A library of logic models to explain how interventions to reduce diagnostic error work

OBJECTIVES: We aimed to create a library of logic models for interventions to reduce diagnostic error. This library can be used by those developing, implementing, or evaluating an intervention to improve patient care, to understand what needs to happen, and in what order, if the intervention is to be effective. METHODS: To create the library, we modified an existing method for generating logic models. The following five ordered activities to include in each model were defined: preintervention; implementation of the intervention; postimplementation, but before the immediate outcome can occur; the immediate outcome (usually behavior change); and postimmediate outcome, but before a reduction in diagnostic errors can occur. We also included reasons for lack of progress through the model. Relevant information was extracted about existing evaluations of interventions to reduce diagnostic error, identified by updating a previous systematic review. RESULTS: Data were synthesized to create logic models for four types of intervention, addressing five causes of diagnostic error in seven stages in the diagnostic pathway. In total, 46 interventions from 43 studies were included and 24 different logic models were generated. CONCLUSIONS: We used a novel approach to create a freely available library of logic models. The models highlight the importance of attending to what needs to occur before and after intervention delivery if the intervention is to be effective. Our work provides a useful starting point for intervention developers, helps evaluators identify intermediate outcomes, and provides a method to enable others to generate libraries for interventions targeting other errors

Genetics and the Archaeology of Ancient Israel

This paper is a call for DNA testing on ancient skeletal materials from the southern Levant to begin to database genetic information of the inhabitants of this crossroads region. Archaeologists and biblical historians view the earliest presence in the region of a group that called itself Israel in the Iron I period, traditionally dated to ca. 1200-1000 BCE. These were in villages in the varied hill countries of the region, contemporary with urban settlements in the coastal plains, inland valleys, and central Hill Country attributed to varied indigenous groups collectively called Canaanite. The remnants of Egyptian imperial presence in the region lasted until around 1150 BCE, postdating the arrival of an immigrant group from the Aegean called the Philistines ca. 1175 BCE. The period that follows the Iron I in the southern Levant is marked by the development of territorial states throughout the region, ca. 1000-800 BCE. These patrimonial kingdoms, including the United Kingdom of Israel and the divided kingdoms of northern Israel and Judah, coalesced varied peoples under central leadership and newly founded administrative and religious bureaucracies. Ancient DNA testing will give us a further refined understanding of the individuals who peopled the region of the southern Levant throughout its varied archaeological and historic periods, and put forward scientific data that will support, refute, or nuance our socio-historic reconstruction of ancient group identities. These social identities may or may not map onto genetic data, and without sampling of ancient DNA we may never know. A database of ancient DNA will also allow for comparisons with modern DNA samples collected throughout the greater region and the Mediterranean littoral, giving a more robust understanding of the long historical trajectories of regional human genetics and the genetics of varied ancestral groups of today’s Jewish populations and other cultural groups in the modern Middle East and Mediterranean

Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor

Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors

Community evaluation of glycoproteomics informatics solutions reveals high-performance search strategies for serum glycopeptide analysis

Glycoproteomics is a powerful yet analytically challenging research tool. Software packages aiding the interpretation of complex glycopeptide tandem mass spectra have appeared, but their relative performance remains untested. Conducted through the HUPO Human Glycoproteomics Initiative, this community study, comprising both developers and users of glycoproteomics software, evaluates solutions for system-wide glycopeptide analysis. The same mass spectrometrybased glycoproteomics datasets from human serum were shared with participants and the relative team performance for N- and O-glycopeptide data analysis was comprehensively established by orthogonal performance tests. Although the results were variable, several high-performance glycoproteomics informatics strategies were identified. Deep analysis of the data revealed key performance-associated search parameters and led to recommendations for improved 'high-coverage' and 'high-accuracy' glycoproteomics search solutions. This study concludes that diverse software packages for comprehensive glycopeptide data analysis exist, points to several high-performance search strategies and specifies key variables that will guide future software developments and assist informatics decision-making in glycoproteomics

F-Fluorodeoxyglucose (FDG)-PET features of focal nodular hyperplasia (FNH) of the liver

