Cigarette and E-Cigarette Harm Perceptions During Pregnancy.

BACKGROUND: Research suggests that pregnancy status (prior, current, and future intention) is associated with differences in perceived harm of electronic cigarette (e-cigarette) use during pregnancy. However, perceptions of health outcomes attributed to cigarette and e-cigarette use during pregnancy have not been explored among a sample of pregnant women who smoke. OBJECTIVES: The purpose of this study was to explore differences in perceived harms of cigarette and e-cigarette use and perceived birth and health outcomes associated with cigarette and e-cigarette use during pregnancy among a sample of pregnant women who currently smoked. METHODS: Using a cross-sectional online survey, we examined perceptions about cigarette and e-cigarette use during pregnancy among a sample of U.S. pregnant women ( n = 267) who smoked in the past 30 days. Participants were grouped into categories based on e-cigarette use status (current, past, and never e-cigarette users). Differences between e-cigarette use status and perceived harm (absolute of cigarettes, e-cigarettes, and relative of e-cigarettes) and perceived health outcomes attributed to smoking/e-cigarette use were examined. RESULTS: Among our sample, 45.7%, 39.7%, and 14.6% were current, ever, and never e-cigarette users, respectively. Associations existed between e-cigarette use status and absolute perceived harm of cigarettes, relative perceived harm of e-cigarettes, and perceived health outcomes. Current e-cigarette users believed pregnant women who smoked cigarettes were more likely to lose a child because of miscarriage or sudden infant death syndrome or give birth to a child with low birth weight, reduced lung function, cleft lip, reduced brain function, or attention-deficit/hyperactivity disorder than never e-cigarette users. No associations were found between perceived birth and health outcomes of e-cigarette use by e-cigarette user status. DISCUSSION: Pregnant women who smoked and used e-cigarettes had lower risk perceptions about e-cigarette use during pregnancy than those who only smoked. Health messages and research about the harms of nicotine exposure during pregnancy should address the risks of dual-use versus only e-cigarette use. In addition, messages about the relative harm of e-cigarettes compared to cigarettes are needed for pregnant women who smoke and have trouble quitting.

Use of Preoperative Endoscopic Capsule-Based pH Testing Before Bariatric Surgery.

BACKGROUND: Vertical sleeve gastrectomy is the most performed bariatric operation in the US; however, a significant number of patients suffer from persistent or new-onset reflux. No consensus for objective preoperative evaluation in these patients exists. We compared capsule-based pH testing vs GERD symptom scoring to determine extent of preoperative GERD to aid in procedure selection for bariatric surgery. STUDY DESIGN: An IRB-approved retrospective review of consecutive patients at a single institution was performed from April 2021 to December 2022. During initial consultation for bariatric surgery, a validated GERD symptom subjective survey was administered. All patients demonstrating interest in sleeve gastrectomy or had a history of reflux underwent upper endoscopy with capsule-based pH testing. RESULTS: Sixty-two patients underwent preoperative endoscopy with capsule-based pH testing and completed GERD symptom assessment survey(s). Median BMI was 43.4 kg/m 2 and 66.1% of patients were not taking a proton-pump inhibitor before performance of pH testing. There was negligible linear association between the objective DeMeester score obtained by capsule-based pH probe and GERD symptom survey scores. Median GERD symptom survey scores did not differ between patients with and without a diagnosis of GERD based on pH testing (all p values >0.11). CONCLUSIONS: An objective method for identifying severe GERD in the preoperative assessment may aid in the decision tree for procedure selection and informed consent process. Patients with significant preoperative GERD may be at higher risk for future GERD-related sleeve complications. Capsule-based pH testing may prove to be superior to subjective symptom scoring systems in this patient population.

School-Based Mental Health Service Utilization Through the COVID-19 Pandemic and Beyond.

