Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

How to set up a mobile X-ray unit in the community - Implementation initiatives for patient-centred care.

BACKGROUND: Mobile X-ray unit have previously been widely used within hospitals in general, predominately for imaging patients admitted to intensive care units or for patients who cannot tolerate a visit to the radiology department. It is now possible to have an X-ray examination outside the hospital in nursing homes or to bring the service to frail, vulnerable or disabled patients. A visit to the hospital can be a frightening experience for vulnerable patients living with dementia or other neurological disorder. It can potentially have a long-term impact on the patient's recovery or behaviour. This technical note aimed to provide insight into the planning and running of a mobile X-ray unit in a Danish setting. METHODS: This technical note draws on the lived experiences of radiographers operating and managing a mobile X-ray service, sharing experiences with the implementation process and the challenges and successes of a mobile X-ray unit. RESULTS AND KEY FINDINGS: Successes include that frail patient, especially those with dementia, benefit from mobile X-ray examinations, as they can remain in familiar surroundings during an X-ray procedure. In general, patients experienced an increased quality of life and less need for sedation medication due to anxiety. Also, working within a mobile X-ray unit is meaningful work for radiographers. Challenges included increased physicality of work, the funding required for the mobile unit, planning a communication strategy to the referring general practitioners, and permission from authorities to perform mobile examinations. CONCLUSION: We have successfully implemented a mobile radiography unit that provides a better service for vulnerable patients through learning from successes and challenges. IMPLICATIONS FOR PRACTICE: The mobile radiography setup can benefit vulnerable patients and provide meaningful work for the radiographers. However, transportation of mobile radiography equipment outside the hospital includes many considerations and challenges.

Magnetic hydrogel particles improve nanopore sequencing of SARS-CoV-2 and other respiratory viruses.

Presented here is a magnetic hydrogel particle enabled workflow for capturing and concentrating SARS-CoV-2 from diagnostic remnant swab samples that significantly improves sequencing results using the Oxford Nanopore Technologies MinION sequencing platform. Our approach utilizes a novel affinity-based magnetic hydrogel particle, circumventing low input sample volumes and allowing for both rapid manual and automated high throughput workflows that are compatible with Nanopore sequencing. This approach enhances standard RNA extraction protocols, providing up to 40 × improvements in viral mapped reads, and improves sequencing coverage by 20-80% from lower titer diagnostic remnant samples. Furthermore, we demonstrate that this approach works for contrived influenza virus and respiratory syncytial virus samples, suggesting that it can be used to identify and improve sequencing results of multiple viruses in VTM samples. These methods can be performed manually or on a KingFisher automation platform.

Human leukocyte antigen system associations in Malassezia-related skin diseases.

BACKGROUND: The human leukocyte antigen system (HLA) is divided into two classes involved in antigen presentation: class I presenting intracellular antigens and class II presenting extracellular antigens. While susceptibility to infections is correlated with the HLA system, data on associations between HLA genotypes and Malassezia-related skin diseases (MRSD) are lacking. Thus, the objective of this study was to investigate associations between HLA alleles and MRSD. MATERIALS AND METHODS: Participants in The Danish Blood Donor Study (2010-2018) provided questionnaire data on life style, anthropometric measures, and registry data on filled prescriptions. Genotyping was done using Illumina Infinium Global Screening Array, and HLA alleles were imputed using the HIBAG algorithm. Cases and controls were defined using filled prescriptions on topical ketoconazole 2% as a proxy of MRSD. Logistic regressions assessed associations between HLA alleles and MRSD adjusted for confounders and Bonferroni corrected for multiple tests. RESULTS: A total of 9455 participants were considered MRSD cases and 24,144 participants as controls. We identified four risk alleles B*57:01, OR 1.19 (95% CI: 1.09-1.31), C*01:02, OR 1.19 (95% CI: 1.08-1.32), C*06:02, OR 1.14 (95% CI: 1.08-1.22), and DRB1*01:01, OR 1.10 (95% CI: 1.04-1.17), and two protective alleles, DQB1*02:01, OR 0.89 (95% CI: 0.85-0.94), and DRB1*03:01, OR 0.89 (95% CI: 0.85-0.94). CONCLUSION: Five novel associations between HLA alleles and MRSD were identified in our cohort, and one previous association was confirmed. Future studies should assess the correlation between Malassezia antigens and antigen-binding properties of the associated HLA alleles.

