Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Spatially disaggregated population estimates in the absence of national population and housing census data.

Population numbers at local levels are fundamental data for many applications, including the delivery and planning of services, election preparation, and response to disasters. In resource-poor settings, recent and reliable demographic data at subnational scales can often be lacking. National population and housing census data can be outdated, inaccurate, or missing key groups or areas, while registry data are generally lacking or incomplete. Moreover, at local scales accurate boundary data are often limited, and high rates of migration and urban growth make existing data quickly outdated. Here we review past and ongoing work aimed at producing spatially disaggregated local-scale population estimates, and discuss how new technologies are now enabling robust and cost-effective solutions. Recent advances in the availability of detailed satellite imagery, geopositioning tools for field surveys, statistical methods, and computational power are enabling the development and application of approaches that can estimate population distributions at fine spatial scales across entire countries in the absence of census data. We outline the potential of such approaches as well as their limitations, emphasizing the political and operational hurdles for acceptance and sustainable implementation of new approaches, and the continued importance of traditional sources of national statistical data.

Association of State Medicaid Expansion Status With Low Birth Weight and Preterm Birth.

Importance: Low birth weight and preterm birth are associated with adverse consequences including increased risk of infant mortality and chronic health conditions. Black infants are more likely than white infants to be born prematurely, which has been associated with disparities in infant mortality and other chronic conditions. Objective: To evaluate whether Medicaid expansion was associated with changes in rates of low birth weight and preterm birth outcomes, both overall and by race/ethnicity. Design, Setting, and Participants: Using US population-based data from the National Center for Health Statistics Birth Data Files (2011-2016), difference-in-differences (DID) and difference-in-difference-in-differences (DDD) models were estimated using multivariable linear probability regressions to compare birth outcomes among infants in Medicaid expansion states relative to non-Medicaid expansion states and changes in relative disparities among racial/ethnic minorities for singleton live births to women aged 19 years and older. Exposures: State Medicaid expansion status and racial/ethnic category. Main Outcomes and Measures: Preterm birth (<37 weeks' gestation), very preterm birth (<32 weeks' gestation), low birth weight (<2500 g), and very low birth weight (<1500 g). Results: The final sample of 15 631 174 births (white infants: 8 244 924, black infants: 2 201 658, and Hispanic infants: 3 944 665) came from the District of Columbia and 18 states that expanded Medicaid (n = 8 530 751) and 17 states that did not (n = 7 100 423). In the DID analyses, there were no significant changes in preterm birth in expansion relative to nonexpansion states (preexpansion to postexpansion period, 6.80% to 6.67% [difference: -0.12] vs 7.86% to 7.78% [difference: -0.08]; adjusted DID: 0.00 percentage points [95% CI, -0.14 to 0.15], P = .98), very preterm birth (0.87% to 0.83% [difference: -0.04] vs 1.02% to 1.03% [difference: 0.01]; adjusted DID: -0.02 percentage points [95% CI, -0.05 to 0.02], P = .37), low birth weight (5.41% to 5.36% [difference: -0.05] vs 6.06% to 6.18% [difference: 0.11]; adjusted DID: -0.08 percentage points [95% CI, -0.20 to 0.04], P = .20), or very low birth weight (0.76% to 0.72% [difference: -0.03] vs 0.88% to 0.90% [difference: 0.02]; adjusted DID: -0.03 percentage points [95% CI, -0.06 to 0.01], P = .14). Disparities for black infants relative to white infants in Medicaid expansion states compared with nonexpansion states declined for all 4 outcomes, indicated by a negative DDD coefficient for preterm birth (-0.43 percentage points [95% CI, -0.84 to -0.02], P = .05), very preterm birth (-0.14 percentage points [95% CI, -0.26 to -0.02], P = .03), low birth weight (-0.53 percentage points [95% CI, -0.96 to -0.10], P = .02), and very low birth weight (-0.13 percentage points [95% CI, -0.25 to -0.01], P = .04). There were no changes in relative disparities for Hispanic infants. Conclusions and Relevance: Based on data from 2011-2016, state Medicaid expansion was not significantly associated with differences in rates of low birth weight or preterm birth outcomes overall, although there were significant improvements in relative disparities for black infants compared with white infants in states that expanded Medicaid vs those that did not.

