Feasibility and face validity of two patient reported outcome measures for nausea: Preferences of children with cancer.

PURPOSE: To optimize recognition and management of nausea in children with cancer using patient reported outcome measures (PROMs) and to identify preferences of children with cancer regarding two validated tools: the Baxter Retching Faces (BARF) scale and the Pediatric Nausea Assessment Tool (PeNAT). DESIGN AND METHODS: This quantitative descriptive cross-sectional study (n = 34) used bespoke questionnaires to measure feasibility and face validity of the BARF and the PeNAT. Feasibility included the items: understanding, ease of use, and communication. Face validity was studied in terms of the degree in which the faces of both PROMs corresponded with children's feelings of nausea. A descriptive and comparative analysis of the data was performed. RESULTS: Both the BARF and the PeNAT were rated by the children as feasible, and no significant differences were found. However, regarding the item communication, the PeNAT did not reach the cut-off value (≥80% of all children scored neutral, agree or totally agree on the Likert scale). Regarding face validity, only the BARF reached the cut-off value and corresponded significantly better with children's feelings of nausea than the PeNAT. CONCLUSION: According to children with cancer, only the BARF is both feasible and meets criteria for face validity. Therefore, the BARF is recommended as a PROM for reporting nausea in children with cancer. However, possible differences between age groups should be taken into account for future research. PRACTICE IMPLICATIONS: This study will help health care professionals in making a patient-centered and informed choice when using a PROM for measuring nausea in children with cancer.

Evaluation of chemotherapy-induced nausea and vomiting in pediatric patients with high-grade glioma treated with lomustine-a case series.

PURPOSE: Although lomustine has been used as a chemotherapeutic agent for decades, no recommendation on appropriate chemotherapy-induced nausea and vomiting (CINV) prophylaxis is available. As CINV is considered one of the most bothersome side effects of chemotherapy, adequate prophylaxis is of relevance to improve quality of life during cancer treatment. The aim of this retrospective case series was to report the incidence and severity of CINV in pediatric patients with high-grade glioma treated with lomustine and to formulate recommendations for appropriate CINV prophylaxis. METHODS: Pediatric patients treated with lomustine for high-grade glioma according to the ACNS 0423 protocol were identified retrospectively. Two researchers independently reviewed and classified complaints of CINV and administered CINV prophylaxis. Treatment details, tumor localization, and response to therapy were systematically extracted from the patients' files. RESULTS: Seventeen children aged 8-18 years received a median of four cycles of lomustine. CINV complaints and administered prophylaxis were evaluable in all patients. Moderate or severe CINV was observed in 13/17 (76%) patients. Administered prophylactic CINV regimens varied from no prophylaxis to triple-agent combinations. CONCLUSION: In this case series, we identified lomustine as a highly emetogenic chemotherapeutic agent. According to the current guidelines, CINV prophylaxis with a 5-HT3 receptor antagonist in combination with dexamethasone and (fos)aprepitant is recommended.

Beyond Encapsulation: Exploring Macrophage-Fibroblast Cross Talk in Implant-Induced Fibrosis.

The foreign body response (FBR) and organ fibrosis are complex biological processes involving the interaction between macrophages and fibroblasts. Understanding the molecular mechanisms underlying macrophage-fibroblast cross talk is crucial for developing strategies to mitigate implant encapsulation, a major cause of implant failure. This article reviews the current knowledge on the role of macrophages and fibroblasts in the FBR and organ fibrosis, highlighting the similarities between these processes. The FBR is characterized by the formation of a fibrotic tissue capsule around the implant, leading to functional impairment. Various factors, including material properties such as surface chemistry, stiffness, and topography, influence the degree of encapsulation. Cross talk between macrophages and fibroblasts plays a critical role in both the FBR and organ fibrosis. However, the precise molecular mechanisms remain poorly understood. Macrophages secrete a wide range of cytokines that modulate fibroblast behavior such as abundant collagen deposition and myofibroblast differentiation. However, the heterogeneity of macrophages and fibroblasts and their dynamic behavior in different tissue environments add complexity to this cross talk. Experimental evidence from in vitro studies demonstrates the impact of material properties on macrophage cytokine secretion and fibroblast physiology. However, the correlation between in vitro response and in vivo encapsulation outcomes is not robust. Adverse outcome pathways (AOPs) offer a potential framework to understand and predict process complexity. AOPs describe causal relationships between measurable events leading to adverse outcomes, providing mechanistic insights for in vitro testing and predictive modeling. However, the development of an AOP for the FBR does require a comprehensive understanding of the molecular initiating events and key event relationships to identify which events are essential. In this article, we describe the current knowledge on macrophage-fibroblast cross talk in the FBR and discuss how targeted research can help build an AOP for implant-related fibrosis.

