Nevin Manimala

Proc Natl Acad Sci U S A. 2021 Jul 6;118(27):e2105873118. doi: 10.1073/pnas.2105873118.

ABSTRACT

Weighing technology was invented around 3000 BCE between Mesopotamia and Egypt and became widely adopted in Western Eurasia within ∼2,000 y. For the first time in history, merchants could rely on an objective frame of reference to quantify economic value. The subsequent emergence of different weight systems goes hand in hand with the formation of a continental market. However, we still do not know how the technological transmission happened and why different weight systems emerged along the way. Here, we show that the diffusion of weighing technology can be explained as the result of merchants’ interaction and the emergence of primary weight systems as the outcome of the random propagation of error constrained by market self-regulation. We found that the statistical errors of early units between Mesopotamia and Europe overlap significantly. Our experiment with replica weights gives error figures that are consistent with the archaeological sample. We used these figures to develop a model simulating the formation of primary weight systems based on the random propagation of error over time from a single original unit. The simulation is consistent with the observed distribution of weight units. We demonstrate that the creation of the earliest weight systems is not consistent with a substantial intervention of political authorities. Our results urge a revaluation of the role of individual commercial initiatives in the formation of the first integrated market in Western Eurasia.

PMID:34183401 | DOI:10.1073/pnas.2105873118

Cancer Discov. 2021 Jun 28:candisc.1647.2020. doi: 10.1158/2159-8290.CD-20-1647. Online ahead of print.

ABSTRACT

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 TGS, 152 RNA-Seq, 67 SNP Arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA and RB1 mutations; MDM4, MYC amplifications; ARID1A deletions. An increase in clonality was observed in driver genes like ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-Enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune permissive cells. High TMB correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could impact treatment strategies in MBC.

PMID:34183353 | DOI:10.1158/2159-8290.CD-20-1647

BMJ Open. 2021 Jun 28;11(6):e052312. doi: 10.1136/bmjopen-2021-052312.

ABSTRACT

INTRODUCTION: Major depressive disorder (MDD) in people with advanced life-limiting illnesses can have significant impact on the quality-of-life of those affected. The management of MDD in the palliative care setting can be challenging as typical antidepressants may not work in time nor be tolerated due to coexisting organ dysfunctions, symptom burden and frailty. Parenteral ketamine was found to exhibit effective and rapid-onset antidepressant effect even against treatment-resistant depression in the psychiatric population. However, there is currently neither feasibility study nor available prospective study available to inform of the safety, tolerability and efficacy of such for MDD in the palliative setting.

METHODS AND ANALYSIS: This is an open-labelled, single arm, phase II pilot feasibility study involving adult patients with advanced life-limiting illnesses and MDD across four palliative care services in Australia. It has an individual dose-titration design (0.1-0.4 mg/kg) with weekly treatments of subcutaneous ketamine infusion over 2 hours. The primary outcome is feasibility. The secondary outcomes are related to the safety, tolerability and antidepressant efficacy of ketamine, participants’ satisfaction in relation to the trial process and the reasons for not completing the study at various stages. The feasibility data will be reported using descriptive statistics. Meanwhile, side effects, tolerability and efficacy data will be analysed using change of assessment scores from baseline.

ETHICS AND DISSEMINATION: Ethics approval was acquired (South Western Sydney Local Health District: HREC/18/LPOOL/466). The results of this study will be submitted for publication in peer-reviewed journals and presented at relevant conferences.

TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry Number: ACTRN12618001586202; Pre-results.

PMID:34183351 | DOI:10.1136/bmjopen-2021-052312

BMJ Open. 2021 Jun 28;11(6):e048178. doi: 10.1136/bmjopen-2020-048178.

ABSTRACT

OBJECTIVES: Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports.

STUDY DESIGN: Methodological review.

METHODS: We searched four journals through PubMed: British Medical Journal Open, Pilot and Feasibility Studies, Trials and Public Library of Science One. Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics.

RESULTS: We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified.

CONCLUSIONS: Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial.

PMID:34183348 | DOI:10.1136/bmjopen-2020-048178

BMJ Open. 2021 Jun 28;11(6):e048030. doi: 10.1136/bmjopen-2020-048030.

ABSTRACT

OBJECTIVES: To examine the association between low birth weight (LBW) and cardiometabolic diseases (CMDs, including heart disease, stroke and type 2 diabetes mellitus) in adulthood, and to explore whether genetic, early-life environmental and healthy lifestyle factors play a role in this association.

