Patient-reported outcome (PRO) measurements in chronic and malignant diseases: ten years' experience with PRO-algorithm-based patient-clinician interaction (telePRO) in AmbuFlex.

BACKGROUND: Patient-reported Outcome (PRO) measures may be used as the basis for out-patient follow-up instead of fixed appointments. The patients attend follow-up from home by filling in questionnaires developed for that specific aim and patient group (telePRO). The questionnaires are handled in real time by a specific algorithm, which assigns an outcome color reflecting clinical need. The specific questionnaires and algorithms (named solutions) are constructed in a consensus process with clinicians. We aimed to describe AmbuFlex' telePRO solutions and the algorithm outcomes and variation between patient groups, and to discuss possible applications and challenges. METHODS: TelePRO solutions with more than 100 processed questionnaires were included in the analysis. Data were retrieved together with data from national registers. Characteristics of patients, questionnaires and outcomes were tabulated for each solution. Graphs were constructed depicting the overall and within-patient distribution of algorithm outcomes for each solution. RESULTS: From 2011 to 2021, 29 specific telePRO solutions were implemented within 24 different ICD-10 groups. A total of 42,015 patients were referred and answered 171,268 questionnaires. An existing applicable instrument with cut-off values was available for four solutions, whereas items were selected or developed ad hoc for the other solutions. Mean age ranged from 10.7 (Pain in children) to 73.3 years (chronic kidney disease). Mortality among referred patients varied between 0 (obesity, asthma, endometriosis and pain in children) and 528 per 1000 patient years (Lung cancer). There was substantial variation in algorithm outcome across patient groups while different solutions within the same patient group varied little. DISCUSSION: TelePRO can be applied in diseases where PRO can reflect clinical status and needs. Questionnaires and algorithms should be adapted for the specific patient groups and clinical aims. When PRO is used as replacement for clinical contact, special carefulness should be observed with respect to patient safety.

Loco-regional morbidity after breast conservation and axillary lymph node dissection for early breast cancer with or without regional nodes radiotherapy, perspectives in modern breast cancer treatment: the Skagen Trial 1 is active.

BACKGROUND: Axillary lymph node dissection (ALND) and adjuvant radiotherapy (RT) in early breast cancer are associated with a risk of morbidity, including lymphedema and impaired shoulder mobility. The aim of this study was to evaluate loco-regional morbidity after breast conserving surgery (BCS), ALND, taxane-based chemotherapy and whole breast irradiation (WBI) with or without regional nodes RT. MATERIAL AND METHODS: Eligible patients had BCS and ALND from 2007 to 2012 followed by adjuvant taxane-based chemotherapy and if indicated, trastuzumab and endocrine treatment. The RT consisted of WBI and regional nodes RT in case of ≥ pN1 disease (group 1) and WBI only in case of pN0-1(mic) disease (group 2). The dose was 50 Gy in 25 fractions. The patients were invited to participate in a cross-sectional study evaluating morbidity. RESULTS: Of the 347 eligible patients, 277 patients (79%) accepted the invitation. Of these, 185 patients (67%) belonged to group 1 and 92 patients (33%) to group 2. The median time from RT to evaluation of morbidity was 3.3 years (group 1) and 4.3 years (group 2). In group 1, 34 patients (18%) and in group 2, 15 patients (16%) had ≥2 cm enlargement in circumference of ipsilateral upper or lower arm (p = .67). The frequence of impairment of ipsilateral shoulder abduction to ≤120° was 3% in both groups and of shoulder flexion to ≤120° was 1% and 2% (group 1 versus 2). No difference in patient reported outcome measure (PROM) data regarding heaviness or enlargement of ipsilateral upper and lower arm or mobility and sensory disturbances. CONCLUSION: The risk of lymphedema was low in patients after ALND and not related to use of regional nodes RT. Impairment of shoulder function was rare, and no differences in PROM were detected regarding use or not of regional nodes RT.

Unrecognised myocardial infarction in patients with schizophrenia.

