Patient and clinician preferences for biologic treatments for severe uncontrolled asthma: a discrete choice experiment (DCE).

OBJECTIVES: To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients' and clinicians' preferences, and to better understand the reasons for their preferences. METHODS: Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated. Clinicians were also asked about the value of biomarker agnostic biologic treatments. The survey was followed by qualitative interviews targeting a sub-sample of survey participants, in which the rationale behind their survey responses was discussed. RESULTS: In the DCE, both patients and clinicians placed the most importance on exacerbation and hospitalization rate reduction, and risk of injection site reaction. Patients valued location of administration more than clinicians. Rationale for individual-level preferences varied, with patients and clinicians reporting their preference depended on event frequency and anticipated quality of life impacts. Clinicians mentioned compliance and financial impacts, while patients mentioned personal experience, particularly around site reactions. Most patients and clinicians would value a biomarker agnostic asthma treatment. CONCLUSIONS: Asthma treatment preferences are largely driven by treatment efficacy and minimizing the risk of site reactions, although preferences differ between patients and clinicians across other attributes, highlighting the need for shared decision-making and individualized care.

Evaluating construct validity of the Asthma Impairment and Risk Questionnaire using a 3-month exacerbation recall.

BACKGROUND: Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes or no, composite control tool evaluating previous 2-week symptoms and previous 12-month exacerbations. OBJECTIVE: To evaluate the construct validity of the AIRQ using a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items. METHODS: At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patient-reported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments was administered at months 3, 6, and 9, and SGRQ at month 6. RESULTS: A total of 1112 patients aged 12 years or older were enrolled (mean [SD] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT plus exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P < .001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with 1 or more and 2 or more exacerbations in the previous 3 months and patient global self-assessments indicating greater asthma morbidity (all P < .001). CONCLUSION: The AIRQ using exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments.

Patients' preferences for once-daily oral versus once-weekly injectable diabetes medications: The REVISE study.

AIMS: To understand patient preferences for once-daily oral versus once-weekly injectable type 2 diabetes mellitus (T2DM) medication administration profiles, and reasons for their preferences. MATERIALS AND METHODS: The REVISE study, a cross-sectional online survey of 600 participants with T2DM (United Kingdom, n = 300; United States, n = 300), elicited general preferences for once-daily oral versus once-weekly injectable diabetes medications, and reasons for the preference. Participants then viewed two videos describing the administration procedures for injectable dulaglutide and oral semaglutide, based on the product instructions for use. Thereafter, participants indicated their preference for a once-weekly injectable or a once-daily oral medication based on the video descriptions. Participants who switched preferences were asked to identify the reasons influencing their decision. RESULTS: The participants were predominantly male (n = 349; 58.2%), with a mean (SD) age of 64 (11.3) years. Nearly all (n = 557; 92.8%) were taking an oral T2DM medication, and 158 (26.3%) were using an injectable. Initially, 76.5% (n = 459; 95% confidence interval [CI] 73.1-79.9) preferred a once-daily oral and 23.5% a once-weekly injectable (n = 141; 95% CI 20.1-26.9; P < 0.0001). After viewing the videos describing the product-specific administration, the proportions of participants preferring each option were not statistically different (oral semaglutide administration description (n = 315; 52.5%; 95% CI 48.5-56.5; dulaglutide administration description (n = 285; 47.5%; 95% CI 43.5-51.5; NS, P = 0.2207). The most common reason for switching preferences was the timing and steps of administration. CONCLUSION: Several treatment-related characteristics, including route, frequency and complexity of the treatment, play a role in patients' preferences for T2DM treatments and should be considered during treatment selection.

Variation in growth rate, carbon assimilation, and photosynthetic efficiency in response to nitrogen source and concentration in phytoplankton isolated from upper San Francisco Bay.