Degradation of polymer banknotes through handling, and effect on fingermark visualisation.

The surface structure of mint (as-issued) and handled polymer five pounds sterling banknotes was studied by atomic force microscopy and laser scanning confocal microscopy. A total of 1856 fingermarks on mint and handled banknotes from four different issuing banks (Bank of England, Bank of Scotland, Royal Bank of Scotland and Clydesdale Bank) were visualised with Vacuum Metal Deposition (VMD), Cyanoacrylate Fuming (CAF) and, on Clydesdale Bank notes, magnetic fluorescent powder. VMD was significantly more effective in developing fingermarks on handled banknotes, across all the banks studied, although effectiveness varied with issuing bank. For example, on handled Bank of England notes 45% of marks showed ridge detail with VMD development and 28% with CAF; for Bank of Scotland handled notes success rates were 17% with VMD and 1% with CAF. Microscopy of degraded banknotes showed the loss of intaglio printing and the formation of a cracked surface structure in the handled notes. These features can lead to the trapping of powder, or contaminants, increasing quantity of development agent in fingermark background between the ridges, decreasing contrast and decreasing performance of powder-based fingermark development techniques. These same features can restrict the migration of components of the fingermark, preventing fingermarks degrading through spread of material and thus reducing potential formation of empty prints, so that VMD development is not adversely affected.

[Partial or full component exchange in hip revision? : The relevance of off-label use and mix & match]. / Partieller oder vollständiger Wechsel in der Hüftrevisionsendoprothetik? : Bedeutung von Off-Label-Anwendung und Mix & Match.

Off-label use is frequently practiced in hip revision arthroplasty, as there may be indications for the application of implants for purposes outside the one the manufacturers intended (i.e. large bone and soft tissue defects, obesity). Patients may also benefit from selective application of mix & match in hip revision, when the exchange of one component only is necessary and the invasiveness of surgery can be reduced. Currently, there are no formal guidelines for these situations. Therefore, within a recent EFORT initiative, evidence- and consensus-based recommendations have been developed for the safe application of off-label use and mix & match in revision hip and knee arthroplasty.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).

In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe.

Exploring radiographers' experience with mobile X-ray of patients in their homes.

INTRODUCTION: To offer citizens with frailty or dementia living in nursing homes or other institutions a less stressful and anxious X-ray examination, a Danish hospital offers to perform the examination in the citizen's residence. This has changed the working procedure for the radiographers performing the examination. The aim of this study was to explore if the radiographers self-perceived competencies have changed whilst working in the mobile X-ray unit and if so, how these competencies are utilised within the department-based medical imaging team. METHOD: This study had a qualitative design following a hermeneutic approach. Individual semi structured interviews included nine radiographers, four radiographers working in the mobile X-ray unit and five radiographers working exclusively in the medical imaging team. RESULTS: Radiographers who worked in the mobile X-ray unit did acquire new competencies such as better communication and creative positioning skills. All nine participants recognised the advantage of sharing experiences and competencies with colleagues, and recommended a formal forum to do so. They sought opportunities for the use of the mobile X-ray unit to be more widespread within their own region, and within the profession. CONCLUSION: This study indicates that radiographers working with mobile X-ray unit gained new competencies in communication and positioning, but without spread of new knowledge to colleagues in the medical imaging team. IMPLICATION FOR PRACTICE: The use of home-based mobile X-ray is a new way to provide health care services and gain new competencies for the radiographers to focus on patient centred care.

Kinematic gait characteristics of straight line walk in clinically sound dairy cows.

