Warming alters life-history traits and competition in a phage community.

Host-parasite interactions are highly susceptible to changes in temperature due to mismatches in species thermal responses. In nature, parasites often exist in communities, and responses to temperature are expected to vary between host-parasite pairs. Temperature change thus has consequences for both host-parasite dynamics and parasite-parasite interactions. Here, we investigate the impact of warming (37°C, 40°C, and 42°C) on parasite life-history traits and competition using the opportunistic bacterial pathogen Pseudomonas aeruginosa (host) and a panel of three genetically diverse lytic bacteriophages (parasites). We show that phages vary in their responses to temperature. While 37°C and 40°C did not have a major effect on phage infectivity, infection by two phages was restricted at 42°C. This outcome was attributed to disruption of different phage life-history traits including host attachment and replication inside hosts. Furthermore, we show that temperature mediates competition between phages by altering their competitiveness. These results highlight phage trait variation across thermal regimes with the potential to drive community dynamics. Our results have important implications for eukaryotic viromes and the design of phage cocktail therapies.IMPORTANCEMammalian hosts often elevate their body temperatures through fevers to restrict the growth of bacterial infections. However, the extent to which fever temperatures affect the communities of phages with the ability to parasitize those bacteria remains unclear. In this study, we investigate the impact of warming across a fever temperature range (37°C, 40°C, and 42°C) on phage life-history traits and competition using a bacterium (host) and bacteriophage (parasite) system. We show that phages vary in their responses to temperature due to disruption of different phage life-history traits. Furthermore, we show that temperature can alter phage competitiveness and shape phage-phage competition outcomes. These results suggest that fever temperatures have the potential to restrict phage infectivity and drive phage community dynamics. We discuss implications for the role of temperature in shaping host-parasite interactions more widely.

Motivations for and against Participation in Neonatal Research: Insights from Interviews of Diverse Parents Approached for Neonatal Research in the US.

OBJECTIVE: To describe parents' motivations for and against participation in neonatal research, including the views of those who declined participation. STUDY DESIGN: We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation. RESULTS: Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a "guinea pig" were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations. CONCLUSIONS: Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes.

Host microbiota can facilitate pathogen infection.

Animals live in symbiosis with numerous microbe species. While some can protect hosts from infection and benefit host health, components of the microbiota or changes to the microbial landscape have the potential to facilitate infections and worsen disease severity. Pathogens and pathobionts can exploit microbiota metabolites, or can take advantage of a depletion in host defences and changing conditions within a host, to cause opportunistic infection. The microbiota might also favour a more virulent evolutionary trajectory for invading pathogens. In this review, we consider the ways in which a host microbiota contributes to infectious disease throughout the host's life and potentially across evolutionary time. We further discuss the implications of these negative outcomes for microbiota manipulation and engineering in disease management.

Within- and between-host dynamics of producer and non-producer pathogens.

For infections to be maintained in a population, pathogens must compete to colonize hosts and transmit between them. We use an experimental approach to investigate within-and-between host dynamics using the pathogen Pseudomonas aeruginosa and the animal host Caenorhabditis elegans. Within-host interactions can involve the production of goods that are beneficial to all pathogens in the local environment but susceptible to exploitation by non-producers. We exposed the nematode host to 'producer' and two 'non-producer' bacterial strains (specifically for siderophore production and quorum sensing), in single infections and coinfections, to investigate within-host colonization. Subsequently, we introduced infected nematodes to pathogen-naive populations to allow natural transmission between hosts. We find that producer pathogens are consistently better at colonizing hosts and transmitting between them than non-producers during coinfection and single infection. Non-producers were poor at colonizing hosts and between-host transmission, even when coinfecting with producers. Understanding pathogen dynamics across these multiple levels will ultimately help us predict and control the spread of infections, as well as contribute to explanations for the persistence of cooperative genotypes in natural populations.

Genomic landscape of neutrophilic leukemias of ambiguous diagnosis.

Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

Targeted Sequencing Improves DIPSS-Plus Prognostic Scoring in Myelofibrosis Patients Undergoing Allogeneic Transplantation.

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the sole therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematologic, and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 patients with MF to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with ≥3 mutations in addition to JAK2 or CALR mutations had a higher post-transplantation relapse rate and nonrelapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the greatest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for patients who do not undergo HCT and support the proposed transplantation risk classification incorporating mutational information.

