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Abstract Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

The rapid growth of cultural evolutionary science, its expansion into numerous fields, its use of diverse methods, and several conceptual problems have outpaced corollary developments in theory and philosophy of science. This has led to concern, exemplified in results from a recent survey conducted with members of the Cultural Evolution Society, that the field lacks ‘knowledge synthesis’, is poorly supported by ‘theory’, has an ambiguous relation to biological evolution and uses key terms (e.g. ‘culture’, ‘social learning’, ‘cumulative culture’) in ways that hamper operationalization in models, experiments and field studies. Although numerous review papers in the field represent and categorize its empirical findings, the field's theoretical challenges receive less critical attention even though challenges of a theoretical or conceptual nature underlie most of the problems identified by Cultural Evolution Society members. Guided by the heterogeneous ‘grand challenges’ emergent in this survey, this paper restates those challenges and adopts an organizational style requisite to discussion of them. The paper's goal is to contribute to increasing conceptual clarity and theoretical discernment around the most pressing challenges facing the field of cultural evolutionary science. It will be of most interest to cultural evolutionary scientists, theoreticians, philosophers of science and interdisciplinary researchers.

BackgroundConversational agents (CAs) are a promising solution to support people in improving physical activity (PA) behaviors. However, there is a lack of CAs targeted at adolescents that aim to provide support to overcome barriers to PA. This study reports the results of the co-design, development, and evaluation of a prototype CA called “Phyllis” to support adolescents in overcoming barriers to PA with the aim of improving PA behaviors. The study presents one of the first theory-driven CAs that use existing research, a theoretical framework, and a behavior change model. ObjectiveThe aim of the study is to use a mixed methods approach to investigate the potential of a CA to support adolescents in overcoming barriers to PA and enhance their confidence and motivation to engage in PA. MethodsThe methodology involved co-designing with 8 adolescents to create a relational and persuasive CA with a suitable persona and dialogue. The CA was evaluated to determine its acceptability, usability, and effectiveness, with 46 adolescents participating in the study via a web-based survey. ResultsThe co-design participants were students aged 11 to 13 years, with a sex distribution of 56% (5/9) female and 44% (4/9) male, representing diverse ethnic backgrounds. Participants reported 37 specific barriers to PA, and the most common barriers included a “lack of confidence,” “fear of failure,” and a “lack of motivation.” The CA’s persona, named “Phyllis,” was co-designed with input from the students, reflecting their preferences for a friendly, understanding, and intelligent personality. Users engaged in 61 conversations with Phyllis and reported a positive user experience, and 73% of them expressed a definite intention to use the fully functional CA in the future, with a net promoter score indicating a high likelihood of recommendation. Phyllis also performed well, being able to recognize a range of different barriers to PA. The CA’s persuasive capacity was evaluated in modules focusing on confidence and motivation, with a significant increase in students’ agreement in feeling confident and motivated to engage in PA after interacting with Phyllis. Adolescents also expect to have a personalized experience and be able to personalize all aspects of the CA. ConclusionsThe results showed high acceptability and a positive user experience, indicating the CA’s potential. Promising outcomes were observed, with increasing confidence and motivation for PA. Further research and development are needed to create further interventions to address other barriers to PA and assess long-term behavior change. Addressing concerns regarding bias and privacy is crucial for achieving acceptability in the future. The CA’s potential extends to health care systems and multimodal support, providing valuable insights for designing digital health interventions including tackling global inactivity issues among adolescents.

Objective: We describe the prevalence of COVID-19 vaccine uptake, substance use, and other factors associated with vaccine hesitancy among participants from nine North American cohort studies following a diverse group of individuals at risk for or living with HIV. Methods: Between May 2021 and January 2022, participants completed a survey related to COVID-19 vaccination. Participants included those with and without substance use. Those responding as ‘no’ or ‘undecided’ to the question “Do you plan on getting the COVID-19 vaccine?” were categorized as vaccine hesitant. Differences between groups were evaluated using chi-square methods and multivariable log-binomial models were used to calculate prevalence ratios (PR) of COVID-19 vaccine hesitancy with separate models for each substance. Results: Among 1,696 participants, COVID-19 vaccination was deferred or declined by 16%. Vaccine hesitant participants were younger, with a greater proportion unstably housed (14.8% vs. 10.0%; p = 0.02), and not living with HIV (48.% vs. 36.6%; p

Mature cystic teratomas are common benign neoplasms of the ovary. These tumors rarely undergo malignant transformation, the most frequent transformation is to a squamous cell carcinoma. Malignant transformation carries a poor prognosis. Herein, we present a case of a patient with a pelvic mass whose initial biopsy showed a benign teratoma, but subsequently underwent malignant transformation with fistulation to the small and large bowel.

In this study, the authors use electronic health record data from the US to characterise post-acute sequelae of SARS-CoV-2 infection (PASC). They identify 17 common PASC conditions and find an overall ~12% increase in risk of PASC conditions in the post-acute period among people with a SARS-CoV-2 positive test compared to matched test-negative controls.

