Fosmanogepix Therapy of Disseminated Fusarium Infection.

Invasive Fusarium infections cause high mortality. Fosmanogepix, a first-in-class antifungal agent, has potent activity against Fusarium. A patient with acute leukemia with invasive fusariosis, probably involving the central nervous system and caused by Fusarium lactis resistant to currently available antifungal agents, was cured of her infection with fosmanogepix. Fosmanogepix was well tolerated.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Filgrastim associations with CAR T-cell therapy.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.

Asking the Right Questions About Secondhand Smoke.

INTRODUCTION: Despite knowledge about major health effects of secondhand tobacco smoke (SHS) exposure, systematic incorporation of SHS screening and counseling in clinical settings has not occurred. METHODS: A three-round modified Delphi Panel of tobacco control experts was convened to build consensus on the screening questions that should be asked and identify opportunities and barriers to SHS exposure screening and counseling. The panel considered four questions: (1) what questions should be asked about SHS exposure; (2) what are the top priorities to advance the goal of ensuring that these questions are asked; (3) what are the barriers to achieving these goals; and (4) how might these barriers be overcome. Each panel member submitted answers to the questions. Responses were summarized and successive rounds were reviewed by panel members for consolidation and prioritization. RESULTS: Panelists agreed that both adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from any tobacco products in their usual environment. The panel found that consistent clinician training, quality measurement or other accountability, and policy and electronic health records interventions were needed to successfully implement consistent screening. CONCLUSIONS: The panel successfully generated screening questions and identified priorities to improve SHS exposure screening. Policy interventions and stakeholder engagement are needed to overcome barriers to implementing effective SHS screening. IMPLICATIONS: In a modified Delphi panel, tobacco control and clinical prevention experts agreed that all adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from tobacco products. Consistent training, accountability, and policy and electronic health records interventions are needed to implement consistent screening. Increasing SHS screening will have a significant impact on public health and costs.

B-cell lymphomas associated with breast implants: Report of three cases and review of the literature.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

Results from a prospective study of individuals' symptoms and patient activation after hepatitis C treatment.

The treatment of the hepatitis C virus has been revolutionized by the discovery of direct-acting antiviral medications, which offer more effective treatment with fewer potential side effects. Few studies have examined changes in patient-reported outcomes in individuals undergoing treatment for the hepatitis C virus in the immediate time period after the first treatment (within 1 month). This study is one of the first to use quantitative and qualitative methods to investigate changes in quality of life, patient activation, and symptom burden in adults undergoing treatment for hepatitis C virus with direct-acting antiviral medications. Seventy-three patients were followed in a prospective, longitudinal mixed-methods design. Changes pre and posttreatment in quality of life, patient activation, and symptom burden were very small in magnitude when looking across the entire sample. However, patients with lower self-reported health at baseline reported improved physical and psychological functioning 1-month posttreatment. Patients with higher self-reported health at baseline reported decreased general health posttreatment, although these effects were small. Qualitative results suggested that most patients found symptoms to be manageable despite experiencing both psychological and physical symptoms during treatment. We also found that 25% of patients had low levels of patient activation and may lack the basic knowledge and confidence to be an active participant in their health care. These findings suggest that patients may benefit from tailored information based on current health status about what to expect during and immediately after beginning direct-acting antiviral medication treatment.

When Family Don't Acknowledge: A Hermeneutic Study of the Experience of Kinship Stigma in Community-Dwelling People With Inflammatory Bowel Disease.

Recent evidence suggests that kinship stigma-the experience of being or feeling stigmatized by family members-arises in the stories of people with inflammatory bowel disease (IBD). Adopting Goffman's definition of stigma as "an attribute which is deeply discrediting," we used hermeneutic (interpretive) phenomenology to further explore the meaning of kinship stigma for people with IBD and reveal its significance. In total, 18 unstructured interviews took place in participants' own homes in the United Kingdom, between July 2015 and April 2016. Transcripts were analyzed using a hermeneutic method to reveal three relational themes and one constitutive pattern. Referring to relevant literature, the presence and impact of kinship stigma on people with IBD is revealed. Kinship stigma-experienced as and meaning a lack of acknowledgment-may have wide-ranging implications for health and social care professionals caring for persons with IBD or other chronic illness and their families.

Adjusting to sex and intimacy: Gynecological cancer survivors share about their partner relationships.

This study describes what gynecological (GYN) cancer survivors relate about their intimate partners and adjustments in their sexual lives following diagnosis and treatment. Conventional descriptive content analysis was used to examine participant responses about partner relationships following their diagnosis. Responses revealed three clusters and 15 codes of data. Findings report the influence of cancer treatment on sexual activity and functioning, women's sex lives, and their relationships. Health-care providers have a vital role in supporting women and their partners during the cancer care trajectory and should include both the survivor and the partner in conversations focused on sexual concerns and sexual well-being.

