Simulation of ultrasonic scattering from scatterer size distributions using Field II.

Quantitative analysis of radio frequency (RF) signals obtained from ultrasound scanners can yield objective parameters that are gaining clinical relevance as imaging biomarkers. These include the backscatter coefficient (BSC) and the effective scatterer diameter (ESD). Biomarker validation is typically performed in phantoms which do not provide the flexibility of systematic variation of scattering properties. Computer simulations, such as those from the ultrasound simulator Field II, can allow more flexibility. However, Field II does not allow simulation of RF data from a distribution of scatterers with finite size. In this work, a simulation method is presented which builds upon previous work by including Faran theory models representative of distributions of scatterer size. These are systematically applied to RF data simulated in Field II. The method is validated by measuring the root mean square error of the estimated BSC and percent bias of the ESD and comparing to experimental results. The results indicate the method accurately simulates distributions of scatterer sizes and provides scattering similar to that seen in data from clinical scanners. Because Field II is widely used by the ultrasound community, this method can be adopted to aid in validation of quantitative ultrasound imaging biomarkers.

Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair.

The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood-brain-barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated. Targeting and activation of CB2R was accomplished by a novel and highly specific chromenopyrazole based CB2R agonist, PM289. This study demonstrates that CB2R upregulation is induced as early as 8 h in the cortical vasculature in an experimental mouse model of TBI. Unlike CB2R, CB1R was marginally detected and not significantly induced. In the human brain endothelial cell line, hCMEC/D3 cells, similar induction of CB2R was observed upon stimulation with TNFα. Analysis of transendothelial electrical resistance shows that PM289 markedly prevented the barrier-leakiness induced by TNFα. The BBB is also responsible for maintaining an immunological barrier. The five-fold increase in ICAM1 expression in stimulated endothelial cells was significantly diminished due to CB2R activation. Utilizing wounding assays, results showed that wound repair could be accomplished in nearly half the time when the novel CB2R agonist is present compared to the untreated control. Lastly, mechanistically, the effects of CB2R may be explained by the observed inhibition of the p65 NFκB subunit. Overall, these studies support the notion that targeting and activating CB2R in the brain vasculature could aid in BBB and vascular protection in the context of neuroinflammation.

An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature.

Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs). We performed two rounds of in vivo selection with an AAV capsid scaffold displaying a heptamer peptide library to isolate capsids that traffic to the brain after intravenous delivery. One identified capsid, termed AAV-PR, demonstrated high transduction of the brain vasculature, in contrast to the parental capsid, AAV9, which transduces mainly neurons and astrocytes. Further analysis using tissue clearing, volumetric rendering, and colocalization revealed that AAV-PR enabled high transduction of cerebral pericytes located on small-caliber vessels and SMCs in the larger arterioles and penetrating pial arteries. Analysis of tissues in the periphery indicated that AAV-PR also transduced SMCs in large vessels associated with the systemic vasculature. AAV-PR was also able to transduce primary human brain pericytes with higher efficiency than AAV9. Compared with previously published AAV capsids tropisms, AAV-PR represents the first capsid to allow for effective transduction of brain pericytes and SMCs and offers the possibility of genetically modulating these cell types in the context of neurodegeneration and other neurological diseases.

Disabled-by-design: effects of inaccessible urban public spaces on users of mobility assistive devices - a systematic review.

PURPOSE: Despite the increase of users of Mobility Assistive Devices (MobAD), there has been a lack of accessibility in urban environments in many parts of the world. We present a systematic review of how the inaccessible design of public spaces affects quality-of-life - including aspects of health and safety, independence, and social participation - of MobAD users. MATERIALS AND METHODS: We conducted a literature search in three databases (i.e., Scopus, Web of Science, and PubMed) and initially discovered 3980 publications. We analysed 48 peer-reviewed journal articles published in English from 2005 to 2021 and assessed their quality of evidence via the Mixed Methods Appraisal Tool. RESULTS: Findings indicated a substantial number of inaccessible elements for MobAD users in public spaces. Pathway characteristics, boarding ramps, entrance features, confined spaces, and service surfaces were deemed to be the least accessible elements. These barriers had multifaceted effects on MobAD users' quality of life with aspects of physical health, mobility, and use of public transport being most affected. CONCLUSIONS: Notwithstanding that the reviewed studies mostly ocused on wheelchair users residing in high-income countries, this review outlines the critical role of the design of the built environment as a factor of disablement for MobAD users. We conclude by highlighting a few recommendations for future research and practice, especially inclusive approaches and adaptive techniques to assist MobAD users with performing tasks in public spaces independently. Implications for RehabilitationUsers of Mobility Assistive Devices experience a lack of accessibility provisions in public open spaces and buildings internationally.Physical barriers in public spaces substantially diminish the health and safety, autonomy, and social participation of users of Mobility Assistive Devices.There is a definite need for the adoption of inclusive strategies and adaptive techniques in placemaking processes so that users of Mobility Assistive Devices can have equitable access to public spaces.

