Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer has increased markedly over the past decade. Although established for older adults, there are limited data on socioeconomic and racial disparities in screening, treatment, and outcomes in this distinct group. METHODS: Adults with primary colorectal cancer diagnosed at age <50 were identified from the Surveillance, Epidemiology, and End Results database. The exposure of interest was neighborhood socioeconomic status based on the Yost Index, a census-tract level composite score of neighborhood economic health. Univariate analysis was performed with χ2 analyses. Logistic regression models were created to evaluate the association of neighborhood socioeconomic status (Yost Index quintile) with metastasis at presentation and surgical intervention. Kaplan-Meier and Cox proportional hazards models were created. RESULTS: In total, 45,660 early-onset colorectal cancer patients were identified; 16.8% (7,679) were in the lowest quintile of neighborhood socioeconomic status. Patients with the lowest neighborhood socioeconomic status were 1.13 times (95% confidence interval 1.06-1.21) more likely to present with metastases and had lower survival (hazard ratio 1.45, 95% confidence interval 1.37-1.53) compared to those with the highest neighborhood socioeconomic status. Non-Hispanic Black patients were more likely to present with metastatic disease (odds ratio 1.11, 95% confidence interval 1.05-1.19), less likely to undergo surgery for localized or regional disease (odds ratio 0.48, 95% confidence interval 0.43-0.53), and had lower survival (hazard ratio 1.21, 95% confidence interval 1.15-1.27) than non-Hispanic White patients. CONCLUSION: Socioeconomic and racial disparities in early-onset colorectal cancer span diagnosis, treatment, and survival. As the disease burden of early-age onset colorectal cancer increases, interventions to boost early diagnosis and access to surgery are necessary to improve survival among minorities and patients with low neighborhood socioeconomic status.

Outcome evaluation of technical strategies on reduction of patient waiting time in the outpatient department at Kilimanjaro Christian Medical Centre-Northern Tanzania.

BACKGROUND: The Tanzania healthcare system is beset by prolonged waiting time in its hospitals particularly in the outpatient departments (OPD). Previous studies conducted at Kilimanjaro Christian Medical Centre (KCMC) revealed that patients typically waited an average of six hours before receiving the services at the OPD making KCMC have the longest waiting time of all the Zonal and National Referral Hospitals. KCMC implemented various interventions from 2016 to 2021 to reduce the waiting time. This study evaluates the outcome of the interventions on waiting time at the OPD. METHODS: This is an analytical cross-sectional mixed method using an explanatory sequential design. The study enrolled 412 patients who completed a structured questionnaire and in-depth interviews (IDI) were conducted among 24 participants (i.e., 12 healthcare providers and 12 patients) from 3rd to 14th July, 2023. Also, a documentary review was conducted to review benchmarks with regards to waiting time. Quantitative data analysis included descriptive statistics, bivariable and multivariable. All statistical tests were conducted at 5% significance level. Thematic analysis was used to analyse qualitative data. RESULTS: The findings suggest that post-intervention of technical strategies, the overall median OPD waiting time significantly decreased to 3 h 30 min IQR (2.51-4.08), marking a 45% reduction from the previous six-hour wait. Substantial improvements were observed in the waiting time for registration (9 min), payment (10 min), triage (14 min for insured patients), and pharmacy (4 min). Among the implemented strategies, electronic medical records emerged as a significant predictor to reduced waiting time (AOR = 2.08, 95% CI, 1.10-3.94, p-value = 0.025). IDI findings suggested a positive shift in patients' perceptions of OPD waiting time. Problems identified that still need addressing include, ineffective implementation of block appointment and extension of clinic days was linked to issues of ownership, organizational culture, insufficient training, and ineffective follow-up. The shared use of central modern diagnostic equipment between inpatient and outpatient services at the radiology department resulted in delays. CONCLUSION: The established technical strategies have been effective in reducing waiting time, although further action is needed to attain the global standard of 30 min to 2 h OPD waiting time.

