Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short‐term outcomes

Aim: Significant recent changes in management of locally advanced rectal cancer include preoperative staging, use of extended neoadjuvant therapies, and minimally invasive surgery (MIS). This study was aimed at characterizing those changes and associated short‐term outcomes. Method: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ locally advanced rectal cancer ≤15 cm from the anal verge who were evaluated at a comprehensive cancer center in 2009–2015. Results: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009‐2010, 2011, 2012, 2013, and 2014‐2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009‐2010 to 98% in 2014‐2015 (p < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (p < 0.001); and increased use of MIS, from 33% to 70% (p < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; p < 0.001), as did the rates of grade III‐V complications (from 13% to 7%; p < 0.05), surgical site infections (from 24% to 8%; p < 0.001), anastomotic leak (from 11% to 3%; p < 0.05), and positive circumferential resection margin (from 9% to 4%; p < 0.05). TNM downstaging increased from 62% to 74% (p = 0.002). Conclusion: Shifts toward MRI‐based staging, total neoadjuvant therapy, and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

India's National Action Plan on Antimicrobial Resistance: a critical perspective

Antimicrobial resistance (AMR) is widely recognised as a global health threat, which is projected to account for more deaths than cancer by 2050. The Government of India has formulated a National Action Plan to tackle AMR (NAP-AMR), largely modelled on the World Health Organization's Global Action Plan on AMR. While the NAP-AMR successfully mirrors the Global Action Plan and lays out ambitious goals, we find that the lack of financial allocation across states, poor enforcement and inadequate multisectoral co-ordination have hampered progress. A broader focus on improving infrastructure for water and sanitation, linking the issue of AMR to existing vertical health programmes for human immunodeficiency virus (HIV) and tuberculosis (TB), prioritising infection prevention and control, strengthening the frontline healthcare workforce in rural and peri-urban settings to reduce reliance on antibiotics, leveraging pointof-care testing and mobile app-based health interventions for diagnosis and surveillance, and adopting a socioecological approach to health and development would help to create an enabling environment for concrete action on AMR in India. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/

Birth size, risk factors across life and cognition in late life: protocol of prospective longitudinal follow-up of the MYNAH cohort

Introduction: For late-life neurocognitive disorders, as for other late-life chronic diseases, much recent interest has focused on the possible relevance of Developmental Origins of Health and Disease (DOHaD). Programming by undernutrition in utero, followed by overnutrition in adult life may lead to an increased risk, possibly mediated through cardiovascular and metabolic pathways. This study will specifically examine, if lower birth weight is associated with poorer cognitive functioning in late life in a south Indian population.Methods and analysis: From 1934 onwards, the birth weight, length and head circumference of all babies born in the CSI Holdsworth Memorial Hospital, Mysore, India, were recorded in obstetric notes. Approximately 800 men and women from the Mysore Birth Records Cohort aged above 55 years, and a reliable informant for each, will be asked to participate in a single cross-sectional baseline assessment for cognitive function, mental health and cardiometabolic disorders. Participants will be assessed for hypertension, type-2 diabetes and coronary heart disease, nutritional status, health behaviours and lifestyles, family living arrangements, economic status, social support and social networks. Additional investigations include blood tests (for diabetes, insulin resistance, dyslipidaemia, anaemia, vitamin B12 and folate deficiency, hyperhomocysteinemia, renal impairment, thyroid disease and Apolipoprotein E genotype), anthropometry, ECG, blood pressure, spirometry and body composition (bioimpedance). We will develop an analysis plan, first using traditional univariate and multivariable analytical paradigms with independent, dependent and mediating/confounding/interacting variables to test the main hypotheses.Ethics and dissemination: This study has been approved by the research ethics committee of CSI Holdsworth Memorial Hospital. The findings will be disseminated locally and at international meetings, and will be published in open access peer reviewed journals

Preoperative portal vein recanalization–transjugular intrahepatic portosystemic shunt for chronic obliterative portal vein thrombosis: Outcomes following liver transplantation

High-grade portal vein thrombosis (PVT) is often considered to be a technically challenging scenario for liver transplantation (LT) and in some centers a relative contraindication. This study compares patients with chronic obliterative PVT who underwent portal vein recanalization–transjugular intrahepatic portosystemic shunt (PVR-TIPS) and subsequent LT to those with partial nonocclusive PVT who underwent LT without an intervention. This institutional review board-approved study analyzed 49 patients with cirrhosis with PVT from 2000 to 2020 at our institution. Patients were divided into two groups, those that received PVR-TIPS due to anticipated surgical challenges from chronic obliterative PVT and those who did not because of partial PVT. Demographic data and long-term outcomes were compared. A total of 35 patients received PVR-TIPS while 14 did not, with all receiving LT. Patients with PVR-TIPS had a higher Yerdel score and frequency of cavernoma than those that did not. PVR-TIPS was effective in decreasing portosystemic gradient (16 down to 8 mm HG; p 90% of cases. However, veno–veno bypass was used significantly more in patients who did not receive PVR-TIPS. Additionally, patients without PVR-TIPS required significantly more intraoperative red blood cells. Overall survival was not different between groups. PVR-TIPS demonstrated efficacy in resolving PVT and allowed for end-to-end portal vein anastomoses. PVR-TIPS is a viable treatment option for chronic obliterative PVT with or without cavernoma that simplifies the surgical aspects of LT. © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]