OBJECTIVE: Schizophrenia is associated with a reduction of the lifespan by 20 years, with type II diabetes and cardiovascular disease contributing the most to the increased mortality. Unrecognised or silent myocardial infarction (MI) occurs in ~30% of the population, but the rates of unrecognised MI in patients with schizophrenia have only been sparsely investigated. METHOD: Electrocardiograms (ECG) from three psychiatric hospitals in Denmark were manually interpreted for signs of previous MI. Subsequently, ECGs were linked to the National Patient Registry in order to determine whether patients had a diagnosis consistent with previous MI. RESULTS: A total of 937 ECGs were interpreted, 538 men (57.4%) and 399 women (42.6%). Mean age at the time of ECG acquisition was 40.6 years (95% CI: 39.7-41.5, range: 15.9-94.6). We identified 32 patients with positive ECG signs of MIs. Only two of these patients had a diagnosis of MI in the National Patient Registry. An additional number of eight patients had a diagnosis of MI in the Danish National Patient Registry, but with no ECG signs of previous MI. This means that 30 out of 40 (75%) MIs were unrecognised. Only increasing age was associated with unrecognised MI in a stepwise multiple logistic regression model compared with patients with no history of MI, OR: 1.03 per year of age, 95% CI: 1.00-1.06, p=0.021. CONCLUSION: Unrecognised MI is common among patients with schizophrenia and may contribute to the increased mortality found in this patient group.

Multiplex lateral flow assay development for snake venom detection in biological matrices.

Bothrops and Lachesis are two of Brazil's medically most relevant snake genera, causing tens of thousands of bites annually. Fortunately, Brazil has good accessibility to high-quality antivenoms at the genus and inter-genus level, enabling the treatment of many of these envenomings. However, the optimal use of these treatments requires that the snake species responsible for the bite is determined. Currently, physicians use a syndromic approach to diagnose snakebite, which can be difficult for medical personnel with limited training in clinical snakebite management. In this work, we have developed a novel monoclonal antibody-based multiplex lateral flow assay for differentiating Bothrops and Lachesis venoms within 15 min. The test can be read by the naked eye or (semi)-quantitatively by a smartphone supported by a 3D-printed attachment for controlling lighting conditions. The LFA can detect Bothrops and Lachesis venoms in spiked plasma and urine matrices at concentrations spanning six orders of magnitude. The LFA has detection limits of 10-50 ng/mL in spiked plasma and urine, and 50-500 ng/mL in spiked sera, for B. atrox and L. muta venoms. This test could potentially support medical personnel in correctly diagnosing snakebite envenomings at the point-of-care in Brazil, which may help improve patient outcomes and save lives.

Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.

Patient-reported outcomes used actively in cancer patients undergoing antineoplastic treatment: A mini-review of the Danish landscape.

Introduction: Many studies using Patient-reported outcomes (PRO) data have been conducted to monitor symptoms and health-related quality of life during follow-up after cancer treatment. However new ways of using (e)PROs have emerged. We aimed to explore the Danish landscape of the use of PRO in a research setting, where PRO is used actively in cancer patients undergoing treatment, and give an overview of how it is embraced by patients and clinicians. Methods and materials: A literature search was performed in June 2023, using the keywords Denmark, cancer, and patient-reported outcomes. An expert on literature searches identified the search terms, and double screening was performed at both abstract and screening levels and full-text stage. The software tool Covidence was used. Results: 467 articles were retrieved and 19 studies were included. They described the type of ePRO instrument used and the application of active ePRO i.e. a dialogue tool in the clinical encounter, release of alerts to clinicians, and enhancement of self-management. Finally, a development in the use of active ePROs over time is elucidated and we show how it is embraced by patients and clinicians. Conclusion: This mini-review gives an overview of how ePRO solutions are tested in oncological research in Denmark and embraced by patients and clinicians. ePRO solutions in a Danish setting seem well-suited for self-management. However, if more impact is warranted, clinicians need to engage in reviewing and using ePROs. Moreover, for successful implementation, the integration of ePROs in electronic health records must be supported by IT specialists and management.

Prototyping of a lateral flow assay based on monoclonal antibodies for detection of Bothrops venoms.