Multidimensional and Longitudinal Impact of a Genetic Diagnosis for Critically Ill Infants.

Background and Objectives: Many genetic conditions present in the neonatal intensive care unit (NICU), where a diagnostic evaluation is pursued. However, understanding of the impact of a genetic diagnosis on clinical outcomes and health-related quality of life for these infants remains incomplete. We therefore evaluated parent-reported outcomes complemented by clinical outcomes measures over one year for a cohort of infants in the NICU undergoing genetic evaluation. Methods: Prospective cohort study evaluating outcomes after genetics consultation in a level IV NICU via parent-report and electronic medical records (EMR) review. Eligible infants were genetically undiagnosed at enrollment. Parent surveys were administered at baseline and three, six-, and 12-months following enrollment and assessed genetic testing utility as well as parent-reported infant health-related quality of life using the Infant Toddler Quality of Life Questionnaire. Results: 110 infant-parent pairs were enrolled. Infants had a median age at enrollment of 15 days (interquartile range 8-37.75). At baseline, 74% (81/110) of parents endorsed high importance of finding a genetic diagnosis, but perceived importance significantly decreased over time. Over the study period, 38 infants received a molecular diagnosis per parent report, though this was discordant with EMR review. Identification of a diagnosis did not significantly impact health-related quality of life across most domains, which was lower overall than population norms. Conclusions: A genetic diagnosis is highly desired by parents in the NICU, though waning interest over time for undiagnosed families may reflect parental emotional adaptation and acceptance. Additional supports are needed to improve perceived quality of life.

International differences in the selection and outcome of minimally invasive and open distal pancreatectomy: A transatlantic analysis.

BACKGROUND: The efficacy and safety of minimally invasive distal pancreatectomy have been confirmed by randomized trials, but current patient selection and outcome of minimally invasive distal pancreatectomy in large international cohorts is unknown. This study aimed to compare the use and outcome of minimally invasive distal pancreatectomy in North America, the Netherlands, Germany, and Sweden. METHODS: All patients in the 4 Global Audits on Pancreatic Surgery Group (GAPASURG) registries who underwent minimally invasive distal pancreatectomy or open distal pancreatectomy during 2014-2020 were included. RESULTS: Overall, 20,158 distal pancreatectomies were included, of which 7,316 (36%) were minimally invasive distal pancreatectomies. Use of minimally invasive distal pancreatectomy varied from 29% to 54% among registries, of which 13% to 35% were performed robotically. Both the use of minimally invasive distal pancreatectomy and robotic surgery were the highest in the Netherlands. Patients undergoing minimally invasive distal pancreatectomy tended to have a younger age (Germany and Sweden), female sex (North America, Germany), higher body mass index (North America, the Netherlands, Germany), lower comorbidity classification (North America, Germany, Sweden), lower performance status (Germany), and lower rate of pancreatic adenocarcinoma (all). The minimally invasive distal pancreatectomy group had fewer vascular resections (all) and lower rates of severe complications and mortality (North America, Germany). In the multivariable regression analysis, country was associated with severe complications but not with 30-day mortality. Minimally invasive distal pancreatectomy was associated with a lower risk of 30-day mortality compared with open distal pancreatectomy (odds ratio 1.633, 95% CI 1.159-2.300, P = .005). CONCLUSIONS: Considerable disparities were seen in the use of minimally invasive distal pancreatectomy among 4 transatlantic registries of pancreatic surgery. Overall, minimally invasive distal pancreatectomy was associated with decreased mortality as compared with open distal pancreatectomy. Differences in patient selection among countries could imply that countries are in different stages of the learning curve.

Respiratory Severity Score and Oxygen Saturation Index during the First 2 Hours of Life as Predictors for Noninvasive Respiratory Support Failure in Respiratory Distress Syndrome.

