The development of senescence in tissues of different organs and in the immune system are usually investigated independently of each other although during ageing, senescence in both cellular systems develop concurrently. Senescent T cells are highly inflammatory and secrete cytotoxic mediators and express natural killer cells receptors (NKR) that bypass their antigen specificity. Instead they recognize stress ligands that are induced by inflammation or infection of different cell types in tissues. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non‐lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID‐19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation. Senescence occurs in tissues as well as in the immune system but the interaction between this is poorly understood. Senescent T cells are pro‐inflammatory, express NK receptors that can act independent of the TCR, and are highly cytotoxic. They recognise stress ligands expressed by cells in inflamed or infected tissues or as a consequence of cellular senescence. Here, we discuss how senescent T cells might contribute to exacerbated tissue damage in infectous contexts by interacting with senescent stromal cells. We focus on cutaneous leishmaniasis as a model for this but suggest that this occurs in other infections such as COVID‐19 and indeed autoimmune diseases such as rheumatoid arthritis. These cells are senescent, defined as being in a state of cell cycle arrest associated with phenotypic and functional changes Campisi, . This prSenescence is triggered by activation and subsequent maintenance of DNA damage repair (DDR) signalling pathways. This can by induced by oncogene activation, replicative stress related to telomere erosion and oxidative stress Allsopp,  that kic+ T cells that exhibit all the hallmarks of senescence as described above (henceforth referred to as Tsen). We will focus on patients infected with Leishmania braziliensis where the increased Tsen numbers in the skin may induce the characteristic skin lesions associated with this disease. We propose a hypothesis, bases on existing data, that this pathology occurs because senescent non‐lymphoid cells in the skin are be killed by infiltrating Tsen, a novel interaction between senescent lymphoid and non‐lymphoid cells that may also have implications for ageing.While senescence was first discovered in fibroblasts and extensively worked on in other non‐leukocytic cells, it has become increasingly clear that immune cells undergo senescence as well. Within the immune system, the existence of non‐proliferative leukocyte populations that have high capacity for biologically active mediator secretion has been recognized for many decades, albeit under a different name. These are the effector T lymphocytes that secrete pro‐inflammatory cytokines and cytotoxic granules but do not proliferate after activation  complex  families compared to undifferentiated and non‐senescent CD28+CD27+ CD8+ T cells  .Despite the evidence for senescent cell clearance by the immune system, it is not yet clear why senescent cells accumulate during ageing and persist at sites of age‐related pathology  in Brazil, where destructive cutaneous lesions develop , have reduced proliferative activity and increased expression of the nuclear DNA‐damage response protein  or anti‐CD3 stimulation compared to controls in vitro. Although Tsen accumulate in patients . Compared to young subjects, elderly patients displayed larger cutaneous lesions, longer duration of illness and were more likely to develop mucocutaneous leishmaniasis, the most inflammatory and severe clinical form of the tegumentary leishmaniasis  that have been shown to drive T cell senescence and therefore the acquisition of NK characteristics . This is supported by previous observations that the bystander activation of memory CD8+ T cells in the skin may contribute to the chronic inflammation and tissue damage in an NKG2D‐dependent manner during murine cutaneous leishmaniasis (Crosby et al., +NKG2D+ T cells, supporting the possibility that tissue damage can occur independently of the antigen specificity of the infiltrating cells (Crosby et al., + and CD8+ T cells are able to proliferate and produce IFN‐γ in response not only to Leishmania antigens but also to other pathogens (Da‐Cruz et al., We hypothesize that dermal macrophages infected by Leishmania initiate an inflammatory response that preferentially attracts 7+ Tsen within the tissue. It is also crucial to identify the source of inflammation at these sites, are the myeloid cells, the stromal cells, the leukocytes or all of them involved? The hypothetical positive feedback loop described here that involves Tsen and excessive inflammation and non‐specific tissue damage may also be involved in other non‐resolving inflammatory diseases where accumulation of Tsen cells have been demonstrated including Chagas disease (Molina & Kierszenbaum, sen cells needs to be investigated and might offer new opportunities for prevention and treatment (Andersson et al., sen recruitment and induction of non‐antigen specific damage in the lung and other tissues. Furthermore, it is currently unclear how senolytic drugs that are being used to clear senescent cells will affect senescent leukocyte populations and if this may have beneficial or detrimental consequences. Collectively we suggest that T cells that have been driven to extreme differentiation and senescence by infectious agents acquire potent MHC‐I‐unrestricted cytotoxic and capacity for inflammatory cytokine secretion together with the ability to cause non‐specific NK‐related damage. Given the increased burden of tumours and infections with age, the expansion of NK cell‐like functions in CD8+ T cells could be an advantageous adaptation that would enable the recognition and elimination of infected and transformed cells. However, the accumulation of senescent T cells during ageing is a double‐edged sword that may induce pathology, especially in inflammatory environments.The investigation of the cellular infiltrate in patients with cutaneous leishmaniasis by gene expression (Amorim et al., None declared.All four authors conceived and wrote the manuscript.