The aim of this study is to describe the kinematic gait characteristics of straight line walk in clinically sound dairy cows using body mounted Inertial Measurement Units (IMUs) at multiple anatomical locations. The temporal parameters used are speed and non-speed normalized stance duration, bipedal and tripedal support durations, maximal protraction and retraction angles of the distal limbs and vertical displacement curves of the upper body. Gait analysis was performed by letting 17 dairy cows walk in a straight line at their own chosen pace while equipped with IMU sensors on tubera sacrale, left and right tuber coxae (LTC and RTC), back, withers, head, neck and all four lower limbs. Data intervals with stride by stride regularity were selected based on video data. For temporal parameters, the median was calculated and 95% confidence intervals (CI) were estimated based on linear mixed model (LMM) analysis, while for limb and vertical displacement curves, the median and most typical curves were calculated. The temporal parameters and distal limb angles showed consistent results with low variance and LMM analysis showed non-overlapping CI for all temporal parameters. The distal limb angle curves showed a larger and steeper retraction angle range for the distal front limbs compared with the hind limbs. The vertical displacement curves of the sacrum, withers, LTC and RTC showed a consistent sinusoidal pattern while the head, back and collar curves were less consistent and showed more variation between and within cows. This kinematic description might allow to objectively differentiate between normal and lame gait in the future and determine the best anatomical location for sensor attachment for lameness detection purposes.

Spatial filtering of a six-wavelength DBR-RW laser in a MOPA system.

Lasing emission at multiple wavelengths can be used in different sensing applications and in optical telecommunication. In this work, we report a six-wavelength distributed Bragg reflector (DBR) laser, emitting around 976 nm with six ridge waveguide (RW) structures, where individual DBR gratings are combined into a common front section. These six elements are individually addressable and biased one at a time for individual wavelength selection. The drawback of this RW combination is observable in spatial characteristics where higher-order modes are supported. We addressed this issue by using a master oscillator power amplifier (MOPA) system that combines the six-wavelength MO laser with a tapered PA. Through this configuration, the PA acts as a spatial filter of the MO beam, providing a nearly diffraction-limited beam with M1/e22<1.5. In addition, the described MOPA system provides output powers around 4 W with spectral single-mode operation, with up to 9.36 nm of thermal wavelength tuning. We believe that the described MOPA configuration can be used in different applications, such as absorption spectroscopy.

Exploring the patient perspectives of mobile X-ray in nursing homes - A qualitative explorative pilot study.

INTRODUCTION: For patients with dementia, behaviour and reactions to stimuli can change and an X-ray examination in the hospital can have be a frightening experience. The aim of this study was to identify the experiences and perspectives of patients with dementia and their caregivers on receiving a mobile x-ray examination in nursing homes. METHODS: This study was designed as a qualitative study using patient observation and semi structured interviews, with a phenomenology-hermeneutic approach. In total, 23 patients were observed during X-ray examinations in nursing homes, and six semi structured interviews were conducted with the caregivers who participated in the examination. RESULTS: The observations and interviews indicated that a known environment, a recognizable framework and calmness were central for a patient with dementia. The patients appeared calm and relaxed during the examination in their usual environment (nursing homes) where there are less stimuli and impressions based of the observations. CONCLUSION: Mobile X-ray examinations for patients with dementia living in nursing homes had a positive impact on patients' reactions towards the X-ray examination. The examinations were performed in the patients' usual and safe environments, where impressions and stimuli were less disturbing for patients with dementia. IMPLICATIONS FOR PRACTICE: The mobile x-ray unit can be of benefit for patients suffering from dementia and result in less impact. The patients living in nursing homes have the opportunity to be examined in their familiar environment, because of the mobile x-ray unit.

Hydrogel particles improve detection of SARS-CoV-2 RNA from multiple sample types.