Cardiac Complications in the Adult Bone Marrow Transplant Patient.

PURPOSE OF REVIEW: Due to advancements in oncologic treatment strategies and techniques, the number of survivors who have undergone hematopoetic stem cell transplant (HCT) continues to increase in the United States; this number is projected to reach 502,000 by the year 2030. There is significant interest within the field of cardio-oncology to identify cardiotoxicity and cardiovascular disease in the HCT population. Epidemiologic studies analyzing both short- and long-term cardiovascular effects, risk stratification modeling, cardioprotective strategies, and expert consensus documents for cardiotoxicity surveillance recommendations are reviewed. RECENT FINDINGS: Patients who have undergone HCT are at increased risk of cardiovascular events and mortality compared to matched controls. The type of cardiotoxicity and the incidence rates vary based on specific therapeutic regimens and pre-existing cardiovascular risk factors. Life-threatening cardiotoxicity can present during HCT as acute heart failure, arrhythmias, pericardial tamponade, or cardiac arrest; or it can present late after treatment as cardiomyopathy, ischemic heart disease, vascular disease, stroke, or comorbid conditions, such as hypertension and diabetes mellitus that are associated with cardiac events. HCT is associated with excess cardiovascular risk partially due to exposure to cardiotoxic chemotherapy and radiation, as well as indirect and direct detrimental effects on cardiovascular reserve. This review discusses the epidemiology and the known cardiotoxic effects of historical chemoradiation agents in addition to newer targeted therapies. Recent expert consensus statements from cardiology and hematology/oncology societies are reviewed in regard to risk stratification of the cancer patient based on the type of treatments. Finally, gaps in knowledge are identified with proposed avenues of research that will allow for more accurate risk assessment, prediction, and potential treatment of the HCT patient in attenuating the risk of developing both short- and long-term cardiovascular comorbidities.

S100B and Inflammatory Cytokine Levels in Blood as Potential Markers of Blood-Brain Barrier Damage and Psychiatric Impairment in Comorbid Hepatitis C Viral Infection and Alcohol Use Disorder.

BACKGROUND: Hepatitis C virus (HCV) infection and alcohol use disorder (AUD) both adversely affect the immune system resulting in alterations in immune cell signaling and inflammatory processes. The aim of this study was to investigate how comorbid AUD contributes to abnormalities in inflammatory mediators and psychiatric impairments in adults with HCV. METHODS: Alcohol use, mood, and inflammatory factors were evaluated at 3 time points (baseline, week 4, and week 12) in Veterans with HCV, with (n = 42) and without (n = 13) comorbid AUD. Peripheral indices of immune activation, blood-brain barrier (BBB) damage (S100 calcium-binding protein B [S100B]), liver function, and viral load were measured using immunoassays and polymerase chain reaction assays. RESULTS: Comorbid AUD was associated with increased symptoms of depression and anxiety, elevated levels of liver enzymes, and altered expression of inflammatory factors. Alcohol consumption was positively correlated with the severity of psychiatric symptoms. Univariate analysis identified significant group differences in interleukin (IL)-8 (p = 0.006), IL-10 (p = 0.03), and S100B (p = 0.048), with increased levels in participants with AUD, which persisted over time despite reductions in alcohol use and no significant change in HCV viral load. Statistically significant effects of study group or time were not found for the other immune factors assessed. Exploratory receiver operating characteristic curve analysis evaluated the ability of IL-8, IL-10, and S100B to differentiate between levels of alcohol consumption and generated biomarker cutoff values used to identify low risk and unhealthy alcohol use groups. CONCLUSIONS: These results demonstrate that HCV and comorbid AUD are associated with greater psychiatric impairments, potentially resulting from increased inflammation, dysregulated cytokine expression, and compromised BBB function. Alcohol-induced BBB damage may increase the risk of neuropathological consequences within the context of chronic HCV infection.

Revisiting Young Children's Understanding of the Psychological Causes of Behavior.

In 1989, Miller and Aloise challenged the prevailing belief that preschoolers tend to explain others' behavior in terms of external events or a person's physical attributes and have little understanding of psychological causes. That review documented preschoolers' understanding of, and even preference for, psychological causes as part of an emerging renaissance in developmental social-cognitive research. The present, updated review (97 articles, participant ages 3 months to 6 years) suggests the emergence of a transformative new perspective in which social-cognition is balanced between social and cognitive aspects rather than tilted toward cognition. Recent research on infants' awareness of mental states, young children's understanding of social categories and their judgments of the trustworthiness of informants, and cultural context reveals various ways in which preschoolers' social-causal reasoning is social.