Extensive clinical research has provided robust evidence that exercise is a cost‐effective measure to substantially alleviate the burden of a large number of diseases, many of which belong to the cardiovascular (CV) spectrum. In terms of cardiac benefit, the positive effects of exercise are attributed to improvements in standard risk factors for atherosclerosis, as well as to its positive impact on several pathophysiological mechanisms for CV diseases. For secondary prevention, exercise, optimally in the context of a cardiac rehabilitation program, has been shown to improve functional capacity and survival. Clinicians should encourage physical activity and provide exercise recommendations for all patients, taking into consideration any underlying pathology. In the present review, the benefits of exercise for the prevention and treatment of major CV risk factors and heart conditions are analyzed. It is estimated that one in five adults lack acceptable PA and that only half the population in developed countries follow the widely applied recommendation of a minimum of 150 minutes of moderate‐intensity exercise weekly.Physical inactivity is a principal contributor to the global burden of disease. Calculations of population‐attributable fractions have shown that PA not meeting current recommendations is the cause of 6% of the burden of coronary artery disease (CAD), 7% of type 2 diabetes mellitus (T2DM), and 9% of premature death.2A number of different terms related to PA have been examined in clinical research relating to CV and non‐CV outcomes Table .2 SedeClassification of exercise is largely based on the principal form of energy production, the extent of body movement, the participating muscles, and the main benefitting component of physical fitness.The most studied training modality is continuous exercise training, characterized by predominantly dynamic, moderate‐intensity exercise at a constant workload for a prolonged period of time. This modality has been shown to effectively improve maximum work capacity and reduce mortality in health and CV disease. High‐intensity interval training (HIIT) has been derived from standard athletic training programs and has emerged as one of the fastest growing exercise programs in recent years. A typical session consists of four to six repeated, short (1‐4 minutes) bouts of vigorous effort interspersed with brief periods (1‐3 minutes) of active recovery of moderate effort. High‐IIT may be more effective compared to continuous training in improving CRF, reducing weight and improving glycaemic control but its long‐term prognostic effect in CV disease needs further study. Pyramid training, characterized by stepwise increase and decrease of workload, is another interesting modality that may improve physical fitness in the shortest time, but also warrants further evaluation. Finally, resistance training is gaining ground as it improves muscle strength and aerobic capacity, with the maximum effect seen when it is combined with endurance exercise. Resistance training is particularly important for improving muscle tone, bone density, and coordination which become increasingly important with senescence.3Forty years of thorough research has examined the epidemiological effects of PA on CV prognosis and mortality. Unsurprisingly, sedentarism/physical inactivity on one side and exercise/CRF on the other exhibit opposite associations with CV outcomes, including heart failure (HF) and CAD, and mortality Table .9, 103.1A remarkably consistent association of sedentary behavior with all‐cause and CV mortality and CV disease has been documented. A recent meta‐analysis of 34 studies and over 1.3 million participants revealed a nonlinear relationship between total sedentary behavior and all‐cause and CV mortality independent of PA.It is clear that an individual may be physically active, perhaps even following the current exercise recommendations, and still be sedentary for prolonged periods either at work or during leisure time. It has been estimated that half of the time spent awake is characterized by sedentary behavior. Recent data, however, suggest that concurrent increasing levels of PA may positively alter the association of sedentarism with a worse outcome. In a meta‐analysis that stratified patients by quartiles of PA, there was a dose‐response association between sitting time and CV mortality in the lowest PA quartile (9%‐32% higher risk), but this association was progressively ameliorated and eventually disappeared across increasing levels of PA.3.2PA and exercise are independently associated with lower CV morbidity and CV and all‐cause mortality in a dose‐response manner. All types of PA are efficient in preventing CV disease irrespective of gender, age, and race and CV risk factors. Clinical guidelines of major societies recommend a minimum of 150 min/week of moderate intensity  or 75 min/week of vigorous intensity aerobic exercise, with an optimal benefit in terms of longevity and protection from CV events expected in three to five times as much for either.Little exercise is better than none and even simple standing exhibits a dose‐response relationship with lower rates of mortality.Exercise inevitably improves CRF, which is optimally evaluated by measurement of peak VO2 during cardiopulmonary exercise testing but may also be assessed by exercise time, maximum power output and other exams such as the 6‐minute walk test. CRF is actually a stronger predictor of outcome compared to PA or exercise training, as evident in studies in healthy populations and populations with or at risk of CV disease.4The beneficial effect of exercise on CV outcome