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Background: Axial spondyloarthritis (axSpA) is associated with accelerated atherosclerosis driven by chronic inflammation. Achieving LDA may result in significant benefits in articular disease, little is known about its effect on extra-articular disease, including CVD risk in axSpA. To investigate the effect of achieving Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA) using a protocolized treatment strategy on the progression of subclinical atherosclerosis and arterial stiffness in axial spondyloarthritis (axSpA) patients. Methods: One hundred consecutive AxSpA patients will participate in this 2-year prospective, hospital-based, cohort study. All participants will receive 2 years of tight-control treatment. Treatment will be adjusted according to a standardized protocol every 3-6 monthly aiming at ASDAS LDA (ASDAS

Abstract Background The Coronavirus disease-2019 (COVID-19) vaccines were rolled out in many countries; however, sub-optimal COVID-19 vaccine uptake remains a major public health concern globally. This study aimed at assessing the factors that affected the uptake, hesitancy, and resistance of the COVID-19 vaccine among university undergraduate students in Malawi, a least developed country in Africa. Methods A descriptive cross-sectional study design was conducted using an online semi-structured questionnaire. A total of 343 University undergraduate students in Blantyre participated in this study after obtaining ethical clearance. Data was exported from Survey Monkey to Microsoft Excel version-21 for cleaning and was analysed using SPSS version-29. Descriptive statistics, including percentages, were performed to define the sample characteristics. Pearson Chi-square and Fisher’s exact test were performed to identify significant relationships between vaccine uptake and demographics. A 95% confidence interval was set, and a p-value of

Background: Axial spondyloarthritis (axSpA) is associated with accelerated atherosclerosis driven by chronic inflammation. Achieving LDA may result in significant benefits in articular disease, little is known about its effect on extra-articular disease, including CVD risk in axSpA. To investigate the effect of achieving Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA) using a protocolized treatment strategy on the progression of subclinical atherosclerosis and arterial stiffness in axial spondyloarthritis (axSpA) patients. Methods: One hundred consecutive AxSpA patients will participate in this 2-year prospective, hospital-based, cohort study. All participants will receive 2 years of tight-control treatment. Treatment will be adjusted according to a standardized protocol every 3-6 monthly aiming at ASDAS LDA (ASDAS <2.1). Carotid intima-media thickness (IMT) and total plaque area (TPA) will be measured using high-resolution ultrasound. Arterial stiffness is measured by pulse wave velocity (PWV) and augmentation index (AIx). The main outcome measure is the change in subclinical atherosclerosis over a period of 2 years comparing between patients who achieve sustained LDA at year 2 (sLDA group: achieved LDA at both year 1 and year 2) to those who cannot achieve LDA (non-sLDA group). Secondary outcomes include differences in the changes in AIx and PWV over 2 years between the 2 groups. Results: In this interim analysis, a total of 56 axSpA patients (age: 38± 10 years, 43 (76.8%) male) who completed 2 year of follow-up were included. A significant improvement in disease activity was observed after 2 years of treatment (ASDAS-CRP at baseline: 2.9± 0.6 vs 1.9± 0.7 at year 2, p<0.001). Forty-one patients achieved LDA at year 1 and 31 patients achieved sustained LDA (sLDA) at year 2. The baseline traditional CV risk factors were comparable between the sLDA and non-sLDA groups. The multivariate analysis demonstrated that the sLDA group exhibited a smaller increase in mean IMT (β : -0.04, 95%CI -0.07 to -0.01, P=0.025) and max IMT (β : -0.06, 95%CI -0.12 to -0.004, P=0.038) after adjustment for covariates compared to the non-sLDA group. However, there were no significant differences in the progression of carotid plaque and arterial stiffness markers between the two groups in the multivariate analysis. Conclusion: Patients with AxSpA who are able to achieve sLDA through a protocolized treatment algorithm experience reduced progression of subclinical atherosclerosis compared to patients who cannot achieve sLDA. This indicates that effective suppression of inflammation in AxSpA patients who reach sLDA may potentially lower CV risk. [ABSTRACT FROM AUTHOR]

When localised prostate cancer recurs after treatment, it occurs predictably in sites such as the prostatic bed, pelvic lymph nodes, spine, lung, and liver. Urethral metastasis of prostate cancer is exceedingly rare. We report a case of urethral recurrence of prostate cancer presenting as new lower urinary tract symptoms in an 82-year-old male 10 years after robotic radical prostatectomy with a very low PSA level of 0.05μg/L. This rare case highlights the need to maintain a degree of suspicion for prostate cancer recurrence in patients with a late onset of or changing lower urinary tract symptoms after radical prostatectomy.

Abstract Human-Earth System Models and Integrated Assessment Models used to explore the land-atmosphere implications of future land-use transitions generally lack dynamic representation of urban lands. Here, we conduct an experiment incorporating dynamic urbanization in a multisector model framework. We integrate projected dynamic non-urban lands from a multisector model with projected dynamic urban lands from 2015 to 2100 at 1-km resolution to examine 1st-order implications to the land system, crop production, and net primary production that can arise from the competition over land resources. By 2100, future urban extensification could displace 0.1 to 1.4 million km2 of agriculture lands, leading to 22 to 310 Mt of compromised corn, rice, soybean, and wheat production. When considering increased corn production required to meet demands by 2100, urban extensification could cut increases in yields by half. Losses in net primary production from displaced forest, grassland, and croplands ranged from 0.24 to 2.24 Gt C yr−1, potentially increasing land emissions by 1.19 to 6.59 Gt CO2 yr−1. Although these estimates do not consider adaptive responses, 1st-order experiments can elucidate the individual role of sub-sectors that would otherwise be masked by model complexity.