Palliative care for people with advanced liver disease: A feasibility trial of a supportive care liver nurse specialist.

BACKGROUND: Liver disease is an increasing cause of death worldwide but palliative care is largely absent for these patients. AIM: We conducted a feasibility trial of a complex intervention delivered by a supportive care liver nurse specialist to improve care coordination, anticipatory care planning and quality of life for people with advanced liver disease and their carers. DESIGN: Patients received a 6-month intervention (alongside usual care) from a specially trained liver nurse specialist. The nurse supported patients/carers to live as well as possible with the condition and acted as a resource to facilitate care by community professionals. A mixed-method evaluation was conducted. Case note analysis and questionnaires examined resource use, care planning processes and quality-of-life outcomes over time. Interviews with patients, carers and professionals explored acceptability, effectiveness, feasibility and the intervention. SETTING/PARTICIPANTS: Patients with advanced liver disease who had an unplanned hospital admission with decompensated cirrhosis were recruited from an inpatient liver unit. The intervention was delivered to patients once they had returned home. RESULTS: We recruited 47 patients, 27 family carers and 13 case-linked professionals. The intervention was acceptable to all participants. They welcomed access to additional expert advice, support and continuity of care. The intervention greatly increased the number of electronic summary care plans shared by primary care and hospitals. The Palliative care Outcome Scale and EuroQol-5D-5L questionnaire were suitable outcome measurement tools. CONCLUSION: This nurse-led intervention proved acceptable and feasible. We have refined the recruitment processes and outcome measures for a future randomised controlled trial.

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation: CRITICAL ROLES OF LYSINES 60 AND 191.

The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor.

Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1): IDENTIFICATION OF CLUSTER IV ON LRP1 AS THE MAJOR BINDING SITE.

Hemophilia A is a bleeding disorder caused by a deficiency in coagulation factor VIII (fVIII) that affects 1 in 5,000 males. Current prophylactic replacement therapy, although effective, is difficult to maintain due to the cost and frequency of injections. Hepatic clearance of fVIII is mediated by the LDL receptor-related protein 1 (LRP1), a member of the LDL receptor family. Although it is well established that fVIII binds LRP1, the molecular details of this interaction are unclear as most of the studies have been performed using fragments of fVIII and LRP1. In the current investigation, we examine the binding of intact fVIII to full-length LRP1 to gain insight into the molecular interaction. Chemical modification studies confirm the requirement for lysine residues in the interaction of fVIII with LRP1. Examination of the ionic strength dependence of the interaction of fVIII with LRP1 resulted in a Debye-Hückel plot with a slope of 1.8 ± 0.5, suggesting the involvement of two critical charged residues in the interaction of fVIII with LRP1. Kinetic studies utilizing surface plasmon resonance techniques reveal that the high affinity of fVIII for LRP1 results from avidity effects mediated by the interactions of two sites in fVIII with complementary sites on LRP1 to form a bivalent fVIII·LRP1 complex. Furthermore, although fVIII bound avidly to soluble forms of clusters II and IV from LRP1, only soluble cluster IV competed with the binding of fVIII to full-length LRP1, revealing that cluster IV represents the major fVIII binding site in LRP1.

A Longitudinal Examination of the Relation Between Internalizing Problem Behaviors and Early Adolescent Cigarette Smoking.

OBJECTIVE: The purpose of the present study was to investigate the longitudinal relation between internalizing problem behaviors (measured with the anxious/depressed and somatic complaints subscales of the Achenbach Teacher's Report Form) and self-reported cigarette smoking behavior and intentions during early adolescence. In addition, a possible mediating role of perceived harm was investigated. METHODS: Sixth graders and their teachers were surveyed in the sixth grade and students were surveyed again in the seventh grade. Smoking behavior and intentions were assessed with five items including lifetime use, 30-day use, tobacco user status (nonsmoker to heavy smoker), and two intentions/behavioral expectations items. In addition to perceived harm from smoking, reasons for smoking and reasons for not smoking were included on the survey. RESULTS: As hypothesized, teacher reports of sixth-grade internalizing problem behaviors were negatively related to seventh-grade smoking behavior and intentions. Moreover, perceived harm from smoking was negatively related to smoking and intentions. The hypothesized mediating role of perceived harm in the internalizing to smoking relationship was not supported. CONCLUSIONS: Potential differences in the relation between internalizing and smoking across adolescence are discussed. Specifically, the results of the present study and an examination of prior literature suggest that in early adolescence internalizing problems are negatively related to cigarette smoking, whereas in middle and late adolescence the opposite is true.