BACKGROUND: We examined trends in mental health service utilization before, during, and in the immediate return to in-person learning throughout the COVID-19 pandemic. METHODS: Retrospective chart review was assessed for changes in odds of any visit being a mental health encounter from five school-based health centers from the 2018-2019 to the 2021-2022 school years. Data are limited to the in-person school year from mid-August to early June. RESULTS: Data were assessed from 1239 students seen through 2256 visits over the 4 school years (Mage = 12.93). The odds of any visit being related to a mental health encounter increased each school year, with the 2020 to 2021 and 2021 to 2022 school years having significant increases in odds (both compared to the first and to the antecedent school year). In addition, during the 2019 to 2020 and 2020 to 2021 school years, the odds of a repeated mental health encounter significantly increased from year to year. CONCLUSIONS: Findings indicate a steadily increasing number of mental health service utilization needs among adolescent students that was significantly exponentiated throughout the COVID-19 pandemic.

Fundamental Niche Narrows through Larval Stages of a Filter-Feeding Marine Invertebrate.

AbstractOntogenetic niche theory predicts that resource use should change across complex life histories. To date, studies of ontogenetic shifts in food niches have mainly focused on a few systems (e.g., fish), with less attention on organisms with filter-feeding larval stages (e.g., marine invertebrates). Recent studies suggest that filter-feeding organisms can select specific particles, but our understanding of whether niche theory applies to this group is limited. We characterized the fundamental niche (i.e., feeding proficiency) by examining how niche breadth changes across the larval stages of the filter-feeding marine polychaete Galeolaria caespitosa. Using a no-choice experimental design, we measured feeding rates of trochophore, intermediate-stage, and metatrochophore larvae on the prey phytoplankton species Nannochloropsis oculata, Tisochrysis lutea, Dunaliella tertiolecta, and Rhodomonas salina, which vary 10-fold in size, from the smallest to the largest. We formally estimated Levins's niche breadth index to determine the relative proportions of each species in the diet of the three larval stages and also tested how feeding rates vary with algal species and stage. We found that early stages eat all four algal species in roughly equal proportions, but niche breadth narrows during ontogeny, such that metatrochophores are feeding specialists relative to early stages. We also found that feeding rates differed across phytoplankton species: the medium-sized cells (Tisochrysis and Dunaliella) were eaten most, and the smallest species (Nannochloropsis) was eaten the least. Our results demonstrate that ontogenetic niche theory describes changes in fundamental niche in filter feeders. An important next step is to test whether the realized niche (i.e., preference) changes during the larval phase as well.

Prevalence and Persistence of Antibiotic Resistance Determinants in the Gut of Travelers Returning to the United Kingdom is Associated with Colonization by Pathogenic Escherichia coli.

The gut microbiota constitutes an ideal environment for the selection, exchange, and carriage of antibiotic resistance determinants (ARDs), and international travel has been identified as a risk factor for acquisition of resistant organisms. Here, we present a longitudinal metagenomic analysis of the gut resistome in travellers to "high-risk" countries (Gutback). Fifty volunteers, recruited at a travel clinic in London, United Kingdom, provided stool samples before (pre-travel), immediately after (post-travel), and 6 months after their return (follow-up) from a high-risk destination. Fecal DNA was extracted, metagenomic sequencing performed and the resistome profiled. An increase in abundance and diversity of resistome was observed after travel. Significant increases in abundance were seen in antimicrobial genes conferring resistance to macrolides, third-generation cephalosporins, aminoglycosides, and sulfonamides. There was a significant association with increased resistome abundance if the participant experienced diarrhea during travel or took antibiotics, but these two variables were co-correlated. The resistome abundance returned to pre-travel levels by the 6-month sample point but there was evidence of persistence of several ARDs. The post-travel samples had an increase in abundance Escherichia coli which was positively associated with many acquired resistant determinants. Virulence and phylogenetic profiling revealed pathogenic E. coli significantly contributed to this increase abundance. In summary, in this study, foreign travel remains a significant risk factor for acquisition of microbes conferring resistance to multiple classes of antibiotics, often associated with symptomatic exposure to diarrhoeagenic E. coli. IMPORTANCE A future where antimicrobial therapy is severely compromised by the increase in resistant organisms is of grave concern. Given the variability in prevalence and diversity of antimicrobial resistance determinants in different geographical settings, international travel is a known risk factor for acquisition of resistant organisms into the gut microbiota. In this study, we show the utility of metagenomic approaches to quantify the levels of acquisition and carriage of resistance determinants after travel to a "high-risk" setting. Significant modulation to the resistome was seen after travel that is largely resolved within 6 months, although evidence of persistence of several ARDs was observed. Risk factors for acquisition included experiencing a diarrheal episode and the use of antibiotics. Colonization by pathogenic Escherichia coli was correlated with an increase in acquisition of antimicrobial resistance determinants, and as such established public health guidance to travelers on food and water safety remain an important message to reduce the spread of antibiotic resistance.