OBJECTIVE: Noninvasive respiratory support (NRS) failure is common in preterm infants with respiratory distress syndrome (RDS). We evaluated the utility of respiratory severity score (RSS) and oxygen saturation index (OSI) during the first 2 hours of life (HOL) as predictors for NRS failure in moderate preterm infants. STUDY DESIGN: We conducted a retrospective cohort study of infants born between 280/7 and 336/7 weeks with RDS. Univariate and multivariable logistic regression analyses were used to assess whether the RSS and OSI summary measures were associated with NRS failure. RESULTS: A total of 282 infants were included in the study. Median gestational age and birth weights were 32 weeks and 1.7 kg, respectively. Fifty-eight infants (21%) developed NRS failure at the median age of 10.5 hours. RSS and OSI summary measures in the first 2 HOL were associated with NRS failure within 72 HOL. CONCLUSION: RSS and OSI during the first 2 HOL can predict NRS failure. Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined in large cohort studies. KEY POINTS: · Nearly one in five moderate preterm infants on NRS at 2 hours of life developed NRS failure.. · RSS and OSI during the first 2 HOL can predict NRS failure.. · Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined..

Blood Pressure Pattern and Prevalence of Hypertension amongst Apparently Healthy Primary School Pupils in Abuja, Nigeria.

OBJECTIVES: The objective of this study was to determine the blood pressure (BP) pattern and prevalence of hypertension amongst apparently healthy primary school pupils in Abuja. METHODOLOGY: This was a descriptive, cross-sectional study carried out on apparently healthy primary school children aged 6-12 years. BP was measured using a standard mercury sphygmomanometer according to standard guidelines. Data were analysed using SPSS version 17.0. Pearson's correlation coefficient (r) and analysis of variance were used to determine the relationship between BP and various variables where applicable. P = 0.05 was considered statistically significant. RESULTS: Out of 1011 pupils recruited for the study, 457 (42.2%) were male. The mean systolic and diastolic BP (SBP and DBP) increased significantly with age from 94.5 mmHg to 101.0 mmHg and from 61.5 mmHg to 65.3 mmHg from 6 to 12 years for SBP and DBP, respectively (P < 0.05). The prevalence of high BP was 9.1%. Age was the only predictor of SBP (ß = -0.629, 95% confidence interval [CI] -1.115, -0.142), while age, height and body mass index (BMI) were the predictors of DBP (ß = -0.686, 95% CI of -1.152, -0.221; ß = 0.490, 95% CI of 0.172, 0.809; ß = 1.753, 95% CI of 0.374, 3.160) for age, height and BMI, respectively, at P < 0.05. CONCLUSION: The predictors of SBP and DBP as shown in this study support the recommendations by various reports for taking body size into consideration in developing reference values for various populations. Age and body size are important determinants of BP in children. Its measurement should be encouraged in schools.

Non-invasive prenatal testing of beta-hemoglobinopathies using next generation sequencing, in-silico sequence size selection, and haplotyping.

AIM: To develop a non-invasive prenatal test for beta-hemoglobinopathies based on analyzing maternal plasma by using next generation sequencing. METHODS: We applied next generation sequencing (NGS) of maternal plasma to the non-invasive prenatal testing (NIPT) of autosomal recessive diseases, sickle cell disease and beta-thalassemia. Using the Illumina MiSeq, we sequenced plasma libraries obtained via a Twist Bioscience probe capture panel covering 4 Kb of chromosome 11, including the beta-globin (HBB) gene and >450 genomic single-nucleotide polymorphisms (SNPs) used to estimate the fetal fraction (FF). The FF is estimated by counting paternally transmitted allelic sequence reads present in the plasma but absent in the mother. We inferred fetal beta-globin genotypes by comparing the observed mutation (Mut) and reference (Ref) read ratios to those expected for the three possible fetal genotypes (Mut/Mut; Mut/Ref; Ref/Ref), based on the FF. RESULTS: We bioinformatically enriched the FF by excluding reads over a specified length via in-silico size selection (ISS), favoring the shorter fetal reads, which increased fetal genotype prediction accuracy. Finally, we determined the parental HBB haplotypes, which allowed us to use the read ratios observed at linked SNPs to help predict the fetal genotype at the mutation site(s). We determined HBB haplotypes via Oxford Nanopore MinION sequencing of a 2.2 kb amplicon and aligned these sequences using Soft Genetics' NextGENe LR software. CONCLUSION: The combined use of ISS and HBB haplotypes enabled us to correctly predict fetal genotypes in cases where the prediction based on variant read ratios alone was incorrect.

