Hepatitis C donor positive to recipient negative solid organ transplants: Early direct acting antiviral insurance approval rates with and without documented viremia.

BACKGROUND: Current guidelines support early initiation of direct-acting antivirals (DAA) in hepatitis C virus (HCV) donor positive and recipient negative (D+/R-) solid organ transplants (SOTs). According to experts, access to DAA therapy is a key barrier to early treatment. METHODS: This single-center, retrospective study assessed the rate of DAA prescription approval with or without confirmed HCV viremia, time to approval, and reasons for denial in HCV D+/R- SOTs. RESULTS: All 51 patients received insurance approval for DAA therapy following transplantation regardless of confirmed HCV viremia at time of prior authorization (PA) submission. Same day PA approval was obtained in 51% of cases. Appeals received approval within a median of 2 days from submission. CONCLUSION: Our findings suggest confirmed HCV viremia may not be as significant of a barrier to DAA access and may encourage other health systems to consider early initiation of DAA therapy in their HCV D+/R- transplants.

Safe co-administration of direct-acting antivirals and direct oral anticoagulants among patients with hepatitis C virus infection: An international multicenter retrospective cohort study.

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct-acting antivirals inhibit DOAC transport through P-glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56-2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC.

Tyrosine kinase inhibitors and tumor lysis syndrome in hematologic malignancies: A systemic review.

BACKGROUND: Effective treatments for hematologic malignancies include therapies that target tyrosine kinase (TK) signaling pathways. Tumor lysis syndrome (TLS) is an oncologic emergency that can occur due to rapid turnover following the initiation of treatments for hematologic malignancy. The incidence of TLS is under-reported and it is unclear as to whether TK inhibitors (TKIs) are associated with TLS. OBJECTIVE: To conduct a systematic review to determine the incidence of TLS with TKIs. METHODS: A search was performed using EMBASE, MEDLINE, and Web of Science electronic databases, as well as a manual search of the American Society of Hematology and American Society of Clinical Oncology abstract databases. Keywords included: "tumor lysis syndrome," "tyrosine kinase inhibitors," "lymphoma," and "leukemia." RESULTS: We identified a total of 57 publications that commented on the incidence of TLS with TKIs for hematologic malignancy. Thirty-nine of those publications reported TLS as an adverse event. TLS was described as an adverse event among essentially all the subclasses of TKIs that are used to manage hematologic malignancies. CONCLUSION: The overall number of articles commenting on TLS as an adverse event is sparse and there needs to be more transparency regarding the incidence of TLS when employing newer targeted therapies. Physicians should consider the risk of TLS on an individual basis and the added risk of TLS when using TKIs to treat hematologic malignancy.

Rehabilitation outcomes after major lower limb amputation in the oldest old: a systematic review.

BACKGROUND: Because the population grows older and the burden of chronic disease increases, many individuals will undergo major lower limb amputation (LLA) at advanced ages. There is a scarcity of literature focusing on the outcomes of rehabilitation for people who acquire LLA at 80 years of age and older. OBJECTIVES: To determine the scope of empirical evidence regarding prosthetic rehabilitation for newly acquired LLA in the oldest old (≥80 years of age). STUDY DESIGN: Systematic Review. METHODS: The databases CINAHL, EMBASE, MEDLINE, and Scopus were searched from inception through June 6, 2020 (PROSPERO: #CRD 42020188623). Two authors independently reviewed all titles and abstracts for inclusion. Inclusion criteria, LLA of any etiology at the transtibial level or above, those who were ≥80 years of age at the time of amputation, and had rehabilitation outcomes reported. RESULTS: Of 11,738 articles identified from databases, 117 underwent full-text review and 10 met inclusion criteria. Multiple rehabilitation outcomes were assessed by the selected studies, including general outcomes, prosthetic-related outcomes, and functional abilities. Individuals ≥80 years of age were able to successfully use a prosthesis, discharged home, and performed activities independently or with support. However, increased age was negatively associated with prosthesis fitting and rehabilitation success was not uniform in some participants. CONCLUSIONS: The oldest old with major LLA can be successful in prosthetic rehabilitation. Age alone should not disqualify individuals from assessment or participation in an amputee rehabilitation program. More research is needed to better understand the rehabilitation outcomes in this population of people with LLA.

Exploring the use and challenges of implementing virtual visits during COVID-19 in primary care and lessons for sustained use.