Mapping the correlations and gaps in studies of complex life histories.

For species with complex life histories, phenotypic correlations between life-history stages constrain both ecological and evolutionary trajectories. Studies that seek to understand correlations across the life history differ greatly in their experimental approach: some follow individuals ("individual longitudinal"), while others follow cohorts ("cohort longitudinal"). Cohort longitudinal studies risk confounding results through Simpson's Paradox, where correlations observed at the cohort level do not match that of the individual level. Individual longitudinal studies are laborious in comparison, but provide a more reliable test of correlations across life-history stages. Our understanding of the prevalence, strength, and direction of phenotypic correlations depends on the approaches that we use, but the relative representation of different approaches remains unknown. Using marine invertebrates as a model group, we used a formal, systematic literature map to screen 17,000+ papers studying complex life histories, and characterized the study type (i.e., cohort longitudinal, individual longitudinal, or single stage), as well as other factors. For 3315 experiments from 1716 articles, 67% focused on a single stage, 31% were cohort longitudinal and just 1.7% used an individual longitudinal approach. While life-history stages have been studied extensively, we suggest that the field prioritize individual longitudinal studies to understand the phenotypic correlations among stages.

Protection Motivation Theory and Intentions to Receive the COVID-19 Vaccine.

Background. Declared a "public health threat of international concern" by the World Health Organization, the COVID-19 virus has caused the deaths of over half a million individuals in the United States in just the first 23 months after detection. The vaccine has recently been introduced to reduce this public health threat. However, due, in part, to the rapidity with which the vaccine was developed, many individuals display vaccine hesitancy. Purpose. The current study examined the utility of the Protection Motivation Theory of Health (PMT) in predicting intentions to receive the COVID-19 vaccine. Method. One hundred twenty-nine unvaccinated respondents (drawn from an initial sample of 255 participants) completed a survey assessing the components of the PMT and intentions to receive the vaccine. Respondents could also provide an open-ended response regarding any concerns they had with the vaccine. Conclusions. The PMT accounted for 76% of the variance in vaccine intentions. Vulnerability, outcome efficaciousness, and maladaptive response rewards each accounted for unique variance. Open-ended responses reflecting concerns with the vaccine fell into 8 categories, with the most common being concern with the long-term side effects of the vaccine. These results suggest that public health campaigns promoting the vaccine should focus on vulnerability to COVID-19, protective functions of the vaccine, and overcoming what people perceive as benefits of not receiving the vaccine.

Ruminal Fiber Degradation Kinetics within and among Warm-Season Annual Grasses as Affected by the Brown Midrib Mutation.

