The utilization and safety of apixaban for therapeutic anticoagulation in heart transplant population requiring routine endomyocardial biopsies.

PURPOSE: Routine endomyocardial (EM) biopsies pose a challenge in the management of heart transplant recipients requiring anticoagulation. Apixaban is a direct-acting oral anticoagulant (DOAC) with a short half-life allowing for brief interruptions of anticoagulation for procedures. The study objective was to determine the safety and efficacy of apixaban in heart transplant patients undergoing EM biopsies. METHODS: This retrospective case series evaluated patients with a heart transplant from April 1, 2017 to July 30, 2020 who were treated with apixaban within 90 days post-transplant. The primary outcome was the occurrence of a bleeding or thrombotic event. RESULTS: A total of 12 patients with >100 biopsies were included. The median age was 54 years (IQR 37-59) with a mean weight of 91 ± 20 kg. There were no bleeding or thrombotic events. During therapy, patients underwent an average of eight biopsies. The median time from transplant to initiation of apixaban was 39.5 days (range 9-77). Therapy was maintained without any need for reversal for a median of 276 days (IQR 45-245). CONCLUSIONS: Apixaban is safe to use for anticoagulation of heart transplant recipients undergoing routine biopsies. Using apixaban allows for a short interruption of therapeutic anticoagulation to accommodate a biopsy without increased risk of bleeding.

Single-cell transcriptomic profiling provides insights into retinal endothelial barrier properties.

Purpose: To better characterize retinal endothelial barrier properties through analysis of individual transcriptomes of primary bovine retinal microvascular endothelial cells (RMECs). Methods: Individual RMECs were captured on the Fluidigm C1 system, cDNA libraries were prepared using a Nextera XT kit, and sequencing was performed on a NextSeq system (Illumina). Data analysis was performed using R packages Scater, SC3, and Seurat, and the browser application Automated Single-cell Analysis Pipeline (ASAP). Alternative splicing events in single cells were quantified with Outrigger. Cytoscape was used for network analyses. Results: Application of a single-cell RNA sequencing (scRNA-seq) analysis workflow showed that RMECs form a relatively homogeneous population in culture, with the main differences related to proliferation status. Expression of markers from along the arteriovenous tree suggested that most cells originated from capillaries. Average gene expression levels across all cells were used to develop an in silico model of the inner blood-retina barrier incorporating junctional proteins not previously reported within the retinal vasculature. Correlation of barrier gene expression among individual cells revealed a subgroup of genes highly correlated with PECAM-1 at the center of the correlation network. Numerous alternative splicing events involving exons within microvascular barrier genes were observed, and in many cases, individual cells expressed one isoform exclusively. Conclusions: We optimized a workflow for single-cell transcriptomics in primary RMECs. The results provide fundamental insights into the genes involved in formation of the retinal-microvascular barrier.

Impact of obesity on outcomes of hysterectomy.

STUDY OBJECTIVES: To evaluate the impact of obesity on complications of hysterectomy. STUDY DESIGN: Retrospective cohort study (Canadian Task Force II-2). SETTING: The Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI. PATIENTS: Patients who had a hysterectomy at WIH between July 2006 and January 2009. INTERVENTIONS: Hysterectomy by any mode. MEASUREMENTS AND MAIN RESULTS: We collected data from medical records of all laparoscopic hysterectomies during the time period and collected data from a random subset of abdominal and vaginal hysterectomies. The independent variable, body mass index, was grouped according to World Health Organization guidelines. A composite of surgical complications was generated. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We collected data from 907 hysterectomies, and 29.9% (n = 267) of the population was obese. Eighteen percent of patients (n = 154) had at least 1 complication. Compared to non-obese women, obese women were at increased odds of having any complication (OR 1.62, 95% CI 1.12-2-34). Performing subgroup analyses by mode of hysterectomy and controlling for confounding factors, we were unable to detect differences odds of complications between obese and non-obese women who underwent either an abdominal, vaginal, or laparoscopic hysterectomy. CONCLUSION: In our study, we found that among women who had a hysterectomy, obese women had a higher rate of complications than nonobese women.

Science- and Risk-Based Stability Strategies to Support Product Lifecycle Changes.

ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.

circadian rhythms are not captured equal: Exploring Circadian metrics extracted by differentcomputational methods from smartphone accelerometer and GPS sensors in daily life tracking.