Are community health workers more effective in identifying persons in need of home and community-based long-term services than standard-passive approaches.

Consumers prefer home and community-based long-term care (LTC) services (HCBS) but lack information on those services. We examined the use of community health workers (CHWs) to find and help Medicaid beneficiaries with unmet LTC needs access HCBS compared to standard HCBS outreach approaches. We found that CHWs were very effective at finding persons with greater needs and were better able to help them access a greater range of HCBS services. We also found that five times fewer HCBS beneficiaries helped by CHWs had to use nursing home care services than those not helped by the CHWs despite the fact that their health status was poorer than those not helped by the CHWs. Our study provides evidence of the effectiveness of CHWs for HCBS service awareness and navigation.

Financial Performance of Hospitals in the Mississippi Delta Region Under the Hospital Readmissions Reduction Program and Hospital Value-based Purchasing Program.

BACKGROUND: Previous studies showed that the Hospital Readmissions Reduction Program (HRRP) and the Hospital Value-based Purchasing Program (HVBP) disproportionately penalized hospitals caring for the poor. The Mississippi Delta Region (Delta Region) is among the most socioeconomically disadvantaged areas in the United States. The financial performance of hospitals in the Delta Region under both HRRP and HVBP remains unclear. OBJECTIVE: To compare the differences in financial performance under both HRRP and HVBP between hospitals in the Delta Region (Delta hospitals) and others in the nation (non-Delta hospitals). RESEARCH DESIGN: We used a 7-year panel dataset and applied difference-in-difference models to examine operating and total margin between Delta and non-Delta hospitals in 3 time periods: preperiod (2008-2010); postperiod 1 (2011-2012); and postperiod 2 (2013-2014). RESULTS: The Delta hospitals had a 0.89% and 4.24% reduction in operating margin in postperiods 1 and 2, respectively, whereas the non-Delta hospitals had 1.13% and 1% increases in operating margin in postperiods 1 and 2, respectively. The disparity in total margins also widened as Delta hospitals had a 1.98% increase in postperiod 1, but a 0.30% reduction in postperiod 2, whereas non-Delta hospitals had 1.27% and 2.28% increases in postperiods 1 and 2, respectively. CONCLUSIONS: The gap in financial performance between Delta and non-Delta hospitals widened following the implementation of HRRP and HVBP. Policy makers should modify these 2 programs to ensure that resources are not moved from the communities that need them most.

FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases.

BACKGROUND: Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM. MATERIAL AND METHODS: An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care. RESULTS: 78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all >20months from initial treatment. CONCLUSIONS: In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

Outcomes of intensity-modulated radiotherapy as primary treatment for oropharyngeal squamous cell carcinoma - a European singleinstitution analysis.

OBJECTIVES: To analyse survival and toxicity outcomes in patients treated with primary intensity-modulated radiotherapy (IMRT) for oropharyngeal squamous cell carcinoma (OPSCC) in the era of routine human papilloma virus (HPV) testing. DESIGN: Single-institution case series. SETTING: Tertiary Head and Neck Cancer Unit. PARTICIPANTS: A total of 186 patients received IMRT (+/- chemotherapy) for radical primary treatment of OPSCC between March 2010 and December 2013. HPV status was available for 88% of cases. Median radiation dose was 65 Gy in 30 daily fractions. 90% of stage III/IV patients received concurrent chemotherapy or cetuximab. MAIN OUTCOME MEASURES: Overall, disease-free and disease-specific survival; rates of late xerostomia and dysphagia. RESULTS: A total of 177 patients completed treatment (Stage I/II: 23; Stage III/IV: 154), with median follow-up of 26 months. Estimated 3-year overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) rates were 77.2% (70.5-83.9), 72.3% (65.4-79.2) and 80.2% (74.1-86.3). Estimated 3-year OS, DFS and DSS for HPV-positive patients were 90.9% (85.2-96.6), 87.9% (81.4-94.4) and 91.8% (86.3-97.3). A previously identified risk stratification method was validated, showing improved OS for low-risk over high-risk patients (HR 0.09, P < 0.001). The 2-year feeding tube retention rate was 6%, and 2-year grade ≥2 xerostomia rate was 38% (23% if mean contralateral parotid dose <24 Gy). CONCLUSIONS: Outcomes with IMRT are favourable, particularly in the HPV-positive patient group. This data further supports the use of a previously described prognostication model that can be used to select patients for escalation/de-escalation clinical trials.