ObjectivesTo determine the impact of a criteria-led discharge initiative (CLD) on the hospital length of stay of patients undergoing a robotic-assisted laparoscopic prostatectomy (RALP). MethodsThis is a cohort study of prospectively collected data completed at a major tertiary hospital from December 2017 to August 2020. The CLD initiative consists of 4 criteria: clinical haemodynamic stability (heart rate < 100 beats/minute, systolic blood pressure > 100mmHg), a drain output of less than 50 mL, flatulence or bowel movement, and the ability to tolerate an oral diet. The primary outcome was hospital length of stay for patients before and after the introduction of CLD. ResultsOne hundred men undergoing RALP before the implementation of the CLD initiative were compared to 118 men undergoing RALP following the implementation of CLD. The patients had similar baseline demographic features. There was a significant difference found in hospital LOS with the pre-CLD group LOS (mean = 1.8 days, SE = 0.12) being longer than the LOS in the post-CLD group (mean = 1.4 days, SE = 0.09, P = 0.015). There were no significant between-group differences in the proportion of patients discharged on the first postoperative day and the 30-day readmission rate. ConclusionWithin our study population, we have demonstrated that the introduction of CLD was associated with reduced hospital LOS with no increase in adverse events. These findings support the need for the development of CLD in other conditions.

Abstract Water usage is closely linked with societal goals that are both local and global in scale, such as sustainable development and economic growth. It is therefore of value, particularly for long-term planning, to understand how future sectoral water usage could evolve on a global scale at fine resolution. Additionally, future water usage could be strongly shaped by global forces, such as socioeconomic and climate change, and the multi-sector dynamic interactions those forces create. We generate a novel global gridded monthly sectoral water withdrawal and consumption dataset at 0.5° resolution for 2010–2100 for a diverse range of 75 scenarios. The scenarios are harmonized with the five Shared Socioeconomic Pathways (SSPs) and four Representative Concentration Pathways (RCPs) scenarios to support its usage in studies evaluating the implications of uncertain human and earth system change for future global and regional dynamics. To generate the data, we couple the Global Change Analysis Model (GCAM) with a land use spatial downscaling model (Demeter), a global hydrologic framework (Xanthos), and a water withdrawal downscaling model (Tethys).

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Abstract Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.

Introduction Throughout clinical practice, most doctors will encounter patients with urological conditions. Inclusion of urological topics within medical school curriculums is important to allow doctors to effectively diagnose and manage these conditions, independently and with support from urologists. Awareness of urological education interventions and their effectiveness is essential for improving the quality and outcomes of medical student education. No systematic review of medical school education interventions on urological topics has previously been conducted. This mixed-method systematic review will assess the effectiveness of medical school education interventions on urological topics.Methods and analysis This mixed-methods systematic review will include qualitative and quantitative studies involving education interventions or practices regarding urological topics conducted within a medical school curriculum. Studies regarding other curriculums including premedical education, junior doctor prevocational education or vocational urological training will be excluded. A search of CINAHL, ERIC, EMBASE, MEDLINE will be conducted for studies published since the year 2001. Dual independent screening of titles and abstracts prior to full text review will be undertaken for all identified results during the initial searches. Any disagreement will be settled by a third reviewer. A convergent segregated approach will be used to synthesise qualitative and quantitative data independently, with the results juxtaposed to identify shared and divergent findings between study types.Ethics and dissemination No ethical approval was required for this review. Findings from this review will be disseminated via publication, reports and conference presentations.

ABSTRACT Accurate, highly specific immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to evaluate seroprevalence. This study investigated the concordance of results across four immunoassays targeting different antigens for sera collected at the beginning of the SARS-CoV-2 pandemic in the United States. Specimens from All of Us participants contributed between January and March 2020 were tested using the Abbott Architect SARS-CoV-2 IgG (immunoglobulin G) assay (Abbott) and the EuroImmun SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) (EI). Participants with discordant results, participants with concordant positive results, and a subset of concordant negative results by Abbott and EI were also tested using the Roche Elecsys anti-SARS-CoV-2 (IgG) test (Roche) and the Ortho-Clinical Diagnostics Vitros anti-SARS-CoV-2 IgG test (Ortho). The agreement and 95% confidence intervals were estimated for paired assay combinations. SARS-CoV-2 antibody concentrations were quantified for specimens with at least two positive results across four immunoassays. Among the 24,079 participants, the percent agreement for the Abbott and EI assays was 98.8% (95% confidence interval, 98.7%, 99%). Of the 490 participants who were also tested by Ortho and Roche, the probability-weighted percentage of agreement (95% confidence interval) between Ortho and Roche was 98.4% (97.9%, 98.9%), that between EI and Ortho was 98.5% (92.9%, 99.9%), that between Abbott and Roche was 98.9% (90.3%, 100.0%), that between EI and Roche was 98.9% (98.6%, 100.0%), and that between Abbott and Ortho was 98.4% (91.2%, 100.0%). Among the 32 participants who were positive by at least 2 immunoassays, 21 had quantifiable anti-SARS-CoV-2 antibody concentrations by research assays. The results across immunoassays revealed concordance during a period of low prevalence. However, the frequency of false positivity during a period of low prevalence supports the use of two sequentially performed tests for unvaccinated individuals who are seropositive by the first test. IMPORTANCE What is the agreement of commercial SARS-CoV-2 immunoglobulin G (IgG) assays during a time of low coronavirus disease 2019 (COVID-19) prevalence and no vaccine availability? Serological tests produced concordant results in a time of low SARS-CoV-2 prevalence and no vaccine availability, driven largely by the proportion of samples that were negative by two immunoassays. The CDC recommends two sequential tests for positivity for future pandemic preparedness. In a subset analysis, quantified antinucleocapsid and antispike SARS-CoV-2 IgG antibodies do not suggest the need to specify the antigen targets of the sequential assays in the CDC’s recommendation because false positivity varied as much between assays targeting the same antigen as it did between assays targeting different antigens.

