Search

Gene regulatory networks within cells modulate the expression of the genome in response to signals and changing environmental conditions. Reconstructions of gene regulatory networks can reveal the information processing and control principles used by cells to maintain homeostasis and execute cell-state transitions. Here, we introduce a computational framework, D-SPIN, that generates quantitative models of generegulatory networks from single-cell mRNA-seq data sets collected across thousands of distinct perturbation conditions. D-SPIN models the cell as a collection of interacting gene-expression programs, and constructs a probabilistic model to infer regulatory interactions between gene-expression programs and external perturbations. Using large Perturb-seq and drug-response datasets, we demonstrate that D-SPIN models reveal the organization of cellular pathways, sub-functions of macromolecular complexes, and the logic of cellular regulation of transcription, translation, metabolism, and protein degradation in response to gene knockdown perturbations. D-SPIN can also be applied to dissect drug response mechanisms in heterogeneous cell populations, elucidating how combinations of immunomodulatory drugs can induce novel cell states through additive recruitment of gene expression programs. D-SPIN provides a computational framework for constructing interpretable models of gene-regulatory networks to reveal principles of cellular information processing and physiological control.

BackgroundMen who have sex with men (MSM) practicing exclusively receptive anal sex are more likely to present with secondary than primary syphilis, implying primary anorectal lesions may be missed. If men could detect anorectal lesions by regular anal self-examination, the duration of infectiousness could be reduced. This study aimed to examine adherence to weekly anal self-examination.MethodWe conducted a longitudinal feasibility study examining the adherence to weekly anal self-examinations among MSM attending a sexual health clinic in Melbourne, Australia between December 2020 and June 2021. Adherence to weekly anal self-examinations over 12 weeks was assessed from a logbook and 4-weekly surveys. Participants who identified abnormalities in their anus were recommended to seek medical review.ResultsOf the 30 men who completed the study, anal self-examination was performed at least weekly for 308 of 360 person-weeks (86% of the weeks, 95% CI: 82–89). The mean adherence was 3.6 (95% CI: 3.3–3.9) examinations per 4-weeks per person in Weeks 1–4, 3.5 (95% CI: 3.1–3.8) in Weeks 5–8 and 3.3 (95% CI: 2.9–3.7) in Weeks 9–12 (Ptrend = 0.06). Six men (20%, 6/30) were seen for medical review after they identified abnormalities, whilst eight men (27%, 8/30) reported abnormalities, but did not seek medical review. No participants were diagnosed with syphilis during the study period.ConclusionWe conclude that men adhered well to weekly anal self-examination. Therefore, it is feasible to trial this as a routine practice among MSM. Future studies should investigate possible reductions in adherence over time and ways to increase medical review for abnormalities that men find.

PurposeFertility preservation (FP) services are part of comprehensive care for those newly diagnosed with cancer. The capacity to offer these services to children and adolescents with cancer is unknown.MethodsA cross-sectional survey was sent to 220 Children's Oncology Group member institutions regarding institutional characteristics, structure and organization of FP services, and barriers to FP. Standard descriptive statistics were computed for all variables. The association between site-specific factors and selected outcomes was examined using multivariable logistic regression.ResultsOne hundred forty-four programs (65.5%) returned surveys. Fifty-three (36.8%) reported a designated FP individual or team. Sperm banking was offered at 135 (97.8%) institutions, and testicular tissue cryopreservation at 37 (27.0%). Oocyte and embryo cryopreservation were offered at 91 (67.9%) and 62 (46.6%) institutions, respectively; ovarian tissue cryopreservation was offered at 64 (47.8%) institutions. The presence of dedicated FP personnel was independently associated with the ability to offer oocyte or embryo cryopreservation (odds ratio [OR], 4.7; 95% CI, 1.7 to 13.5), ovarian tissue cryopreservation (OR, 2.7; 95% CI, 1.2 to 6.0), and testicular tissue cryopreservation (OR, 3.3; 95% CI, 1.4 to 97.8). Only 26 (18.1%) participating institutions offered all current nonexperimental FP interventions. Barriers included cost (70.9%), inadequate knowledge or training (60.7%), difficulty characterizing fertility risk (50.4%), inadequate staffing (45.5%), and logistics with reproductive specialties (38%-39%).ConclusionThis study provides the most comprehensive view of the current landscape of FP infrastructure for children and adolescents with cancer and demonstrates that existing infrastructure is inadequate to offer comprehensive services to patients. We discuss modifiable factors to improve patient access to FP.

