Anti-Stress and Anti-ROS Effects of MnOx-Functionalized Thermosensitive Nanohydrogel Protect BMSCs for Intervertebral Disc Degeneration Repair.

Stem cell transplantation has been proven to be a promising strategy for intervertebral disc degeneration (IDD) repair. However, replicative senescence of bone marrow-derived mesenchymal stem cells (BMSCs), shear damage during direct injection, mechanical stress, and the reactive oxygen species (ROS)-rich microenvironment in degenerative intervertebral discs (IVDs) cause significant cellular damage and limit the therapeutic efficacy. Here, an injectable manganese oxide (MnOx)-functionalized thermosensitive nanohydrogel was proposed for BMSC transplantation for IDD therapy. The MnOx-functionalized thermosensitive nanohydrogel not only successfully protected BMSCs from shear force and mechanical stress before and after injection but also repaired the harsh high-ROS environment in degenerative IVDs, thus effectively increasing the viability of BMSCs and resident nucleus pulposus cells (NPCs). The MnOx-functionalized thermosensitive nanohydrogel provides mechanical protection for stem cells and helps to remove endogenous ROS, providing a promising stem cell delivery platform for the treatment of IDD. This article is protected by copyright. All rights reserved.

Crossbreeding Effect of Chalcogenation and Iodination on Benzene Additives Enables Optimized Morphology and 19.68% Efficiency of Organic Solar Cells.

Volatile solid additives have attracted increasing attention in optimizing the morphology and improving the performance of currently dominated non-fullerene acceptor-based organic solar cells (OSCs). However, the underlying principles governing the rational design of volatile solid additives remain elusive. Herein, a series of efficient volatile solid additives are successfully developed by the crossbreeding effect of chalcogenation and iodination for optimizing the morphology and improving the photovoltaic performances of OSCs. Five benzene derivatives of 1,4-dimethoxybenzene (DOB), 1-iodo-4-methoxybenzene (OIB), 1-iodo-4-methylthiobenzene (SIB), 1,4-dimethylthiobenzene (DSB) and 1,4-diiodobenzene (DIB) are systematically studied, where the widely used DIB is used as the reference. The effect of chalcogenation and iodination on the overall property is comprehensively investigated, which indicates that the versatile functional groups provided various types of noncovalent interactions with the host materials for modulating the morphology. Among them, SIB with the combination of sulphuration and iodination enabled more appropriate interactions with the host blend, giving rise to a highly ordered molecular packing and more favorable morphology. As a result, the binary OSCs based on PM6:L8-BO and PBTz-F:L8-BO as well as the ternary OSCs based on PBTz-F:PM6:L8-BO achieved impressive high PCEs of 18.87%, 18.81% and 19.68%, respectively, which are among the highest values for OSCs.

GCNFORMER: graph convolutional network and transformer for predicting lncRNA-disease associations.

BACKGROUND: A growing body of researches indicate that the disrupted expression of long non-coding RNA (lncRNA) is linked to a range of human disorders. Therefore, the effective prediction of lncRNA-disease association (LDA) can not only suggest solutions to diagnose a condition but also save significant time and labor costs. METHOD: In this work, we proposed a novel LDA predicting algorithm based on graph convolutional network and transformer, named GCNFORMER. Firstly, we integrated the intraclass similarity and interclass connections between miRNAs, lncRNAs and diseases, and built a graph adjacency matrix. Secondly, to completely obtain the features between various nodes, we employed a graph convolutional network for feature extraction. Finally, to obtain the global dependencies between inputs and outputs, we used a transformer encoder with a multiheaded attention mechanism to forecast lncRNA-disease associations. RESULTS: The results of fivefold cross-validation experiment on the public dataset revealed that the AUC and AUPR of GCNFORMER achieved 0.9739 and 0.9812, respectively. We compared GCNFORMER with six advanced LDA prediction models, and the results indicated its superiority over the other six models. Furthermore, GCNFORMER's effectiveness in predicting potential LDAs is underscored by case studies on breast cancer, colon cancer and lung cancer. CONCLUSIONS: The combination of graph convolutional network and transformer can effectively improve the performance of LDA prediction model and promote the in-depth development of this research filed.