is primarily through modulation of standard CV risk factors for atherosclerosis including hypertension (HTN), diabetes, dyslipidemia, and obesity.4.1The effectiveness of exercise in reducing BP is evident from the phenomenon of acute postexercise hypotension that may last for up to 24 hours. In turn, chronic reduction in BP in response to exercise training has been well‐studied and attributed predominantly to improvements in nitric oxide‐mediated endothelial function and attenuations in systemic vascular resistance, and reduced activity of the sympathetic nervous system and the renin‐angiotensin‐aldosterone axis.Isometric and resistance exercise were previously approached with skepticism in hypertensive patients due to fear of an exaggerated BP response, increases in arterial stiffness and further deterioration of HTN. In recent years, it has been shown that these are safe exercise modalities for hypertensive patients that also lower BP but perhaps to a lower extent compared to aerobic training. However, a meta‐analysis of 64 controlled studies of moderate‐intensity dynamic resistance training in patients with pre‐HTN showed a BP‐lowering effect comparable to aerobic exercise, and also identified a dose‐response effect that was greater in individuals with a higher resting BP and in populations who were not taking antihypertensive drugs.Regular exercise is also effective in preventing HTN, with some data supporting that higher exercise loads are associated with lower rates of developing HTN. In a meta‐analysis of 29 studies on over 3000 normotensives, it was shown that the risk of HTN decreased by 6% for every 10 METs of task hours/week increase in leisure‐time PA.It is self‐explanatory that the estimated BP‐lowering effect of exercise in patients with HTN is also associated with significant improvements in CV outcomes. A decrease in BP of 6 to 7 mmHg would translate to a CV risk reduction of up to 20% to 30%. Accordingly, exercise capacity has been associated with lower mortality in both prehypertensive and hypertensive individuals. Even among older hypertensive individuals, every 1‐MET increase in exercise capacity is associated with an 11% lower risk of death.4.2Aerobic exercise has been associated with a beneficial effect on lipoprotein levels in both normolipidemic and hyperlipidemic individuals, even though the overall effect is small and concurrent weight loss may have contributed in the positive findings of some of the relevant studies. Beneficial effects have been noted mostly for high‐density lipoprotein‐cholesterol (HDL‐C) levels but also for low‐density lipoprotein‐cholesterol (LDL‐C) particle size and apolipoprotein B and triglyceride levels.4.3Regular leisure‐time activity of different intensities has been associated with a 25% to 40% reduction in the risk of T2DM.A single session of low intensity exercise leads to acute improvements in insulin sensitivity and uptake of fatty acids from skeletal muscles. However, the benefits are more substantial with longer periods and more intense bouts of exercise. An earlier meta‐analysis has shown that a 20‐week program of moderate‐intensity aerobic exercise improves CRF and glycated hemoglobin (HbA1c), the latter decreasing in parallel with more intense exercise.4.4Regular PA protects against weight gain throughout life, maintains long‐term weight loss and preserves lean body mass during caloric restriction.5In the setting of secondary prevention, multiple studies have shown that PA and exercise as well as CRF reduce the risk of new CV events. Exercise may be performed at home, in community facilities or, ideally, in the context of a cardiac rehabilitation program.5.1Lack of PA is an independent predictor for CAD development. In a case control study evaluating multiple CV risk factors for acute myocardial infarction (MI) across 52 countries, regular exercise was associated with a 14% lower risk of MI among men and women of all age groups and ethnicities.A number of benefits of exercise in patients with established CAD have been observed. Regular exercise contributes to greater functional capacity and higher thresholds of angina presentation. At the myocardial level, the effects of exercise may include retardation of disease progression and regression of coronary plaques, improvements in endothelial function, favorable mechanisms for healing endothelial damage, coronary collateralization, and a positive effect on left ventricular function and remodeling.With respect to hard endpoints, there is consistent evidence that exercise in the context of cardiac rehabilitation programs is associated with lower CV mortality in patients after MI or after coronary revascularisation. In a large meta‐analysis of 63 studies examining variable intensities and periods of aerobic exercise as part of cardiac rehabilitation in patients post‐MI or revascularization, a 26% reduction in CV death and an 18% reduction in hospital admissions was documented.5.2Historically, exercise was prohibited in patients with HF due to fear of haemodynamic compromise. Since the 1980's, a large set of evidence has been accumulated that supports exercise as a strong preventive, prognostic, and therapeutic modality in HF both in the setting of primary and secondary prevention. PA is associated with a lower risk of HF across a wide range of body weights and independently of comorbidities.In patients with established HF, the lack of PA has been shown to be accompanied by a doubling of risk of all‐cause and CV mortality.Most early studies of exercise in HF were small and single‐centered and were based on continuous moderate‐intensity aerobic training. Altogether, they