Background: We aimed to evaluate the utility of prostate-specific membrane antigen (PSMA) PET/CT for the detection of local disease within the prostate. Methods: This is a retrospective review of a single-center experience evaluating intraprostatic detection rates compared with final histopathology in a radical prostatectomy (RP) population. Seventy-two patients had PSMA PET/CT scan performed as part of their primary staging. Intraprostatic PSMA PET/CT avidity was assessed. PSMA PET/CT uptake was retrospectively correlated with patient characteristics including final histopathology, MRI Prostate Imaging Reporting and Data System (PI-RADS) score, clinical tumor stage, prostate-specific antigen (PSA) level, and patient age. Results: The sensitivity of PSMA PET/CT for the detection of RP-confirmed prostate cancer was 81.2%. Much higher sensitivity was found within certain subpopulations. The patient characteristics that most strongly correlated with focal intraprostatic PSMA PET/CT uptake were patient age (Kendall's tau coefficient τb = 0.24, p

Abstract Background The World Health Organization (WHO) has targeted a reduction in viral hepatitis-related mortality by 65% and incidence by 90% by 2030, necessitating enhanced hepatitis B treatment and prevention programmes in low- and middle-income countries. Hepatitis B e antigen (HBeAg) status is used in the assessment of eligibility for antiviral treatment and for prevention of mother-to-child transmission (PMTCT). Accordingly, the WHO has classified HBeAg rapid diagnostic tests (RDTs) as essential medical devices. Methods We assessed the performance characteristics of three commercially available HBeAg RDTs (SD Bioline, Alere, South Africa; Creative Diagnostics, USA; and Biopanda Reagents, UK) in two hepatitis B surface antigen-positive cohorts in Blantyre, Malawi: participants of a community study (n = 100) and hospitalised patients with cirrhosis or hepatocellular carcinoma (n = 94). Two investigators, blinded to the reference test result, independently assessed each assay. We used an enzyme-linked immunoassay (Monolisa HBeAg, Bio-Rad, France) as a reference test and quantified HBeAg concentration using dilutions of the WHO HBeAg standard. We related the findings to HBV DNA levels, and evaluated treatment eligibility using the TREAT-B score. Results Among 194 HBsAg positive patients, median age was 37 years, 42% were femaleand 26% were HIV co-infected. HBeAg prevalence was 47/194 (24%). The three RDTs showed diagnostic sensitivity of 28% (95% CI 16–43), 53% (38–68) and 72% (57–84) and specificity of 96–100% for detection of HBeAg. Overall inter-rater agreement κ statistic was high at 0.9–1.0. Sensitivity for identifying patients at the threshold where antiviral treatment is recommended for PMTCT, with HBV DNA > 200,000 IU/ml (39/194; 20%), was 22, 49 and 54% respectively. Using the RDTs in place of the reference HBeAg assay resulted in 3/43 (9%), 5/43 (12%) and 8/43 (19%) of patients meeting the TREAT-B treatment criteria being misclassified as ineligible for treatment. A relationship between HBeAg concentration and HBeAg detection by RDT was observed. A minimum HBeAg concentration of 2.2–3.1 log10IU/ml was required to yield a reactive RDT. Conclusions Commercially available HBeAg RDTs lack sufficient sensitivity to accurately classify hepatitis B patients in Malawi. This has implications for hepatitis B public health programs in sub-Saharan Africa. Alternative diagnostic assays are recommended.

Abstract Background Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200–399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial registration ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Objective:The purpose of this study is to compare small lymphatic vessel sealing using LigasureTM (LS) and Hem-o-lok® (HML) clips in an ex vivo canine spermatic cord model.Materials and Methods:Canine testes with spermatic cord attached were harvested. By random distribution, the spermatic cord of each testis was either (i) sealed with LS, (ii) clipped with one HML clip, or (iii) had no intervention. The testis was then injected with a Patent Blue V dye solution. At 5 minutes and 12 hours after injection, the distal spermatic cord was inspected for macroscopically visible dye. One random spermatic cord from each of the LS and HML cohorts free of macroscopic evidence of dye was examined using the frozen section histology of the cross sections proximal and distal to the intervention site to detect the microscopic presence of dye.Results:During the study period, 18 canine testes were harvested. After randomization, five, six, and seven testes were included in the control, HML, and LS groups, respectively. In the control group, all 5 testes had leaked blue dye from the cut end of the spermatic cord at 5 minutes. Further, in the HML group, dye was macroscopically visible distal to the intervention site (intervention failure) in 2 out of 6 cases at 5 minutes. In the LS group, 2 out of 7 testes had leaked blue dye at 5 minutes. All testes that did not fail at 5 minutes also did not fail at 12 hours in both LS and HML groups.Conclusion:LS is an effective alternative option to HML clips to seal small lymphatic vessels.