CD44 and HAP-Conjugated hADSCs as Living Materials for Targeted Tumor Therapy and Bone Regeneration.

Combining targeted tumor therapy with tissue regeneration represents a promising strategy for synergistic tumor therapy. In this study, a multifunctional living material is constructed with human-derived adipose stem cells (hADSCs) and antibody-modified hydroxyapatite nanorods (nHAP) for targeted drug delivery and bone regeneration following surgery. The living material delivers the therapeutics to the tumor site efficiently based on the strength of the inherent tumor tropism of hADSCs. The bioconjugation of nHAP with hADSCs via specific antibody modification is found to be biocompatible, even when loaded with the chemotherapeutic drug doxorubicin (Dox). The endocytosis of nHAP stimulates the osteogenic differentiation of hADSCs, promoting bone tissue regeneration. Moreover, the antibody-modified nHAP-hADSC conjugate exhibits targeted tumor delivery, which is further facilitated by pH-triggered release of Dox, inducing apoptosis of tumor cells with low toxicity to healthy tissues. Therefore, the present study provides a general strategy for engineering living materials to achieve targeted tumor therapy and bone tissue regeneration after surgery, which can be extended to other disease types.

Nickel(II) Nitrate Hole-Transporting Layers for Single-Junction Bulk Heterojunction Organic Solar Cells with a Record 19.02 % Efficiency.

A facile strategy was developed here to improve the film quality of nickel-based hole transporting layer (HTL) for efficient organic solar cell (OSC) applications. To prevent the agglomeration of Ni(NO3 )2 during film deposition, acetylacetonate was added into the precursor solution, which led to the formation of an amorphous and glass-like state. After thermal annealing (TA) treatment, the film-forming ability could be further improved. The additional UV-ozone (UVO) treatment continuously improved the film quality and increased the work function and conductivity of such HTL. The resulting TA & UVO modified Ni(NO3 )2 & Hacac HTL produced highly efficient organic solar cells with exciting power conversion efficiencies of 18.42 % and 19.02 % for PM6 : BTP-eC9 and D18 : BTP-Th devices, respectively, much higher than the control PEDOT : PSS devices.

Telehealth Use Following COVID-19 Within Patient-Sharing Physician Networks at a Rural Comprehensive Cancer Center: Cross-sectional Analysis.

BACKGROUND: In response to the COVID-19 pandemic, cancer centers rapidly adopted telehealth to deliver care remotely. Telehealth will likely remain a model of care for years to come and may not only affect the way oncologists deliver care to their own patients but also the physicians with whom they share patients. OBJECTIVE: This study aimed to examine oncologist characteristics associated with telehealth use and compare patient-sharing networks before and after the COVID-19 pandemic in a rural catchment area with a particular focus on the ties between physicians at the comprehensive cancer center and regional facilities. METHODS: In this retrospective observational study, we obtained deidentified electronic health record data for individuals diagnosed with breast, colorectal, or lung cancer at Dartmouth Health in New Hampshire from 2018-2020. Hierarchical logistic regression was used to identify physician factors associated with telehealth encounters post COVID-19. Patient-sharing networks for each cancer type before and post COVID-19 were characterized with global network measures. Exponential-family random graph models were performed to estimate homophily terms for the likelihood of ties existing between physicians colocated at the hub comprehensive cancer center. RESULTS: Of the 12,559 encounters between patients and oncologists post COVID-19, 1228 (9.8%) were via telehealth. Patient encounters with breast oncologists who practiced at the hub hospital were over twice as likely to occur via telehealth compared to encounters with oncologists who practiced in regional facilities (odds ratio 2.2, 95% CI 1.17-4.15; P=.01). Patient encounters with oncologists who practiced in multiple locations were less likely to occur via telehealth, and this association was statistically significant for lung cancer care (odds ratio 0.26, 95% CI 0.09-0.76; P=.01). We observed an increase in ties between oncologists at the hub hospital and oncologists at regional facilities in the lung cancer network post COVID-19 compared to before COVID-19 (93/318, 29.3%, vs 79/370, 21.6%, respectively), which was also reflected in the lower homophily coefficients post COVID-19 compared to before COVID-19 for physicians being colocated at the hub hospital (estimate: 1.92, 95% CI 1.46-2.51, vs 2.45, 95% CI 1.98-3.02). There were no significant differences observed in breast cancer or colorectal cancer networks. CONCLUSIONS: Telehealth use and associated changes to patient-sharing patterns associated with telehealth varied by cancer type, suggesting disparate approaches for integrating telehealth across clinical groups within this health system. The limited changes to the patient-sharing patterns between oncologists at the hub hospital and regional facilities suggest that telehealth was less likely to create new referral patterns between these types of facilities and rather replace care that would otherwise have been delivered in person. However, this study was limited to the 2 years immediately following the initial outbreak of COVID-19, and longer-term follow-up may uncover delayed effects that were not observed in this study period.