BACKGROUND: Brazil is home to a multitude of venomous snakes; perhaps the most medically relevant of which belong to the Bothrops genus. Bothrops spp. are responsible for roughly 70% of all snakebites in Brazil, and envenomings caused by their bites can be treated with three types of antivenom: bothropic antivenom, bothro-lachetic antivenom, and bothro-crotalic antivenom. The choice to administer antivenom depends on the severity of the envenoming, while the choice of antivenom depends on availability and on how certain the treating physician is that the patient was bitten by a bothropic snake. The diagnosis of a bothropic envenoming can be made based on expert identification of the dead snake or a photo thereof or based on a syndromic approach wherein the clinician examines the patient for characteristic manifestations of envenoming. This approach can be very effective but requires staff that has been trained in clinical snakebite management, which, unfortunately, far from all relevant staff has. RESULTS: In this article, we describe a prototype of the first lateral flow assay (LFA) capable of detecting venoms from Brazilian Bothrops spp. The monoclonal antibodies for the assay were generated using hybridoma technology and screened in sandwich enzyme-linked immunosorbent assays (ELISAs) to identify Bothrops spp.-specific antibody sandwich pairs. The prototype LFA is able to detect venom from several Bothrops spp. The LFA has a limit of detection (LoD) of 9.5 ng/mL in urine, when read with a commercial reader, and a visual LoD of approximately 25 ng/mL. SIGNIFICANCE: The work presented here serves as a proof of concept for a genus-specific venom detection kit that could support physicians in diagnosing Bothrops envenomings. Although further optimisation and testing is needed before the LFA can find clinical use, such a device could aid in decentralising antivenoms in the Brazilian Amazon and help ensure optimal snakebite management for even more victims of this highly neglected disease.

Synthetic antibodies block receptor binding and current-inhibiting effects of α-cobratoxin from Naja kaouthia.

Each year, thousands of people fall victim to envenomings caused by cobras. These incidents often result in death due to paralysis caused by α-neurotoxins from the three-finger toxin (3FTx) family, which are abundant in elapid venoms. Due to their small size, 3FTxs are among the snake toxins that are most poorly neutralized by current antivenoms, which are based on polyclonal antibodies of equine or ovine origin. While antivenoms have saved countless lives since their development in the late 18th century, an opportunity now exists to improve snakebite envenoming therapy via the application of new biotechnological methods, particularly by developing monoclonal antibodies against poorly neutralized α-neurotoxins. Here, we describe the use of phage-displayed synthetic antibody libraries and the development and characterization of six synthetic antibodies built on a human IgG framework and developed against α-cobratoxin - the most abundant long-chain α-neurotoxin from Naja kaouthia venom. The synthetic antibodies exhibited sub-nanomolar affinities to α-cobratoxin and neutralized the curare-mimetic effect of the toxin in vitro. These results demonstrate that phage display technology based on synthetic repertoires can be used to rapidly develop human antibodies with drug-grade potencies as inhibitors of venom toxins.

Patient-Reported Outcome Measures Used in Routine Care Predict for Survival at Disease Progression in Patients With Advanced Lung Cancer.

BACKGROUND: Patient-reported outcome (PRO) measures have been increasingly implemented in routine care to aid in clinical decision-making. However, the prognostic value of PRO measures as a tool for decision making is not easily interpreted by clinicians. Our aims were to explore the prognostic value of PRO measures at disease progression and the changes in PRO measures between treatment start (baseline) and disease progression. PATIENTS AND METHODS: Since 2014, patients with lung cancer have completed an electronic version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and LC-13 before every outpatient visit at the Department of Oncology, Hospital Unit West, Jutland, Denmark. The patients' responses were used in routine care. Patients receiving palliative antineoplastic treatment were eligible for analysis if the questionnaire had been completed at the initiation of first-line treatment and at disease progression. The prognostic value of the scores was evaluated using a Cox proportional hazard model. A P value < .01 was considered statistically significant. RESULTS: A total of 94 screened patients were included. At disease progression, survival could be predicted from the absolute score of the global health scale, 3 functional scales (physical, role, emotional), and 7 symptom scales (fatigue, pain, dyspnea, hemoptysis, lung cancer dyspnea, chest pain). In addition, changes in hemoptysis, dysphagia, dyspnea, and chest pain predicted for survival at progression. CONCLUSION: PRO measures used in routine care can provide clinicians with relevant prognostic information about patients with lung cancer at disease progression. These results show the potential value of PRO measures when used in clinical decision-making.