Introduction Bladder cancer is the third most common urological malignancy affecting Australians, with key modifiable risk factors. Aboriginal and Torres Strait Islander people suffer from a higher prevalence of cancer-modifiable risk factors, are diagnosed with bladder cancer at a younger age, and have poorer survival rates compared with the general population. A comprehensive overview of the state of current knowledge on bladder cancer in this population is required.Methods and analysis A search of MEDLINE, CINAHL, EMBASE and Web of Science databases, along with appropriate grey literature sources will be conducted between the 1 April 2022 and 30 April 2022. The reference lists of all included studies will be reviewed for additional appropriate sources. The national bladder cancer dataset compiled by the Australian Institute of Health and Welfare will also be included as a source. All relevant sources meeting inclusion criteria, published in English, from inception onwards will be included. Dual independent screening of titles and abstracts prior to full-text review will be undertaken for all identified results during the initial searches. Preliminary findings will be reviewed with stakeholders, to seek culturally appropriate feedback on the implications of the results. Results will be reported in tabular form, accompanied by a narrative synthesis with comparisons to the wider bladder cancer population.Ethics and dissemination Ethics review will not be required, as only publicly available data will be analysed. Findings from the scoping review will be published in a peer-reviewed journal and presented at scientific meetings to stakeholders.

Metallic ureteric stents are increasingly used for the management of malignant ureteric obstruction, a commonly encountered complication in urological and other malignancies. However, there has been limited evaluation of complications associated with these stents, including those that might arise from the use of magnetic resonance imaging (MRI). While most devices are deemed nominally “MRI-safe,” their implication on the quality of imaging produced has not been evaluated in clinical trials, and in our practice, significant artefact has been encountered with some ureteric stents—specifically, the Teleflex Rüsch DD tumour stent—compromising image quality and diagnostic certainty.

Summary: The COVID-19 pandemic revealed an urgent need for rapid profiling of neutralizing antibody responses and development of antibody therapeutics. The current Food and Drug Administration-approved serological tests do not measure antibody-mediated viral neutralization, and there is a need for standardized quantitative neutralization assays. We report a high-throughput two-step profiling approach for identifying neutralizing convalescent plasma. Screening and downselection for serum antibody binding to the receptor-binding domain are followed by quantitative neutralization testing using a chimeric vesicular stomatitis virus expressing spike protein of SARS-CoV-2 in a real-time cell analysis assay. This approach enables a predictive screening process for identifying plasma units that neutralize SARS-CoV-2. To calibrate antibody neutralizing activity in serum from convalescent plasma donors, we introduce a neutralizing antibody standard reagent composed of two human antibodies that neutralize SARS-CoV strains, including SARS-CoV-2 variants of concern. Our results provide a framework for establishing a standardized assessment of antibody-based interventions against COVID-19.

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Summary: A detailed understanding of the adaptive host response to SARS-CoV-2 infection in humans is urgently needed. We developed a sensitive, high-throughput, and efficient assay using liquid bead array technology. We observed advantages over traditional ELISA for the detection and quantification of binding IgG against the receptor binding domain (RBD) of SARS-CoV-2. To determine whether COVID-19 symptom severity correlates with SARS-CoV-2 IgG, we measured anti-RBD IgG levels from 67 subjects recovered from PCR-confirmed COVID-19. We found that COVID-19 symptom severity strongly correlated with RBD IgG level (p < 0.001). These findings have substantial implications for public policy surrounding assessments of antibody responses and possible immunity, as not all cases of COVID-19 can be assumed to generate a protective antibody response, and mild disease in particular is capable of generating very low-level anti-RBD IgG levels. These findings also have important implications for the selection of donors for convalescent plasma to be used therapeutically.

A collision tumour of the kidney is a very rare condition defined by two immediately adjacent but histologically distinct neoplasms that coexist within one organ without histological admixture. We present a collision tumour in a transplant kidney treated with open partial nephrectomy. This case also highlights key surgical principles the enhanced risk of oncogenesis in transplant recipients, and some key principles for surgical resection of a tumour in a transplant kidney.

Abstract Background Integration of family planning counselling and method provision into safe abortion services is a key component of quality abortion care. Numerous barriers to post-abortion family planning (PAFP) uptake exist. This study aimed to evaluate the effect of a quality management intervention for providers on PAFP uptake. Methods We conducted a pre- and post-intervention study between November 2015 and July 2016 in nine private clinics in Western Kenya. We collected baseline and post-intervention data using in-person interviews on the day of procedure, and follow-up telephone interviews to measure contraceptive uptake in the 2 weeks following abortion. We also conducted semi-structured interviews with providers. The intervention comprised a 1-day orientation, a counselling job-aide, and enhanced supervision visits. The primary outcome was the proportion of clients receiving any method of PAFP (excluding condoms) within 14 days of obtaining an abortion. Secondary outcomes were the proportion of clients receiving PAFP counselling, and the proportion of clients receiving long-acting reversible contraception (LARC) within 14 days of the service. We used chi-squared tests and multivariate logistic regression to determine whether there were significant differences between baseline and post-intervention, adjusting for potential confounding factors and clustering at the clinic level. Results Interviews were completed with 769 women, and 54% (414 women) completed a follow-up telephone interview. Reported quality of counselling and satisfaction with services increased between baseline and post-intervention. Same-day uptake of PAFP was higher at post-intervention compared to baseline (aOR 1.94, p