Impact of a Virtual Professional Development Coaching Program on the Professional Fulfillment and Well-Being of Women Surgery Residents: A Randomized Controlled Trial.

OBJECTIVE: Evaluate the effect of a virtual coaching program offered to women surgery residents in a surgical society. BACKGROUND: Randomized controlled experiments evaluating the effect of coaching on trainee well-being and burnout is lacking. METHODS: Women surgery residents in the Association of Women Surgeons were recruited to participate in a randomized controlled trial of the effects of a virtual coaching program on trainee well-being. Attending surgeons served as coaches after completing in-person training. Residents (n=237) were randomized to intervention (three 1:1 coaching sessions over 9 mo) or control (e-mailed wellness resources). Participants were surveyed at baseline and postintervention using validated measures of well-being, burnout, and resilience. Changes in outcome measures between presurvey and postsurvey were compared between study arms. RESULTS: Survey response rates were 56.9% (n=66) in the control group and 69.4% (n=84) in the intervention group ( P =0.05). The intervention group showed significant improvement in professional fulfillment ( P =0.021), burnout (0.026), work exhaustion (0.017), self-valuation (0.003), and well-being ( P =0.002); whereas the control group showed significant improvement in self-valuation ( P =0.015) and significant decline in resilience ( P =0.025). The intervention group had a significant improvement in well-being ( P =0.015) and intolerance of uncertainty ( P =0.015) compared to controls. CONCLUSIONS: Women surgery residents who participated in a remote coaching program offered by a surgical society demonstrated improvement in aspects of well-being relative to peers who did not receive coaching. Therefore, remote coaching offered by a professional society may be a useful component of initiatives directed at trainee well-being.

Pulse width and intensity effects of pulsed electric fields on cancerous and normal skin cells.

Microsecond pulsed electric fields (PEF) have previously been used for various tumour therapies, such as gene therapy, electrochemotherapy and irreversible electroporation (IRE), due to its demonstrated ability. However, recently nanosecond pulsed electric fields (nsPEF) have also been used as a potential tumor therapy via inducing cell apoptosis or immunogenic cell death to prevent recurrence and metastasis by interacting with intracellular organelles. A large proportion of the existing in-vitro studies of nsPEF on cells also suggests cell necrosis and swelling/blebbing can be induced, but the replicability and potential for other effects on cells suggesting a complicated process which requires further investigation. Therefore, this study investigated the effects of pulse width and intensity of nsPEF on the murine melanoma cells (B16) and normal murine fibroblast cells (L929) through electromagnetic simulation and in-vitro experiments. Through examining the evolution patterns of potential difference and electric fields on the intracellular compartments, the simulation has shown a differential effect of nsPEF on normal and cancerous skin cells, which explains well the results observed in the reported experiments. In addition, the modelling has provided a clear evidence that a few hundreds of ns PEF may have caused a mixed mode of effects, i.e. a 'cocktail effect', including cell electroporation and IRE due to an over their threshold voltage induced on the plasma membrane, as well as cell apoptosis and other biological effects caused by its interaction with the intracellular compartments. The in-vitro experiments in the pulse range of the hundreds of nanoseconds showed a possible differential cytotoxicity threshold of electric field intensity between B16 cells and L929 cells.