Fundamental Use of Surgical Energy (FUSE) certification: validation and predictors of success.

INTRODUCTION: The Fundamental Use of Surgical Energy (FUSE) program includes a Web-based didactic curriculum and a high-stakes multiple-choice question examination with the goal to provide certification of knowledge on the safe use of surgical energy-based devices. The purpose of this study was (1) to set a passing score through a psychometrically sound process and (2) to determine what pretest factors predicted passing the FUSE examination. METHODS: Beta-testing of multiple-choice questions on 62 topics of importance to the safe use of surgical energy-based devices was performed. Eligible test takers were physicians with a minimum of 1 year of surgical training who were recruited by FUSE task force members. A pretest survey collected baseline information. RESULTS: A total of 227 individuals completed the FUSE beta-test, and 208 completed the pretest survey. The passing/cut score for the first test form of the FUSE multiple-choice examination was determined using the modified Angoff methodology and for the second test form was determined using a linear equating methodology. The overall passing rate across the two examination forms was 81.5%. Self-reported time studying the FUSE Web-based curriculum for a minimum of >2 h was associated with a passing examination score (p < 0.001). Performance was not different based on increased years of surgical practice (p = 0.363), self-reported expertise on one or more types of energy-based devices (p = 0.683), participation in the FUSE postgraduate course (p = 0.426), or having reviewed the FUSE manual (p = 0.428). Logistic regression found that studying the FUSE didactics for >2 h predicted a passing score (OR 3.61; 95% CI 1.44-9.05; p = 0.006) independent of the other baseline characteristics recorded. CONCLUSION(S): The development of the FUSE examination, including the passing score, followed a psychometrically sound process. Self-reported time studying the FUSE curriculum predicted a passing score independent of other pretest characteristics such as years in practice and self-reported expertise.

A Qualitative Study of Smoker Identity Among College Student Smokers.

BACKGROUND: This research was motivated by findings that college students who smoke cigarettes often self-categorize as nonsmokers, that is, they reject the social identity of "smoker." OBJECTIVES: The goal of the present study was to shed light on college students' smoker identities beyond the smoker/nonsmoker dichotomy. METHODS: Focus groups were conducted to investigate how college students categorize their own smoking patterns and to identify what behaviors and attitudes are associated with these different categories of smoker identities. Forty-one students from a western university participated in this study in November 2011. RESULTS: The focus group results indicated that there were five distinct smoker identities on campus. Light and regular smokers were the daily smoker identities present, while stress, social, and drunk smokers were the occasional smoker identities. Moreover, each of these smoker identities was defined by a unique pattern of smoking behavior, attitudes, and motives. CONCLUSIONS/IMPORTANCE: These findings support the notion that there are different types of smokers, both daily and occasional, in the college population. We suggest that researchers, healthcare providers, and prevention/intervention programs may all benefit from distinguishing between these different types of smokers.

Fluid role boundaries: exploring the contribution of the advanced nurse practitioner to multi-professional palliative care.

AIMS AND OBJECTIVES: To evaluate the introduction of Advanced Nurse Practitioners in a specialist, multi-professional palliative care context. The objective is to explore the core domains and competencies of the advanced nurse practitioner role in a multi-professional palliative care context. BACKGROUND: New models of health care and service delivery are emerging alongside expanded levels of autonomy, skills and decision-making for nurses and midwives. This has resulted in some confusion in the health service community internationally about the professional role and scope of the advanced nurse practitioner. DESIGN: A qualitative evaluation study (n = 21). METHODS: Three phases of data collection were conducted over 10 months. Twenty-one participants took part from a specialist palliative care unit in one health board in a U.K. region spanning ANPs (n = 2) multi-professional staff (n = 14) and patients/carers (n = 5). Data collection methods included individual and focus group interviews with key stakeholders and observation of the advanced nurse practitioners at work and their reflexive diaries. RESULTS: The findings of this evaluation demonstrate that if the advanced nurse practitioner role can flourish it has the potential to shape 'new identities', re-construct the boundaries of nursing roles and emphasise the relationship based elements of excellent nursing work. CONCLUSIONS: The advanced nurse practitioner has the potential to enhance specialist palliative care service delivery through fluid role boundaries. The context in which advanced nurse practitioner roles are developed is important as acceptance of the role is linked to the co-construction of a different nursing identity. Our findings support the need to define, defend and name the work of advanced nursing roles. RELEVANCE TO CLINICAL PRACTICE: The advanced nurse practitioner roles were regarded as providing a unique contribution to service delivery and were characterised by fluid role boundaries which crossed the traditional disciplinary boundaries between nursing and medicine.