BackgroundIt is evident that physical activity (PA) programmes implemented in schools were not effective in improving PA behaviours among adolescents. This study investigated students’ perceptions of barriers to PA among inactive English adolescents in secondary schools based on the Capability, Opportunity, Motivation, and Behaviour (COM-B) model, the Behaviour Change Wheel (BCW), and Theoretical Domains Framework (TDF). The study compared barriers faced by inactive and active groups participating in sports and PA in secondary schools to identify sources of behaviour contributing to inactivity.MethodsA pre-intervention online survey was distributed to affiliated schools by 233 Teaching Schools Alliances (TSAs) as part of the monitoring and evaluation of the Secondary Teacher Training study. Data were cross-tabulated to analyse activity levels and behavioural barriers for active and inactive groups, using the COM-B domains. The research team followed a seven-step process to categorise barriers based on their relevant domain in the TDF mapped to the COM-B.ResultsThe findings were derived from one of the most extensive surveys of adolescents ever undertaken involving 200,623 active and 8,231 inactive respondents. The study identified 52 barriers and 68 behaviours that prevent adolescents from participating in PA. Psychological and social barriers were found to affect all activity levels, genders, and ethnic groups, with a lack of confidence and self-consciousness being the most prevalent. Certain demographic groups, such as those from minority ethnic groups and disabled individuals, were found to be overrepresented among inactive populations. The finding of the study indicated that there were common barriers that affected both inactive and active groups, with further similarity when examining barriers between active and inactive girls. The study also found that girls were more likely to experience the main barriers compared to boys, while inactive boys were more likely to encounter these barriers compared to active boys. The findings suggest that common barriers could be addressed across the population, while recognising some differences in demographics, and the need to provide personalised support. Targeted interventions are also suggested for all girls and inactive boys.ConclusionThis study highlights the range of barriers that impact adolescents and provides insight into potential mechanisms for behaviour change, including intervention functions, policy categories, and evidence-based behaviour change tools. The study highlights the need for further research to address the barriers to PA among adolescents, particularly those who are inactive. Utilising the findings of this study, future research should investigate the effectiveness of novel digital exercise interventions and policies in increasing PA levels among children and adolescents. Complex digital exercise interventions, including conversational AI solutions, could provide personalised tools to identify and revolutionise support around the multitude of barriers that impact adolescents globally.“For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.”

We present a genome assembly of Caretta caretta (the Loggerhead sea turtle; Chordata, Testudines, Cheloniidae), generated from genomic data from two unrelated females. The genome sequence is 2.13 gigabases in size. The assembly has a busco completion score of 96.1% and N50 of 130.95 Mb. The majority of the assembly is scaffolded into 28 chromosomal representations with a remaining 2% of the assembly being excluded from these.

BackgroundPrevious studies indicated that physical education programs in schools were unsuccessful to ameliorate physical activity (PA) behaviors among adolescents. This study investigated PE teachers’ perceptions of barriers and facilitators to PA and further digital exercise interventions among inactive British adolescents in secondary schools based on the Capability, Opportunity, Motivation, and Behavior (COM-B) model, the Behavior Change Wheel (BCW), and Theoretical Domains Framework (TDF).MethodA qualitative study was conducted among 156 PE teachers in England. deductive thematic analysis approach was applied to analyze data.ResultsA comprehensive perception of PE teachers revealed 21 barriers to PA among inactive adolescents in secondary schools. The study findings show that barriers exist across all categories of the COM-B model in physical opportunity (7), reflective motivation (5), social opportunity (4), psychological capability (4) and physical capability (1). The majority of these barriers were reported in previous studies as being barriers to PA from the perspective of children and adolescents. This shows that the findings are consistent with the views of children and adolescents that participated in these studies. Particular salient barriers for inactive adolescents were reported and greater insight into their experiences was highlighted. The study reported the main sources of behavior, intervention functions, policy functions, and behavior change tools that can be used for future behavior change interventions to support inactive adolescents.ConclusionThe study recommends using its findings to design interventions for inactive adolescents to achieve recommended levels of physical activity (PA). The study’s comprehensive approach and evidence-based solutions provide extensive reference points for future intervention design, informing policy and contributing to enhancing support for inactive adolescents. Further development of digital exercise interventions, including conversational artificial intelligence (AI), is suggested to engage adolescents at scale and provide personalized support to overcome multiple barriers to PA.

Pelvic involvement of chronic lymphocytic leukemia (CLL) is exceptionally rare. Herein, we present a case series of a 61-year-old, 88-year-old, and 79-year-old female, all with a history of CLL who underwent exploratory surgery with gynecologic oncologists for newly diagnosed pelvic masses and endometrial pathology. Intraoperative findings and pathology were consistent with CLL.