Objective: To identify the differences between circadian rhythm (CR) metrics characterized by different mobile sensors and computational methods. Methods: We used smartphone tracking and daily survey data from 225 college student participants, applied four methods (survey construct automation, cosinor regression, non-parametric method, Fourier analysis) on two types of smartphone sensor data (GPS, accelerometer) to characterize CR. We explored the inter-relations among the extracted circadian metrics as well as between the circadian metrics and participants' self-reported mood and sleep outcomes. Results: Compared to GPS signals, smartphone accelerometer activity follows an intradaily distribution that starts earlier in the day, winds down later, reaches half cumulative activity about the same time, conforms less to a sinusoidal wave, and exhibits more intradaily fragmentation but higher CR strength and lower interdaily disruption. We found a notable negative correlation between intradaily variability and CR strength especially pronounced in GPS activity. Self-reported sleep and mood outcomes showed significant correlations with particular CR metrics. Conclusions: We revealed significant inter-relations and discrepancies in the circadian metrics discovered from two smartphone sensors and four CR algorithms and their bearings on wellbeing indicators such as sleep quality and loneliness.

Neural regions associated with gain-loss frequency and average reward in older and younger adults.

Research on the biological basis of reinforcement-learning has focused on how brain regions track expected value based on average reward. However, recent work suggests that humans are more attuned to reward frequency. Furthermore, older adults are less likely to use expected values to guide choice than younger adults. This raises the question of whether brain regions assumed to be sensitive to average reward, like the medial and lateral PFC, also track reward frequency, and whether there are age-based differences. Older (60-81 years) and younger (18-30 years) adults performed the Soochow Gambling task, which separates reward frequency from average reward, while undergoing fMRI. Overall, participants preferred options that provided negative net payoffs, but frequent gains. Older adults improved less over time, were more reactive to recent negative outcomes, and showed greater frequency-related activation in several regions, including DLPFC. We also found broader recruitment of prefrontal and parietal regions associated with frequency value and reward prediction errors in older adults, which may indicate compensation. The results suggest greater reliance on average reward for younger adults than older adults.

Rest-activity rhythms and white matter microstructure across the lifespan.

STUDY OBJECTIVES: The purpose of this study was to examine how rest-activity (RA) rhythm stability may be associated with white matter microstructure across the lifespan in healthy adults free of significant cardiovascular risk. METHODS: We analyzed multi-shell diffusion tensor images from 103 healthy young and older adults using tract-based spatial statistics (TBSS) to examine relationships between white matter microstructure and RA rhythm stability. RA measures were computed using both cosinor and non-parametric methods derived from 7 days of actigraphy data. Fractional anisotropy (FA) and mean diffusivity (MD) were examined in this analysis. Because prior studies have suggested that the corpus callosum (CC) is sensitive to sleep physiology and RA rhythms, we also conducted a focused region of interest analysis on the CC. RESULTS: Greater rest-activity rhythm stability was associated with greater FA across both young and older adults, primarily in the CC and anterior corona radiata. This effect was not moderated by age group. While RA measures were associated with sleep metrics, RA rhythm measures uniquely accounted for the variance in white matter integrity. CONCLUSIONS: This study strengthens existing evidence for a relationship between brain white matter structure and RA rhythm stability in the absence of health risk factors. While there are differences in RA stability between age groups, the relationship with brain white matter was present across both young and older adults. RA rhythms may be a useful biomarker of brain health across both periods of adult development.

Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report.

Letermovir is an antiviral agent indicated for primary prophylaxis of cytomegalovirus (CMV) infection and disease in adult allogeneic hematopoietic stem cell transplant recipients. In this case, UL97 mutation that conferred resistance to ganciclovir was seen in a patient 8 months after renal transplant. We report the off-label use of letermovir with adjunct hyperimmune CMV immunoglobulin in the successful treatment of CMV disease. This report is the first to use this combination for treatment of CMV infection with a high viral load. It contributes to the limited available literature supporting the use of letermovir in the treatment of resistant CMV, where current therapeutic options can be suboptimal due to adverse effects and the risk of cross-resistance.

Considerations for Updates to ICH Q1 and Q5C Stability Guidelines: Embracing Current Technology and Risk Assessment Strategies.