Six species of phytoplankton recently isolated from upper San Francisco Bay were tested for their sensitivity to growth inhibition by ammonium (NH4+ ), and for differences in growth rates according to inorganic nitrogen (N) growth source. The quantum yield of photosystem II (Fv /Fm ) was a sensitive indicator of NH4+ toxicity, manifested by a suppression of Fv /Fm in a dose-dependent manner. Two chlorophytes were the least sensitive to NH4+ inhibition, at concentrations of >3,000 µmoles NH4+  · L-1 , followed by two estuarine diatoms that were sensitive at concentrations >1,000 µmoles NH4+  · L-1 , followed lastly by two freshwater diatoms that were sensitive at concentrations between 200 and 500 µmoles NH4+  · L-1 . At non-inhibiting concentrations of NH4+ , the freshwater diatom species grew fastest, followed by the estuarine diatoms, while the chlorophytes grew slowest. Variations in growth rates with N source did not follow taxonomic divisions. Of the two chlorophytes, one grew significantly faster on nitrate (NO3- ), whereas the other grew significantly faster on NH4+ . All four diatoms tested grew faster on NH4+ compared with NO3- . We showed that in cases where growth rates were faster on NH4+ than they were on NO3- , the difference was not larger for chlorophytes compared with diatoms. This holds true for comparisons across a number of culture investigations suggesting that diatoms as a group will not be at a competitive disadvantage under natural conditions when NH4+ dominates the total N pool and they will also not have a growth advantage when NO3- is dominant, as long as N concentrations are sufficient.

Attribute Development Using Continuous Stakeholder Engagement to Prioritize Treatment Decisions: A Framework for Patient-Centered Research.

OBJECTIVES: To develop a methodological approach for selecting, validating, and prioritizing attributes for health care decision making. METHODS: Participants (n = 48) were recruited from community support groups if they had a child aged 26 years or younger diagnosed with a coexisting mental health condition and cognitive impairment. Six in-depth interviews eliciting care management experiences were transcribed and coded into themes following the principles of grounded theory and the constant comparative method. Six focus groups involving 42 participants assessed the relevance, priority, and meaning and inter-relationship among the themes. The positive predictive value and sensitivity assessed agreement on thematic meaning. A final list was selected from the top priorities with good agreement as candidate attributes. Attribute levels reflecting the range of experiences in care management decisions emerged from the verbatim passages within each coded theme. RESULTS: Participants were the child's mother (73%), white (77%), married (69%), and on average 48 years old. The children were on average 14 years old; 44% had an intellectual disability, 25% had autism, and more than half had anxiety or attention-deficit/hyperactivity disorder. All 14 attributes identified from the in-depth interviews were deemed relevant. The positive predictive value exceeded 90%, and the sensitivity ranged from 64% to 89%. The final set of attributes formed the framework for care management decisions consisting of six attributes (medication, behavior, services, social, treatment effects, and school) each with three levels. CONCLUSIONS: A systematic approach grounded in qualitative methods produced a framework of relevant, important, and actionable attributes representing competing alternatives in clinical decisions.

LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence.

Liver kinase ß1 (LKB1, also known as STK11) is a serine/threonine kinase that has multiple cellular functions including the regulation of cell polarity and motility. Murine proteomic studies show that LKB1 loss causes aberrant adhesion signaling; however, the mechanistic underpinnings of this relationship are unknown. We show that cells stably depleted of LKB1 or its co-activator STRADα have increased phosphorylation of focal adhesion kinase (FAK) at Tyr(397)/Tyr(861) and enhanced adhesion to fibronectin. LKB1 associates in a complex with FAK and LKB1 accumulation at the cellular leading edge is mutually excluded from regions of activated Tyr(397)-FAK. LKB1-compromised cells lack directional persistence compared with wild-type cells, but this is restored through subsequent pharmacological FAK inhibition or depletion, showing that cell directionality is mediated through LKB1-FAK signaling. Live cell confocal imaging reveals that LKB1-compromised cells lack normal FAK site maturation and turnover, suggesting that defects in adhesion and directional persistence are caused by aberrant adhesion dynamics. Furthermore, re-expression of full-length wild-type or the LKB1 N-terminal domain repressed FAK activity, whereas the kinase domain or C-terminal domain alone did not, indicating that FAK suppression is potentially regulated through the LKB1 N-terminal domain. Based upon these results, we conclude that LKB1 serves as a FAK repressor to stabilize focal adhesion sites, and when LKB1 function is compromised, aberrant FAK signaling ensues, resulting in rapid FAK site maturation and poor directional persistence.

Heterogeneity in non-cystic fibrosis bronchiectasis: insights from ASPEN trial participants.

ASPEN trial participant characteristics highlight the heterogeneity of non-cystic fibrosis bronchiectasis and global variations in clinical practice patterns https://bit.ly/447XeP0.

Impact of Clinical Characteristics and Biomarkers on Asthma Impairment and Risk Questionnaire Exacerbation Prediction Ability.

BACKGROUND: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models. OBJECTIVE: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers. METHODS: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared. RESULTS: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05). CONCLUSION: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ.

Top Ten Tips Palliative Care Clinicians Should Know About Providing Care for People With Disabilities.