Airborne NASA Langley Research Center (LaRC) High Spectral Resolution Lidar-2 (HSRL-2) measurements acquired during the recent NASA Earth Venture Suborbital-3 (EVS-3) Aerosol Cloud Meteorology Interactions over the Western Atlantic Experiment (ACTIVATE) revealed elevated particulate linear depolarization associated with aerosols within the marine boundary layer. These observations were acquired off the east coast of the United States during both winter and summer 2020 and 2021 when the HSRL-2 was deployed on the NASA LaRC King Air aircraft. During 20 of 63 total flight days, particularly on days with cold air outbreaks, linear particulate depolarization at 532 nm exceeded 0.15–0.20 within the lowest several hundred meters of the atmosphere, indicating that these particles were non-spherical. Higher values of linear depolarization typically were measured at 355 nm and lower values were measured at 1,064 nm. Several lines of evidence suggest that these non-spherical particles were sea salt including aerosol extinction/backscatter ratio (“lidar ratio”) values of 20–25 sr measured at both 355 and 532 nm by the HSRL-2, higher values of particulate depolarization measured at low (< 60%) relative humidity, coincident airborne in situ size and composition measurements, and aerosol transport simulations. The elevated aerosol depolarization values were not correlated with wind speed but were correlated with salt mass fraction and effective radius of the aerosol when the relative humidity was below 60%. HSRL-2 measured median particulate extinction values of about 20 Mm−1 at 532 nm associated with these non-spherical sea salt particles and found that the aerosol optical depth (AOD) contributed by these particles remained small (0.03–0.04) but represented on average about 30%–40% of the total column AOD. Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) spaceborne lidar aerosol measurements during several cold air outbreaks and CALIOP retrievals of column aerosol lidar ratio using column AOD constraints suggest that CALIOP operational aerosol algorithms can misclassify these aerosols as dusty marine rather than marine aerosols. Such misclassification leads to ∼40–50% overestimates in the assumed lidar ratio and in subsequent retrievals of aerosol optical depth and aerosol extinction.

Pregnancy luteomas are rare, nonmalignant lesions thought to be caused by hormonal changes during pregnancy. Granulosa cell tumor is a rare type of ovarian cancer; 10% occur during pregnancy and typically present with elevated inhibin levels. Herein, we present a case of a pregnant female with a pelvic mass and elevated inhibin B suggestive of a granulosa cell tumor, yet with final pathology consistent with a pregnancy luteoma.

Pelvic metastasis of melanoma is extremely rare and may pose a diagnostic challenge. We present a case report of a female with a history of colon cancer who underwent exploratory surgery for a pelvic mass that was suspicious for ovarian malignancy. Pathology was consistent with both recurrent colon cancer as well as synchronous newly diagnosed metastatic melanoma.

Abstract Aerosol mass extinction efficiency (MEE) is a key aerosol property used to connect aerosol optical properties with aerosol mass concentrations. Using measurements of smoke obtained during the Fire Influence on Regional to Global Environments and Air Quality (FIREX‐AQ) campaign we find that mid‐visible smoke MEE can change by a factor of 2–3 between fresh smoke (

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society–USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL

Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.

Abstract The ability of nanopore sequencing to simultaneously detect modified nucleotides while producing long reads makes it ideal for detecting and phasing allele-specific methylation. However, there is currently no complete software for detecting SNPs, phasing haplotypes, and mapping methylation to these from nanopore sequence data. Here, we present NanoMethPhase, a software tool to phase 5-methylcytosine from nanopore sequencing. We also present SNVoter, which can post-process nanopore SNV calls to improve accuracy in low coverage regions. Together, these tools can accurately detect allele-specific methylation genome-wide using nanopore sequence data with low coverage of about ten-fold redundancy.

Globally, new particle formation represents a major source of cloud condensation nuclei. Here, the authors present evidence of frequent occurrence of new particle formation in the upper part of remote marine boundary layer following cold front passages.

Abstract Background Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. Results We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37 °C or 6 °C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37 °C), which are minimized by dissociation with a cold active protease (6 °C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. Conclusions The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.

Abstract Background Neutrophils release neutrophil extracellular traps (NETs) in response to invading pathogens. Although NETs play an important role in host defense against microbial pathogens, they have also been shown to play a contributing mechanistic role in pathologic inflammation in the absence of infection. Although a role for NETs in bacterial pneumonia and acute respiratory distress syndrome (ARDS) is emerging, a comprehensive evaluation of NETs in the alveolar space of critically ill patients has yet to be reported. In this study, we evaluated whether markers of NET formation in mechanically ventilated patients are associated with ventilator-associated pneumonia (VAP). Methods We collected bronchoalveolar lavage fluid from 100 critically ill patients undergoing bronchoscopy for clinically suspected VAP. Subjects were categorized by the absence or presence of VAP and further stratified by ARDS status. NETs (myeloperoxidase (MPO)-DNA complexes) and the NET-associated markers peroxidase activity and cell-free DNA were analyzed by enzyme-linked immunosorbent assay and colorimetric assays, respectively. Quantitative polymerase chain reaction of nuclear and mitochondrial DNA was used to determine the origin of the extruded DNA. Interleukin (IL)-8 and calprotectin were assayed as measures of alveolar inflammation and neutrophil activation. Correlations between NETs and markers of neutrophil activation were determined using Spearman’s correlation. We tested for associations with VAP and bacterial burden by logistic and linear regression, respectively, using log10-transformed NETs. Results MPO-DNA concentrations were highly correlated with other measures of NET formation in the alveolar space, including cell-free DNA and peroxidase activity (r = 0.95 and r = 0.87, p