BACKGROUND: The COVID-19 pandemic has rapidly transformed how healthcare is delivered to limit the transmission of the virus. This descriptive cross-sectional study explored the current use of virtual visits in providing care among primary care providers in southwestern Ontario during the first wave of the COVID-19 pandemic and the anticipated level of utilization post-pandemic. It also explored clinicians' perceptions of the available support tools and resources and challenges to incorporating virtual visits within primary care practices. METHODS: Primary care physicians and nurse practitioners currently practicing in the southwestern part of Ontario were invited to participate in an online survey. The survey invite was distributed via email, different social media platforms, and newsletters. The survey questions gathered clinicians' demographic information and assessed their experience with virtual visits, including the proportion of visits conducted virtually (before, during the pandemic, and expected volume post-pandemic), overall satisfaction and comfort level with offering virtual visits using modalities, challenges experienced, as well as useful resources and tools to support them in using virtual visits in their practice. RESULTS: We received 207 responses, with 96.6% of respondents offering virtual visits in their practice. Participants used different modalities to conduct virtual visits, with the vast majority offering visits via phone calls (99.5%). Since the COVID-19 pandemic, clinicians who offered virtual visits have conducted an average of 66.4% of their visits virtually, compared to an average of 6.5% pre-pandemic. Participants anticipated continuing use of virtual visits with an average of 43.9% post-pandemic. Overall, 74.5% of participants were satisfied with their experience using virtual visits, and 88% believed they could incorporate virtual visits well within the usual workflow. Participants highlighted some challenges in offering virtual care. For example, 58% were concerned about patients' limited access to technology, 55% about patients' knowledge of technology, and 41% about the lack of integration with their current EMR, the increase in demand over time, and the connectivity issues such as inconsistent Wi-Fi/Internet connection. There were significant differences in perception of some challenges between clinicians in urban vs, rural areas. Clinicians in rural areas were more likely to consider the inconsistent Wi-Fi and limited connectivity as barriers to incorporating virtual visits within the practice setting (58.8% vs. 40.2%, P = 0.030). In comparison, clinicians in urban areas were significantly more concerned about patients overusing virtual care services (39.4% vs. 21.6%, P = 0.024). As for support tools, 47% of clinicians advocated for virtual care standards outlined by their profession's college. About 32% identified change management support and technical training as supportive tools. Moreover, 39% and 28% thought local colleagues and in-house organizational support are helpful resources, respectively. CONCLUSION: Our study shows that the adoption of virtual visits has exponentially increased during the pandemic, with a significant interest in continuing to use virtual care options in the delivery of primary care post-pandemic. The study sheds light on tools and resources that could enhance operational efficiencies in adopting virtual visits in primary care settings and highlights challenges that, when addressed, can expand the health system capacity and sustained use of virtual care.

Reliability, validity, and agreement of the short-form Activities-specific Balance Confidence Scale in people with lower extremity amputations.

BACKGROUND: Clinicians use the Activities-specific Balance Confidence Scale to understand balance confidence. A short-form Activities-specific Balance Confidence scale, was developed using the six most difficult tasks from the original Activities-specific Balance Confidence scale; however, short-form the short-form scale psychometrics and agreement with the original scale have yet to be explored in people with lower extremity amputations. OBJECTIVE: To determine the relative and absolute reliability, construct validity, and agreement of the short-form Activities-specific Balance Confidence scale. STUDY DESIGN: Test-retest with a 2-week interval. METHODS: Analysis for relative reliability and internal consistency was intraclass correlation coefficient and Cronbach's α, respectively. Absolute reliability was measured using standard error of measurement and minimal detectable change. Bland-Altman plots measured agreement between scales. Construct validity was evaluated against the L Test using a Pearson-product moment correlation. RESULTS: The short-form Activities-specific Balance Confidence (intraclass correlation coefficient = 0.92) and Activities-specific Balance Confidence (intraclass correlation coefficient = 0.91) scales had excellent relative reliability. Both scales demonstrated good internal consistency. Worse absolute reliability was observed in the short-form Activities-specific Balance Confidence scale. Construct validity against the L Test was confirmed. Bland-Altman plots indicated poor agreement between scales. CONCLUSION: Both scales exhibit excellent relative reliability and good internal consistency and construct validity. Poor agreement between short-form Activities-specific Balance Confidence and Activities-specific Balance Confidence indicates the scales should not be used interchangeably. Inadequate absolute reliability of the short-form Activities-specific Balance Confidence scale suggests the Activities-specific Balance Confidence should be the balance confidence scale of choice. CLINICAL RELEVANCE: Balance confidence is an important metric for our understanding of rehabilitation and community re-integration in people with lower extremity amputations. Due to inferior absolute reliability and a lack of appropriate items composing the short-form Activities-specific Balance Confidence scale, the full-scale Activities-specific Balance Confidence is recommended for the assessment of balance confidence in this population.