Palliative care (PC) clinicians are well poised to help people with disabilities (PWD) live well in the context of serious illness. PC prioritizes person-centered care with a focus on function, autonomy, and quality of life. This approach aligns with principles of high-quality care for PWD. An understanding of the unique experiences and needs of PWD can advance the delivery of comprehensive, equitable PC for this population. In this article, we provide 10 tips to help PC clinicians develop an informed disability lens in their approach to care.

Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.

BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Crossover of Engagement Among Academic Staff and Students During COVID-19.

Purpose: Globally, the pandemic had adverse consequences on the engagement and overall well-being of individuals. From a positive psychological perspective, this study drew on processes of social exchange, Kahn's theory on personal engagement and crossover theory, to explore the impact of mutual influences among academic staff and students on the engagement of both parties. Subsequently, the study explored the positive outcomes of engagement for both academic staff and students. Participants and Methods: Purposive, non-probability sampling was used, and cross-sectional data were collected through electronic surveys. The sample consisted of a total of 1594 students who were nested within 160 academic staff members. Results: Findings highlighted the influence of interpersonal factors such as high student leader-member exchange on student engagement and the impact of students' lack of reciprocity on the emotional engagement of academic staff. Findings further revealed that student engagement was positively related to a deep-learning approach and negatively related to a surface-learning approach. Furthermore, this study found a positive significant association between the emotional engagement and the psychological well-being of academic staff. Conclusion: Against the backdrop of the COVID-19 pandemic and to reduce the negative psychological and behavioural challenges resulting from the pandemic, this research intended to inform policy-makers in higher education of the impact that mutual influences among academic staff and students have on their engagement and the benefits of engagement in cultivating a culture of life-long learning among students and improving the psychological well-being of academic staff.

Patient Preferences for Multi-Cancer Early Detection (MCED) Screening Tests.

BACKGROUND: Emerging blood-based multi-cancer early detection (MCED) tests can detect a variety of cancer types across stages with a range of sensitivity, specificity, and ability to predict the origin of the cancer signal. However, little is known about the general US population's preferences for MCED tests. OBJECTIVE: To quantify preferences for MCED tests among US adults aged 50-80 years using a discrete choice experiment (DCE). METHODS: To quantify preferences for attributes of blood-based MCED tests, an online DCE was conducted with five attributes (true positives, false negatives, false positives, likelihood of the cancer type unknown, number of cancer types detected), among the US population aged 50-80 years recruited via online panels and social media. Data were analyzed using latent class multinomial logit models and relative attribute importance was obtained. RESULTS: Participants (N = 1700) were 54% female, mean age 63.3 years. Latent class modeling identified three classes with distinct preferences for MCED tests. The rank order of attribute importance based on relative attribute importance varied by latent class, but across all latent classes, participants preferred higher accuracy (fewer false negatives and false positives, more true positives) and screenings that detected more cancer types and had a lower likelihood of cancer type unknown. Overall, 72% of participants preferred to receive an MCED test in addition to currently recommended cancer screenings. CONCLUSIONS: While there is significant heterogeneity in cancer screening preferences, the majority of participants preferred MCED screening and the accuracy of these tests is important. While the majority of participants preferred adding an MCED test to complement current cancer screenings, the latent class analyses identified a small (16%) and specific subset of individuals who value attributes differently, with particular concern regarding false-negative and false-positive test results, who are significantly less likely to opt-in.

Strategies to improve the experience of patients with brain tumors in the inpatient rehabilitation setting: development of a care coordination checklist.

PURPOSE: To develop a checklist to facilitate coordination of care and communication of patients with brain tumors and assess the benefit of the checklist using a quality improvement survey. MATERIALS AND METHODS: Rehabilitation teams are challenged to respond to the unique needs of patients with brain tumors as this population requires coordinated care across multiple disciplines with frequent communication. To improve care of this patient population in an IRF setting, we developed a novel checklist using a multidisciplinary team of clinicians. Our checklist aims to improve communication between multiple treatment teams, achieve appropriate goals during the IRF stay, involve services as needed and arrange post-discharge services for patients with brain tumors. We then used a quality improvement survey among clinicians to assess the efficacy and general opinion of the checklist. RESULTS: A total of 15 clinicians completed the survey. 66.7% felt that the checklist improved care delivery, and 66.7% felt the checklist improved communication between providers internally and with external institutions. More than half felt the checklist improved the patient experience and care delivery. CONCLUSIONS: A care coordination checklist has the potential to address the unique challenges experienced by patients with brain tumors to improve overall care for this population.IMPLICATIONS FOR REHABILITATIONSuccessful clinical care and rehabilitation of patients with brain tumors requires the coordinated efforts of an interdisciplinary team that often spans multiple care settings.A care coordination checklist has the potential to address the unique challenges experienced by patients with brain tumors to improve overall care for this population in the inpatient rehabilitation setting.