In consideration of the recent ICH Quality Discussion Group (QDG) recommended revision to the ICH series of stability guidelines, the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Science- and Risk-based Stability Working Group conducted a comprehensive review of ICH Q1A, Q1B, Q1C, Q1D, Q1E, and Q5C to identify areas where the guidelines could be clarified, updated, and amended to reflect the potential knowledge gained from current risk-based predictive stability tools and to consider other science- and risk-based stability strategies in accordance with ICH Q8-12. The recommendations propose a holistic approach to stability understanding, utilizing historical data, prior knowledge, modeling, and a risk assessment process to expand the concept of what could be included (or would be acceptable) in the core stability data package, including type and amount of stability evidence, assignment of retest period and shelf-life for a new product, and assessment of the impact of post-approval changes.

Workplace discrimination for persons with hearing loss: Before and after the 2008 ADA Amendments Act.

BACKGROUND: Individuals with hearing loss experience unique barriers to employment frequently documented in the areas of communication and education. The purpose of this article is to contribute to extend this inquiry to the uniqueness of workplace discrimination involving persons with hearing loss. OBJECTIVE: This study investigated differences in allegations of workplace discrimination filed by persons with hearing loss ("Hearing") compared to those filed by persons with other physical or neurological disabilities (General Disability, or "GENDIS") before and after the enactment of the 2008 Americans with Disabilities Act Amendments Act (2008 Amendments). METHODS: Using secondary data collected from the Equal Employment Opportunity Commission (EEOC) Integrated Mission System, we employ simple measures of proportion and odds ratios to describe differences between allegations derived from GENDIS and Hearing loss populations. These are population statistics, and not samples, of all allegations of discrimination reported to the EEOC through 2016. The comparisons involve Characteristics of the Charging Parties, Issues or discriminatory behaviors alleged, and closure statuses or Merit Rate of the EEOC's investigations - both before and after the 2008 Amendments. RESULTS: Following the 2008 Amendments, Charging Parties changed dramatically on age and gender status. Reasonable Accommodation, Hiring, Harassment, and employment Terms and Conditions showed unique features between groups and/or time periods. The "veracity" (confirmed truthfulness or merit) of the EEOC allegation (or Merit) rate also changed following the Amendments: higher for GENDIS; lower for Hearing. CONCLUSIONS: Possible rationale for these findings are offered, and new research questions are raised. Finally, implications for the cross-disability movement are presented.

Science and Risked-Based Stability Testing Strategies-a Test Case on the Global Implementation and Regulatory Reception.

The global regulatory implementation and acceptance of a science and risk-based stability (SRB) strategies for a stable drug product is reviewed. This stability strategy may also be referred to as "lean stability" since it includes a stability protocol reduction in the number of tests and time points than might normally be applied. A product line extension (new solid dosage form) for a well-understood product was used as a test case for this stability strategy. The drug product line extension was filed globally with a proposed reduction to analytical stability tests and frequency. This stability protocol is aligned with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q1A (R2) stability guidelines (ICH: Guideline Q1A(R2), 2003), the World Health Organization (WHO) (WHO INT. [Online], 2020), and most country regulatory guidelines. Although this strategy was not accepted universally, the strategy enabled opportunities to engage in productive dialogs with regulatory authorities in several countries on how the case leveraged product understanding and development knowledge to develop a fit for purpose stability protocol. A persistent and consistent effort from industry to move toward product-specific protocols based on product knowledge and stability risk assessments should lead to further acceptance of science and risk-based stability strategies in all regions.

Rhythmic calcium transients in smooth muscle cells of the mouse internal anal sphincter.

BACKGROUND: The internal anal sphincter (IAS) exhibits slow waves (SWs) and tone that are dependent upon L-type Ca2+ channels (CavL ) suggesting that phasic events (ie, SWs) play a fundamental role in tone generation. The present study further examined phasic activity in the IAS by measuring the spatiotemporal properties of Ca2+ transients (CTs) in IAS smooth muscle cells (SMCs). METHODS: Ca2+ transients were recorded with spinning disk confocal microscopy from the IAS of SM-GCaMP mice. Muscles were pinned submucosal surface up at two different lengths. Drugs were applied by inclusion in the superfusate. KEY RESULTS: Ca2+ transients displayed ongoing rhythmic firings at both lengths and were abolished by nifedipine and the KATP channel activator pinacidil indicating their dependence upon CavL . Like SWs, CTs were greatest in frequency (average 70.6 cpm) and amplitude at the distal extremity and conducted proximally. Removal of the distal IAS reduced but did not abolish CTs. The time constant for clearing cytoplasmic Ca2+ averaged 0.46 seconds and basal Ca2+ levels were significantly elevated. CONCLUSIONS & INFERENCES: The similarities in spatiotemporal and pharmacological properties of CTs and SWs suggest that SW gives rise to CTs while muscle stretch is not required. Elevated relative basal Ca2+ in the IAS is likely due to the inability of cells to clear or sequester Ca2+ between rapid frequency voltage-dependent Ca2+ entry events, that is, conditions that will lead to tone development. The conduction of CTs from distal to proximal IAS will lead to orally directed contractions and likely contribute to the maintenance of fecal continence.