Older adults are susceptible to severe coronavirus disease 2019 (COVID-19) outcomes as a consequence of their age and, in some cases, underlying health conditions (1). A COVID-19 outbreak in a long-term care skilled nursing facility (SNF) in King County, Washington that was first identified on February 28, 2020, highlighted the potential for rapid spread among residents of these types of facilities (2). On March 1, a health care provider at a second long-term care skilled nursing facility (facility A) in King County, Washington, had a positive test result for SARS-CoV-2, the novel coronavirus that causes COVID-19, after working while symptomatic on February 26 and 28. By March 6, seven residents of this second facility were symptomatic and had positive test results for SARS-CoV-2. On March 13, CDC performed symptom assessments and SARS-CoV-2 testing for 76 (93%) of the 82 facility A residents to evaluate the utility of symptom screening for identification of COVID-19 in SNF residents. Residents were categorized as asymptomatic or symptomatic at the time of testing, based on the absence or presence of fever, cough, shortness of breath, or other symptoms on the day of testing or during the preceding 14 days. Among 23 (30%) residents with positive test results, 10 (43%) had symptoms on the date of testing, and 13 (57%) were asymptomatic. Seven days after testing, 10 of these 13 previously asymptomatic residents had developed symptoms and were recategorized as presymptomatic at the time of testing. The reverse transcription-polymerase chain reaction (RT-PCR) testing cycle threshold (Ct) values indicated large quantities of viral RNA in asymptomatic, presymptomatic, and symptomatic residents, suggesting the potential for transmission regardless of symptoms. Symptom-based screening in SNFs could fail to identify approximately half of residents with COVID-19. Long-term care facilities should take proactive steps to prevent introduction of SARS-CoV-2 (3). Once a confirmed case is identified in an SNF, all residents should be placed on isolation precautions if possible (3), with considerations for extended use or reuse of personal protective equipment (PPE) as needed (4).

Additional file 1: Table S1. Example quotes of participants��� fear of HIV and the impact a HIV diagnosis would have on their lives.

Additional file 3. Results of univariate and multivariate analysis using HIV testing frequency as response with three ordered categories for each of key population.

Additional file 2. Score test for the proportional odds assumption of all the variables in PPOMs.

Additional file 1.

Additional file 1. Sample size calculation.

With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p

Single-cell RNA sequencing (scRNA-seq) of tissues has revealed remarkable heterogeneity of cell types and states but does not provide information on the spatial organization of cells. To better understand how individual cells function within an anatomical space, we developed XYZeq, a workflow that encodes spatial metadata into scRNA-seq libraries. We used XYZeq to profile mouse tumor models to capture spatially barcoded transcriptomes from tens of thousands of cells. Analyses of these data revealed the spatial distribution of distinct cell types and a cell migration-associated transcriptomic program in tumor-associated mesenchymal stem cells (MSCs). Furthermore, we identify localized expression of tumor suppressor genes by MSCs that vary with proximity to the tumor core. We demonstrate that XYZeq can be used to map the transcriptome and spatial localization of individual cells in situ to reveal how cell composition and cell states can be affected by location within complex pathological tissue.

PurposeGiven the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making.MethodsA retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs.ResultsMean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib's mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239).ConclusionContemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.

Additional file 2. Anal self-examination positions

Additional file 1. Qualitative research review guidelines - RATS

Additional file 3. Output parameters for Chlamydia trachomatis models. Tables S 8.1-8.219.

Additional file 1. Details of model equations, model calibration and sensitive analysis.

Additional file 4. Additional results: model calibration, estimating the composition of incidence, and sensitivity analysis. Figs. S2a-32c.

Background There are no available lifetime risk estimates of lower-extremity peripheral artery disease (PAD). Methods and Results Using data from 6 US community-based cohorts and the vital statistics, we estimated the prevalence and incidence of PAD, defined as an ankle-brachial index&nbsp

Sample multiplexing facilitates scRNA-seq by reducing costs and identifying artifacts such as cell doublets. However, universal and scalable sample barcoding strategies have not been described. We therefore developed MULTI-seq: multiplexing using lipid-tagged indices for single-cell and single-nucleus RNA sequencing. MULTI-seq reagents can barcode any cell type or nucleus from any species with an accessible plasma membrane. The method involves minimal sample processing, thereby preserving cell viability and endogenous gene expression patterns. When cells are classified into sample groups using MULTI-seq barcode abundances, data quality is improved through doublet identification and recovery of cells with low RNA content that would otherwise be discarded by standard quality-control workflows. We use MULTI-seq to track the dynamics of T-cell activation, perform a 96-plex perturbation experiment with primary human mammary epithelial cells and multiplex cryopreserved tumors and metastatic sites isolated from a patient-derived xenograft mouse model of triple-negative breast cancer.