Sex differences in the association of pretransfusion haemoglobin and cognition in preterm infants.

OBJECTIVES: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function. DESIGN: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017. MAIN OUTCOME MEASURES: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates. RESULTS: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81). CONCLUSIONS: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age.

Evaluation of Ilex guayusa and Piper marginatum Extract Cytotoxicity on Human Dental Pulp Mesenchymal Stem Cells.

BACKGROUND: Amelogenesis imperfecta is a hereditary disorder affecting dental enamel. Among its phenotypes, hypocalcified AI is characterized by mineral deficiency, leading to tissue wear and, consequently, dental sensitivity. Excessive fluoride intake (through drinking water, fluoride supplements, toothpaste, or by ingesting products such as pesticides or insecticides) can lead to a condition known as dental fluorosis, which manifests as stains and teeth discoloration affecting their structure. Our recent studies have shown that extracts from Colombian native plants, Ilex guayusa and Piper marginatum, deposit mineral ions such as phosphate and orthophosphate into the dental enamel structure; however, it is unknown whether these extracts produce toxic effects on the dental pulp. OBJECTIVE: To assess cytotoxicity effects on human dental pulp stem cells (hDPSCs) exposed to extracts isolated from I. guayusa and P. marginatum and, hence, their safety for clinical use. METHODS: Raman spectroscopy, fluorescence microscopy, and flow cytometry techniques were employed. For Raman spectroscopy, hDPSCs were seeded onto nanobiochips designed to provide surface-enhanced Raman spectroscopy (SERS effect), which enhances their Raman signal by several orders of magnitude. After eight days in culture, I. guayusa and P. marginatum extracts at different concentrations (10, 50, and 100 ppm) were added. Raman measurements were performed at 0, 12, and 24 h following extract application. Fluorescence microscopy was conducted using an OLIMPUS fv1000 microscope, a live-dead assay was performed using a kit employing a BD FACS Canto TM II flow cytometer, and data analysis was determined using a FlowJo program. RESULTS: The Raman spectroscopy results showed spectra consistent with viable cells. These findings were corroborated using fluorescence microscopy and flow cytometry techniques, confirming high cellular viability. CONCLUSIONS: The analyzed extracts exhibited low cytotoxicity, suggesting that they could be safely applied on enamel for remineralization purposes. The use of nanobiochips for SERS effect improved the cell viability assessment.

Polychlorinated biphenyls and incident coronary heart disease-related outcomes in Great Lakes fish consumers.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) has been linked to risk factors for cardiovascular disease such as increased inflammation, accelerated atherosclerosis, diabetes, and sex hormone dysregulation. Furthermore, there is increasing evidence suggesting associations between internal dose of PCBs and cardiovascular outcomes. OBJECTIVES: The purpose of this study is to investigate longitudinal associations of PCBs with coronary heart disease (CHD)-related outcomes in a cohort of Great Lakes sport fish consumers. METHODS: The Great Lakes Sport Fish Consumer cohort was established in the early 1990's. Eight hundred nineteen participants were followed from 1993 to 2017. Serum PCBs were measured in 1994/1995 (baseline), in 2001, and in 2004, while health history questionnaires were administered in 1996, 2003, 2010, and 2017. Cox models were used to prospectively investigate associations of total PCBs and PCB groupings, based on aryl hydrocarbon receptor activity, with incident self-reported physician diagnosis of coronary heart disease (CHD), myocardial infarction (MI), and angina pectoris. RESULTS: A 2-fold increase in phenobarbital-type PCBs was associated with a 72% increase in likelihood of self-reported incident diagnosis of CHD (HR=1.72, 95% CI: 1.06-2.81; p=0.0294). Similar results were observed for total PCBs (HR=1.68, 95% CI: 1.05-2.69; p=0.0306) and mixed methacholine/phenobarbital type (mixed-type) PCBs (HR=1.60, 95% CI: 1.02-2.52; p=0.0427), but not methacholine-type PCBs. PCBs were not strongly associated with risk of MI or angina. CONCLUSIONS: This study presents evidence that exposure to PCBs increases the risk of developing coronary heart disease. Given the large number of risk factors and causal pathways for CHD, future research is required to better understand biological mechanisms of action for PCBs on CHD.