The Impact of Substantial Improvements in HbA1c and Weight Loss on the Medication Preferences of People with Type 2 Diabetes.

Purpose: To quantify the preferences of people with type 2 diabetes (T2D) for treatment attributes of a glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) versus an injectable GLP-1 RA medication profile. Patients and Methods: Injection-naive people taking oral medications for T2D in the US and UK completed a web survey including a discrete choice experiment to quantify patients' preferences for five treatment attributes: delivery system, frequency of nausea, frequency of hypoglycemia, HbA1c reduction, and weight reduction. Attributes and levels were based on head-to-head clinical trial data of tirzepatide 5mg, 10mg, and 15mg versus semaglutide 1mg. Preference data were analyzed separately by country using multinomial mixed logit (MXL) models. MXL parameters were used to estimate the predicted preference for each tirzepatide dose versus semaglutide 1mg. Direct preferences for each dose of tirzepatide versus semaglutide 1mg were elicited. Results: Participants (N=620) in the US (N=301) and UK (N=319) were 50.8% and 50.5% female with mean ages of 60.7 years and 58.9 years, respectively. The order and magnitude of relative attribute importance (RAI) scores differed between countries. HbA1c reduction (26.3%) had the greatest impact on US participants' preferences, and hypoglycemia (32.8%) did among UK participants. Attribute-level marginal utility results indicated preferences for greater HbA1c improvements, the single-use pre-filled pen, lower hypoglycemia, greater weight reductions, and lower frequency of nausea. Assuming the availability of only tirzepatide or semaglutide 1mg, the predicted preference for tirzepatide (5, 10, and 15mg) in the US is 95.6% (vs 4.4% for semaglutide 1mg) and in the UK was 86.3% (vs 13.7% for semaglutide 1mg). Conclusion: HbA1c reduction, frequency of hypoglycemia, and weight reduction are key drivers of preferences among people with T2D when considering medication options. Overall, people with T2D are likely to prefer the tirzepatide over the semaglutide 1mg medication profiles.

Treatment preferences of patients with relapsed or refractory multiple myeloma in the United States, United Kingdom, Italy, Germany, France, and Spain: results from a discrete choice experiment.

Introduction: Newer treatment options for relapsed/refractory multiple myeloma (RRMM) with efficacy and safety profiles that differ from traditional therapies have facilitated personalized management strategies to optimize patient outcomes. In the context of such personalized management, understanding how treatment characteristics influence patients' preferences is essential. This study assessed patients' preferences for RRMM treatment attributes and determined trade-offs between potential benefits, administration procedures, and adverse effects. Methods: Patients' preferences were evaluated using a discrete choice experiment (DCE). Patients with RRMM who reported failing two lines of anti-myeloma treatment (immunomodulatory agent and a proteasome inhibitor [PI]) or ≥ 3 lines (including ≥1 PI, immunomodulatory agent, or anti-CD38 monoclonal antibody), were recruited across the US, UK, Italy, Germany, France, and Spain. DCE attributes and levels were identified using a targeted literature review, a review of clinical data for relevant RRMM treatments, qualitative patient interviews, and input from clinical and myeloma patient experts. The DCE was administered within an online survey from February-June 2022. Preference data were analyzed using an error-component logit model and willingness to make trade-offs for potential benefits, and relative attribute importance scores were calculated. Results: Overall, 296 patients from the US (n = 100), UK (n = 49), Italy (n = 45), Germany (n = 43), France (n = 39), and Spain (n = 20) participated in the DCE. Mean (standard deviation) age was 63.8 (8.0) years, 84% had a caregiver, and patients had a median of 3 (range: 2-8) prior lines of therapy. Efficacy attributes most influenced patients' preferences, with increasing overall response rate (25-85%) and overall survival (6 months to 2 years) contributing to ~50% of treatment decision-making. Administration procedures were also considered important to patients. Avoiding individual side effects was considered relatively less important, with patients willing to tolerate increases in side effects for gains in efficacy. Patient characteristics such as rate of disease progression, sociodemographics, or clinical characteristics also influenced treatment preferences. Conclusion: Patients with RRMM were willing to tolerate increased risk of side effects for higher efficacy. Preferences and risk tolerance varied between patients, with preference patterns differing by certain patient characteristics. This highlights the importance of shared decision-making for optimal treatment selection and patient outcomes.