Abstract Background The 2012 London declaration which committed to “sustaining, expanding and extending drug access programmes to ensure the necessary supply of drugs and other interventions to help control soil-transmitted helminths (STH) by 2020” has seen many countries in Africa roll out mass drug administration (MDA) especially among school age children. In Kenya, however, during the National school-based deworming exercise, pre-school aged children (PSAC) have to access treatment at primary schools as the pre-school teachers are not trained to carry out deworming. With studies being conducted on the effectiveness of MDAs, the experiences of key education stakeholders which could improve the programme by giving best practices, and challenges experienced have not been documented. Methods This was a cross-sectional qualitative study using Focus group discussions (FGDs) and Key informant interviews (KIIs). It was conducted in 4 sub-counties with high STH prevalence at the Kenyan coast (Matuga, Malindi, Lunga Lunga and Msambweni) to understand best practices for implementing MDA among PSAC.FGDs categorized by gender were conducted among local community members, whereas KIIs involved pre-school teachers, primary school teachers, community health extension workers (CHEWs) and opinion leaders. Participants were purposefully selected with the saturation model determining the number of interviews and focus groups. Voice data collected was transcribed verbatim then coded and analyzed using ATLAS.Ti version 6. Results Majority of the primary school teachers and CHEWs reported that they were satisfied with the method of mobilization used and the training tools. This was however not echoed by the pre-school teachers, parents and chiefs who complained of being left out of the process. Best practices mentioned included timely drug delivery, support from pre-school teachers, and management of side effects. Overcrowding during the drug administration day, complexity of the forms (for instance the ‘S form’) and long distance between schools were mentioned as challenges. Conclusion There is need to utilize better sensitization methods to include the local administration as well as the parents for better uptake of the drugs. Extending deworming training to pre-school teachers will enhance the national deworming programme.

A 1-year-old male child presented with progressive jaundice. Investigations were suggestive of an obstructive pathology with a suspected choledochal cyst on imaging. Intraoperative cholangiogram demonstrated runoff of contrast from the cystic duct into the common bile duct with no opacification of the biliary system proximal to this. Intraoperatively, the right hepatic artery was found anteriorly crossing the common hepatic duct (CHD) causing extrinsic compression leading to complete obstruction. Following stricture excision and anastomosis of the dilated bulbous CHD to a Roux-en-Y jejunal loop, the child recovered completely. An anteriorly crossing right hepatic artery causing obstruction to the biliary duct is a rare occurrence, more so in infancy. An excision with a hepaticojejunostomy is straight forward and curative.

Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors under evaluation as vaccine antigens. Clinical S. aureus isolates have the biosynthetic capability to express either CP5 or CP8 and an understanding of the relationship between CP genotype/phenotype and S. aureus epidemiology is valuable. Using whole genome sequencing, the clonal relatedness and CP genotype were evaluated for disease-associated S. aureus isolates selected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) to represent different geographic regions in the United States (US) during 2004 and 2009-10. Thirteen prominent clonal complexes (CC) were identified, with CC5, 8, 30 and 45 representing >80% of disease isolates. CC5 and CC8 isolates were CP type 5 and, CC30 and CC45 isolates were CP type 8. Representative isolates from prevalent CC were susceptible to in vitro opsonophagocytic killing elicited by anti-CP antibodies, demonstrating that susceptibility to opsonic killing is not linked to the genetic lineage. However, as not all S. aureus isolates may express CP, isolates representing the diversity of disease isolates were assessed for CP production. While approximately 35% of isolates (primarily CC8) did not express CP in vitro, CP expression could be clearly demonstrated in vivo for 77% of a subset of these isolates (n = 20) despite the presence of mutations within the capsule operon. CP expression in vivo was also confirmed indirectly by measuring an increase in CP specific antibodies in mice infected with CP5 or CP8 isolates. Detection of antigen expression in vivo in relevant disease states is important to support the inclusion of these antigens in vaccines. Our findings confirm the validity of CP as vaccine targets and the potential of CP-based vaccines to contribute to S. aureus disease prevention.

Aim: The aim of the study is to review 7 patients with congenital esophageal stenosis treated in our institution from a diagnostic and therapeutic point of view. Materials and Methods: This is a retrospective cohort study of 7 patients treated in Christian Medical College, Vellore from 2008 to 2014. The data were analyzed with regards to age at onset of symptoms, investigative findings, age at definitive treatment, pathology, modalities of treatment, and outcomes. Results: Symptoms started within the 1 st year of life in all children with a median age of 4 months. The time of delay in diagnosis ranged from 8 months to 81 months with a mean period of 37 months. About 6 patients had a lower esophageal stenosis and 1 patient had a mid-esophageal stenosis. About 4 of the 7 children underwent endoscopic balloon dilatation from elsewhere, with 2 of the above 4 undergoing a myotomy for a wrongly diagnosed achalasia. The number of dilatations ranged from 2 to 7 with a mean of 4 dilatations. Resection of the stenotic segment with end to end anastomosis was employed in 6 of the 7 patients, and a transverse colon interpositioning was done in 1 patient. An antireflux procedure was performed in one patient. Histopathological examination of the resected specimen revealed tracheobronchial remnant in 3 patients, fibromuscular thickening in 3 patients, and membranous web in 1 patient. Postoperatively, 2 of the 7 patients had asymptomatic gastroesophageal reflux and 1 patient had postoperative stricture requiring one session of endoscopic balloon dilatation. The mean follow-up period was 42 months (range 18-72 months). At the time of the last follow-up, all 7 patients were able to eat solid food, and none of the children were found to have symptoms suggestive of obstruction or gastroesophageal reflux. There was a statistically significant increase in the weight for age after the operation. Conclusion: Congenital esophageal stenosis is rare and often confused with other causes of esophageal obstruction. Although endoscopic balloon dilatation offers an effective temporary relief, we feel that definitive surgery is curative. Long-term results following definitive surgery have been good, especially with respect to symptoms and weight gain.