Cadmium and Lead Decrease Cell-Cell Aggregation and Increase Migration and Invasion in Renca Mouse Renal Cell Carcinoma Cells.

Metastatic renal cell carcinoma (RCC) remains an important clinical issue; the 5-year survival rate of patients with metastasis is approximately 12%, while it is 93% in those with localized disease. There is evidence that blood cadmium and lead levels are elevated in RCC. The current studies were designed to assess the impact of cadmium and lead on the progression of RCC. The disruption of homotypic cell-cell adhesion is an essential step in epithelial-to-mesenchymal transition and tumor metastasis. Therefore, we examined the impact of cadmium and lead on the cadherin/catenin complex in Renca cells-a mouse RCC cell line. Lead, but not cadmium, induced a concentration-dependent loss of E-cadherin, while cadmium, but not lead, increased p120-catenin expression, specifically isoform 1 expression. Lead also induced a substantial increase in matrix metalloproteinase-9 levels. Both cadmium and lead significantly decreased the number of Renca cell aggregates, consistent with the disruption of the cadherin/catenin complex. Both metals enhanced wound healing in a scratch assay, and increased cell migration and invasion. These data suggest that cadmium and lead promote RCC progression.

Hematopoietic Cell Transplantation for Myelofibrosis: the Dynamic International Prognostic Scoring System Plus Risk Predicts Post-Transplant Outcomes.

Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia, and RBC transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival, and nonrelapse mortality. The 5-year overall survival (OS), relapse, and treatment-related mortality (TRM) rates for patients with low/intermediate-1 risk MF were 78%, 5%, and 20%, respectively. The 5-year OS, relapse, and TRM rates for patients with high-risk MF were 35%, 28%, and 40%, respectively. The HCT-specific comorbidity index of 3 or greater was associated with higher nonrelapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR, 3.02; P = .0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance after adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant.

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia.

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days -6 to -4 and i.v. fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.

Genomic medicine and targeted therapy for solid tumors.

A marked paradigm shift in cancer therapy has occurred over the past 20 years. Systemic treatment has evolved from nonspecific cytotoxic chemotherapy to targeting cancer-associated pathways, profoundly changing treatment approaches in the metastatic and adjuvant settings. This review will highlight some of the major clinical advances in targeted cancer therapy in select epithelial malignancies made possible by the understanding of the molecular mechanisms driving tumor growth through genomic methods.

Parental experience learning to feed their preterm infants.

PURPOSE: Although extensive research has been conducted on preterm infant oral feeding, few investigations have examined parents' experiences learning to feed orally their preterm infant while in the neonatal intensive care unit (NICU). As such, the aim of this study was to explore parental learning experiences to gain a better understanding of the process parents use in learning to feed their preterm infant. SUBJECTS: Parents included in the investigation were 18 years of age or older with a medically stable preterm infant who was less than 36 weeks' gestational age at birth, free of congenital malformations, and feeding orally. DESIGN: This investigation used phenomenology to explore the depth and richness of parental experience with the process of learning to feed orally their preterm infant. METHODS: Participants were recruited from a university-affiliated women's hospital with a level III NICU. Purposive sampling was used to ensure that all participants were familiar with the experience of interest. Data collection consisted of personal interviews, which were conducted in a private consultation room located within the NICU. In instances where both the infant's mother and father chose to participate, the interviews were conducted separately on the same day. MAIN OUTCOME MEASURES: Twelve mothers and 8 fathers participated in semistructured interviews. For 8 mothers and 6 fathers, this was their first child. This was the first preterm infant for all participants. From the parental experience, the following 3 themes were identified: an emotional experience, learn as you go, and it is technical. PRINCIPAL RESULTS: Parents noted that feeding encompassed both positive and negative emotions, that learning was a process that nurses played an instrumental role in, and that feeding a preterm infant could be very technical, requiring extra skills for feeding success. CONCLUSIONS: Nurses can play a key role in helping parents learn by acknowledging both positive and negative feelings about the feeding process, recognizing parents' learning needs, and by teaching and demonstrating appropriate feeding techniques.

The association of depressive symptoms and female sexual functioning in the menopause transition: a cross-sectional study.