Enrichment of serum IgG4 in MuSK myasthenia gravis patients.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

Smoking Cessation in Lower Socioeconomic Groups: Adaptation and Pilot Test of a Rolling Group Intervention.

BACKGROUND: Socioeconomic inequalities in smoking rates persist and tend to increase, as evidence-based smoking cessation programs are insufficiently accessible and appropriate for lower socioeconomic status (SES) smokers to achieve long-term abstinence. Our study is aimed at systematically adapting and pilot testing a smoking cessation intervention for this specific target group. METHODS: First, we conducted a needs assessment, including a literature review and interviews with lower SES smokers and professional stakeholders. Next, we selected candidate interventions for adaptation and decided which components needed to be adopted, adapted, or newly developed. We used Intervention Mapping to select effective methods and practical strategies and to build a coherent smoking cessation program. Finally, we pilot tested the adapted intervention to assess its potential effectiveness and its acceptability for lower SES smokers. RESULTS: The core of the adapted rolling group intervention was the evidence-based combination of behavioral support and pharmacotherapy. The intervention offered both group and individual support. It was open to smokers, smokers who had quit, and quitters who had relapsed. The professional-led group meetings had a fixed structure. Themes addressed included quitting-related coping skills and health-related and poverty-related issues. Methods applied were role modeling, practical learning, reinforcement, and positive feedback. In the pilot test, half of the 22 lower SES smokers successfully quit smoking. The intervention allowed them to "quit at their own pace" and to continue despite a possible relapse. Participants appraised the opportunities for social comparison and role modeling and the encouraging atmosphere. The trainers were appreciated for their competencies and personal feedback. CONCLUSIONS: Our adapted rolling group intervention for lower SES smokers was potentially effective as well as feasible, suitable, and acceptable for the target group. Further research should determine the intervention's effectiveness. Our detailed report about the adaptation process and resulting intervention may help reveal the mechanisms through which such interventions might operate effectively.

Chronic rhinitis in South Africa - more than just allergy!

Chronic rhinitis is a troublesome condition for sufferers. It is tempting to label all patients with chronic nasal symptoms as having allergic rhinitis (AR), but many such patients have other causes of chronic rhinitis that need a specific diagnosis and management strategy. Even when the patient fully fits the definition of AR, their condition will be best served by combining medication with ongoing patient education.

Multi-component meningococcal serogroup B (MenB)-4C vaccine induces effective opsonophagocytic killing in children with a complement deficiency.

Vaccination against meningococcal serogroup B is recommended for patients with a complement deficiency; however, although immunogenicity in this patient group has been shown, efficacy has not yet been established. In this study, we collected serum from children with a complement deficiency in the alternative pathway or in late terminal pathway before and after vaccination with multi-component meningococcal serogroup B (MenB)-4C. MenB-4C is a multi-component, protein-based vaccine against MenB consisting of factor H-binding protein, Neisserial heparin-binding protein, Neisserial adhesion A and outer membrane vesicles containing Porin A. We assessed the vaccine immunogenicity and vaccine-mediated protection by a whole cell enzyme-linked immunosorbent assay with Neisseria meningitidis serogroup B strains H44/76, 5/99 and NZ98/254, which shows that vaccination induced antibody titers against meningococcus. We show that the classical serum bactericidal activity assay with exogenous serum indicates the presence of vaccine-induced antibodies and capacity to activate complement-mediated pathogen lysis. However, in children with a late terminal pathway deficiency, no complement-mediated pathogen lysis was observed when autologous serum was applied in the serum bactericidal activity assay, demonstrating a lack of serum bactericidal activity in children with complement deficiencies. However, MenB-4C vaccination still induced effective complement-dependent opsonophagocytic killing against N. meningitidis serogroup B in reconstituted whole blood with autologous serum from children with an alternative pathway or late terminal pathway deficiency. These findings support the recommendation to vaccinate all complement-deficient children against MenB.

Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.

BACKGROUND: Many cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique. We hypothesized that cough is related to a fast inhalation. MATERIALS AND METHODS: In this prospective observational study, CF patients ≥ 6 years old on TIP maintenance therapy from four Dutch CF centers were visited twice at home. Video recordings were obtained and peak inspiratory flow (PIF) was recorded while patients inhaled TIP. Between the two home visits, the patients made three additional videos. CF questionnaire-revised, spirometry data, and computed tomography scan were collected. Two observers scored the videos for PIF, cough, and mistakes in inhalation technique. The associations between PIF and cough were analyzed using a logistic mixed-effects model accounting for FEV1 % predicted and capsule number. RESULTS: Twenty patients were included, median age 22 (18-28) years. No significant associations were found between PIF and cough. The risk of cough was highest after inhalation of the first capsule when compared to the second, third, and fourth capsule (P ≤ .015). Fourteen patients (70%) coughed at least once during TIP inhalation. A breath-hold of less than 5 seconds after inhalation and no deep expiration before inhalation were the most commonly observed mistakes. CONCLUSION: PIF is not related to cough in CF patients using TIP.

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. METHODS: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

Understanding the multitude of barriers that prevent smokers in lower socioeconomic groups from accessing smoking cessation support: A literature review.

One explanation for the increasing smoking-related health inequalities is the limited access of lower socioeconomic status (SES) smokers to smoking cessation support. In order to understand this limited access - and to eventually improve accessibility - we provide a structured overview of the barriers that lower SES smokers face in the successive phases of access to cessation support. Our literature review included 43 papers on barriers of access to cessation support for lower SES smokers, published before June 2016. We used the access to health care framework to categorize the extracted barriers into (a) either the abilities of smokers or dimensions of cessation support and (b) one of the successive phases of access to support. We found that lower SES smokers encounter many barriers. They are present in all phases of access to cessation support, and different barriers may be important in each of these phases. We also found that each phase transition is hampered by barriers related to both the abilities of smokers and the dimensions of cessation support, and that these barriers tend to interact, both with each other and with the disadvantaged living conditions of lower SES smokers. In conclusion, reducing smoking-related health inequalities by improving lower SES smokers' access to smoking cessation support requires a comprehensive approach. Our structured overview of barriers may serve as a starting point for tailoring such an approach to the multitude of barriers that prevent lower SES smokers from accessing cessation support, while simultaneously taking into account their disadvantaged living conditions.

Opportunities for Tailored Support to Implement Smoke-Free Homes: A Qualitative Study among Lower Socioeconomic Status Parents.

With the aim of preventing children from being exposed to secondhand smoke, we examined to which level lower socio-economic status (SES) households had implemented home smoking rules and the factors that hampered parents in their process of change toward a complete smoke-free home (SFH). We conducted a qualitative study including semi-structured in-depth interviews with 14 parents of young children living in a lower SES neighborhood of a provincial town in the Netherlands. Interview transcripts were subjected to a qualitative content analysis. Three distinct levels of SFH implementation emerged: complete SFH, flexible SFH, and partial SFH. Differences between parents at these three levels essentially concerned: (1) the role of child-related moral considerations in their motivation for an SFH; (2) whether they felt they had the agency to set and enforce home smoking rules; (3) the difficulties they experienced in changing their smoking habit from smoking indoors to smoking outdoors. Parents also had different opinions about the role their children could play in facilitating the parental process of change. We conclude that the current level of SFH implementation may serve as a starting point for developing tailored interventions. Such interventions should probably address other factors than the commonly used awareness-knowledge-commitment approach.