Snakebite Envenoming Diagnosis and Diagnostics.

Snakebite envenoming is predominantly an occupational disease of the rural tropics, causing death or permanent disability to hundreds of thousands of victims annually. The diagnosis of snakebite envenoming is commonly based on a combination of patient history and a syndromic approach. However, the availability of auxiliary diagnostic tests at the disposal of the clinicians vary from country to country, and the level of experience within snakebite diagnosis and intervention may be quite different for clinicians from different hospitals. As such, achieving timely diagnosis, and thus treatment, is a challenge faced by treating personnel around the globe. For years, much effort has gone into developing novel diagnostics to support diagnosis of snakebite victims, especially in rural areas of the tropics. Gaining access to affordable and rapid diagnostics could potentially facilitate more favorable patient outcomes due to early and appropriate treatment. This review aims to highlight regional differences in epidemiology and clinical snakebite management on a global scale, including an overview of the past and ongoing research efforts within snakebite diagnostics. Finally, the review is rounded off with a discussion on design considerations and potential benefits of novel snakebite diagnostics.

Electronic symptom monitoring in patients with metastatic lung cancer: a feasibility study.

OBJECTIVES: To design an electronic questionnaire for symptom monitoring and to evaluate the feasibility, usability and acceptability when applied to patients with metastatic lung cancer. SETTING: Single-centre feasibility study. PARTICIPANTS: Patients with stage IV lung cancer in antineoplastic treatment. INTERVENTIONS: This study describes the first three phases of a complex intervention design: phase 1, development of the intervention; phase 2, feasibility testing and phase 3, evaluation of the intervention. In phase 1, items were selected for the questionnaire and adjusted following patient interviews. In phase 2, patients completed the electronic questionnaire weekly during a 3-week feasibility test. In case of symptom deterioration, a nurse was notified with the aim to contact the patient. In phase 3, patients evaluated phase 2 by paper questionnaires, and interviews were conducted with the participating nurses. PRIMARY OUTCOME MEASURES: The study outcomes: phase 1, usability and relevance; phase 2, recruitment rate, compliance and threshold functionality and phase 3, usability, acceptability and relevance. RESULTS: In phase 1, a questionnaire was designed and reviewed by patients (n=8). The interviews revealed high usability and relevance of the intervention.For phases 2 and 3, 20 of 29 approached patients (69%) responded to the questionnaire on a weekly basis. Two patients did not complete any questionnaires (compliance 90%). The remaining 18 patients completed 65 of a total of 72 possible questionnaires (7 missed, 93% completed). Reported symptoms led to a phone call from a nurse in 30% of the responses.The patients reported high usability and acceptability of questionnaire and software. The substance of the telephonic conversations was relevant, and the study set-up was logistically acceptable. CONCLUSIONS: An electronic questionnaire designed for symptom monitoring revealed high usability, acceptability and relevance in the target population. In conclusion, the study set-up was considered feasible for a randomised controlled trial. TRIAL REGISTRATION NUMBER: NCT03529851.

Snake Venomics Display: An online toolbox for visualization of snake venomics data.

With the introduction of powerful mass spectrometry equipment into the field of snake venom proteomics, a large body of venomics data is accumulating. To allow for better comparison between venom compositions from different snake species and to provide an online database containing this data, we devised the Snake Venomics Display toolbox for visualization of snake venomics data on linear scales. This toolbox is freely available to be used online at https://tropicalpharmacology.com/tools/snake-venomics-display/ and allows researchers to visualize venomics data in a Relative Abundance (%) visualization mode and in an Absolute Abundance (mg) visualization mode, the latter taking venom yields into account. The curated venomics data for all snake species included in this database is also made available in a downloadable Excel file format. The Snake Venomics Display toolbox represents a simple way of handling snake venomics data, which is better suited for large data sets of venom compositions from multiple snake species.

Comparison of three nudge interventions (priming, default option, and perceived variety) to promote vegetable consumption in a self-service buffet setting.