Effects of Surgeon-Preferred Staff and Staff Turnover on Operating Time and Complication Rates in Reverse and Anatomic Total Shoulder Arthroplasty.

BACKGROUND: This study focuses on investigating the risk factors of increased operating room time and patient complication rates after total shoulder arthroplasty cases (both reverse and anatomic). We hypothesize that the use of surgeon-preferred staff will improve operating room efficiency and reduce complication rates while increased staff turnover will decrease efficiency and increase complications. METHODS: This is a single-center, retrospective study focused on determining the effects of staffing on operating room time and efficiency in total shoulder arthroplasty. The study included patients who underwent total shoulder arthroplasty by a single fellowship-trained orthopaedic surgeon from 2018 to 2023. RESULTS: Four hundred twenty-three patients were included in the study from August 2018 to April 2023, 264 of which were reverse total shoulder arthroplasty (rTSA) and 159 were anatomic total shoulder arthroplasty (aTSA). In both rTSA and aTSA, the presence of surgeon-preferred staff markedly decreased operating room time. In rTSA, staff turnover increased risk of 90-day complications. CONCLUSION: Because the presence of surgeon-preferred staff affects operating room time and efficiency, orthopaedic surgeons should train multiple surgical teams so that efficiency is not affected by the loss of personnel during a case. To reduce 90-day complication rates in rTSA, staff breaks and turnover should be minimized as much as possible because this has a direct effect on patient outcomes. Effort from hospital administration and management should be put toward reducing turnover to improve patient outcomes.

A study protocol to characterise pathophysiological and molecular markers of rheumatic heart disease and degenerative aortic stenosis using multiparametric cardiovascular imaging and multiomics techniques.

INTRODUCTION: Rheumatic heart disease (RHD), degenerative aortic stenosis (AS), and congenital valve diseases are prevalent in sub-Saharan Africa. Many knowledge gaps remain in understanding disease mechanisms, stratifying phenotypes, and prognostication. Therefore, we aimed to characterise patients through clinical profiling, imaging, histology, and molecular biomarkers to improve our understanding of the pathophysiology, diagnosis, and prognosis of RHD and AS. METHODS: In this cross-sectional, case-controlled study, we plan to recruit RHD and AS patients and compare them to matched controls. Living participants will undergo clinical assessment, echocardiography, CMR and blood sampling for circulatory biomarker analyses. Tissue samples will be obtained from patients undergoing valve replacement, while healthy tissues will be obtained from cadavers. Immunohistology, proteomics, metabolomics, and transcriptome analyses will be used to analyse circulatory- and tissue-specific biomarkers. Univariate and multivariate statistical analyses will be used for hypothesis testing and identification of important biomarkers. In summary, this study aims to delineate the pathophysiology of RHD and degenerative AS using multiparametric CMR imaging. In addition to discover novel biomarkers and explore the pathomechanisms associated with RHD and AS through high-throughput profiling of the tissue and blood proteome and metabolome and provide a proof of concept of the suitability of using cadaveric tissues as controls for cardiovascular disease studies.