Frequent Pap testing is recommended among women living with HIV (WLWH) due to their elevated risk for cervical cancer. However, there are few recent longitudinal evaluations of utilization and determinants of Pap testing among WLWH. Medical and pathology records of WLWH seen at Johns Hopkins Hospital between 2005 and 2014 were assessed using Prentice, Williams, Peterson models.Of 554 WLWH in care for ≥ 18 months, 79% received Pap testing, however only 11% consistently received Pap testing at the recommended interval. Some women (5%) were consistently under-screened (tested at longer intervals) and 21% did not receive any Pap testing at during follow-up.WLWH with decreased likelihood of screening included older women, injection drug users, whites and those who had lived for longer with HIV. In contrast, only women with a prior abnormal Pap result were more likely to receive Pap testing. CD4 cell count and health insurance were not significant determinants.Although many WLWH in care received Pap testing, some WLWH were unscreened or underscreened. Determinants of Pap testing for WLWH include socio-demographic factors and a prior abnormal result; these present potential targets in an urban HIV care setting for closer monitoring and directed interventions to improve utilization among WLWH. Keywords: Cancer screening, Pap testing, Cervical cancer, HIV, Prentice, William, Peterson models, Adherence

Purpose: With multiple phase 2 trials supporting the use of stereotactic body radiation therapy (SBRT) in oligo-metastatic disease, we evaluated practices that could inform effective implementation of an oligo-metastasis SBRT program. Methods and Materials: Using a context-focused realist methodology, an advisory committee of interprofessional clinicians met over a series of semistructured teleconference meetings to identify challenges in implementing an oligo-metastasis SBRT program. Consideration was given to 2 models of care: a subspecialist anatomic expertise model versus a single-practitioner “quarterback” model. Results: The advisory committee structured recommendations within a context-mechanism-outcome framework. In summary, the committee recommends that during patient workup, a single practitioner arranges the minimum number of necessary tests, with case presentation at an appropriate multidisciplinary tumor board, including careful review of all previous treatments, and enrollment on clinical trials when possible. At simulation, common patient positions and immobilization on a single simulation scan for multiple sites is recommended. During radiation planning, dose-fractionation regimens should safely facilitate cumulative dose calculations, a single isocenter should be considered for multiple close targets to reduce treatment time, and adherence to strict quality assurance protocols is strongly recommended. Treatment duration should be minimized by treating multiple sites on the same day or choosing shorter dose fractionations. Team communication, thorough documentation, and standardized nomenclature can reduce system errors. Follow-up should aim to minimize redundant clinical appointments and imaging scans. Expert radiology review may be required to interpret post-SBRT imaging. Conclusions: These guidelines inform best clinical practices for implementing an oligo-metastasis SBRT program. Iterations using a realist approach may further expand on local contexts.

Pink salmon (Oncorhynchus gorbuscha) adults are the smallest of the five Pacific salmon native to the western Pacific Ocean. Pink salmon are also the most abundant of these species and account for a large proportion of the commercial value of the salmon fishery worldwide. A two-year life history of pink salmon generates temporally isolated populations that spawn either in even-years or odd-years. To uncover the influence of this genetic isolation, reference genome assemblies were generated for each year-class and whole genome re-sequencing data was collected from salmon of both year-classes. The salmon were sampled from six Canadian rivers and one Japanese river. At multiple centromeres we identified peaks of Fst between year-classes that were millions of base-pairs long. The largest Fst peak was also associated with a million base-pair chromosomal polymorphism found in the odd-year genome near a centromere. These Fst peaks may be the result of a centromere drive or a combination of reduced recombination and genetic drift, and they could influence speciation. Other regions of the genome influenced by odd-year and even-year temporal isolation and tentatively under selection were mostly associated with genes related to immune function, organ development/maintenance, and behaviour.

Early virus detection and characterization is key to successful avian influenza virus (AIV) surveillance for the health of humans as well as domestic poultry. We explored a novel sampling approach and molecular strategy using sediment from wetlands and outdoor waterbodies on poultry farms as a population-level proxy of AIV activity in waterfowls. RNA was extracted using the MoBio RNA PowerSoil Total RNA isolation kit with additional chloroform extraction steps to reduce PCR inhibition. AIV matrix protein (MP) gene was detected in 42/345 (12.2%) samples by RT-qPCR; an additional 64 (18.6%) samples showed evidence of amplification below the threshold and were categorized as “suspect positive.” Enrichment-based targeted resequencing (TR) identified AIV sequences in 79/345 (22.9%) samples. TR probes were designed for MP, hemagglutinin (HA), and neuraminidase (NA), however PB2 and PA were also identified. Although RT-qPCR and TR only had fair-moderate agreement, RT-qPCR positivity was predictive of TR-positivity both when using only strictly positive RT-qPCR samples (OR = 11.29) and when coding suspect positives as positive (OR = 7.56). This indicates that RT-qPCR could be used as a screening tool to select samples for virus characterization by TR and that future studies should consider RT-qPCR suspect positives to be positive samples for subsequent resequencing when avoiding false negatives is the priority, for instance in a diagnostic test, and to consider suspect positives to be negative samples when cost efficiency over a large number of samples is the priority, for instance in a surveillance program. A total of 13 HA (H1-7, H9-13, H16) and 9 NA (N1-9) subtypes were identified, with a maximum of 8 HA and 8 NA subtypes detected in a single sample. The optimized RNA extraction and targeted resequencing methods provided increased virus detection and subtyping characterization that could be implemented in an AIV surveillance system.

