incompatibility between host rodent IL-6 and human IL-6 receptor (IL-6R) on donor hepatocytes. Restoration of hepatic IL-6-GP130 signaling, through ectopic expression of rodent IL-6R, constitutive activation of GP130 in human hepatocytes, or humanization of an Il6 allele in recipient mice, substantially reduced hepatosteatosis. Notably, providing human Kupffer cells via hematopoietic stem cell engraftment in humanized liver mice also corrected the abnormality. Our observations suggest an important role of IL-6-GP130 pathway in regulating lipid accumulation in hepatocytes and not only provide a method to improve humanized liver models but also suggest therapeutic potential for manipulating GP130 signaling in human liver steatosis.