Evaluating antitumor activity of Escherichia coli purine nucleoside phosphorylase against head and neck patient-derived xenografts.

BACKGROUND: Purine nucleoside phosphorylase (PNP) gene transfer represents a promising approach to treatment of head and neck malignancies. We tested recombinant adenovirus already in phase I/II clinical testing and leading-edge patient-derived xenografts (PDX) as a means to optimize this therapeutic strategy. METHODS: Our experiments investigated purine base cytotoxicity, PNP enzyme activity following treatment of malignant tissue, tumor mass regression, viral receptor studies, and transduction by tropism-modified adenovirus. RESULTS: Replication deficient vector efficiently transduced PDX cells and mediated significant anticancer effect following treatment with fludarabine phosphate in vivo. Either 6-methylpurine or 2-fluoroadenine (toxic molecules generated by the PNP approach) ablated head and neck cancer cell proliferation. High levels of adenovirus-3 specific receptors were detected in human tumor models, and vector was evaluated that utilizes this pathway. CONCLUSIONS: Our studies provide the scientific foundation necessary to improve PNP prodrug cleavage and advance a new treatment for head and neck cancer.

Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer.

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the 'gas' and 'breaks' to finely tune iron-regulated tumor progression.

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process.

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies.

Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.

Oncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.

Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age-inappropriate levels of inattention, hyperactivity and impulsivity, and is associated with long-term social, academic and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Children and adolescents with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega-3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. OBJECTIVES: To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents. SEARCH METHODS: We searched the following databases in August 2011: CENTRAL (The Cochrane Library 2011, Issue 2), MEDLINE (1948 to July Week 3, 2011), EMBASE (1980 to 2011 Week 29), PsycINFO (1806 to current), CINAHL (1937 to current), BIOSIS (1969 to 30 July 2011), Science Citation Index (1970 to 30 July 2011), Social Science Citation Index (1970 to 30 July 2011), Conference Proceedings Citation Index - Science (1990 to 30 July 2011), Conference Proceedings Citation Index - Social Science and Humanities (1990 to 30 July 2011), Cochrane Database of Systematic Reviews (2011, Issue 7), DARE (2011 Issue 2), Dissertation Abstracts (via Dissertation Express) and the metaRegister of Controlled Trials (mRCT). In addition, we searched the following repositories for theses on 2 August 2011: DART, NTLTD and TROVE. We also checked reference lists of relevant studies and reviews for additional references. SELECTION CRITERIA: Two review authors independently assessed the results of the database searches. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, by consultation with a third member of the review team. DATA COLLECTION AND ANALYSIS: Two members of the review team independently extracted details of participants and setting, interventions, methodology and outcome data. If differences were identified, we resolved them by consensus or referral to a third member of the team. We made all reasonable attempts to contact the authors where further clarification or missing data were needed. MAIN RESULTS: We included 13 trials with 1011 participants in the review. After screening 366 references, we considered 23 relevant and obtained the full text for consideration. We excluded five papers and included 18 papers describing the 13 trials. Eight of the included trials had a parallel design: five compared an omega-3 PUFA supplement to placebo; two compared a combined omega-3 and omega-6 supplement to placebo, and one compared an omega-3 PUFA to a dietary supplement. Five of the included trials had a cross-over design: two compared combined omega-3/6 PUFA to placebo; two compared omega-6 PUFA with placebo; one compared omega-3 to omega-6 PUFA, and one compared omega-6 PUFA to dexamphetamine. Supplements were given for a period of between four and 16 weeks.There was a significantly higher likelihood of improvement in the group receiving omega-3/6 PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62). However, there were no statistically significant differences in parent-rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) -0.17, 95% CI -0.38 to 0.03); inattention (six trials, 469 participants; SMD -0.04, 95% CI -0.29 to 0.21) or hyperactivity/impulsivity (five trials, 416 participants; SMD -0.04, 95% CI -0.25 to 0.16) when all participants receiving PUFA supplements were compared to those receiving placebo.There were no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI -0.18 to 0.27); inattention (three trials, 260 participants; SMD 0.26, 95% CI -0.22 to 0.74) or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI -0.16 to 0.35).There were also no differences between groups in behaviour, side effects or loss to follow-up.Overall, there were no other differences between groups for any other comparison. AUTHORS' CONCLUSIONS: Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents. The majority of data showed no benefit of PUFA supplementation, although there were some limited data that did show an improvement with combined omega-3 and omega-6 supplementation.It is important that future research addresses current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, short follow-up times and other methodological weaknesses.