Abstract Background Gonorrhoea is one of the most common sexually transmissible infections in men who have sex with men (MSM). Gonorrhoea rates have increased substantially in recent years. There is concern that increasing gonorrhoea prevalence will increase the likelihood of worsening antibiotic resistance in Neisseria gonorrhoeae. A recent randomised controlled trial (RCT) demonstrated that a single-dose of mouthwash has an inhibitory effect against oropharyngeal gonorrhoea. We are conducting the first RCT to evaluate whether daily use of mouthwash could reduce the risk of acquiring oropharyngeal gonorrhoea. Methods/design The OMEGA (Oral Mouthwash use to Eradicate GonorrhoeA) study is a double-blind RCT and will be conducted at several sexual health clinics and high caseload General Practice (GP) clinics in Melbourne and Sydney, Australia. A total of 504 MSM attending the participating sites will be recruited. Participants will be randomised to either using ‘Study mouthwash A’ or ‘Study mouthwash B’ for 12 weeks. Study mouthwash A was inhibitory against N. gonorrhoeae in vitro, whereas study mouthwash B was not. Participants will be instructed to rinse and gargle the study mouthwash for 60 seconds every day. The primary outcome is the proportion of participants with oropharyngeal gonorrhoea detected by nucleic acid amplification test by 12 weeks. Discussion The results from this trial may provide a novel way to reduce gonorrhoea prevalence and transmission without the use of antibiotics that may be associated with development of resistance. If shown to be effective, the widespread use of mouthwash will reduce the prevalence of oropharyngeal gonorrhoea, which plays key role in driving the emergence of gonococcal antimicrobial resistance through DNA exchange with oral commensal bacteria. The anticipated net effect will be interruption of onward transmission of N. gonorrhoeae within high density sexual networks within MSM populations. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12616000247471 , registered on 23rd February 2016.

Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.

Background HIV+ people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low‐density lipoprotein receptor–independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that PCSK9 levels are increased and that abnormal coronary endothelial function is related to PCSK9 serum levels in HIV+ individuals. Methods and Results Forty‐eight HIV+ participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age‐ and low‐density lipoprotein cholesterol–matched healthy HIV− subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross‐sectional area during isometric handgrip exercise, an endothelial‐dependent stressor; and blood was obtained for serum PCSK9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum PCSK9 was 65% higher in the HIV+ subjects (302±146 ng/mL) than in the HIV− controls (183±52 ng/mL, P

OBJECTIVES/SPECIFIC AIMS: The National HIV/AIDS strategy aims to increase retention in care (RIC) to reduce HIV transmission and mortality. Previous studies have evaluated clinic-level interventions such as appointment reminders and peer navigation. However, few studies have investigated the association between multiple clinic-level factors and RIC among PLWH across the United States. We conducted a multi-site cohort study to identify clinic-level factors associated with RIC in the United States from 2010-2016. METHODS/STUDY POPULATION: We included PLWH with at least one HIV primary care visit from 2010-2016 at seven sites of the Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS). Individual-level data collected as part of routine clinical care were abstracted from the electronic health record. Clinic-level data were gathered through a survey and included questions on site characteristics (i.e. clinic volume) as well as services available at the site during each year of the study: peer navigation, RIC posters/brochures, laboratory test timing, flexible scheduling, appointment reminder types, and stigma support services defined as intensive HIV education and advocacy regarding support to address stigma at outreach visits. RIC was defined as ≥2 encounters per year, ≥90 days apart, observed until death, administrative censoring (December 31, 2016), or loss to follow-up (no visit for >12 months with no future visits). Poisson panel regression with robust error variance, clustering by site and adjusting for calendar year, age (modeled with a cubic spline), sex, race/ethnicity, and HIV transmission risk factor, was used to estimate incident rate ratios (IRR) with 95% confidence intervals (CI) for RIC. Clustering by site has been shown to absorb for clustering that could occur at the individual level as well. RESULTS/ANTICIPATED RESULTS: Among 21,046 patients contributing 103,348 person-years, 67% of person-years were RIC. Text appointment reminders (IRR = 1.13; 95% CI: 1.03-1.24) and stigma support services (IRR=1.11; 95% CI:1.04-1.19) were significantly associated with RIC. RIC disparities in individual-level patient characteristics were observed even after accounting for clinic-level characteristics. Older patients were more likely to be RIC demonstrated through year comparisons due to the use of a spline; for age 50 years (IRR = 1.07, 95% CI: 1.06-1.08) and 60 years (IRR = 1.15, 95% CI: 1.13-1.17) compared to 45 years. Female PLWH were more likely to be RIC compared to males (IRR = 1.03, 95% CI: 1.02-1.05) and Hispanic PLWH were more likely to be RIC compared to white, non-Hispanic PLWH (IRR = 1.09, 95% CI: 1.05-1.13). Although commonly found to be associated with worse RIC, Black race and injection drug use were not associated with RIC in this population. DISCUSSION/SIGNIFICANCE OF IMPACT: In this multi-site US cohort study from 2010-2016, availability of text appointment reminders and stigma support services at a clinic were associated with approximately 10% higher probability of RIC than at clinics without those services. RIC disparities persisted with respect to individual-level characteristics of age, sex, and race/ethnicity even after accounting for these clinic-level factors. Prospective studies examining the impact of these clinic-level factors and individual-level uptake of these services on RIC are needed.