Variation in the receipt of human papilloma virus co-testing for cervical screening: Individual, provider, facility and healthcare system characteristics.

Since 2012, cervical cancer screening guidelines allow for choice of screening test for women age 30-65 years (i.e., Pap every 3 years or Pap with human papillomavirus co-testing every 5 years). Intended to give patients and providers options, this flexibility reflects a trend in the growing complexity of screening guidelines. Our objective was to characterize variation in cervical screening at the individual, provider, clinic/facility, and healthcare system levels. The analysis included 296,924 individuals receiving screening from 3626 providers at 136 clinics/facilities in three healthcare systems, 2010 to 2017. Main outcome was receipt of co-testing vs. Pap alone. Co-testing was more common in one healthcare system before the 2012 guidelines (adjusted odds ratio (AOR) of co-testing at the other systems relative to this system 0.00 and 0.50) but was increasingly implemented over time in a second with declining uptake in the third (2017: AORs shifted to 7.32 and 0.01). Despite system-level differences, there was greater heterogeneity in receipt of co-testing associated with providers than clinics/facilities. In the three healthcare systems, providers in the highest quartile of co-testing use had an 8.35, 8.81, and 25.05-times greater odds of providing a co-test to women with the same characteristics relative to the lowest quartile. Similarly, clinics/ facilities in the highest quartile of co-testing use had a 4.20, 3.14, and 6.56-times greater odds of providing a co-test relative to the lowest quartile. Variation in screening test use is associated with health system, provider, and clinic/facility levels even after accounting for patient characteristics.

Patient, provider, and clinic factors associated with the use of cervical cancer screening.

Cervical cancer screening delivery remains suboptimal. Understanding the multiple influences on use of screening is important to designing interventions. We describe the influence of patient, primary care provider (PCP), and clinic characteristics on whether a woman is up-to-date with cervical screening as of December 2016. PCPs (n = 194) and their female screen-eligible patients age 21-65 years (n = 32,115) were included in this cross-sectional analysis of patients from two primary care networks linked to a contemporaneous PCP survey. Principal independent variables for patients included: age, race, insurance, continuity of care; for PCP included: overall satisfaction with the practice of medicine, gender, hours worked per week, financial support for achieving clinical targets; and for clinic included: routine receipt of data on preventive care performance and language translation resources. Overall, 66.6% of women were up-to-date. Women were less likely to be up-to-date with cervical cancer screening if they were younger and were more likely to be screened if they were Black, Hispanic or Asian vs. White. Women with greater continuity of primary care or with a female PCP were more likely to be up-to-date (1.52; 1.33-1.75); those who received care in a clinic that was less prepared to manage language translation were less likely to be up-to-date (0.78; 0.65-0.95). Patient, provider, and clinic factors all influence use of cervical cancer screening. Systems interventions like improving continuity of care, promoting translation services, or enhanced efforts to track screening among patients of male PCPs may improve delivery.

Novel microsimulation model of tobacco use behaviours and outcomes: calibration and validation in a US population.