BACKGROUND: Dietary choices in out-of-home eating are key for individual as well as for public health. These dietary choices are caused by a wide array of determinants, one of which is automatic decision-making. Nudging is attracting considerable interest due to its understanding and application of heuristic biases among consumers. The aim of this study is to test and compare three nudges in promoting vegetable consumption among test persons in a food lab-based experiment. METHODS: The initial sample consisted of 88 participants recruited in Copenhagen, Denmark. Each study participant was randomly assigned to one of the three experiments: priming, default and perceived variety. The priming arm of the experiment consisted of creating a leafy environment with green plants and an odour of herbs. In the default arm of the experiment, the salad was pre-portioned into a bowl containing 200g of vegetables. The third experiment divided the pre-mixed salad into each of its components, to increase the visual variety of vegetables, yet not providing an actual increase in items. Each individual was partaking twice thus serving as her/his own control, randomly assigned to start with control or experimental setting. RESULTS: The default experiment successfully increased the energy intake from vegetables among the study participants (124 kcal vs. 90 kcal in control, p<0.01). Both the priming condition and perceived variety reduced the total energy intake among the study participants (169 kcal, p<0.01 and 124 kcal, p<0.01, respectively), mainly through a decrease in the meat-based meal component. CONCLUSIONS: Considerable progress has been made with regard to understanding the use of nudging in promoting a healthier meal composition, including increasing vegetable intake. This study suggests that the nature of a nudge-based intervention can have different effects, whether it is increasing intake of healthy components, or limiting intake of unhealthy meal components. This work has demonstrated that consumer behaviour can be influenced without restricting or providing incentives for behaviour change. The present findings have promising application to the foodservice sector.

Comparative effectiveness of risperidone long-acting injectable vs first-generation antipsychotic long-acting injectables in schizophrenia: results from a nationwide, retrospective inception cohort study.

OBJECTIVE: To compare in a generalizable sample/setting objective outcomes in patients receiving first-generation antipsychotic long-acting injectables (FGA-LAIs) or risperidone-LAI (RIS-LAI). METHODS: Nationwide, retrospective inception cohort study of adults with International Classification of Diseases-10 schizophrenia using Danish registers from 1995 to 2009 comparing outcomes between clinician's/patient's choice treatment with FGA-LAIs or RIS-LAI. Primary outcome was time to psychiatric hospitalization using Cox-regression adjusting for relevant covariates. Secondary outcomes included time to all-cause discontinuation and psychiatric hospitalization in patients without LAI possession gap >28 days, and number of bed-days after psychiatric hospitalization. RESULTS: Among 4532 patients followed for 2700 patient-years, 2078 received RIS-LAI and 2454 received FGA-LAIs (zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.0%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%). RIS-LAI was similar to FGA-LAIs regarding time to hospitalization (RIS-LAI = 246.2±323.7 days vs FGA-LAIs = 276.6±383.3 days; HR = 0.95, 95% confidence interval (CI) = 0.87-1.03, P = 0.199) and time to all-cause discontinuation (RIS-LAI = 245.8±324.0 days vs FGA-LAIs = 287.0±390.9 days; HR = 0.93, 95% CI = 0.86-1.02, P = 0.116). Similarly, in patients without LAI discontinuation, RIS-LAI and FGA-LAIs did not differ regarding time to hospitalization (RIS-LAI = 175.0±268.1 days vs FGA-LAIs = 210.7±325.3 days; HR = 0.95, 95% CI = 0.86-1.04, P = 0.254). Finally, duration of hospitalization was also similar (incidence rate ratio = 0.97, 95% CI = 0.78-1.19, P = 0.744). Results were unchanged when analyzing only patients treated after introduction of RIS-LAI. CONCLUSIONS: In this nationwide cohort study, RIS-LAI was not superior to FGA-LAIs regarding time to psychiatric hospitalization, all-cause discontinuation, and duration of hospitalization. Given the cost of hospitalization and second-generation antipsychotic (SGA)-LAIs, these findings require consideration when making treatment choices, but also need to be balanced with the individual relevance of adverse effects/patient centered outcomes. In future, head-to-head trials and additional nationwide database studies including other SGA-LAIs is needed.