Structural Characterization of Pan-Ebolavirus Antibody 6D6 Targeting the Fusion Peptide of the Surface Glycoprotein.

Ebola virus infection causes severe disease in humans and represents a global health threat. Candidates for immunotherapeutics and vaccines have shown promise in clinical trials, although they are ineffective against other members of the Ebolavirus genus that also cause periodic, lethal outbreaks. In this study, we present a crystal structure of a pan-ebolavirus antibody, 6D6, as well as single-particle electron microscopy reconstructions of 6D6 in complex with Ebola and Bundibugyo virus glycoproteins. 6D6 binds to the conserved glycoprotein fusion peptide, implicating it as a site of immune vulnerability that could be exploited to reliably elicit a pan-ebolavirus neutralizing antibody response.

Moral Mentation: What Neurocognitive Studies of Psychopathy May Really Offer the Internalism/Externalism Debate.

A persistent debate about moral capacity - and neuroethics - focuses upon the internalism-externalism controversy. Internalism holds that moral judgments necessarily motivate an agent's actions; externalism views moral judgments as not inherently motivating an agent to perform moral actions. Neuroethical discussions of the putative cognitive basis of moral thought and action would be better informed if neurocognitive research would yield data sufficient for validating one side or the other. Neuroscientific studies of psychopaths have been employed in this regard. However, it seems that neuroscientific investigations to date have been inadequate to wholly define the nature of moral knowledge, and thus fail to preferentially support (or foster) an exclusively internalist or externalist view. Thus, moving forward it will be necessary to carefully define questions that neuroscience is employed to address and answer, and to ensure that empirical findings are not distorted to support preconceived theoretical assumptions. In this way, neuroscientific investigations can be used in a conciliatory way to both balance views of processes operative in moral cognition, and raise ethical, legal, and social questions about what research findings actually mean, and what medicine - and societies - will do with such information and meanings.

Once-Daily Versus Twice-Daily Enoxaparin for the Treatment of Acute Venous Thromboembolism in Cancer Patients.

BACKGROUND: No randomized controlled trials have investigated enoxaparin once versus twice daily for venous thromboembolism (VTE) treatment in cancer patients. OBJECTIVE: To compare the safety and efficacy of enoxaparin 1 mg/kg twice daily versus enoxaparin 1.5 mg/kg/day for the treatment of acute VTE in cancer patients. METHODS: This was a single-center, retrospective, observational cohort study. Adults with active cancer and an acute VTE were included. The primary outcome evaluated was the incidence of clinically relevant (major and nonmajor) bleeding (CRB) within 30 days of enoxaparin initiation. Secondary outcomes included the incidence of CRB, thrombosis, and death at 30, 90, and 180 days. The study protocol was approved by the institutional review board. RESULTS: A total of 123 patients met inclusion criteria; 85 patients (69%) were treated with once-daily and 38 patients (31%) with twice-daily enoxaparin. CRB was numerically higher at 30 days in the twice-daily enoxaparin group compared with the once-daily group (5.3% vs 2.4%, P = 0.587). There was a nonsignificant higher incidence of CRB in the once-daily enoxaparin group compared with the twice-daily group at 90 days (8.3% vs 8%, P = 1.0) and 180 days (12.5% vs 7.1%, P = 1.0). The composite outcome of CRB, thrombosis, and death was higher at all time points with enoxaparin once daily. CONCLUSIONS: Lack of statistical power in this study precludes definitive conclusions. Clinicians may consider twice-daily enoxaparin because of potentially fewer adverse events but may be limited by patient preference and/or financial constraints.

Transplant eligibility for patients with affective and psychotic disorders: a review of practices and a call for justice.

BACKGROUND: The scarcity of human organs requires the transplant community to make difficult allocation decisions. This process begins at individual medical centers, where transplant teams decide which patients to place on the transplant waiting list. Each transplant center utilizes its own listing criteria to determine if a patient is eligible for transplantation. These criteria have historically considered preexisting affective and psychotic disorders to be relative or absolute contraindications to transplantation. While attitudes within the field appear to be moving away from this practice, there is no data to confirm that eligibility criteria have changed. MAIN BODY: There are no nationwide guidelines detailing the manner in which affective and psychotic disorders should impact transplant eligibility. Individual transplant centers thus form their own transplant eligibility criteria, resulting in significant inter-institution variability. Data from the 1990s indicates that the majority of transplant programs considered certain psychiatric illnesses, such as active schizophrenia, to be absolute contraindications to transplantation. A review of literature reveals that no comprehensive data has been collected on the topic since that time. Furthermore, the limited data available about current practices suggests that psychiatric illness continues to be viewed as a contraindication to transplantation at some transplant centers. In light of this finding, we review psychiatric literature that examines the impact of affective and psychotic disorders on transplant outcomes and conclude that the presence of these disorders is not an accurate predictor of transplant success. We then discuss the requirements of justice as they relate to the creation of a just organ allocation system. CONCLUSION: We conclude that transplant eligibility criteria that exclude patients with affective and psychotic disorders on the basis of their psychiatric diagnosis alone are unjust. Just listing criteria must incorporate only those factors that have a causative effect on posttransplant morbidity and mortality. Justice also demands that we eliminate current inter-institution practice variations in favor of national transplant eligibility criteria. Given the limited data available about current practices, we call for an updated study investigating the manner in which affect and psychotic disorders impact transplant eligibility determinations.