BACKGROUND AND OBJECTIVE: Simulation models can project effects of tobacco use and cessation and inform tobacco control policies. Most existing tobacco models do not explicitly include relapse, a key component of the natural history of tobacco use. Our objective was to develop, calibrate and validate a novel individual-level microsimulation model that would explicitly include smoking relapse and project cigarette smoking behaviours and associated mortality risks. METHODS: We developed the Simulation of Tobacco and Nicotine Outcomes and Policy (STOP) model, in which individuals transition monthly between tobacco use states (current/former/never) depending on rates of initiation, cessation and relapse. Simulated individuals face tobacco use-stratified mortality risks. For US women and men, we conducted cross-validation with a Cancer Intervention and Surveillance Modeling Network (CISNET) model. We then incorporated smoking relapse and calibrated cessation rates to reflect the difference between a transient quit attempt and sustained abstinence. We performed external validation with the National Health Interview Survey (NHIS) and the linked National Death Index. Comparisons were based on root-mean-square error (RMSE). RESULTS: In cross-validation, STOP-generated projections of current/former/never smoking prevalence fit CISNET-projected data well (coefficient of variation (CV)-RMSE≤15%). After incorporating smoking relapse, multiplying the CISNET-reported cessation rates for women/men by 7.75/7.25, to reflect the ratio of quit attempts to sustained abstinence, resulted in the best approximation to CISNET-reported smoking prevalence (CV-RMSE 2%/3%). In external validation using these new multipliers, STOP-generated cumulative mortality curves for 20-year-old current smokers and never smokers each had CV-RMSE ≤1% compared with NHIS. In simulating those surveyed by NHIS in 1997, the STOP-projected prevalence of current/former/never smokers annually (1998-2009) was similar to that reported by NHIS (CV-RMSE 12%). CONCLUSIONS: The STOP model, with relapse included, performed well when validated to US smoking prevalence and mortality. STOP provides a flexible framework for policy-relevant analysis of tobacco and nicotine product use.

Developing protein arginine methyltransferase 1 (PRMT1) inhibitor TC-E-5003 as an antitumor drug using INEI drug delivery systems.

Injectable implants with the ability to form in situ are one of the most promising carriers for the delivery of chemotherapeutic drugs to tumor sites. We have reported a novel injectable in situ-forming implant system composed of n-butyl-2-cyanoacrylate (NBCA), ethyl oleate, along with the sol-gel phase transition. The chemotherapeutic drug-loaded injectable NBCA ethyl oleate implant (INEI) exhibited excellent therapeutic efficacy for local chemotherapy. Herein, we utilize this INEI to carry N, N'-(Sulfonyldi-4,1-phenylene)bis(2-chloroacetamide) (TE-C-5003), which is a selective protein arginine methyltransferase 1 (PRMT1) inhibitor, to treat the lung cancer mice model. The in vitro experiment shows that TE-C-5003 has a good anti-tumor effect on lung cancer (IC50 = 0.7022 µM for A549; IC50 = 0.6844 µM for NCL-H1299) and breast cancer (IC50 = 0.4128 µM for MCF-7; IC50 = 0.5965 µM for MDA-MB-231). Anti-tumor experiments in animal models showed that the average growth inhibition rate of xenografted human lung cancer cells by the TE-C-5003-loaded INEI (40% NBCA) was 68.23%, which is far more than TC-E-5003 alone (31.76%). Our study further confirms that INEI is an effective technique to improve the anti-tumor effect. The druggability of small molecule compounds can be improved with the help of the mentioned technology. Also, TC-E-5003 may be developed as a broad spectrum anti-tumor drug.

Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation.

T follicular helper cells (TFH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2-/- spleens. These effects were the result of excessive cell-autonomous TFH development caused by unrestricted Bcl6 nuclear translocation in Prkd2-/- CD4+ T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting TFH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4+ T cells, thereby committing them to TFH development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naïve CD4+ T cells to TFH during the adaptive immune response.

Risk of Ischemic Stroke and Major Bleeding in Patients with Atrial Fibrillation and Cancer.