PET imaging. The lesions were found incidentally. The 18F-FDG PET of Vienna, Vienna, Austria imaging was performed with a dedicated PET tomograph after intravenous injection of 300-370 MBq 18F-FDG. The 18F-FDG accumulation in the lesions was (semi)quantified by calculating the standardized uptake value (SUV) and SUV has been corrected for the lean body mass (LBM). Eight patients with liver metastases spread from melanoma (nΩ2) and colorectal carcinoma (nΩ6) served as controls. The size of the FNH lesions and of the control group ranged from 2.0 to 8.5 cm (mean 4.83 cm∫2.37) and from 1.5 to 6 cm (mean 3.28∫1.52), respectively. Results: While in malignant liver lesions the accumulation of 18F-FDG was significantly increased, all FNH lesions showed normal or even decreased accumulation of 18F-FDG. In FNH lesions, SUV ranged between 1.5 and 2.6 (mean 2.12∫0.38), whereas all liver metastases showed an increased SUV rang- PET is a new imaging method that has been successfully applied to image malignant tumors. While a large number of studies has been published in the last years about the usefulness of 18F-FDG PET in a variety of malignant diseases, the glucose metabolism of FNH in vivo has not bee

Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity

Background: The aim of this study was to investigate the possibility that a decreased mitochondrial ATP synthesis causes muscular and mental fatigue and plays a role in the pathophysiology of the chronic fatigue syndrome (CFS/ME).Methods: Female patients (n = 15) and controls (n = 15) performed a cardiopulmonary exercise test (CPET) by cycling at a continuously increased work rate till maximal exertion. The CPET was repeated 24 h later. Before the tests, blood was taken for the isolation of peripheral blood mononuclear cells (PBMC), which were processed in a special way to preserve their oxidative phosphorylation, which was tested later in the presence of ADP and phosphate in permeabilized cells with glutamate, malate and malonate plus or minus the complex I inhibitor rotenone, and succinate with rotenone plus or minus the complex II inhibitor malonate in order to measure the ATP production via Complex I and II, respectively. Plasma CK was determined as a surrogate measure of a decreased oxidative phosphorylation in muscle, since the previous finding that in a group of patients with external ophthalmoplegia the oxygen consumption by isolated muscle mitochondria correlated negatively with plasma creatine kinase, 24 h after exercise.Results: At both exercise tests the patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls and this worsened in the second test. This implies an increase of lactate, the product of anaerobic glycolysis, and a decrease of the mitochondrial ATP production in the patients. In the past this was also found in patients with defects in the mitochondrial oxidative phosphorylation. However the oxidative phosphorylation in PBMC was similar in CFS/ME patients and controls. The plasma creatine kinase levels before and 24 h after exercise were low in patients and controls, suggesting normality of the muscular mitochondrial oxidative phosphorylation.Conclusion: The decrease in mitochondrial ATP synthesis in the CFS/ME patients is not caused by a defect in the enzyme complexes catalyzing oxidative phosphorylation, but in another factor

A randomised controlled trial of compression therapies for the treatment of venous leg ulcers (VenUS 6) : study protocol for a pragmatic, multicentre, parallel group, three arm randomised controlled trial

Background Venous leg ulcer(s), are common, recurring, open wounds on the lower leg, resulting from diseased or damaged leg veins impairing blood flow. Wound healing is the primary treatment aim for venous leg ulceration, alongside management of pain, wound exudate and infection. Full (high) compression therapy delivering 40mmHg of pressure at the ankle is the recommended first line treatment for venous leg ulcers. There are several different forms of compression therapy available including wraps, two-layer hosiery, and two-layer or four-layer bandages. There is good evidence for the clinical and cost effectiveness of four-layer bandage and two-layer hosiery but more limited evidence for other treatments (two-layer bandage and compression wraps). Robust evidence is required to compare clinical and cost effectiveness of these and to investigate which is the best compression treatment for reducing time to healing of venous leg ulcers whilst offering value for money. VenUS 6 will therefore investigate the clinical and cost effectiveness of evidence-based compression, two-layer bandage and compression wraps for time to healing of venous leg ulcers. Methods VenUS 6 is a pragmatic, multi-centre, three arm, parallel group, randomised controlled trial. Adult patients with a venous leg ulcer will be randomised to receive 1) compression wraps, 2) two-layer bandage or 3) evidence-based compression (two-layer hosiery or four-layer bandage). Participants will followed up for between 4 and 12 months. The primary outcome will be time to healing (full epithelial cover in absence of a scab) in days since randomisation. Secondary outcomes will include key clinical events (e.g., healing of the reference leg; ulcer recurrence; ulcer/skin deterioration, amputation, admission/discharge, surgery to close/remove incompetent superficial veins, infection, or death), treatment changes, adherence and ease of use, ulcer related pain, health-related quality of life and resource use. Discussion VenUS 6 will provide robust evidence on the clinical and cost-effectiveness of the different forms of compression therapies for venous leg ulceration. VenUS 6 opened to recruitment in January 2021 and is currently recruiting across 30 participating centres. Clinical Trial Registry: ISRCTN 67321719 (https://doi.org/10.1186/ISRCTN67321719). Prospectively Registered: 14.09.202