Effect of chamber capacitance on Doppler flow pattern across restrictive defects in obligatory atrial-level shunts

The right atrium has a significantly higher capacitance than the left atrium, and this may affect the Doppler flow pattern across an atrial septal defect (ASD) in unilateral atrioventricular (AV) valve atresia. This Doppler flow pattern is often used to assess ASD adequacy in this setting. We studied the effect of atrial capacitance and ASD size on the trans-ASD Doppler flow pattern in an in vivo flow model of alternate left or right AV valve atresia (LAVVA and RAVVA). We assessed trans-ASD Doppler flow patterns using the max/min velocity ratio and mean interatrial pressure gradients (PGs). In both models, ASD flow rate correlated with mean trans-ASD PG, but for similar flow rates the slope was higher in the LAVVA model. In LAVVA, a persistent PG was consistently observed, with low max/min ratio (median, 1.46; range, 1.03-3.13), whereas in RAVVA, phasic flow was common (median, 8.0; range, 2.8-20). Because atrial capacitance affects mean PG and Doppler flow pattern across the ASD, we propose that the assessment of ASD adequacy in RAVVA should not rely on Doppler findings.     

Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice

Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)⁺ in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

The Role of Oxidative Stress in Aseptic Loosening of Total Hip Arthroplasties

This study investigated the hypothesis that wear particle-induced oxidative stress initiates osteolysis after total hip arthroplasty (THA). Patient radiographs were scored for osteolysis and periprosthetic tissues were immunostained and imaged to quantify polyethylene wear, inflammation, and five osteoinflammatory and oxidative stress-responsive factors. These included high mobility group protein-B1 (HMGB1), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), 4-hydroxynonenal (4-HNE), and nitrotyrosine (NT). The results show wear debris correlated with inflammation, 4-HNE, NT and HMGB1, whereas inflammation only correlated with NT and HMGB1. Similar to wear debris and inflammation, osteolysis correlated with HMGB1. Additionally, osteolysis correlated with COX2 and 4-HNE, but not iNOS or NT. Understanding the involvement of oxidative stress in wear-induced osteolysis will help identify diagnostic biomarkers and therapeutic targets to prevent osteolysis after THA.     

Micropapillary bladder cancer: Current treatment patterns and review of the literature

ObjectivesNo guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature.Materials and methodsA survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network–sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review.ResultsMost survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease.ConclusionsThe management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC.     

Interventions to Increase Medication Adherence in African-American and Latino Populations: A Literature Review

The objective of this systematic review was to investigate the effectiveness of interventions to improve medication adherence in ethnic minority populations. A literature search from January 2000 to August 2012 was conducted through PubMed/Medline, Web of Science, The Cochrane Library, and Google Scholar. Search terms used included: medication (MeSH), adherence, medication adherence (MeSH), compliance (MeSH), persistence, race, ethnicity, ethnic groups (MeSH), minority, African-American, Hispanic, Latino, Asian, Pacific Islander, and intervention. Studies which did not have ≥75% of the sample population comprised of individuals of any one ethnic background were excluded, unless the authors performed sub-group analyses by race/ethnicity. Of the 36 studies identified, 20 studies showed significant post-intervention differences. Sample population sizes ranged from 10 to 520, with a median of 126.5. The studies in this review were conducted with patients of mainly African-American and Latino descent. No studies were identified which focused on Asians, Pacific Islanders, or Native Americans. Interventions demonstrating mixed results included motivational interviewing, reminder devices, community health worker (CHW) delivered interventions, and pharmacist-delivered interventions. Directly observed therapy (DOT) was a successful intervention in two studies. Interventions which did not involve human contact with patients were ineffective. In this literature review, studies varied significantly in their methods and design as well as the populations studied. There was a lack of congruence among studies in the way adherence was measured and reported. No single intervention has been seen to be universally successful, particularly for patients from ethnic minority backgrounds.Keyword: Medication adherence, compliance, intervention, ethnic minority     

Inpatient Prescribing and Monitoring of Fentanyl Transdermal Systems: Adherence to Safety Regulations

Background:

National safety guidelines were developed to minimize the occurrence of serious adverse drug events (ADEs) associated with the use of the fentanyl transdermal system (FTS), however, reports of use in opioid-naïve patients for treatment of acute pain and associated ADEs continue to occur.

Objective:

To evaluate the prescribing patterns of the FTS for adherence to recent US regulatory recommendations and identify the impact of health information technology (HIT) on adherence rates.

Methods:

A retrospective pre- and postintervention analysis was performed in hospitalized adult patients receiving FTS. Electronic medication order instructions and text questions were incorporated into FTS electronic medication orders. The primary outcome measure was adherence of FTS medication orders to regulatory guidelines defined as (a) a new order in an opioid-tolerant patient for use in moderate to severe chronic pain or (b) continuation of the documented home dose in use for at least 7 days. Safety measures included respiratory rate and documented ADEs.

Results:

Adherence rates were significantly increased in the postintervention cohort as compared to the preintervention cohort (48.7% vs 85.0%; P < .0001). Incidence of ADEs was significantly lower post intervention (34.7% vs 23.3%; P = .043), including a lower incidence of respiratory depression (16.7% vs 8.3%; P = .043). Documentation was increased in the postintervention cohort (76% vs 100%). However, supporting documentation confirmed responses in only 59.2% of records reviewed.

Conclusions:

Incorporation of HIT via electronic order text questions increased overall adherence rates to regulatory recommendations, increased documentation, and decreased the rate of associated ADEs.     

Gaps in Serologic Immunity against Contemporary Swine-Origin Influenza A Viruses among Healthy Individuals in the United States

Influenza A Viruses (IAV) in domestic swine (IAV-S) are associated with sporadic zoonotic transmission at the human–animal interface. Previous pandemic IAVs originated from animals, which emphasizes the importance of characterizing human immunity against the increasingly diverse IAV-S. We analyzed serum samples from healthy human donors (n = 153) using hemagglutination-inhibition (HAI) assay to assess existing serologic protection against a panel of contemporary IAV-S isolated from swine in the United States (n = 11). Age-specific seroprotection rates (SPR), which are the proportion of individuals with HAI ≥ 1:40, corresponded with lower or moderate pandemic risk classifications for the multiple IAV-S examined (one H1-δ1, one H1-δ2, three H3-IVA, one H3-IVB, one H3-IVF). Individuals born between 2004 and 2013 had SPRs of 0% for the five classified H3 subtype IAV-S, indicating youth may be particularly predisposed to infection with these viruses. Expansion of existing immunologic gaps over time could increase likelihood of future IAV-S spillover to humans and facilitate subsequent sustained human-to-human transmission resulting in disease outbreaks with pandemic potential.