Extent of Resection and Long-Term Outcomes for Appendiceal Adenocarcinoma: a SEER Database Analysis of Mucinous and non-Mucinous Histologies.

BACKGROUND: Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. PATIENTS AND METHODS: Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000-2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan-Meier estimates and examined using Cox proportional hazards modeling. RESULTS: Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81-1.22]. CONCLUSIONS: Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required.

Operative trends for pancreatic and hepatic malignancies during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic disrupted routine health care, including many elective and non-cancer operations in the United States. Most hepato-pancreato-biliary malignancy patients require outpatient imaging, tissue sampling, and staging, and many undergo neoadjuvant therapy before operative intervention. The aims of this study were to evaluate the effect of the COVID-19 pandemic on hepato-pancreato-biliary oncologic operations and to determine whether trends in neoadjuvant therapy were altered by the pandemic. METHODS: Adult patients in the United States undergoing oncologic operations for pancreatic, primary and secondary hepatic malignancies, with or without neoadjuvant therapy, were extracted from the Vizient Clinical Data Base. Control chart analysis was used to plot trends over time and to determine whether changes were statistically significant. Wilcoxon rank-sum tests also compared monthly operative volume from pre-pandemic (12 month) and pandemic (28 months) periods. RESULTS: A total of 36,553 patients were identified over 40 months. Mean monthly pancreatic oncologic operations were unaffected by the pandemic (P = .257). Operations for pancreatic oncologic operations with prior neoadjuvant therapy increased throughout the pandemic (P = .002). Oncologic operations for primary and secondary hepatic malignancies were significantly reduced for 4 and 2 months, respectively, at the beginning of the pandemic but returned to their pre-pandemic baseline within 4 months (P = .169 and P = .598). CONCLUSION: Pancreatic operation volumes for cancer did not change, but pancreatic operations after neoadjuvant therapy continued to increase during the pandemic. Operations for hepatic malignancy were transiently disrupted but quickly normalized. These observations suggest that surgery for hepato-pancreato-biliary malignancies was prioritized during the pandemic.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Patients' subjective well-being: Determinants and its usage as a metric of healthcare service quality.

It is commonly suggested that patients' subjective well-being (SWB) can be affected by pre-treatment conditions and treatment experiences, and hence SWB can be used to measure and improve healthcare quality. With data collected in a hospital in the UK (N = 446), we investigated the determinants of patients' SWB and evaluated its use in healthcare research. Our findings showed strong relationships between pre-treatment conditions and patients' SWB: anxiety and depression negatively predicted SWB across all three domains, mobility positively predicted the life satisfaction and happiness domains, while the ability to self care and pain and discomfort also predicted SWB in some domains. In contrast, patients' satisfaction with the treatment only played minor roles in determining SWB, much less so the characteristics of their nurses. The general lack of associations between treatment experiences and patient's SWB highlighted the challenges of using SWB to measure healthcare quality and inform policy making.

Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability in Drosophila melanogaster.

Pioneer factors are critical for gene regulation and development because they bind chromatin and make DNA more accessible for binding by other transcription factors. The pioneer factor Grainy head (Grh) is present across metazoans and has been shown to retain a role in epithelium development in fruit flies, nematodes, and mice despite extensive divergence in both amino acid sequence and length. Here, we investigate the evolution of Grh function by comparing the effects of the fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) Grh orthologs on chromatin accessibility, gene expression, embryonic development, and viability in transgenic D. melanogaster. We found that the Caenorhabditis elegans ortholog rescued cuticle development but not full embryonic viability in Drosophila melanogaster grh null mutants. At the molecular level, the C. elegans ortholog only partially rescued chromatin accessibility and gene expression. Divergence in the disordered N-terminus of the Grh protein contributes to these differences in embryonic viability and molecular phenotypes. These data show how pioneer factors can diverge in sequence and function at the molecular level while retaining conserved developmental functions at the organismal level.