The objective of this study was to compare the nutritional composition and the neutral detergent fiber (NDF) degradation kinetics of brown midrib (BMR) and non-BMR genotypes within and across warm-season annual grasses. Four commercial varieties (two non-BMR and two BMR) of corn, sorghum, and pearl millet were planted in plots. Forage samples were incubated in the rumen of three rumen-cannulated cows for 0, 3, 6, 12, 24, 48, 96, and 240 h. On an NDF basis, all forage types showed lower acid detergent lignin (ADL) concentrations for BMR genotypes, but the magnitude of the difference differed among forage types. The concentration of undegraded NDF (uNDF; NDF basis) differed among forage types and between genotypes. Corn had the least, pearl millet had the intermediate, and sorghum had the greatest concentration of uNDF. Non-BMR genotypes had greater concentrations of uNDF than BMR genotypes. No interaction existed between forage type and genotype for the concentration of uNDF. In conclusion, although BMR forages may show lower ADL concentrations in the cell wall and greater NDF degradability than non-BMR forages of the same forage type, BMR forages do not always have the least ADL concentration or the greatest NDF degradability when comparing different forage types.

K-12, college/university, and mass shootings: similarities and differences.

In a 2003 study, we examined five antecedents of school shootings - a history of rejection, acute rejection experience, history of psychological problems, fascination with death or violence, and fascination with guns. In three studies, the current project examined the role of these factors in 57 K-12 shootings, 24 college/university shootings, and 77 mass shootings that occurred since the original study. Over half of all shooters had a history of psychological problems. More K-12 shooters than college or mass shooters displayed a history of rejection. However, more mass than school shooters had experienced an acute rejection, such as a workplace firing. The characteristics identified in the original study appeared as common antecedent conditions of not only K-12 shootings but college/university and mass shootings as well. These results identify problems that can be addressed to minimize the occurrence of school and mass shootings.

A multi-targeting pre-clinical candidate against drug-resistant tuberculosis.

FNDR-20081 [4-{4-[5-(4-Isopropyl-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-piperazin-1-yl}-7-pyridin-3-yl-quinoline] is a novel, first in class anti-tubercular pre-clinical candidate against sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). In-vitro combination studies of FNDR-20081 with first- and second-line drugs exhibited no antagonism, suggesting its compatibility for developing new combination-regimens. FNDR-20081, which is non-toxic with no CYP3A4 liability, demonstrated exposure-dependent killing of replicating-Mtb, as well as the non-replicating-Mtb, and efficacy in a mouse model of infection. Whole genome sequencing (WGS) of FNDR-20081 resistant mutants revealed the identification of pleotropic targets: marR (Rv0678), a regulator of MmpL5, a transporter/efflux pump mechanism for drug resistance; and Rv3683, a putative metalloprotease potentially involved in peptidoglycan biosynthesis. In summary, FNDR-20081 is a promising first in class compound with the potential to form a new combination regimen for MDR-TB treatment.

Radical genome remodelling accompanied the emergence of a novel host-restricted bacterial pathogen.

The emergence of new pathogens is a major threat to public and veterinary health. Changes in bacterial habitat such as a switch in host or disease tropism are typically accompanied by genetic diversification. Staphylococcus aureus is a multi-host bacterial species associated with human and livestock infections. A microaerophilic subspecies, Staphylococcus aureus subsp. anaerobius, is responsible for Morel's disease, a lymphadenitis restricted to sheep and goats. However, the evolutionary history of S. aureus subsp. anaerobius and its relatedness to S. aureus are unknown. Population genomic analyses of clinical S. aureus subsp. anaerobius isolates revealed a highly conserved clone that descended from a S. aureus progenitor about 1000 years ago before differentiating into distinct lineages that contain African and European isolates. S. aureus subsp. anaerobius has undergone limited clonal expansion, with a restricted population size, and an evolutionary rate 10-fold slower than S. aureus. The transition to its current restricted ecological niche involved acquisition of a pathogenicity island encoding a ruminant host-specific effector of abscess formation, large chromosomal re-arrangements, and the accumulation of at least 205 pseudogenes, resulting in a highly fastidious metabolism. Importantly, expansion of ~87 insertion sequences (IS) located largely in intergenic regions provided distinct mechanisms for the control of expression of flanking genes, including a novel mechanism associated with IS-mediated anti-anti-sense decoupling of ancestral gene repression. Our findings reveal the remarkable evolutionary trajectory of a host-restricted bacterial pathogen that resulted from extensive remodelling of the S. aureus genome through an array of diverse mechanisms in parallel.