A Qualitative Study of Intimate Partner Violence Among Young Gay and Bisexual Men.

Intimate partner violence (IPV) is prevalent among young gay and bisexual men (YGBM) and is associated with physical and mental health problems, as well as deleterious psychosocial conditions. Most previous studies of IPV among YGBM have been quantitative in nature and have not examined the numerous subtypes of IPV, the chronicity of IPV experiences, and how is IPV manifested in the context of these same-sex relationships. Thus, a qualitative approach may be useful in exploring these multidimensional and understudied experiences. The present qualitative study sought to (a) explore dimensions of IPV victimization, perpetration, and bidirectional IPV among a sample of (n = 26) YGBM living in New York City and (b) explore the chronicity of IPV experiences among these YGBM. Participants were recruited from an ongoing cohort study of YGBM. Participants completed semistructured interviews that included questions about IPV victimization, perpetration, and bidirectional IPV. A modified version of the consensual qualitative research method was used to analyze the data. The YGBM in this study reported numerous forms of physical, psychological, sexual, and financial IPV victimization and perpetration. Bidirectional experiences of IPV were common. The various subtypes of IPV victimization and perpetration are explored in detail in this manuscript. In addition, many participants reported multiple experiences of abuse within the same relationship, and some participants experienced a pattern of abusive relationships over time. This study corroborates findings from quantitative studies, which indicate that IPV is a prevalent and significant health problem among YGBM, and one that warrants additional attention from researchers, practitioners, and policy-makers. Furthermore, this study adds rich qualitative data to the existing literature-data that can be used to help develop and refine future measures of IPV that are tailored for use with YGBM.

Role of pregaming motives in accounting for links between maladaptive personality traits and drinking consequences.

College students are at heightened risk of engaging in unhealthy alcohol use that leads to negative consequences (e.g., motor vehicle accidents, poor academic performance). Understanding how individual differences, such as maladaptive personality traits, contribute to that risk could improve intervention efforts. A potential pathway through which personality confers risk for consequences is by influencing students' motivation to drink. In this study of 441 college students, we investigated whether different motivations to pregame, a particularly risky and common drinking practice on college campuses, accounts for links between maladaptive traits and alcohol-related consequences. Results of bivariate analyses showed that all pregaming motives and maladaptive traits (except detachment) were strongly correlated with negative consequences. In path analytic models that adjusted for shared variance between pregaming motives and between maladaptive traits, results showed that traits had indirect effects on total drinking consequences via individual differences in pregaming motives as well as direct effects that were independent of motives. Specifically, antagonism, disinhibition, and negative affectivity predicted more drinking consequences via stronger motives to pregame for instrumental reasons over and above the general motivation to pregame, whereas detachment predicted fewer consequences via weaker instrumental pregaming motives. Antagonism and disinhibition were also associated with more drinking consequences, and detachment with fewer consequences, over and above pregaming motives and general personality problems. Our study indicates that one way maladaptive personality traits may shape alcohol-related consequences in college students is by associations with their motivations to pregame. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro.

Tissue engineering of the blood-brain barrier (BBB) in vitro has been rapidly expanding to address the challenges of mimicking the native structure and function of the BBB. Most of these models utilize 2D conventional microfluidic techniques. However, 3D microvascular models offer the potential to more closely recapitulate the cytoarchitecture and multicellular arrangement of in vivo microvasculature, and also can recreate branching and network topologies of the vascular bed. In this perspective, we discuss current 3D brain microvessel modeling techniques including templating, printing, and self-assembling capillary networks. Furthermore, we address the use of biological matrices and fluid dynamics. Finally, key challenges are identified along with future directions that will improve development of next generation of brain microvasculature models.

Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV-1 Signifying Unresolved Inflammation.