Upon reaching 40 households, an Amish church district typically divides into two smaller, relatively equally sized districts. This article analyzes the relationship between Amish church divisions and topographic demarcation lines within Clark Township, Holmes County, Ohio, from 1930 to 2010. In findings, divisions often follow physical geography boundaries, such as ridges that outline the edge of a watershed, or rivers and streams that essentially define topography within a watershed. Further, Amish leaders divide churches with objectives based on several socioreligious factors, from the maintenance of the faith community to the goal of preserving Amish neighborhoods and rural identity, while also facilitating the continuation of traditional agricultural practices.

BackgroundDepression affects 20-30% of HIV-infected patients and is associated with worse HIV outcomes. Although effective depression treatment is available, depression is largely untreated or undertreated in this population.MethodsWe quantified gaps in antidepressant treatment, treatment adjustments, and outcomes among US patients in routine HIV care in the nationally distributed CNICS observational clinical cohort. This cohort combines detailed clinical data with regular, self-reported depressive severity assessments (Patient Health Questionnaire-9, PHQ-9). We considered whether participants with likely depression received antidepressants, whether participants on antidepressants with persistently high depressive symptoms received timely dose adjustments, and whether participants achieved depression remission. We considered a cross-sectional analysis (6,219 participants in care in 2011-2012) and a prospective analysis (2,936 participants newly initiating CNICS care when PHQ-9 screening was active).ResultsThe cross-sectional sample was 87% male, 53% Caucasian, 25% African American, and 18% Hispanic; the prospective sample was similar. In both samples, 39-44% had likely depression, with 44-60% of those receiving antidepressants. Of participants receiving antidepressants, 20-26% experienced persistently high depressive symptoms; only a small minority of those received antidepressant dose adjustments. Overall, 35-40% of participants on antidepressants achieved full depression remission. Remission among participants with persistently high depressive symptoms was rare regardless of dose adjustments.ConclusionsIn this large, diverse cohort of US patients engaged in routine HIV care, we observed large gaps in antidepressant treatment, timely dose adjustment to address persistently high depressive symptoms, and antidepressant treatment outcomes. These results highlight the importance of more effective pharmacologic depression treatment models for HIV-infected patients.

BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and findingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

OBJECTIVES/SPECIFIC AIMS: The aim of this study was to assess the ultra-dose Na18F dPET protocol feasibility for skeleton imaging in a canine model with reduced radiation dose and preserved quantitative characteristics. We hypothesized that administering an ultra-low Na18F dose would provide suitable image quality while reducing subject’s exposure to radiation. METHODS/STUDY POPULATION: In total, 13 adult male beagles [weight (kg) mean±SD; 14.3±2.2] were scanned. The dogs were administered 3 different Na18F doses: 3 (standard dose/SD), 1 (low dose/LD), and 0.05 (ultra-low dose/ULD) mCi. Imaging started ≃45 minutes post injection for ≃ 33 minute total acquisition time. Covering the whole body, 11 bed positions, acquiring 120 (3 mCi) and 180 (1, 0.05 mCi) seconds per bed position. All imaging was performed on a digital photon counting system (Philips Vereos, pre-commercial release). PET list mode data were reconstructed using Time-of-flight with 4, 2, and 1 mm3 voxel volumes. Point spread function, and Gaussian filtering were applied. Two experienced blinded readers evaluated image sets overall quality, tissue characterization, and quality of background in the whole body skeleton. Three-dimensional (3D) regions of interest (ROI) were traced over the distal femur, first lumbar vertebra, and a portion of the liver, recording standard uptake values (SUVmax and SUVmean). RESULTS/ANTICIPATED RESULTS: All the scans and reconstructions were successfully completed in all subjects. Decreasing Na18F dose from the standard dose (3 mCi) to the ultra-low dose/ULDO (0.05 mCi), demonstrated acceptable image quality and quantification. Ultra-low dose Na18F SUVmean values for the 3D ROIs reported (mean±SD) 2.6±0.7, 2.5±1.1, 9±1.6, and 0.6±0.3 from the right and left distal femur, first lumbar vertebra, and a portion of the liver, respectively. When compared the SD with the LD and ULD, dPET demonstrated acceptable image quality and definition for qualitative overall assessment. This was also found for the overall quantitative ROI assessment of the healthy canine skeletons. DISCUSSION/SIGNIFICANCE OF IMPACT: Ultra-low dose Na18F at a level of 50 μCi for a 14 kg canine appears to be diagnostically feasible and a robust option to reduce (60-fold) radiotracer doses in a translational animal model using a dPET system. Furthermore, it allows us to move preclinical nuclear medicine imaging forward with substantial reduced exposure levels while preserving image quality. Both visual and quantitative results indicate that the standard-dose bone Na18F dPET can be decreased with a satisfactory diagnostic image quality. Ultra-low Na18F dose is indeed important for younger populations, control patients, and nononcological diseases/conditions. Favorable pharmacokinetics of Na18F (such as high bone uptake, minimal binding to serum proteins, rapid single-pass extraction, and fast clearance from the soft tissues) in addition to the technological capabilities of dPET/CT demonstrated feasibility enabling dose reduction strategies. Ultra-low dose has diagnostic reproducibility and lower radiation burden compared with higher fixed dose techniques in current available guidelines [Society of Nuclear Medicine and Molecular Imaging; SNMMI (5–10 mCi)]. Na18F dPET/CT provides higher sensitivity and diagnostic accuracy, which enables high-quality images with lower tracer activity in this translational animal model. Future research will apply the same methodology to other anatomical targets as well as to the use of different tracers. Preclinical nuclear medicine imaging using ultra-low tracer doses, demonstrated the potential to obtain reasonable quality images and diminishing radiation surveillance in accordance with as low as reasonably achievable tracer levels.