Childhood Respiratory Morbidity after Late Preterm and Early Term Delivery: a Study of Medicaid Patients in South Carolina.

BACKGROUND: There is a growing body of research documenting an increased risk of neonatal morbidity for late preterm infants (LPI, 34(0/7) weeks to 36(6/7) weeks) and early term infants (ETI, 37(0/7) weeks to 38(6/7) weeks) compared with term infants (TI, 39(0/7) to 41(6/7) ); however, there has been little research on outcomes beyond the first year of life. In this study, we examined respiratory outcomes of LPI and ETI in early childhood. METHODS: South Carolina Medicaid claims data for maternal delivery and infant birth hospitalisations were linked to vital records data for the years 2000 through 2003. Medicaid claims for all infants were then followed until their fifth birthday or until a break in their eligibility. Infants born between 34(0/7) and 41(6/7) weeks were eligible. Infants with congenital anomaly, birthweight below 500 g or above 6000 g, and multiple births were excluded. We fit Cox proportional hazard models from which adjusted hazard ratio (HR) and 95% confidence interval (CI) were derived. RESULTS: A total of 3476 LPI, 12 398 ETI, and 25 975 term infants were included. Both LPI and ETI were associated with an increased risk for asthma (LPI: HR 1.24, 95% CI 1.10, 1.40; ETI: HR 1.12, 95% CI 1.06, 1.19), and bronchitis (LPI: HR 1.15, 95% CI 1.00, 1.34; ETI: HR 1.13, 95% CI 1.05, 1.2) at 3 to 5 years of age. CONCLUSIONS: Late preterm infants and early term infants are at increased risk for asthma and bronchitis.

Controlling turbulence in present and future stellarators.

Turbulence is widely expected to limit the confinement and, thus, the overall performance of modern neoclassically optimized stellarators. We employ novel petaflop-scale gyrokinetic simulations to predict the distribution of turbulence fluctuations and the related transport scaling on entire stellarator magnetic surfaces and reveal striking differences to tokamaks. Using a stochastic global-search optimization method, we derive the first turbulence-optimized stellarator configuration stemming from an existing quasiomnigenous design.

Birth statistics of high birth weight infants (macrosomia) in Arkansas.

The incidence of macrosomia in Arkansas was relatively unchanged from 2004 to 2010 with the incidence being 7.7%. Some risk factors identified through the analysis of hospital discharge data include male fetus, gestational age, maternal weight gain during pregnancy, and pregestational and gestational diabetes.

Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.

Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant multisystem disorder caused by the expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK protein kinase gene on chromosome 19q13.3 (refs 1-3). Although the DM mutation was identified more than five years ago, the pathogenic mechanisms underlying this most prevalent form of hereditary adult neuromuscular disease remain elusive. Previous work from our laboratory demonstrated that a DNase l-hypersensitive site located adjacent to the repeats on the wild-type allele is eliminated by repeat expansion, indicating that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Analysis of DMAHP expression in the cells of DM patients with loss of the hypersensitive site revealed a two- to fourfold reduction in steady-state DMAHP transcript levels relative to wild-type controls. Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wild-type allele. Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis.

Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A.

Charcot-Marie-Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein-22 (pmp-22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP-22 gene to the duplicated region. These observations further implicate PMP-22 as a candidate gene for CMT1A, and suggest that over-expression of this gene may be one mechanism that produces the CMT1A phenotype.

Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA.