DESIGN: A population-based twin study.

SETTING: Twins from the Swedish Twin Registry who were born in 1958 or earlier participated in the Screening Across the Lifespan Twin (SALT) study for a full-scale screening during 1998-2002 and were followed up until 2014.

PARTICIPANTS: 19 779 twin individuals in Sweden with birthweight data available (mean age: 55.45 years).

PRIMARY AND SECONDARY OUTCOME MEASURES: CMDs were assessed based on self-reported medical records, medication use and records from the National Patient Registry. A lifestyle index encompassing smoking status, alcohol consumption, exercise levels and Body Mass Index was derived from the SALT survey and categorised as unfavourable, intermediate or favourable. Data were analysed using generalised estimating equation (GEE) models and conditional logistic regression models.

RESULTS: Of all participants, 3998 (20.2%) had LBW and 5335 (27.0%) had incident CMDs (mean age at onset: 63.64±13.26 years). In GEE models, the OR of any CMD was 1.39 (95% CI 1.27 to 1.52) for LBW. In conditional logistic regression models, the LBW-CMD association became non-significant (OR=1.21, 95% CI 0.94 to 1.56). The difference in ORs from the two models was statistically significant (p<0.001). In the joint effect analysis, the multiadjusted OR of CMDs was 3.47 (95% CI 2.72 to 4.43) for participants with LBW plus an unfavourable lifestyle and 1.25 (95% CI 0.96 to 1.62) for those with LBW plus a favourable lifestyle.

CONCLUSION: LBW is associated with an increased risk of adult CMDs, and genetic and early-life environmental factors may account for this association. However, a favourable lifestyle profile may modify this risk.

PMID:34183347 | DOI:10.1136/bmjopen-2020-048030

BMJ Open. 2021 Jun 28;11(6):e047859. doi: 10.1136/bmjopen-2020-047859.

ABSTRACT

INTRODUCTION: Congenital anomalies (CAs) are a major cause of infant mortality, childhood morbidity and long-term disability. Over 130 000 children born in Europe every year will have a CA. This paper describes the EUROlinkCAT study, which is investigating the health and educational outcomes of children with CAs for the first 10 years of their lives.

METHODS AND ANALYSIS: EUROCAT is a European network of population-based registries for the epidemiological surveillance of CAs. EUROlinkCAT is using the EUROCAT infrastructure to support 22 EUROCAT registries in 14 countries to link their data on births with CAs to mortality, hospital discharge, prescription and educational databases. Once linked, each registry transforms their case data into a common data model (CDM) format and they are then supplied with common STATA syntax scripts to analyse their data. The resulting aggregate tables and analysis results are submitted to a central results repository (CRR) and meta-analyses are performed to summarise the results across all registries. The CRR currently contains data on 155 594 children with a CA followed up to age 10 from a population of 6 million births from 1995 to 2014.

ETHICS: The CA registries have the required ethics permissions for routine surveillance and transmission of anonymised data to the EUROCAT central database. Each registry is responsible for applying for and obtaining additional ethics and other permissions required for their participation in EUROlinkCAT.

DISSEMINATION: The CDM and associated documentation, including linkage and standardisation procedures, will be available post-EUROlinkCAT thus facilitating future local, national and European-level analyses to improve healthcare. Recommendations to improve the accuracy of routinely collected data will be made.Findings will provide evidence to inform parents, health professionals, public health authorities and national treatment guidelines to optimise diagnosis, prevention and treatment for these children with a view to reducing health inequalities in Europe.

PMID:34183346 | DOI:10.1136/bmjopen-2020-047859

BMJ Open. 2021 Jun 28;11(6):e047709. doi: 10.1136/bmjopen-2020-047709.

ABSTRACT

INTRODUCTION: Standards for Reporting of Diagnostic Accuracy Study (STARD) was developed to improve the completeness and transparency of reporting in studies investigating diagnostic test accuracy. However, its current form, STARD 2015 does not address the issues and challenges raised by artificial intelligence (AI)-centred interventions. As such, we propose an AI-specific version of the STARD checklist (STARD-AI), which focuses on the reporting of AI diagnostic test accuracy studies. This paper describes the methods that will be used to develop STARD-AI.