Eculizumab Maintenance and the Prevention of Atypical Hemolytic Uremic Syndrome Relapse During Pregnancy: A Case Report.

Atypical hemolytic uremic syndrome is a thrombotic microangiopathy that can cause life-threatening anemia, thrombocytopenia, and acute renal failure. When triggered during pregnancy or the acute postpartum period, the disease is referred to as pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS). Women who suffer P-aHUS may later want to consider future pregnancy. These patients are at high, though not well-estimated, risk of relapse. Eculizumab, a monoclonal antibody against complement 5 (C5), has been highly successful in treating acute attacks of P-aHUS, but little is known about the effectiveness of eculizumab maintenance therapy throughout pregnancy. In this case report, we present a woman whose first pregnancy was complicated by severe P-aHUS. In her next pregnancy, she was maintained on eculizumab. She delivered a healthy infant at term and had no recurrences of P-aHUS during the pregnancy or in the postpartum period.

Exploring cancer survivors' attitudes, perceptions, and concerns about using medical cannabis for symptom and side effect management: A qualitative focus group study.

The purpose of this study is to gain a greater understanding of cancer survivors' attitudes, perspectives, and concerns about medical cannabinoids (MCs) for cancer symptom and side effect management. Using qualitative methods, we conducted four focus groups (n = 19) with cancer survivors recruited from a community-based cancer wellness center. Groups were audio-recorded and facilitated by experienced co-moderators who directed discussion using a semi-structured interview guide. Transcripts were coded using principles from Grounded Theory. Analyses revealed the following ten themes and percentages of codes applied: 1) Attitudes & Beliefs (25.3%), 2) Access (17.1%), 3) Information (15.5%), 4) Concern (14%), 5) How MCs Helped (12.6%), 6) Comfort (4.3%), 7) Confusion (3.6%), 8) Trust/Distrust (3.1%), 9) Behaviors (2.3%), and 10) Support (2.2%). Participants reported that MCs offer potential benefits for symptom management and side effect relief, especially in reducing and managing pain. Despite the growing number of states that are legalizing MCs, significant barriers exist that make knowledge and adequate access a challenge for many.

Patterns of workplace discrimination across broad categories of disability.

OBJECTIVE: The aim of this study was twofold: (a) to explore patterns of discrimination in relation to broad-basis categories of disability and (b) to investigate patterns of discrimination between allegations derived from charging parties with sensory impairments versus those with nonsensory impairments. Basis categories included physical, behavioral, neurological, and sensory impairments. RESEARCH METHOD: Database mining, descriptive analysis, and Pearson's chi-square analyses were utilized to compare broad-basis categories. RESULTS: In general, regardless of disability type, individuals experience the highest frequency and proportion of workplace discrimination in the areas of termination and reasonable accommodations. However, there are significant differences in the workplace discrimination experiences of the four broader groups. CONCLUSIONS: Noteworthy differences exist regarding the experience of workplace discrimination among basis categories of disability, especially with respect to sensory impairment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Heated Intraperitoneal Chemotherapy in the Management of Advanced Ovarian Cancer.

Heated intraperitoneal chemotherapy (HIPEC) has several potential benefits. Higher doses of chemotherapy can be used with HIPEC because the plasma-peritoneal barrier results in little absorption into the blood stream. HIPEC offers higher peritoneal penetration in comparison to an intravenous (IV) regimen and does not have the traditional normothermic intraperitoneal (IP) regimen limitation of post-operative adhesions. Hyperthermia itself has cytotoxic effects and can potentiate antineoplastic effects of chemotherapy in part by increasing the depth of tumor penetration by up to 3 mm. For the treatment of ovarian cancer, HIPEC has been evaluated in the recurrent setting with secondary cytoreduction. Recent studies, including a prospective trial, have evaluated its role in primary management of ovarian cancer. This review summarizes previous and ongoing studies regarding the use of HIPEC in the management of ovarian cancer.