List of nucleotide substitutions identified in subject 6’s RV genome. The patient’s RV genome was aligned with the Stuttgart strain (GenBank DQ388280.1). A nucleotide change was considered a substitution only if the change was present in ≥ 4 reads or in 80% of the total reads at that nucleotide position. (PDF 120 kb)

Figure S1. Proportion of individuals tested in each year diagnosed with acute or early HIV infection: newly-arrived Asian-born MSM, Asian-born not newly-arrived MSM, newly-arrived not Asian-born MSM and not newly-arrived not Asian-born MSM. (PDF 13 kb)

Table S1. Proportion of individuals tested in each year and diagnosed with incident HIV infection: newly-arrived Asian-born MSM, Asian-born not newly-arrived MSM, newly-arrived not Asian-born MSM and not newly-arrived not Asian-born MSM, compared to the rest of the MSM population not including that subpopulation (DOCX 14 kb)

Table S1. Systematic review of 347 studies reporting the prevalence of sexually transmitted infections and/or viral hepatitis infections among female sex workers in China. Table S2. Systematic review of 19 studies reporting the co-infection prevalence of sexually transmitted infections and/or viral hepatitis infections among HIV-positive female sex workers in China. Table S3. Heterogeneity in subgroup meta-analyses. (DOCX 687Â kb)

This thesis consists of a series of publications that address the emerging public health issues in the field of HIV/AIDS among men who have sex with men (MSM) in China. Men who have sex with men (MSM) in China are a population group particularly susceptible to HIV transmission and other sexually transmitted infections (STIs) but at the same time they are a hidden population due to social discrimination in Chinese society. The objectives of this thesis were to understand the past and current pattern of HIV epidemic and related risk behaviours of MSM, and estimate the HIV incidence among MSM in China through a modelling approach. This study first commenced with systematic reviews of all available Chinese and English literature and a series of meta-analyses to provide the best combined evidence on the trends of HIV epidemic and high-risk behavioural patterns in Chinese MSM. The second section of this study involved two empirical studies to investigate the HIV disease burden and behaviours among MSM particularly in a rural Chinese setting. Qualitative approach was used to explore the pattern and underlying causes of high-risk sexual practices and multiple sexual identities among MSM. Lastly, based on a mathematical model, this study examined the likelihood of HIV transmission (e.g. HIV incidence) through homosexual intercourses among MSM. As bisexual behaviour is also common among Chinese MSM, this model was then extended to examine HIV transmission to their female sex partners. This study represents an unprecedented and comprehensive integration of China’s HIV epidemiological and behavioural data. It provides strong evidence that HIV epidemic among MSM has been increased rapidly and became the dominant mode of HIV transmission in China. The HIV epidemic in China has clearly entered a new phase of transmission and will demand appropriate changes in its health policies and prevention strategies.

Selection of cases. Table S1a. Urethral chlamydia in couples, after excluding couples with rectal chlamydia. Every MSM included as a “partner 1” and as a “partner 2”. Table S1b. Rectal chlamydia in couples, after excluding couples with urethral chlamydia. Every MSM included as a “partner 1” and as a “partner 2”. Table S2. Chlamydia positivity by site. Men who tested for rectal chlamydia, and their corresponding partner’s urethral chlamydia result. Symptomatic urethritis cases excluded. “Partner 2” includes only men did not have insertive penile-anal sex without condoms with casual and regular partners in the three months before testing. (DOCX 30 kb)

Selection of cases. Table S1a. Urethral chlamydia in couples, after excluding couples with rectal chlamydia. Every MSM included as a “partner 1” and as a “partner 2”. Table S1b. Rectal chlamydia in couples, after excluding couples with urethral chlamydia. Every MSM included as a “partner 1” and as a “partner 2”. Table S2. Chlamydia positivity by site. Men who tested for rectal chlamydia, and their corresponding partner’s urethral chlamydia result. Symptomatic urethritis cases excluded. “Partner 2” includes only men did not have insertive penile-anal sex without condoms with casual and regular partners in the three months before testing. (DOCX 30 kb)