BackgroundThe key objectives of this study were to examine whether HIV infection itself is associated with subclinical coronary atherosclerosis and the potential contributions of cocaine use and antiretroviral therapies (ARTs) to subclinical coronary artery disease (CAD) in HIV‐infected persons. Methods and ResultsBetween June 2004 and February 2015, 1429 African American (AA) adults with/without HIV infection in Baltimore, Maryland, were enrolled in an observational study of the effects of HIV infection, exposure to ART, and cocaine use on subclinical CAD. The prevalence of subclinical coronary atherosclerosis was 30.0% in HIV‐uninfected and 33.7% in HIV‐infected (P=0.17). Stratified analyses revealed that compared to HIV‐uninfected, HIV‐infected ART naïve were at significantly lower risk for subclinical coronary atherosclerosis, whereas HIV‐infected long‐term ART users (≥36 months) were at significantly higher risk. Thus, an overall nonsignificant association between subclinical coronary atherosclerosis and HIV was found. Furthermore, compared to those who were ART naïve, long‐term ART users (≥36 months) were at significantly higher risk for subclinical coronary atherosclerosis in chronic cocaine users, but not in those who never used cocaine. Cocaine use was independently associated with subclinical coronary atherosclerosis. ConclusionsOverall, HIV infection, per se, was not associated with subclinical coronary atherosclerosis in this population. Cocaine use was prevalent in both HIV‐infected and ‐uninfected individuals and itself was associated with subclinical disease. In addition, cocaine significantly elevated the risk for ART‐associated subclinical coronary atherosclerosis. Treating cocaine addiction must be a high priority for managing HIV disease and preventing HIV/ART‐associated subclinical and clinical CAD in individuals with HIV infection.

To describe disparities along the depression treatment cascade, from indication for antidepressant treatment to effective treatment, in HIV-infected individuals by gender and race/ethnicity.The Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) cohort includes 31,000 HIV-infected adults in routine clinical care at 8 sites. Individuals were included in the analysis if they had a depressive symptoms measure within one month of establishing HIV care at a CNICS site. Depressive symptoms were measured using the validated Patient Health Questionnaire-9 (PHQ-9). Indication for antidepressant treatment was defined as PHQ-9 ≥ 10 or a current antidepressant prescription. Antidepressant treatment was defined as a current antidepressant prescription. Evidence-based antidepressant treatment was considered treatment changes based on a person's most recent PHQ-9, in accordance with clinical guidelines. We calculated the cumulative probability of moving through the depression treatment cascade within 24 months of entering CNICS HIV care. We used multivariable Cox proportional hazards models to estimate associations between gender, race/ethnicity, and a range of depression outcomes.In our cohort of HIV-infected adults in routine care, 47% had an indication for antidepressant treatment. Significant drop-offs along the depression treatment cascade were seen for the entire study sample. However, important disparities existed. Women were more likely to have an indication for antidepressant treatment (HR 1.54; 95% CI 1.34, 1.78), receive antidepressant treatment (HR 2.03; 95% CI 1.53, 2.69) and receive evidence-based antidepressant treatment (HR 1.67; 95% CI 1.03, 2.74), even after accounting for race/ethnicity. Black non-Hispanics (HR 0.47, 95% CI 0.35, 0.65), Hispanics (HR 0.63, 95% CI 0.44, 0.89) and other race/ethnicities (HR 0.35, 95% CI 0.17, 0.73) were less likely to initiate antidepressant treatment, compared to white non-Hispanics.In our cohort of HIV-infected adults depressive symptoms were common. Important disparities in the prevalence of depressive symptoms and receipt of antidepressant treatment existed by gender and race/ethnicity.

The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53-MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53.

The US Environmental Protection Agency (USEPA) has historically used an expert-driven approach to water and watershed management. In an effort to create regulatory limits for pollution-loading to streams in the USA, the USEPA is establishing limits to the daily loading of nutrients specific to each watershed, which will affect many communities in America. As a part of this process, the Ohio Environmental Protection Agency ranked the Sugar Creek Watershed as the second "most-impaired" watershed in the State of Ohio. This article addresses an alternative approach to watershed management and that emphasises a partnership of farmers and researchers, using community participation in the Sugar Creek to establish a time-frame with goals for water quality remediation. Of interest are the collaborative efforts of a team of farmers, researchers, and agents from multiple levels of government who established this participatory, rather than expert-driven, programme. This new approach created an innovative and adaptive model of non-point source pollution remediation, incorporating strategies to address farmer needs and household decision making, while accounting for local and regional farm structures. In addition, this model has been adapted for point source pollution remediation that creates collaboration among local farmers and a discharge-permitted business that involves nutrient trading.