BACKGROUND: Atrial fibrillation (AF) is an important risk factor for ischemic stroke. Cancer may increase the risk both of ischemic stroke and of bleeding. Less is known about risk of ischemic stroke and bleeding among cancer patients with AF, complicating the prevention of ischemic stroke in these patients. METHODS: Register based cohort study comprising all Swedish patients hospitalized with a primary diagnosis of AF from July 1, 2005 until December 31, 2014. Patients with cancer diagnosis were compared to the rest of the cohort. We repeated the analysis focusing on recent cancer diagnosis and on cancer types prone to thromboembolism. Associations between predictor and outcome variables were analyzed with Cox regression. RESULTS: The cohort consisted of 294,989 AF patients including 71,882 with prior cancer diagnosis. After adjustments, neither cancer diagnosis overall, recent cancer diagnosis, or any subgroup of cancer were associated with increased risk of ischemic stroke. Several cancer forms were however associated with risk of major bleedings, including risk of intracranial hemorrhage for patients with prostate cancer and risk of gastrointestinal bleeds for patients with colorectal and pancreatic cancer, adjusted hazard ratios with 95% confidence intervals 1.31 (1.06-1.62), 1.74 (1.53-1.97), and 2.86 (1.80-4.55) respectively. CONCLUSION: Cancer diagnosis was not associated with increased risk of ischemic stroke but several cancer forms were associated with risk of major bleedings in this large, Swedish cohort of AF patients. The results may have implications for prevention of ischemic stroke in these patients.

Decision Support Strategies for Hip and Knee Osteoarthritis: Less Is More: A Randomized Comparative Effectiveness Trial (DECIDE-OA Study).

BACKGROUND: As guidelines and payers increasingly recommend use of patient decision aids (DAs), evidence about the comparative effectiveness of available DAs is critical for organizations interested in implementing them. The primary purpose of this study was to compare 2 DAs with regard to their ability to help patients become informed and receive their preferred treatment (that is, make an informed patient-centered decision), shared decision-making, surgical rates, and surgeon satisfaction. METHODS: We performed a multisite factorial randomized trial enrolling patients with hip or knee osteoarthritis. Patients were randomly assigned to use a long, detailed DA (long DA) or short, interactive DA (short DA). Eight surgeons were randomly assigned to receive a patient preference report detailing the patient's goals and treatment preferences or to administer usual care. RESULTS: We distributed 1,636 pre-visit surveys, 1,220 of which were returned (75% response rate), and 1,124 post-visit surveys, 967 of which were returned (86% response rate). The patients in the sample had a mean age (and standard deviation) of 65 ± 10 years, 57% were female, 89% were white non-Hispanic, and 67% had knee osteoarthritis. The majority (67.2%) made informed patient-centered decisions, and the rate did not vary significantly between the DA groups (p = 0.97) or between the surgeon groups (p = 0.23). Knowledge scores were higher for the short-DA group (mean difference = 9%; p < 0.001). More than half of the sample (60.5%) had surgery within 6 months after the visit, and rates did not differ significantly by DA or surgeon group. Overall, the surgeons were highly satisfied and reported that the majority (88.7%) of the visits were of normal duration or shorter. CONCLUSIONS: The DECIDE-OA study is, to our knowledge, the first randomized comparative effectiveness study of 2 orthopaedic DAs. The short DA outperformed the long DA with regard to knowledge scores and was comparable with respect to other outcomes. The surgeons reported high satisfaction and normal visit duration with both DAs. CLINICAL RELEVANCE: Surgeons need to ensure that patients with osteoarthritis are well-informed and have a clear preference regarding whether to undergo hip or knee replacement surgery. The DAs used in this study may help surgeons involve patients in elective surgery decisions and meet the requirements of informed consent.

Cost-effectiveness of urine-based tuberculosis screening in hospitalised patients with HIV in Africa: a microsimulation modelling study.