Growth of the harmful alga, Prymnesium parvum (Prymnesiophyceae), after gradual and abrupt increases in salinity.

Prymnesium parvum is a euryhaline, toxin-producing microalga. Although its abundance in inland waters and growth potential in the laboratory is reduced at high salinity (>20), the ability of inland strains to adjust their growth after long-term residence in high salinity is uncertain. An inland strain of P. parvum maintained at salinity of 5 in modified artificial seawater medium (ASM-5) was subjected to the following treatments over five sequential batch culture rounds: ASM-5 (control); modified ASM at salinity of 30, raised with NaCl; modified ASM at salinity incrementally increased to 30 with NaCl; and Instant Ocean® at salinity of 30 (IO-30). Exponential growth rate (r) was reduced when salinity was increased from 5 to 30 in ASM but returned to control values during the second round. When salinity was incrementally increased, a reduction in r still occurred when salinity reached 25-30. Maximum density was reduced at salinity of 30 in ASM upon abrupt transfer or incremental increase, and compensation did not occur. Growth performance in IO-30 was comparable to control values. In conclusion, (i) long-term compensation for acute inhibitory effects of high salinity occurred for r but not maximum density, (ii) incremental increases in salinity did not prevent growth inhibition, suggesting the existence of a salinity threshold of 25-30 for onset of salinity stress, and (iii) the presence of a seawater-like salt mixture prevented growth inhibition by high salinity. These findings provide new insights on P. parvum's long-term ability to adjust its growth in environments of different salinity and ionic composition.

Evaluation of a novel application of a mindfulness phone application for patients with brain tumours: a feasibility study.

PURPOSE: Despite the large clinical interest in mindfulness, little is known about its effects in patients with brain tumours. Novel delivery methods such as App based Mindfulness training (AMT) may assist in the delivery of mindfulness treatment to this group of patients. METHODS: We aimed to determine the feasibility of administering an 8-week mindfulness treatment by AMT in patients operated on for brain tumours in a publically funded hospital. As a secondary aim we collected preliminary data regarding changes in self-reported psychological distress, quality of life and mindfulness capacity. RESULTS: Uptake was of 40 potentially eligible participants. Of the 20 entering the study, only 10 completed the 8-week post group assessment and only 3 completed the follow-up assessment. There was a positive direction of pre-post change in almost all completers with statistically significant improvement in several mindfulness scales and illness-related quality of life however there was a deterioration in the social/family quality of life domain. The significant variability in individual usage of the AMT appeared to be related more to individual differences rather than tumour histology, progression or treatment. The treatment was well received by those completing the study. CONCLUSIONS: Recruitment and retention feasibility issues were identified. Promising preliminary change and treatment satisfaction scores however suggest that further research with the AMT is warranted. Reduced assessment burden and more regular engagement during treatment is recommended to enhance retention. Large sample sizes however will be needed to address the heterogeneity of this group.

The Relationship Between Acuity of Organ Failure and Predictive Validity of Sepsis-3 Criteria.