Here we present a rapid and versatile method for capturing and concentrating SARS-CoV-2 from contrived transport medium and saliva samples using affinity-capture magnetic hydrogel particles. We demonstrate that the method concentrates virus from 1 mL samples prior to RNA extraction, substantially improving detection of virus using real-time RT-PCR across a range of viral titers (100-1,000,000 viral copies/mL) and enabling detection of virus using the 2019 nCoV CDC EUA Kit down to 100 viral copies/mL. This method is compatible with commercially available nucleic acid extraction kits (i.e., from Qiagen) and a simple heat and detergent method that extracts viral RNA directly off the particle, allowing a sample processing time of 10 min. We furthermore tested our method in transport medium diagnostic remnant samples that previously had been tested for SARS-CoV-2, showing that our method not only correctly identified all positive samples but also substantially improved detection of the virus in low viral load samples. The average improvement in cycle threshold value across all viral titers tested was 3.1. Finally, we illustrate that our method could potentially be used to enable pooled testing, as we observed considerable improvement in the detection of SARS-CoV-2 RNA from sample volumes of up to 10 mL.

Diagnostic benefits of adding EspC, EspF and Rv2348-B to the QuantiFERON Gold In-tube antigen combination.

Interferon (IFN)-γ release assays (IGRAs) are used to diagnose latent tuberculosis (TB) infection (LTBI). To improve the accuracy of these tests, different approaches, such as alternative cytokine detection and using different antigens, are considered. Following this purpose, this study aims to evaluate the addition of EspC, EspF and Rv2348-B to those present in the QuantiFERON-TB Gold In-Tube (QFN-G-IT). We included 115 subjects: 74 active TB patients, 17 LTBI individuals and 24 healthy controls. Whole blood samples were collected in QFN-G-IT and in-house tubes containing different combinations of EspC, EspF and Rv2348-B, together with ESAT-6, CFP-10, and TB7.7. After overnight incubation at 37 ºC, plasma was harvested and IFN-γ quantified. IFN-γ levels in the QFN-G-IT and in-house tubes correlated very good (Spearman Rho(r) > 0.86). In-house antigen combinations distinguished healthy individuals from those with active TB and LTBI (specificities and sensitivities higher than 87.5% and 96.3%, respectively [AUC > 0.938]). Adding EspC, EspF and Rv2348-B, increased the sensitivity of the test, being the addition of EspC and Rv2348-B the combination that yielded a higher sensitivity with no specificity loss. Addition of these antigens could improve diagnosis in patients with impaired or immature immune response who are at high risk of developing TB.

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis.

It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.

Comparison of image quality in chest, hip and pelvis examinations between mobile equipment in nursing homes and static indirect radiography equipment in the hospital.

INTRODUCTION: A hospital environment can be a significant burden and a health risk especially for dementia patients. Mobile x-ray equipment (ME) is used to enable imaging of these patients at home. The aim was to compare image quality (IQ) of chest, hip and pelvis images from ME to the stationary equipment (SE) used in a hospital department. METHODS: We analysed examinations of the chest (n = 20), hip (n = 64) and pelvis (n = 32). Images were equally obtained from each setting of ME and SE. All images were graded using Visual Grading Analysis (VGA) by three radiographers (hip and pelvis) and three radiologists (chest). Technical IQ assessment was done by 80 additional images of a Contrast-Detail Radiography phantom (CDRAD). RESULTS: All chest images were approved for diagnostic use, as well as the hip AP and pelvis images from SE. 'Approved proportion of ME images was for HIP antero-posterior (AP) and pelvis, 78% [95% CI: 52-94%] and 81% [95% CI: 54-96%] respectively. Hip axial had an overall low, but not significant different approval rate. Ordered logistic regression indicated higher IQ of HIP AP and pelvic images from SE. This contrasts that the CDRAD substudy indicated better IQ, expressed as IQFinv, from ME. CONCLUSION: The VGA showed higher IQ for the SE system, while the CDRAD showed higher IQ for the ME system. IMPLICATIONS FOR PRACTICE: Dementia patients can be examined at their home if the acquisition is optimised according to image quality in conjunct to radiation dose. Performing imaging out of the hospital and coordinating the patients' further treatment are new work areas for radiographers and requires excellent communication skills.