Shouldn't Dead Be Dead?: The Search for a Uniform Definition of Death.

In 1968, the definition of death in the United States was expanded to include not just death by cardiopulmonary criteria, but also death by neurologic criteria. We explore the way the definition has been modified by the medical and legal communities over the past 50 years and address the medical, legal and ethical controversies associated with the definition at present, with a particular highlight on the Supreme Court of Nevada Case of Aden Hailu.

Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort.

The purpose of this study was to assess humoral antibody responses as a function of disease progression (DP) in a well-defined HIV+ cohort. We quantified antibodies to HIV-1 gp120, Gag, and CD4 receptor by enzyme-linked immunosorbent assay in sera from a cohort of 97 HIV+ subjects at defined stages of DP. We also measured antibody-dependent cellular cytotoxicity (ADCC) as a function of the clinical status of the patients. We purified antibodies to CD4 and gp120 and assessed them for specificity, ability to block gp120 binding to target cells, ability to block virus infection, and ability to facilitate ADCC. All of the HIV+ patient samples were positive for antibodies to HIV gp120 and p24 and 80% showed evidence of hypergammaglobulinemia. Approximately 10% of cohort members were positive for antibodies to CD4, but we noted no significant correlation relevant to DP. There were statistically significant differences between the groups concerning the level of humoral response to gp120 and Gag. However, we observed no distinction in ability of anti-gp120 antibodies purified from each group to neutralize infection. In addition, there was a statistically significant difference in ADCC, with elite controllers exhibiting significantly lower levels of ADCC than the other five groups. We detected IgA anti-gp120 antibodies, but did not correlate their presence with either DP or ADCC levels. The results are consistent with the interpretation that the humoral antibody response to the antigens assessed here represents a signature of the level of viremia but does not correlate with clinical status of HIV infection.

HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D) as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag) which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from vaccinia-Gag challenge, but the protection was independent of standard immune markers. Soluble multi-trimeric SP-D-4-1BBL and SP-D-BAFF provide a novel technology to enhance adenoviral vector vaccines against HIV-1.

Distribution and culturability of the uncultivated 'AGG58 cluster' of the Bacteroidetes phylum in aquatic environments.

Members of the Bacteroidetes phylum are abundant in aquatic habitats when assessed by fluorescent in situ hybridisation and in some 16S rRNA gene libraries. In this study 16S rRNA gene clone libraries were constructed with bacterial primers that amplify Bacteroidetes sequences well (27F, 1492R) from coastal seawater near Plymouth (UK) during a phytoplankton bloom. Most of the clones (66%, 106/160) affiliated with the Bacteroidetes phylum, and of these 62% (66/106; or 41% 66/160 of the entire library) clustered with marine bacterioplankton clones env.agg58, Arctic97A-17, CF17, CF96 and CF101. This phylogenetic branch of Bacteroidetes was designated the 'AGG58 cluster', and its presence in various aquatic environments was investigated. Two pairs of AGG58-specific 16S rRNA-gene-targeted polymerase chain reaction (PCR) primers were designed and successfully used to detect the cluster in DNA extracts from three UK coastal seawater sites, and from freshwater River Taff epilithon. In addition, 600 putative Bacteroidetes strains were isolated from these sites on relatively high-nutrient agar media. AGG58 cluster specific probes were used to screen the amplified 16S rRNA gene products from the isolates, but no members of the AGG58 cluster were discovered. The least specific probe hybridised with one River Taff water isolate (RW262 NCIMB 13979) which formed a monophyletic group with the genera Crocinitomix, Brumimicrobium and Cryomorpha of the family Cryomorphaceae in the Bacteroidetes phylum. RW262 probably represents the first isolate of a new genus within this family. This study provides new evidence that the uncultivated AGG58 group is abundant, globally distributed, and can be rapidly detected with the new PCR primers described.