The Sepsis-3 taskforce defined sepsis as suspicion of infection and an acute rise in the Sequential Organ Failure Assessment score by 2 points over the preinfection baseline. Sepsis-3 studies, though, have not distinguished between acute and chronic organ failure, and may not accurately reflect the epidemiology, natural history, or impact of sepsis. Our objective was to determine the extent to which the predictive validity of Sepsis-3 is attributable to chronic rather than acute organ failure. DESIGN: Retrospective cohort study. SETTING: General medicine inpatient service at a tertiary teaching hospital. PATIENTS: A total of 3,755 adult medical acute-care encounters (1,864 confirmed acute infections) over 1 year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the total Sequential Organ Failure Assessment score at the onset of infection and separated its components (baseline and acute rise) using case-by-case chart reviews. We compared the predictive validities of acuity-focused (acute rise in Sequential Organ Failure Assessment ≥ 2) and conventional (total Sequential Organ Failure Assessment ≥ 2) implementations of Sepsis-3 criteria. Measures of predictive validity were change in the rate of outcomes and change in the area under receiver operating characteristic curves after adding sepsis criteria to multivariate logistic regression models of baseline risk (age, sex, race, and Charlson comorbidity index). Outcomes were inhospital mortality (primary) and ICU transfer or inhospital mortality (secondary). Acuity-focused implementations of Sepsis-3 were associated with neither a change in mortality (2.2% vs 1.2%; p = 0.18) nor a rise in area under receiver operating characteristic curves compared with baseline models (0.67 vs 0.66; p = 0.75). In contrast, conventional implementations were associated with a six-fold change in mortality (2.4% vs 0.4%; p = 0.01) and a rise in area under receiver operating characteristic curves compared with baseline models (0.70 vs 0.66; p = 0.04). Results were similar for the secondary outcome. CONCLUSIONS: The evaluation of the validity of organ dysfunction-based clinical sepsis criteria is prone to bias, because acute organ dysfunction consequent to infection is difficult to separate from preexisting organ failure in large retrospective cohorts.

Effects of embryo energy, egg size, and larval food supply on the development of asteroid echinoderms.

Organisms have limited resources available to invest in reproduction, causing a trade-off between the number and size of offspring. One consequence of this trade-off is the evolution of disparate egg sizes and, by extension, developmental modes. In particular, echinoid echinoderms (sea urchins and sand dollars) have been widely used to experimentally manipulate how changes in egg size affect development. Here, we test the generality of the echinoid results by (a) using laser ablations of blastomeres to experimentally reduce embryo energy in the asteroid echinoderms (sea stars), Pisaster ochraceus and Asterias forbesi and (b) comparing naturally produced, variably sized eggs (1.7-fold volume difference between large and small eggs) in A. forbesi. In P. ochraceus and A. forbesi, there were no significant differences between juveniles from both experimentally reduced embryos and naturally produced eggs of variable size. However, in both embryo reduction and egg size variation experiments, simultaneous reductions in larval food had a significant and large effect on larval and juvenile development. These results indicate that (a) food levels are more important than embryo energy or egg size in determining larval and juvenile quality in sea stars and (b) the relative importance of embryo energy or egg size to fundamental life history parameters (time to and size at metamorphosis) does not appear to be consistent within echinoderms.

Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183.

The emergence and perseverance of drug resistant strains of Mycobacterium tuberculosis (Mtb) ensures that drug discovery efforts remain at the forefront of tuberculosis research. There are numerous different approaches that can be employed to lead to the discovery of anti-tubercular agents. In this work, we endeavored to optimize the anthraquinone chemical scaffold of a known drug, rhein, converting it from a compound with negligible activity against Mtb, to a series of compounds with potent activity. Two compounds exhibited low toxicity and good liver microsome stability and were further progressed in attempts to identify the biological target. Whole genome sequencing of resistant isolates revealed inactivating mutations in a monoglyceride lipase. Over-expression trials and an enzyme assay confirmed that the designed compounds are prodrugs, activated by the monoglyceride lipase. We propose that rhein is the active moiety of the novel compounds, which requires chemical modifications to enable access to the cell through the extensive cell wall structure. This work demonstrates that re-engineering of existing antimicrobial agents is a valid method in the development of new anti-tubercular compounds.