Understanding retention and loss to follow up in HIV care, in particular the number of people with unknown outcomes, is critical to maximise the benefits of antiretroviral therapy. Individual-level data are not available for these outcomes in Australia, which has an HIV epidemic predominantly focused amongst men who have sex with men.A network of the 6 main HIV clinical care sites was established in the state of Victoria, Australia. Individuals who had accessed care at these sites between February 2011 and June 2013 as assessed by HIV viral load testing but not accessed care between June 2013 and February 2014 were considered individuals with potentially unknown outcomes. For this group an intervention combining cross-referencing of clinical data between sites and phone tracing individuals with unknown outcomes was performed. 4966 people were in care in the network and before the intervention estimates of retention ranged from 85.9%-95.8% and the proportion with unknown outcomes ranged from 1.3-5.5%. After the intervention retention increased to 91.4-98.8% and unknown outcomes decreased to 0.1-2.4% (p

Orang-utans played a communication game in two studies testing their ability to produce and comprehend requestive pointing. While the 'communicator' could see but not obtain hidden food, the 'donor' could release the food to the communicator, but could not see its location for herself. They could coordinate successfully if the communicator pointed to the food, and if the donor comprehended his communicative goal and responded pro-socially. In Study 1, one orang-utan pointed regularly and accurately for peers. However, they responded only rarely. In Study 2, a human experimenter played the communicator's role in three conditions, testing the apes' comprehension of points of different heights and different degrees of ostension. There was no effect of condition. However, across conditions one donor performed well individually, and as a group orang-utans' comprehension performance tended towards significance. We explain this on the grounds that comprehension required inferences that they found difficult - but not impossible. The finding has valuable implications for our thinking about the development of pointing in phylogeny.

Missing outcome data due to loss to follow-up occurs frequently in clinical cohort studies of HIV-infected patients. Censoring patients when they become lost can produce inaccurate results if the risk of the outcome among the censored patients differs from the risk of the outcome among patients remaining under observation. We examine whether patients who are considered lost to follow up are at increased risk of mortality compared to those who remain under observation. Patients from the US Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who newly initiated combination antiretroviral therapy between January 1, 1998 and December 31, 2009 and survived for at least one year were included in the study. Mortality information was available for all participants regardless of continued observation in the CNICS. We compare mortality between patients retained in the cohort and those lost-to-clinic, as commonly defined by a 12-month gap in care. Patients who were considered lost-to-clinic had modestly elevated mortality compared to patients who remained under observation after 5 years (risk ratio (RR): 1.2; 95% CI: 0.9, 1.5). Results were similar after redefining loss-to-clinic as 6 months (RR: 1.0; 95% CI: 0.8, 1.3) or 18 months (RR: 1.2; 95% CI: 0.8, 1.6) without a documented clinic visit. The small increase in mortality associated with becoming lost to clinic suggests that these patients were not lost to care, rather they likely transitioned to care at a facility outside the study. The modestly higher mortality among patients who were lost-to-clinic implies that when we necessarily censor these patients in studies of time-varying exposures, we are likely to incur at most a modest selection bias.

Tomasello and colleagues have offered various arguments to explain why apes find the comprehension of pointing difficult. They have argued that: (i) apes fail to understand communicative intentions; (ii) they fail to understand informative, cooperative communication, and (iii) they fail to track the common ground that pointing comprehension requires. In the course of a review of the literature on apes’ production and comprehension of pointing, I reject (i) and (ii), and offer a qualified defence of (iii). Drawing on work on expressive communication, I sketch an account of a mechanism by which ape gestural communication may proceed: the showing of expressive and naturally meaningful embodied behaviours. Such gestures are easily interpretable because they present rich evidence for a speaker’s message. By contrast, pointing typically provides poor evidence for a speaker’s message, which must therefore be inferred from considerations in the interlocutors’ common ground. This makes pointing comprehension comparatively difficult.

BackgroundCombination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000-2007 in the U.S. and Canada.MethodsParticipants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables.ResultsThe crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000-2002 to 2006-2007. Men and women had comparable life expectancies in all periods except the last (2006-2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts ConclusionsA 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.

We present a genome assembly of Caretta caretta (the Loggerhead sea turtle; Chordata, Testudines, Cheloniidae), generated from genomic data from two unrelated females. The genome sequence is 2.13 gigabases in size. The assembly has a busco completion score of 96.1% and N50 of 130.95 Mb. The majority of the assembly is scaffolded into 28 chromosomal representations with a remaining 2% of the assembly being excluded from these.

We present a genome assembly of Caretta caretta (the Loggerhead sea turtle; Chordata, Testudines, Cheloniidae), generated from genomic data from two unrelated females. The genome sequence is 2.13 gigabases in size. The majority of the assembly is scaffolded into 28 chromosomal representations with a remaining 2% of the assembly being excluded from these.