Trinucleotide repeat expansions have been shown to cause a number of neurodegenerative diseases. A hallmark of most of these diseases is the presence of anticipation, a decrease in the age at onset in consecutive generations due to the tendency of the unstable trinucleotide repeat to lengthen when passed from one generation to the next. The involvement of trinucleotide repeat expansions in a number of other diseases--including familial spastic paraplegia, schizophrenia, bipolar affective disorder and spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples. The involvement of trinucleotide expansions in these diseases, however, can be conclusively confirmed only by the isolation of the expansions present in these populations and detailed analysis to assess each expansion as a possible pathogenic mutation. We describe a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of individual clones containing expanded trinucleotide repeats (RAPID cloning). We have used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.

Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene.

P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22-q23, in the region of the locus for Charcot-Marie-Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (Z = 5.5, theta = 0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Vulvodynia in Arkansas: a survey of Arkansas gynecologists' practice experience and management of vulvar pain.

The objective of this survey was to determine the level of experience OB/GYN (Obstetrics & Gynecology) physicians in the state of Arkansas have in seeing and managing patients with vulvar pain, commonly known as vulvodynia. The 8 question, anonymous survey was mailed to Arkansas OB/GYN physicians. The survey assessed the experience of the providers, the age range of their patients, and whether or not they treat and/or refer. Thirty of 182 surveys were returned for a rate of 16.4%. The survey revealed that physicians are moderately comfortable treating vulvodynia within their practice and refer mostly for treatment failure.

Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis.

BACKGROUND: Sabizabulin is an oral, novel microtubule disruptor that has dual antiviral and anti-inflammatory activities in preclinical models. METHODS: A randomized, multicenter placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 who were at high risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomly assigned (2:1) to 9 mg of oral sabizabulin or placebo daily (up to 21 days). The primary end point was all-cause mortality up to day 60. Key secondary end points were days in the intensive care unit (ICU), days on mechanical ventilation, and days in the hospital. RESULTS: A total of 204 patients were randomly assigned to treatment: 134 to sabizabulin and 70 to placebo. Baseline characteristics were similar. Sabizabulin superiority was demonstrated by a planned interim analysis for the first 150 randomized patients. Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo. For the key secondary end points, sabizabulin treatment resulted in a 43% relative reduction in ICU days (P=0.0013), a 49% relative reduction in days on mechanical ventilation (P=0.0013), and a 26% relative reduction in days in the hospital (P=0.0277) versus placebo. Adverse and serious adverse events were lower in the sabizabulin group compared with the placebo group. CONCLUSIONS: Sabizabulin treatment resulted in a 24.9% absolute reduction in deaths compared with placebo in hospitalized patients with moderate to severe Covid-19 at high risk for ARDS and death, with a lower incidence of adverse and serious adverse events compared with placebo. (Funded by Veru, Inc.; ClinicalTrials.gov number, NCT04842747.)

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Associations of family-centered care with health care outcomes for children with special health care needs.

The objective of this study is to examine the association of family-centered care (FCC) with specific health care service outcomes for children with special health care needs (CSHCN). The study is a secondary analysis of the 2005-2006 National Survey of Children with Special Health Care Needs. Receipt of FCC was determined by five questions regarding how well health care providers addressed family concerns in the prior 12 months. We measured family burden by reports of delayed health care, unmet need, financial costs, and time devoted to care; health status, by stability of health care needs; and emergency department and outpatient service use. All statistical analyses used propensity score-based matching models to address selection bias. FCC was reported by 65.6% of respondents (N = 38,915). FCC was associated with less delayed health care (AOR: 0.56; 95% CI: 0.48, 0.66), fewer unmet service needs (AOR: 0.53; 95% CI: 0.47, 0.60), reduced odds of ≥1 h/week coordinating care (AOR: 0.83; 95% CI: 0.74, 0.93) and reductions in out of pocket costs (AOR: 0.88; 95% CI: 0.80, 0.96). FCC was associated with more stable health care needs (AOR: 1.11; 95% CI: 1.01, 1.21), reduced odds of emergency room visits (AOR: 0.90; 95% CI: 0.82, 0.99) and increased odds of doctor visits (AOR: 1.25; 95% CI: 1.14, 1.37). Our study demonstrates associations of positive health and family outcomes with FCC. Realizing the health care delivery benefits of FCC may require additional encounters to build key elements of trust and partnership.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.