Treatment of HIV-infected patients with antiretroviral therapy (ART) has effectively suppressed viral replication; however, the central nervous system is still a major target and reservoir of the virus leading to the possible development of HIV-associated neurocognitive disorders (HAND). Furthermore, a hallmark feature of HAND is the disruption of the blood-brain barrier that leads to loss of tight junction protein (TJP) complexes. Extracellular vesicles (EVs), released by every cell type in the body, occur in greater quantities in response to cellular activation or injury. We have found that inflammatory insults activate brain endothelial cells (EC) and induce the release of EVs containing TJPs such as Occludin. We thus hypothesized that HIV infection and unresolved neuroinflammation will result in the release of brain-EC derived EVs. Herein, our results show elevated levels of brain-EC EVs in a humanized mouse model of HIV infection. Furthermore, while ART reduced brain-EC EVs, it was unable to completely resolve increased vesicles detectable in the blood. In addition to inflammatory insults, HIV-1 viral proteins (Tat and gp120) increased the release of Occludin + vesicles from human brain microvasculature ECs. This increase in vesicle release could be prevented by knock-down of the small GTPase ARF6. ARF6 has been shown to regulate EV biogenesis in other cell types, and we provide further evidence for the involvement of ARF6 in brain EC derived EVs. Overall, this study offers insight into the process of brain vascular remodeling (via EVs) in the setting of neuroinflammation and thus provides possibilities for biomarker monitoring and targeting of ARF6.

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

Economic Outcomes Associated with Safety Interventions by a Pharmacist-Adjudicated Prior Authorization Consult Service.

BACKGROUND: The establishment of a formulary management system ensures that health care professionals work together in an integrated patient care process to promote clinically sound, safe, and cost-effective medication therapy. Pharmacists have a foundational role within this system. A pharmacist-adjudicated prior authorization drug request (PADR) consult service has the potential to optimize drug therapy by decreasing medication misuse, minimizing adverse drug events (ADEs), and preventing medication errors. OBJECTIVES: To (a) determine cost avoidance associated with pharmacist-adjudicated PADR safety interventions within the Durham Veterans Affairs Health Care System and (b) evaluate cost savings associated with pharmacist-adjudicated PADRs not approved due to a safety intervention, evaluate cost avoidance and direct cost savings based on clinical specialty of pharmacist adjudicating PADR, and characterize severity of avoided ADEs. METHODS: Pharmacist-adjudicated PADRs not approved between July 1, 2016, and June 30, 2017, because of safety interventions were retrospectively reviewed. Cost avoidance was determined by multiplying the probability of ADE occurrence in the absence of PADR safety intervention by the estimated cost avoided based on the type of intervention. Direct cost savings was calculated by totaling the cost of requested medications not approved for each PADR and subtracting the cost of recommended alternative therapies and cost of pharmacist PADR review. All potential ADEs avoided were reviewed by a panel of 3 clinical pharmacists to validate ADE classification and ADE probability and severity scores. Descriptive statistics were used for all analyses. RESULTS: Of the 910 PADRs that were not approved during the study period, 96 met inclusion criteria. Pharmacist-adjudicated PADR safety interventions resulted in a total cost avoidance of $24,485.34 (mean = $255.06) and a direct cost savings of $288,695.63 (mean = $3,007.25). The practice settings of anticoagulation and infectious diseases PADRs resulted in the largest contribution to cost avoidance and direct cost savings, respectively. Prevented ADEs were classified as major for 64.6% of the PADRs. CONCLUSIONS: Pharmacist-adjudicated PADR safety reviews resulted in substantial economic benefit and prevention of major ADEs. This analysis supports the pharmacist's role in a formulary management system to optimize medication therapy. DISCLOSURES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors. The authors have nothing to disclose.

Pharmacy resident involvement in prior-authorization drug request adjudication.

PURPOSE: Results of a study to determine economic outcomes of pharmacy residents' involvement in prior-authorization drug request (PADR) adjudication within a Veterans Affairs (VA) healthcare system are reported. METHODS: A retrospective review was conducted to identify PADRs adjudicated by pharmacy residents under a preceptor's supervision during the 2015-16 residency year. Only PADRs that were not approved as submitted (i.e., only those requiring formulary intervention) and that met other inclusion criteria were included in the analysis. Prior-authorization requests and adjudication decisions were characterized, and cost savings resulting from those decisions were calculated. RESULTS: Of the total of 752 PADRs adjudicated by 6 pharmacy residents during the study period, 42 met the inclusion criteria. About 90% of included PADRs were categorized as general medicine requests, and 9.5% were for oncology medications. The most common rationale for PADR nonapproval (cited in 60% of requests) was the availability of a preferred formulary alternative; the remainder of nonapprovals were due to medication safety concerns (e.g., contraindication to therapy, drug interaction potential, likelihood of adverse drug event resulting in patient harm, history of allergy to requested medication). Resident adjudication of PADRs resulted in total direct cost savings of $169,877.53 over the 12-month period, a mean of $4,044.70 per request. CONCLUSION: Pharmacy residents' involvement in adjudicating PADRs at a VA healthcare system resulted in substantial cost savings over the course of the residency year.