An unusual presentation of a patient with severe hypogammaglobulinemia.

We present a patient who was diagnosed with severe hypogammaglobulinemia after her newborn child presented with two episodes of meningitis. The patient had no history or symptoms suggestive of immunodeficiency. Thus far, a cause for the immunodeficiency has not been found, even after extensive immunological evaluation.

A common antigenic motif recognized by naturally occurring human VH5-51/VL4-1 anti-tau antibodies with distinct functionalities.

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

Stress and sexual reproduction affect the dynamics of the wheat pathogen effector AvrStb6 and strobilurin resistance.

Host resistance and fungicide treatments are cornerstones of plant-disease control. Here, we show that these treatments allow sex and modulate parenthood in the fungal wheat pathogen Zymoseptoria tritici. We demonstrate that the Z. tritici-wheat interaction complies with the gene-for-gene model by identifying the effector AvrStb6, which is recognized by the wheat resistance protein Stb6. Recognition triggers host resistance, thus implying removal of avirulent strains from pathogen populations. However, Z. tritici crosses on wheat show that sex occurs even with an avirulent parent, and avirulence alleles are thereby retained in subsequent populations. Crossing fungicide-sensitive and fungicide-resistant isolates under fungicide pressure results in a rapid increase in resistance-allele frequency. Isolates under selection always act as male donors, and thus disease control modulates parenthood. Modeling these observations for agricultural and natural environments reveals extended durability of host resistance and rapid emergence of fungicide resistance. Therefore, fungal sex has major implications for disease control.

Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination.

This corrects the article DOI: 10.1038/mi.2017.81.

Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination.

Mucosal immunity is often required for protection against respiratory pathogens but the underlying cellular and molecular mechanisms of induction remain poorly understood. Here, systems vaccinology was used to identify immune signatures after pulmonary or subcutaneous immunization of mice with pertussis outer membrane vesicles. Pulmonary immunization led to improved protection, exclusively induced mucosal immunoglobulin A (IgA) and T helper type 17 (Th17) responses, and in addition evoked elevated systemic immunoglobulin G (IgG) antibody levels, IgG-producing plasma cells, memory B cells, and Th17 cells. These adaptive responses were preceded by unique local expression of genes of the innate immune response related to Th17 (e.g., Rorc) and IgA responses (e.g., Pigr) in addition to local and systemic secretion of Th1/Th17-promoting cytokines. This comprehensive systems approach identifies the effect of the administration route on the development of mucosal immunity, its importance in protection against Bordetella pertussis, and reveals potential molecular correlates of vaccine immunity to this reemerging pathogen.

Trunk neural crest origin of dermal denticles in a cartilaginous fish.

Cartilaginous fishes (e.g., sharks and skates) possess a postcranial dermal skeleton consisting of tooth-like "denticles" embedded within their skin. As with teeth, the principal skeletal tissue of dermal denticles is dentine. In the head, cranial neural crest cells give rise to the dentine-producing cells (odontoblasts) of teeth. However, trunk neural crest cells are generally regarded as nonskeletogenic, and so the embryonic origin of trunk denticle odontoblasts remains unresolved. Here, we use expression of FoxD3 to pinpoint the specification and emigration of trunk neural crest cells in embryos of a cartilaginous fish, the little skate (Leucoraja erinacea). Using cell lineage tracing, we further demonstrate that trunk neural crest cells do, in fact, give rise to odontoblasts of trunk dermal denticles. These findings expand the repertoire of vertebrate trunk neural crest cell fates during normal development, highlight the likely primitive skeletogenic potential of this cell population, and point to a neural crest origin of dentine throughout the ancestral vertebrate dermal skeleton.

Immunological memory to hyperphosphorylated tau in asymptomatic individuals.

Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.