METHODS AND ANALYSIS: The development of the STARD-AI checklist can be distilled into six stages. (1) A project organisation phase has been undertaken, during which a Project Team and a Steering Committee were established; (2) An item generation process has been completed following a literature review, a patient and public involvement and engagement exercise and an online scoping survey of international experts; (3) A three-round modified Delphi consensus methodology is underway, which will culminate in a teleconference consensus meeting of experts; (4) Thereafter, the Project Team will draft the initial STARD-AI checklist and the accompanying documents; (5) A piloting phase among expert users will be undertaken to identify items which are either unclear or missing. This process, consisting of surveys and semistructured interviews, will contribute towards the explanation and elaboration document and (6) On finalisation of the manuscripts, the group’s efforts turn towards an organised dissemination and implementation strategy to maximise end-user adoption.

ETHICS AND DISSEMINATION: Ethical approval has been granted by the Joint Research Compliance Office at Imperial College London (reference number: 19IC5679). A dissemination strategy will be aimed towards five groups of stakeholders: (1) academia, (2) policy, (3) guidelines and regulation, (4) industry and (5) public and non-specific stakeholders. We anticipate that dissemination will take place in Q3 of 2021.

PMID:34183345 | DOI:10.1136/bmjopen-2020-047709

BMJ Open. 2021 Jun 28;11(6):e047543. doi: 10.1136/bmjopen-2020-047543.

ABSTRACT

INTRODUCTION: Ulcerative colitis (UC) is a type of inflammatory bowel disease, and 62% of patients with UC felt that it is difficult for them to live a normal life. Furthermore, some researches have shown that about 15% of patients with UC undergo at least one extreme clinical course in their lifetime, and 10%-30% of patients with UC oblige colectomy. Although many investigations have demonstrated that HBO₂ has a beneficial impact on UC treatment, a systematic review and meta-analysis are unavailable. Therefore, a meta-analysis is essential to assess the efficacy and safety of HBO₂ in treating UC.

METHODS AND ANALYSIS: A systematic search plan will be performed in the following seven databases with a restriction of time from inception to September 2020 to filter the eligible studies: PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database (VIP) and Chinese Biomedical Database WanFang. Other related resources will be also searched. Two independent reviewers will choose eligible researches and extract data. The risk of bias will be evaluated based on Cochrane Collaboration’s Risk of Bias tool and Newcastle-Ottawa Scale. Eventually, a systematic review and meta-analysis will be performed via the Review Manager V.5.3 statistical software and STATA V.14.0 software.

ETHICS AND DISSEMINATION: This study will not involve the individual patient and any ethical problems since its outcomes are based on published data. Therefore, no ethical review and approval are required. We plan to publish the study in a peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42020210244.

PMID:34183344 | DOI:10.1136/bmjopen-2020-047543

Rom J Intern Med. 2021 Jun 28. doi: 10.2478/rjim-2021-0025. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the ability of severity scoring systems to predict 30-day mortality in patients with severe community-acquired pneumonia.

METHODS: The study included 98 patients aged ≥18 years with community acquired pneumonia hospitalized at the Intensive Care Unit of the University Clinic for Infectious Diseases in Skopje, Republic of North Macedonia, during a 3-year period. We recorded demographic, clinical and common biochemical parameters. Five severity scores were calculated at admission: CURB 65 (Confusion, Urea, Respiratory Rate, Blood pressure, Age ≥65 years), SCAP (Severe Community Acquired Pneumonia score), SAPS II (Simplified Acute Physiology Score), SOFA (Sequential Organ Failure Assessment Score) and MPM (Mortality Prediction Model). Primary outcome variable was 30-day in-hospital mortality.

RESULTS: The mean age of the patients was 59.08 ± 15.76 years, predominantly males (68%). The overall 30-day mortality was 52%. Charlson Comorbidity index was increased in non-survivors (3.72 ± 2.33) and was associated with the outcome. All severity indexes had higher values in patients who died, that showed statistical significance between the analysed groups. The areas under curve (AUC) values of the five scores for 30-day mortality were 0.670, 0.732, 0,726, 0.785 and 0.777, respectively.

CONCLUSION: Widely used severity scores accurately detected patients with pneumonia that had increased risk for poor outcome, but none of them individually demonstrated any advantage over the others.

PMID:34182618 | DOI:10.2478/rjim-2021-0025

Br J Clin Pharmacol. 2021 Jun 28. doi: 10.1111/bcp.14956. Online ahead of print.

ABSTRACT

AIM: This three-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K γδ) inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease.

METHODS: Healthy men, and women of non-childbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1 mg to 7.7 mg AZD8154 in six cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in three cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12.

RESULTS: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using non-linear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%.

CONCLUSION: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.

PMID:34182611 | DOI:10.1111/bcp.14956