Background: Xpert® MTB/RIF is a molecular test for the detection of Mycobacterium tuberculosis and rifampicin resistance. It is considered to be a great advance over smear microscopy and culture. However, there is very little information regarding the performance characteristics of Xpert MTB/RIF in Malawi. Objective: We aimed to evaluate the performance of Xpert MTB/RIF in a Malawian setting. Methods: Stored sputum pellets were processed on Xpert MTB/RIF between June 2012 andMay 2014. Results were compared to mycobacteria growth indicator tube and Löwenstein-Jensen cultures, LED fluorescent microscopy and GenoType® MTBDRplus assay. Rifampicinresistance was confirmed by DNA sequencing. Results: Of the 348 specimens with valid Xpert MTB/RIF results, 129/348 (37%) were smearpositive and 198/348 (57%) were culture-positive. Xpert MTB/RIF demonstrated a sensitivity of 93.8% (95% CI 89.4% – 96.8%) and specificity of 97.4% (95% CI 93.5% – 99.3%), with a positive predictive value of 97.8% (95% CI 94.6% – 99.4%) and a negative predictive value of 92.6% (95% CI 87.4% – 96.1%). Xpert MTB/RIF correctly identified 185/186 (99.5%) rifampicin sensitive and 2/2 (100%) rifampicin-resistant M. tuberculosis strains. Mutations were notdetected by sequencing in one isolate which was rifampicin resistant on Xpert MTB/RIF butsensitive on MTBDRplus. Four non-tuberculous mycobacteria grew from four smear-negativespecimens, namely, M. avium (n = 1) and M. intracellulare (n = 3). No cross-reactivity wasobserved with any of the non-tuberculous mycobacteria when using Xpert MTB/RIF. Conclusion: When fully implemented, Xpert MTB/RIF may have an impact on patient care inMalawi. The increased diagnostic yield of Xpert MTB/RIF over smear microscopy can increaselaboratory-confirmed tuberculosis detection and ensure that treatment is given to appropriateindividuals or groups.

Background: Availability and access to the detection of resistance to anti-tuberculosis drug sremains a significant challenge in Malawi due to limited diagnostic services. The Xpert® MTB/RIF can detect Mycobacterium tuberculosis and resistance to rifampicin in a single, rapid assay. Rifampicin-resistant M. tuberculosis has not been well studied in Malawi. Objectives: We aimed to determine mutations in the rifampicin resistance determining region (RRDR) of the rpoB gene of M. tuberculosis strains which were defined as resistant to rifampicin by the Xpert MTB/RIF assay. Methods: Rifampicin-resistant isolates from 43 adult patients (≥ 18 years) from various districts of Malawi were characterised for mutations in the RRDR (codons 507–533) of the rpoB gene by DNA sequencing. Results: Mutations were found in 37/43 (86%) of the resistant isolates in codons 511, 512, 513,516, 522, 526 and 531. The most common mutations were in codons 526 (38%), 531 (29.7%) and 516 (16.2%). Mutations were not found in 6/43 (14%) of the resistant isolates. No novel rpoB mutations other than those previously described were found among the rifampicin-resistant M. tuberculosis complex strains. Conclusion: This study is the first to characterise rifampicin resistance in Malawi. The chaintermination DNA sequencing employed in this study is a standard method for the determination of nucleotide sequences and can be used to confirm rifampicin resistance obtained using other assays, including the Xpert MTB/RIF. Further molecular cluster analysis, such as spoligotyping and DNA finger printing, is still required to determine transmission dynamics and the epidemiological link of the mutated strains.