BACKGROUND: Testing urine improves the number of tuberculosis diagnoses made among patients in hospital with HIV. In conjunction with the two-country randomised Rapid Urine-based Screening for Tuberculosis to Reduce AIDS-related Mortality in Hospitalised Patients in Africa (STAMP) trial, we used a microsimulation model to estimate the effects on clinical outcomes and the cost-effectiveness of adding urine-based tuberculosis screening to sputum screening for hospitalised patients with HIV. METHODS: We compared two tuberculosis screening strategies used irrespective of symptoms among hospitalised patients with HIV in Malawi and South Africa: a GeneXpert assay (Cepheid, Sunnyvale, CA, USA) for Mycobacterium tuberculosis and rifampicin resistance (Xpert) in sputum samples (standard of care) versus sputum Xpert combined with a lateral flow assay for M tuberculosis lipoarabinomannan in urine (Determine TB-LAM Ag test, Abbott, Waltham, MA, USA [formerly Alere]; TB-LAM) and concentrated urine Xpert (intervention). A cohort of simulated patients was modelled using selected characteristics of participants, tuberculosis diagnostic yields, and use of hospital resources in the STAMP trial. We calibrated 2-month model outputs to the STAMP trial results and projected clinical and economic outcomes at 2 years, 5 years, and over a lifetime. We judged the intervention to be cost-effective if the incremental cost-effectiveness ratio (ICER) was less than US$750/year of life saved (YLS) in Malawi and $940/YLS in South Africa. A modified intervention of adding only TB-LAM to the standard of care was also evaluated. We did a budget impact analysis of countrywide implementation of the intervention. FINDINGS: The intervention increased life expectancy by 0·5-1·2 years and was cost-effective, with an ICER of $450/YLS in Malawi and $840/YLS in South Africa. The ICERs decreased over time. At lifetime horizon, the intervention remained cost-effective under nearly all modelled assumptions. The modified intervention was at least as cost-effective as the intervention (ICERs $420/YLS in Malawi and $810/YLS in South Africa). Over 5 years, the intervention would save around 51 000 years of life in Malawi and around 171 000 years of life in South Africa. Health-care expenditure for screened individuals was estimated to increase by $37 million (10·8%) and $261 million (2·8%), respectively. INTERPRETATION: Urine-based tuberculosis screening of all hospitalised patients with HIV could increase life expectancy and be cost-effective in resource-limited settings. Urine TB-LAM is especially attractive because of high incremental diagnostic yield and low additional cost compared with sputum Xpert, making a compelling case for expanding its use to all hospitalised patients with HIV in areas with high HIV burden and endemic tuberculosis. FUNDING: UK Medical Research Council, UK Department for International Development, Wellcome Trust, US National Institutes of Health, Royal College of Physicians, Massachusetts General Hospital.

Early Enteral Nutrition Adequacy Mitigates the Neutrophil-Lymphocyte Ratio Improving Clinical Outcomes in Critically Ill Surgical Patients.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a measure of host inflammatory response; a higher NLR is associated with worse clinical outcomes. Enteral nutrition (EN) may mitigate inflammation through interaction with gut-associated lymphoid tissue. We hypothesized that early EN adequacy in critically ill surgical patients is associated with lower NLR and better clinical outcomes. METHODS: In this retrospective study, we analyzed data from adult surgical intensive care unit (ICU) patients receiving EN. NLR at baseline ICU admission (NLR-B), NLR after 3-5 days of EN (F-NLR), nutrition adequacy, caloric deficit (CD), protein deficit (PD), hospital length of stay (LOS), ICU LOS, 28-day ventilator-free days (28-VFD), and in-hospital mortality were collected. Tertiles groups were created for NLR, F-NLR, CD, and PD; the highest (H) and lowest (L) tertiles were compared. Regression analyses were performed to control for effect of age, gender, APACHE II, and NLR. RESULTS: Subjects in the L-CD group had lower median F-NLR (7 [range, 5-11] vs 10 [7-22], P = 0.005) and shorter ICU LOS (9 [6-16]) vs 16 [9-32] days; P = 0.006). The L-NLR group had shorter hospital LOS (18 [10-31] vs 22 [15-38] days, P = 0.023), greater 28-VFD (23 [18-25] vs 19 [11-22] days, P = 0.005), and lower in-hospital mortality (13% vs 41%, P = 0.002). CONCLUSION: In critically ill surgical patients, early enteral caloric adequacy is associated with less inflammation and improved clinical outcomes.