Long-Term Use of Mixed-Oil Lipid Emulsion in Adult Home Parenteral Nutrition Patients: A Case Series.

BACKGROUND: Despite providing significant benefits, home parenteral nutrition (HPN) can be associated with complications such as infections, intestinal failure-associated liver disease, and metabolic abnormalities. Soybean oil (SO)-based intravenous lipid emulsion (ILE) has been noted to contribute to some of these complications, leading to the development of alternative sources of ILE. Mixed-oil (MO) ILE has recently been approved for use in adults with short-term studies revealing a benefit over SO ILE. Currently there is a paucity of data regarding long-term use in the HPN population. METHODS: The current study reports our experience with MO ILE in 9 HPN patients. RESULTS: A total of 9 patients (3 women and 6 men) with average age of 48.1 ± 15.1 years and a median HPN use of 9.9 years (9.0 months-30.7 years) were transitioned from SO ILE to MO ILE as a result of intolerance. The 9 patients tolerated MO ILE well for 140.7 ± 29.7 days. The percentage of calories provided through ILE increased from 7.6 ± 6.5% to 18.4 ± 8.2% (P = .003), whereas the dextrose decreased from 66.9 ± 8.4% to 56.9 ± 5.5% (P = .0007). Although statistical significance was not reached, there was a trend toward improvement in alkaline phosphatase from 138.0 (52-884) to 106 (47-512; P = .09). CONCLUSION: MO ILE was well tolerated in this small cohort and led to improvement in the macronutrient composition of HPN while providing a trend toward improvement in liver studies. These results are promising; however, additional randomized control trials are needed to delineate the true benefit.

Strengths based rehabilitation assessment: Adapted Inventory of Virtues and Strengths.

BACKGROUND: The Values in Action Inventory of Strengths (VIA-IS) operationalizes 24 character strengths that compose the six virtues proposed in Peterson and Seligman's classification theory. Though the utility of the VIA-IS has been demonstrated in the general population, its applicability to the study of psychosocial adaptation in rehabilitation for individuals with disabilities has been controversial. OBJECTIVE: The present study was to develop a measure of rehabilitation clients' positive traits, the Adapted Inventory of Virtues and Strengths (AIVS) designed to complement the applicability issues of the VIA-IS. METHOD: Step-by-step AIVS development procedures are presented, and the AIVS factor structure identified via factor analysis is interpreted from a psychosocial adaptation perspective and compared to the VIA-IS factor structure. RESULTS: AIVS subscales include Courage, Integrity, Practical Wisdom, Committed Action, and Emotional Transcendence. Construct validity was assessed by correlating AIVS factors with measures of resilience, life satisfaction, and well-being. CONCLUSIONS: The AIVS offers a reliable framework that has clinical utility for strengths-based rehabilitation practice.

Challenges Persist Under Americans With Disabilities Act Amendments Act: How Can Oncology Providers Help?

PURPOSE: To determine whether the Amendments to the hallmark Americans with Disabilities Act (ADA; effective January 2009), which provide increased access to the antidiscrimination laws for many with chronic illness, are related to changes in workplace discrimination allegations in individuals with a history of cancer. METHODS: Information collected by the Equal Employment Opportunities Commission was used to compare allegations of discrimination and their merit before (2001 to 2008) and after (2009 to 2011) implementation of the Amendments Act. RESULTS: Allegations related to terms of employment (eg, promotions, wages) were more likely to be filed (odds ratio [OR], 1.34; 95% CI, 1.11 to 1.61) and determined to have merit (OR, 1.35; 95% CI, 1.03 to 1.77) after implementation of the Amendments Act. Allegations related to workplace relations (eg, harassment, discipline, discharge) were also more likely to be filed post Amendments Act (OR, 1.48; 95% CI, 1.23 to 1.78), although the merit of this complaint remained stable. Filing of all other allegations of discrimination (ie, hiring, reasonable accommodation, and termination) and their merit remained unchanged post Amendments Act. CONCLUSION: Despite the implementation of the Amendments Act, discrimination allegations in those with a history of cancer persisted or in certain areas increased. Although prevention of workplace discrimination rests primarily with employers, the oncology care team is uniquely qualified to provide information related to residual symptoms and function that can facilitate more personalized solutions to workplace discrimination, such as successful workplace accommodations. Information is provided that can assist the oncology team in their efforts to improve work outcomes.