OBJECTIVE: Sexual dysfunction is very common among middle-aged females. Several factors are considered to influence sexual functioning, including reproductive aging and associated physiological changes as well as life stressors, mental health, and other socioeconomic influences. The objectives of this study are to evaluate the effect of current depressive symptoms on sexual functioning during menopause and to further analyze whether socioeconomic status, age, and antidepressant usage impact this association. METHODS: Perimenopausal and postmenopausal women aged 40 to 65 years seeking treatment from a specialized menopause clinic completed a self-report survey with the main outcome measure being the 19-item Female Sexual Function Index quantifying sexual dysfunction. We used the 10-item Center for Epidemiological Studies Depression Scale to estimate a major depressive episode. Statistical analyses were completed to assess the potential associations of socioeconomic factors, age, and antidepressant usage. RESULTS: Of the 269 participants, 61.3% met criteria for a major depressive episode and 67.0% had low sexual function. As predicted, women currently experiencing depressive symptoms had a greater risk of low sexual function during perimenopause and postmenopause. Antidepressant usage, low household income, being postmenopausal, and age also predicted low sexual function. CONCLUSIONS: Among perimenopausal and postmenopausal women, current depressive symptoms were associated with low sexual function. A biopsychosocial approach should be considered when exploring effective treatment strategies for sexual concerns among midlife women.

aBnormal motION capture In aCute Stroke (BIONICS): A Low-Cost Tele-Evaluation Tool for Automated Assessment of Upper Extremity Function in Stroke Patients.

BACKGROUND: The incidence of stroke and stroke-related hemiparesis has been steadily increasing and is projected to become a serious social, financial, and physical burden on the aging population. Limited access to outpatient rehabilitation for these stroke survivors further deepens the healthcare issue and estranges the stroke patient demographic in rural areas. However, new advances in motion detection deep learning enable the use of handheld smartphone cameras for body tracking, offering unparalleled levels of accessibility. METHODS: In this study we want to develop an automated method for evaluation of a shortened variant of the Fugl-Meyer assessment, the standard stroke rehabilitation scale describing upper extremity motor function. We pair this technology with a series of machine learning models, including different neural network structures and an eXtreme Gradient Boosting model, to score 16 of 33 (49%) Fugl-Meyer item activities. RESULTS: In this observational study, 45 acute stroke patients completed at least 1 recorded Fugl-Meyer assessment for the training of the auto-scorers, which yielded average accuracies ranging from 78.1% to 82.7% item-wise. CONCLUSION: In this study, an automated method was developed for the evaluation of a shortened variant of the Fugl-Meyer assessment, the standard stroke rehabilitation scale describing upper extremity motor function. This novel method is demonstrated with potential to conduct telehealth rehabilitation evaluations and assessments with accuracy and availability.

The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence.

Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine. Here, we show that MCR provides a selective advantage to Escherichia coli in the presence of key AMPs from humans and agricultural animals by increasing AMP resistance. Moreover, MCR promotes bacterial growth in human serum and increases virulence in a Galleria mellonella infection model. Our study shows how the anthropogenic use of AMPs can drive the accidental evolution of resistance to the innate immune system of humans and animals. These findings have major implications for the design and use of therapeutic AMPs and suggest that MCR may be difficult to eradicate, even if colistin use is withdrawn.

Getting kids active by participating in sport and doing it more often: focusing on what matters.

BACKGROUND: Reduced time dedicated to physical education and free play in recent decades emphasizes the need to promote opportunities for sport participation in adolescents in order to increase physical activity levels. The purpose of this study was to examine the association of sociodemographic and biological characteristics, behavioural patterns, and school-related and sport-specific variables with time spent participating in sport. METHODS: A total of 1837 secondary school students (age: 14.6 ± 1.2 years; 50.9 % boys) from 19 of 23 schools in the Otago Region (New Zealand) completed an online sport survey and Youth Physical Activity Questionnaire in 2009. Using multilevel modeling, we examined the association of individual-, school- and sport-related variables on sport participation and the amount of time spent in sports. RESULTS: Higher rates of sport participation were associated with lower neighbourhood deprivation scores (OR (95%CI): 0.75 (0.49-1.14), 0.57 (0.38-0.86), 0.48 (0.28-0.81)), higher quintiles of physical activity (2.89 (2.10-3.96), 2.81 (1.68-4.70), 3.54 (2.24-5.57), 3.97 (1.99-7.95)), highest quintiles of screen time (1.58 (0.94-2.65), 1.99 (1.42-2.80), 2.17 (1.43-3.30), 1.88 (1.37-2.57)) and boys only school status (2.21 (1.57-3.10)). Greater amount of time spent in sports was associated with male gender (0.56 (0.43-0.74), lower neighbourhood deprivation scores (0.72 (0.59-0.93), 0.78 (0.58-1.04), 0.62 (0.39-1.00)), higher quintiles of physical activity (3.18 (2.29-4.41), 4.25 (2.91-6.20), 8.33 (5.58-12.44), 6.58 (4.07-10.64)), highest quintile of screen time (1.83 (1.31-2.56), greater availability of sports outside school (1.68 (1.22-2.32)), better sport management (2.57 (1.63-4.07)) and provision of sport courts at school (0.57 (0.40-0.81)). Conversely, obesity was associated with less time spent participating in sport (0.50 (0.31-0.80)). CONCLUSION: Results support the use of sport participation as an effective strategy to increase physical activity levels and identify target groups and areas for interventions, program design and policy development. Interventions should focus on improving accessibility to sport programs for all adolescents, providing adequate sport grounds at school, and promoting good sport management practices. Programs and policies encouraging sport participation should address in particular the needs of adolescents living in deprived neighborhoods, those attending coeducational and girls-only schools, and those who are obese.

Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated 3-4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach, we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance-conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICESp23FST81 are often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role.

Microbial evolution and transitions along the parasite-mutualist continuum.

Virtually all plants and animals, including humans, are home to symbiotic microorganisms. Symbiotic interactions can be neutral, harmful or have beneficial effects on the host organism. However, growing evidence suggests that microbial symbionts can evolve rapidly, resulting in drastic transitions along the parasite-mutualist continuum. In this Review, we integrate theoretical and empirical findings to discuss the mechanisms underpinning these evolutionary shifts, as well as the ecological drivers and why some host-microorganism interactions may be stuck at the end of the continuum. In addition to having biomedical consequences, understanding the dynamic life of microorganisms reveals how symbioses can shape an organism's biology and the entire community, particularly in a changing world.

Host genotype and genetic diversity shape the evolution of a novel bacterial infection.

Pathogens continue to emerge from increased contact with novel host species. Whilst these hosts can represent distinct environments for pathogens, the impacts of host genetic background on how a pathogen evolves post-emergence are unclear. In a novel interaction, we experimentally evolved a pathogen (Staphylococcus aureus) in populations of wild nematodes (Caenorhabditis elegans) to test whether host genotype and genetic diversity affect pathogen evolution. After ten rounds of selection, we found that pathogen virulence evolved to vary across host genotypes, with differences in host metal ion acquisition detected as a possible driver of increased host exploitation. Diverse host populations selected for the highest levels of pathogen virulence, but infectivity was constrained, unlike in host monocultures. We hypothesise that population heterogeneity might pool together individuals that contribute disproportionately to the spread of infection or to enhanced virulence. The genomes of evolved populations were sequenced, and it was revealed that pathogens selected in distantly-related host genotypes diverged more than those in closely-related host genotypes. S. aureus nevertheless maintained a broad host range. Our study provides unique empirical insight into the evolutionary dynamics that could occur in other novel infections of wildlife and humans.

Microbiome: Evolution in a World of Interaction.

Ecological interactions can generate strong selection. Two new studies reveal that the tempo and patterns of evolutionary change in a mammalian gut commensal can be altered dramatically during interactions with both the host and its microbiome.

Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis.

Ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with myelofibrosis (MF). Therefore Rux, when given prior to hematopoietic cell transplantation (HCT) in patients with MF was hypothesized to improve engraftment, decrease incidence and severity of graft-versus-host disease, and lower non-relapse mortality (NRM). We conducted a phase II prospective trial to assess the effects of pre-HCT Rux on post-HCT outcomes in patients with MF. The primary endpoint was 2-year overall survival. To date, 28 patients (median age 56 years) have been transplanted. The median time on Rux pre-HCT was 7 months. Twenty-three patients received myeloablative and five reduced intensity conditioning. Donors included 14 HLA-matched siblings, 11 matched unrelated, 1 allele mismatched unrelated, and 3 umbilical cord blood. There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Two patients died from NRM and two patients relapsed. With a median follow-up of 13 months, overall survival is 93% (95% CI: 0.73, 0.98) at 1 year and 86% (95% CI: 0.61, 0.96) at 2 years post-HCT. This study demonstrates that pre-HCT Rux is well tolerated and suggests that pre-HCT Rux may improve post-HCT outcome.