Amaç: Tüberküloz (TB) mycobacterium tuberculosis tarafından oluşmakta ve öksürme, hapşırma, gülme ve şarkı söyleme yoluyla yayılmaktadır. Laboratuvar çalışanları normal populasyona göre 3-9 kat daha fazla enfeksiyon riski altındadırlar. Laboratuvar çalışanları için gerekli güvenliği sağlamak için laboratuvar güvenliği öncelikli hedefler arasına alınmalı ve laboratuar koşulları optimize edilmelidir. Blantyre şehri TB primer mikroskobi merkezi laboratuvar çalışanlarında işçi güvenliğini değerlendirmek. Materyal ve Metod: Blantyre şehri TB primer mikroskobi merkezi ekipman uygunluğu, tesisin yerleşimi ve iş pratiği açısından değerlendirildi. WHO/AFRO ISO 15189 un standardize edilmiş kontrol listesi kullanıldı ve gelişmekte olan ülkeler için minimum güvenlik skoru >80 dir. Her merkez bu skor kullanılarak aldığı puanlara göre derecelendirildi. Bulgular: Ndirande, Lirangve ve Chileka mikroskobi merkezlerindeki güvenlik kabinleri fonksiyonel değildi. South Lunzuda güvenlik kabini bulunamadı. Ndirande ve Limbe de hastaların bekleme odası ve laboratuvar kapılarında bulunan havalandırma kanalları özellikle yayma hazırlama sırasında enfeksiyonun bulaş riskinin artmasına neden olmaktadırlar. Bangwe, Chilomoni, Ndirande, Chileka, Güney Lundzu ve Limbe mikroskobi merkezleri balgam taşıma kutularına sahip değillerdi. Sonuç: Blantyre kenti TB mikroskobi merkezlerinde büyük bir güvenlik tehlikesi vardı. Dokuz merkezeden sadece bir tanesi minumum güvenlik şartlarını karşılamıştır ki bu incelenen merkezlerde toplam %89"luk bir başarısızlığı işaret etmektedir. Sonuç olarak Blantyre şehir merkezindeki TB yayma mikroskopi merkezleri laboratuvar koşulları ve güvenlik prosedürleri oldukça zayıftır. Hükümet ve diğer ilgili makamlar bir araya gelerek ülkedeki TB laboratuvarlarının ve benzer sorunlar yaşayan diğer merkezlerin güvenlik sorunlarını ele alarak laboratuvar çalışanlarının güvenliğini sağlamalıdırlar.

Purpose: Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is transmitted through coughing, sneezing, laughing and singing. Laboratory workers’ risk of infection is 3 to 9 times higher than the general public as they handle potentially infectious samples. Laboratory safety should therefore be prioritized and optimized to provide sufficient safety to laboratory workers. The aim of this study was to assess the safety of the laboratory workers in TB primary microscopy centres in Blantyre urban. Material and Methods: TB primary microscopy centers in Blantyre urban were assessed in aspects of equipment availability, facility layout, and work practice, using a standardized WHO/AFRO ISO 15189 checklist for the developing countries which sets the minimum safety score at ≥80%. Each center was graded according to the score it earned upon assessment. Results: The safety hoods were not functional in Ndirande, Lirangwe and Chileka microscopy centres. No safety hood was found in South Lunzu. In Ndirande and Limbe the exhaust ducts face the patients’ waiting area and door to the laboratory, putting them (patients and laboratory technicians) to a greater risk of infection when smear preparation begins. Bangwe, Chilomoni, Ndirande, Chileka, South Lunzu and Limbe microscopy centres had no sputum transportation boxes. Conclusion: There is a great compromised safety in the TB microscopy centers in Blantyre urban. Only one (1) microscopy center out of nine (9) reached the minimum safety requirement representing an 89 percent (%) failure of TB primary microscopy centers to provide safety to laboratory workers. Laboratory conditions and safety procedures in TB primary smear microscopy centres in Blantyre urban are poor. Government and other stake holders should therefore be committed in addressing the safety challenges of TB laboratories in the country (in primary Tb microscopy centres and other referral centres which face the same challenges) to ensure safety to the laboratory workers. [Cukurova Med J 2014; 39(2.000): 262-270]

Amaç: Diyare çocuklarda Malawi"yide içeren gelir düzeyi düşük ülkelerde sık görülen problemlerden biridir. Diyare, Cryptosporidium parvum and Isospora belli gibi pek çok intestinal parazitlere bağlı olarak ortaya çıkar. Her iki enfeksiyon Her iki enfeksiyon immune direnci düşük olgularda yaşamı tehdit eden diyareye neden olabilir. Çalışmanın temel amacı QECH başvuran diyaresi olan çocuklar arasında enfeksiyonların bu enfeksiyonların sıklığını araştırmaktır Ayrıca Cryptosporidium parvum ve Isospora belliile enfekte olan insane immuneksikliği virusu (HIV) seropozitif ve HIV seronegatif diyareli çocuklarda hastalığın sıklığı yanı sıra tanı yöntemlerinin değerlendirilmesi amaçlanmıştır. Yöntem: Gaita örnekleri akut diyare (3 günden az) ve diyare olmayan cocuklar hariç kliniğimize kabul edilen ve yatmakta olan diyareli çocuklardan alınmıştır. Her bir örnekten dört yayma hazırlanmıştır: İki tanesi Ziehl,Neelsen boyaması diğer ikisi ise Auramine-Fenol boyaması ile incelenmiştir. Elde edilen veriller Microsoft Excel programına kaydedilip, Epi-Info programı kullanılarak analiz edilmiştir. Bulgular: Beş yaşın altında diyareli 25 çocuk çalışmaya dahil edildi. Bunlardan 10 tanesi HIV seropozitif, 7 tanesi HIV seronegatif 8 tanesinin ise durumu bilinmiyordu. 4 çocukta (16%) cryptosporidium parvum güven aralıkları %4.5 ve %36.1 arası ve hiçbir çocukta Isospora belli tespit edilemedi %0.0 ve %86.3 güven aralıklarında. Cryptosporidium parvum tespit edilen 4 çocuğun 3 tanesi HIV-seropozitif frekansı %30, 1 tanesi ise HIV-seronegatifti frekansı ise %14.3 idi. HIV durumu bilinmeyen çocukların hiç birinde enfeksiyon tespit edilmedi. Sonuç: Modifiye edilmiş Ziehl-Neelsen tekniği ve Auramine-Fenol boyaması QECH"e gelen gaita örneklerinin C.parvum and I.belli tespitinde kullanılabilir. Her nekadar, I.belli bizim bölgemizde yaygın olsada çocuklarda tespit edilmemiştir. Ayrıca bu organizmaların endemik patojen olarak evrimleşmedikleri ve halen yetişkinlerde fırsatçı endemik patojenler olarak hayatlarını sürdürdükleri tespit edilmiştir. Bu çalışmanın özellikle altın standart olarak kabul edilen metodlarla yağmurlu sezonda tekrarlanması gerektiği düşünülmektedir. Anahtar Kelimeler:

Purpose: Diarrhoea in children is a common problem in low resourced countries including Malawi. It is caused by many intestinal parasites including Cryptosporidium parvum and Isospora belli. Both infections are prevalent in severely immunocompromised individuals and may cause severe life-threatening diarrhoea. The main aim of the study was to assess the prevalence of Cryptosporidium parvum and Isospora belli infections among children presenting with diarrhoea admitted to QECH - paediatrics wards and methods used for diagnosis. Some specific objectives were to determine the prevalence of Cryptosporidium parvum and Isospora belli infections among human immunodeficiency virus (HIV) seropositive and HIV seronegative children with diarrhoea, to evaluate diagnostic methods used at QECH to identify intestinal parasites and to determine diagnostic methods that can be recommended for implementation. Methods: Faecal samples were collected from all children presenting with diarrhoea upon admission or already hospitalised were recruited excluding all children without or with acute diarrhoea (less than three days). Four smears were prepared from each sample: 2 for Ziehl Neelsen staining and the other 2 for Auramine-phenol staining. The data was entered into Microsoft Excel and analysed using Epi-Info. Results: A total of 25 children with diarrhoea under the age of five years; 10 were human immunodeficiency virus -seropositive, 7 were HIV-seronegative and 8 of them their status was unknown. Cryptosporidium parvum was detected in 4 children (16%) at 4.5% and 36.1% confidence intervals and none had Isospora belli at 0.0% and 86.3% confidence intervals. Out of those 4 who had Cryptosporidium parvum, 3 children were HIV-seropositive and 1 child was HIV-seronegative at a frequency of 30% and 14.3% respectively. No infection was seen in children whose HIV-serostatus was unknown. Conclusion: Modified Ziehl Neelsen technique and auramine-phenol staining can be used to examine stool at QECH for C.parvum and I.belli identification. Although I.belli is prevalent in our environment, it has not yet been detected in children and or evolved as an endemic pathogen and so far remains as an opportunistic pathogen in adults only. There is need to repeat the study in rainy season and include gold standard method. [Cukurova Med J 2012; 37(3.000): 133-138]

Active colloids constitute a novel class of materials composed of colloidal-scale particles locally converting chemical energy into motility, mimicking micro-organisms. Evolving far from equilibrium, these systems display structural organizations and dynamical properties distinct from thermalized colloidal assemblies. Harvesting the potential of this new class of systems requires the development of a conceptual framework to describe these intrinsically nonequilibrium systems. We use sedimentation experiments to probe the nonequilibrium equation of state of a bidimensional assembly of active Janus microspheres and conduct computer simulations of a model of self-propelled hard disks. Self-propulsion profoundly affects the equation of state, but these changes can be rationalized using equilibrium concepts. We show that active colloids behave, in the dilute limit, as an ideal gas with an activity-dependent effective temperature. At finite density, increasing the activity is similar to increasing adhesion between equilibrium particles. We quantify this effective adhesion and obtain a unique scaling law relating activity and effective adhesion in both experiments and simulations. Our results provide a new and efficient way to understand the emergence of novel phases of matter in active colloidal suspensions.

Despite remarkable progress in DNA sequencing technologies there remains a trade-off between short-read platforms, having limited ability to sequence homopolymers, repeated motifs or long-range structural variation, and long-read platforms, which tend to have lower accuracy and/or throughput. Moreover, current methods do not allow direct readout of epigenetic modifications from a single read. With the aim of addressing these limitations, we have developed an optical electrowetting sequencing platform that uses step-wise nucleotide triphosphate (dNTP) release, capture and detection in microdroplets from single DNA molecules. Each microdroplet serves as a reaction vessel that identifies an individual dNTP based on a robust fluorescence signal, with the detection chemistry extended to enable detection of 5-methylcytosine. Our platform uses small reagent volumes and inexpensive equipment, paving the way to cost-effective single-molecule DNA sequencing, capable of handling widely varying GC-bias, and demonstrating direct detection of epigenetic modifications., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A new approach to single-molecule DNA sequencing in which dNTPs, released by pyrophosphorolysis from the strand to be sequenced, are captured in microdroplets and read directly could have substantial advantages over current sequence-by-synthesis methods; however, there is no existing method sensitive enough to detect a single nucleotide in a microdroplet. We have developed a method for dNTP detection based on an enzymatic two-stage reaction which produces a robust fluorescent signal that is easy to detect and process. By taking advantage of the inherent specificity of DNA polymerases and ligases, coupled with volume restriction in microdroplets, this method allows us to simultaneously detect the presence of and distinguish between, the four natural dNTPs at the single-molecule level, with negligible cross-talk., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)