Practice Characteristics and Geographic Distribution of Clinical Pharmacist Practitioners in North Carolina.

BACKGROUND: Clinical pharmacist practitioners (CPPs) are specially credentialed pharmacists in North Carolina. CPPs potentially play an important role in meeting the health care needs of populations in rural and underserved areas. METHODS: A cross-sectional study was conducted using an electronic survey sent to all active and inactive CPPs in North Carolina. The survey consisted of 36 multiple-choice and free text questions. Respondents were queried regarding qualifications, experience, practice characteristics, and perceived rewards and challenges of CPP practice. RESULTS: Survey responses were received from 54 active CPPs and 22 inactive CPPs, for an overall response rate of 65.5%. Forty-one active CPPs (75.9%) and 14 inactive CPPs (63.6%) came from ambulatory care backgrounds. Twenty-eight active CPPs (51.9%) and 11 inactive CPPs (50.0%) practiced in an urban setting, while 7 active CPPs (13.0%) and 3 inactive CPPs (13.6%) practiced in a rural setting. The majority of CPPs work in larger practices. Thirty-three active CPPs (61.1%) and 12 inactive CPPs (54.5%) were paid by the institutions for which they were employed. LIMITATIONS: The overall survey response rate was only 65.5%. Additionally, the majority of survey questions were in a multiple-choice format, which may have prevented more honest reflection. CONCLUSIONS: Active CPPs most often come from ambulatory care backgrounds. Few CPPs are practicing in rural areas, a circumstance that may be related to financial viability, as most CPP practice in, and are compensated by, larger institutions such as academic health centers.

Perceived successes and challenges of clinical pharmacist practitioners in North Carolina.

OBJECTIVES: To describe the successes and challenges reported by current (active) and formerly practicing (inactive) CPPs and to determine the reasons why inactive CPPs discontinued advanced practice. METHODS: A sampling frame, consisting of all active and inactive CPPs, was obtained from the North Carolina Boards of Medicine and Pharmacy. An electronic survey was sent to 84 active and 32 inactive CPPs. Respondents were queried regarding qualifications, experience, and practice characteristics, perceived successes, and perceived challenges. RESULTS: 54 active and 22 inactive CPPs responded. Among active CPPs, 28 (51.9%) reported improved patient care outcomes and 27 (50.0%) reported an expanded scope of practice. Regarding challenges, 30 (55.6%) identified billing for services and 19 (35.2%) noted reimbursement through third parties. Among inactive CPPs, 14 (63.6%) experienced improved patient care outcomes and 11 (50.0%) said their licensure created a practice model for learners. Billing (54.5%) and reimbursement (31.8%) were the top challenges experienced by inactive CPPs. A total of 12 inactive CPPs (54.5%) discontinued CPP licensure because it was not a requirement of their current position. Three (13.6%) discontinued because of insurmountable challenges that made it difficult to continue practice. CONCLUSION: Although CPPs held a perception of improved patient care outcomes, billing for services and obtaining reimbursement were reported as the most prevalent challenges and may have played a major role in CPPs becoming inactive.

Non-small cell lung carcinoma metastatic to the kidney.

INTRODUCTION: Renal metastasis by non-small cell lung cancer is uncommon and usually described at autopsy. CASE PRESENTATION: We report the rare case of a 77-year-old man with localized non-small cell lung carcinoma who underwent extirpative surgery and 2 years later presented with gross hematuria and was noted to have a large infiltrating renal mass on computed tomography. CONCLUSIONS: In patients with a prior history of resected localized non-small cell lung carcinoma, presence of a renal lesion should prompt the clinician to consider the possibility of metastasis. Further evaluation should consider this scenario.

CT findings of perforated rectal carcinoma presenting as Fournier's gangrene in the emergency department.

We report a case of a perforated rectal adenocarcinoma presenting as Fournier's in the emergency department. CT findings in this case confirmed the clinical diagnosis, established the extent of disease, and suggested the presence of an underlying rectal neoplasm as the primary source of infection.