Identification of functionally primitive and immunophenotypically distinct subpopulations in secondary acute myeloid leukemia by mass cytometry.

BACKGROUND: Background: Mass cytometry (CyTOF) is a powerful tool for analyzing cellular networks at the single cell level. Due to the high-dimensional nature of this approach, analysis algorithms have been developed to visualize and interpret mass cytometry data. In this study, we applied these approaches to a cohort of patients with secondary acute myeloid leukemia (sAML). METHODS: We utilized mass cytometry to interrogate localization and intensity of thrombopoietin-mediated intracellular signaling in sAML. Extracellular and intracellular phenotypes were dissected using SPADE, viSNE, and PhenoGraph. RESULTS: Healthy controls exhibited highly localized signaling responses largely restricted to the hematopoietic stem/progenitor cell (HSPC) compartment. In contrast, sAML samples contained subpopulations outside the HSPC compartment exhibiting thrombopoietin (TPO) sensitivity comparable to or greater than immunophenotypically defined HSPCs. We employed unsupervised clustering by PhenoGraph to elucidate distinct subpopulations within these heterogeneous samples. One metacluster composed almost exclusively of Lin- CD61+ CD34- CD38- CD45low cells was identified. This subpopulation was not readily identified by established manual gating approaches, and generally exhibited greater STAT phosphorylation in response to TPO stimulation than did Lin- CD61- CD34+ CD38- cells. Lin- CD61+ CD34- CD38- CD45low cells were identified in three additional sAML patients analyzed independently using a manual gating approach based upon PhenoGraph results. Each patient exhibited a similar TPO hypersensitivity to the PhenoGraph metacluster. CONCLUSIONS: The identification of this cellular subpopulation highlights the limitations of manual gating in sAML. Our study demonstrates the potential for mass cytometry to elucidate rare subpopulations in highly heterogeneous tumors by utilizing unsupervised high dimensional analysis. © 2018 International Clinical Cytometry Society.

Medical Oncologists' Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study.

Background Although almost every state medical marijuana (MM) law identifies cancer as a qualifying condition, little research supports MM's use in oncology. We hypothesized that the discrepancy between these laws and the scientific evidence base poses clinical challenges for oncologists. Oncologists' beliefs, knowledge, and practices regarding MM were examined in this study. Methods In November 2016, we mailed a survey on MM to a nationally-representative, random sample of 400 medical oncologists. Main outcome measures included whether oncologists reported discussing MM with patients, recommended MM clinically in the past year, or felt sufficiently informed to make such recommendations. The survey also queried oncologists' views on MM's comparative effectiveness for several conditions (including its use as an adjunct to standard pain management strategies) and its risks compared with prescription opioids. Bivariate and multivariate analyses were performed using standard statistical techniques. Results The overall response rate was 63%. Whereas only 30% of oncologists felt sufficiently informed to make recommendations regarding MM, 80% conducted discussions about MM with patients, and 46% recommended MM clinically. Sixty-seven percent viewed it as a helpful adjunct to standard pain management strategies, and 65% thought MM is equally or more effective than standard treatments for anorexia and cachexia. Conclusion Our findings identify a concerning discrepancy between oncologists' self-reported knowledge base and their beliefs and practices regarding MM. Although 70% of oncologists do not feel equipped to make clinical recommendations regarding MM, the vast majority conduct discussions with patients about MM and nearly one-half do, in fact, recommend it clinically. A majority believes MM is useful for certain indications. These findings are clinically important and suggest critical gaps in research, medical education, and policy regarding MM.