Adoption of a dedicated multidisciplinary team is associated with improved survival in acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism remains a significant cause of mortality and morbidity worldwide. Benefit of recently developed multidisciplinary PE response teams (PERT) with higher utilization of advanced therapies has not been established. METHODS: To evaluate patient-centered outcomes and cost-effectiveness of a multidisciplinary PERT we performed a retrospective analysis of 554 patients with acute PE at the university of Virginia between July 2014 and June 2015 (pre-PERT era) and between April 2017 through October 2018 (PERT era). Six-month survival, hospital length-of-stay (LOS), type of PE therapy, and in-hospital bleeding were assessed upon collected data. RESULTS: 317 consecutive patients were treated for acute PE during an 18-month period following institution of a multidisciplinary PE program; for 120 patients PERT was activated (PA), the remaining 197 patients with acute PE were considered as a separate, contemporary group (NPA). The historical, comparator cohort (PP) was composed of 237 patients. These 3 groups were similar in terms of baseline demographics, comorbidities and risk, as assessed by the Pulmonary Embolism Severity Index (PESI). Patients in the historical cohort demonstrated worsened survival when compared with patients treated during the PERT era. During the PERT era no statistically significant difference in survival was observed in the PA group when compared to the NPA group despite significantly higher severity of illness among PA patients. Hospital LOS was not different in the PA group when compared to either the NPA or PP group. Hospital costs did not differ among the 3 cohorts. 30-day re-admission rates were significantly lower during the PERT era. Rates of advanced therapies were significantly higher during the PERT era (9.1% vs. 2%) and were concentrated in the PA group (21.7% vs. 1.5%) without any significant rise in in-hospital bleeding complications. CONCLUSIONS: At our institution, all-cause mortality in patients with acute PE has significantly and durably decreased with the adoption of a PERT program without incurring additional hospital costs or protracting hospital LOS. Our data suggest that the adoption of a multidisciplinary approach at some institutions may provide benefit to select patients with acute PE.

EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7.

EML4-ALK is an oncogenic fusion present in ∼5% of non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants of EML4-ALK with different patient outcomes. Here, we show that, in cell models, EML4-ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. EML4-ALK V3 also recruits the NEK9 and NEK7 kinases to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but does not require ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4-ALK patients. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through NEK9 and NEK7, leading to increased cell migration. This represents a novel actionable pathway that could drive metastatic disease progression in EML4-ALK lung cancer.

Sleep problems and psychological symptoms as predictors of musculoskeletal conditions in children and adolescents.

BACKGROUND: Population-based studies show that sleep problems and psychological symptoms may increase the risk of musculoskeletal pain onset in children/adolescents. However, there is no evidence of these associations within primary care settings, where interventions can take place. This study investigated whether children/adolescents who consulted their general practitioner for sleep problems or psychological symptoms are at higher risk of subsequent consultations for musculoskeletal conditions. METHODS: This prospective matched-cohort study used electronic medical records of children/ adolescents (aged 6-19 years) from a UK primary care database. Associations between a consultation for sleep problems or psychological symptoms at baseline and a subsequent consultation for musculoskeletal conditions within the 2-year follow-up were investigated using survival analysis, producing hazard ratio (HR) and 95% confidence interval (CI) with adjustment for confounders. RESULTS: Children/adolescents who consulted for sleep problems had a significant increased risk of consultation for musculoskeletal conditions (HR = 1.72; 95% CI 1.14, 2.60), which became nonsignificant after adjustment for confounders (HR = 1.49; 95% CI 0.98, 2.27). Children/adolescents who consulted for psychological symptoms had a significant increased risk of consultation for musculoskeletal conditions (HR = 1.59; 95% CI 1.31, 1.93), which was attenuated after adjustment (HR = 1.39; 95% CI 1.14, 1.70). CONCLUSIONS: Children and adolescents who visit primary care for sleep problems or psychological symptoms have increased risk of future musculoskeletal consultations. Further work is needed to understand the causal mechanisms that explain these associations, before designing interventions strategies within primary care settings. SIGNIFICANCE: Population-based studies showed that sleep problems and psychological symptoms may be important precursors of musculoskeletal pain in children and adolescents. By investigating these associations in primary care settings, this study showed that children and adolescents with consultations for sleep problems or psychological symptoms were at increased risk of subsequent consultations for musculoskeletal conditions. These findings support results from population-based studies, and identify potential areas for further research and potential intervention within primary care.