have provided promising evidence that exercise training is accompanied by improvements in quality of life and decreases in the risk of hospitalisations and long‐term mortality. An earlier meta‐analysis of the ExTraMATCH Collaborative has shown that exercise training for at least 8 weeks reduces mortality by 45% in patients with HFrEF.5.3A number of studies have shown that regular PA and satisfactory CRF are associated with a lower incidence of atrial fibrillation (AF), a finding at least partially mediated by concurrent improvements in established risk factors for AF such as HTN and obesity. In numbers, moderate PA in individuals aged more than 65 years reduces the risk of AF by 44%.In patients with AF, exercise is safe, as long as sufficient rate control has been achieved, and it has been shown to improve AF‐related symptoms, exercise tolerance, and quality of life. Exercise may also have a favorable effect on AF burden and AF recurrence, while more study data are needed regarding the optimal training regimen as well as the effects on hard endpoints in these patients.6There are emerging studies reporting a J‐shaped relationship between exercise dose and CV morbidity and mortality. Some studies have also shown there are diminishing returns beyond an exercise capacity of 12 METs.7The strong assets of regular moderate exercise are its free availability at low cost and its simultaneous benefits for preventing and improving several cardiac diseases. Integration of exercise in the daily routine of all individuals is essential to improve global health. It is important to emphasize that current evidence suggest that exercising for three to five times the current recommendations is the ideal dose for maximum benefit to prevent several CV diseases, although even 1 hour per week of exercise is associated with a health benefit. Some individuals engaging in lifelong endurance exercise show a high prevalence of CAC, myocardial fibrosis and AF, the long‐term significance of which is uncertain. Overall regular exercise is associated with a significant reduction in CV morbidity and mortality and longevity of an additional 2 to 7 years of life.The authors declare no potential conflict of interests.


To describe nurses’ activities and time management during HHC visits from the perspective of master’s‐level nursing students.The shift from community‐based hospitals to home‐based, person‐centred services for patients with a variety of acute or chronic health problems challenges nurses’ professional competence and time management during home healthcare visits.A cross‐sectional study in accordance with STROBE guidelines. Observation sheets (n = 196) from two municipal home healthcare organisations were analysed with descriptive quantitative analysis.While no external ethical committee evaluation was necessary for this quality improvement study, research ethical principles were followed.The nurses spent 50% of each eight‐hour shift on indirect patient contact activities and about 38% on direct patient contact activities. The majority of activities underlying the home visits could be linked to long‐term illnesses: medication (57%), blood samples (23%), wound care (17%) or measurement of blood pressure (14%). Patient education was offered during only 3.5% of visits.The accuracy of the students’ observations is related to their individual capacity to objectively and selectively observe.for the patient, to promote continuous intra‐ and interprofessional patient care, but fewer nursing activities conducted with the patient. To ensure integrated, person‐centred, safe patient care, vital reforms are needed.There were a number of activities conducted The appropriate balance between indirect and direct patient contact activities should be discussed intra‐ and interprofessionally, delineated and made explicit in nurses’ work plans and nursing documentation, alongside discussions pertaining to relevant resource allocation. Recognising that patients prefer to be treated at home and that home‐based care can reduce care delivery costs system‐wide, politicians and leaders have begun to prioritise noninstitutional care settings Traditionally, the aim of HHC has been to facilitate discharge from hospital and prolong individuals’ prospects of living at home, even for those with chronic conditions. HHC has generally been offered when other healthcare services have been deemed inconvenient or unsuitable for individuals with altered functional capacity or somatic illnesses. In Finland, HHC is comprised of physician‐ordered interventions and social services. This can include the taking of blood samples; monitoring of medicine compliance and/or patients’ clinical condition; or provision of functional support for activities of daily living. HHC in Finland can accordingly be considered integrated, highly interprofessional care. The majority of HHC patients have typically been older persons with primary care needs As seen in a scoping review The home as a context for care not only can promote patients’ autonomy and well‐being, but also can increase safety risks A patient‐centred approach is one of the key components of high‐quality integrated care. Integrated care has been linked to increased service efficiency, decreased costs  guidelines were followed throughout. In autumn 2017, students in a master’s‐level caring science programme (n = 18) received training in observation technique and, under the auspices of a healthcare administration course part of their degree programme, collected data at two municipal HHC organisations. The healthcare administration course that the students participated in encompassed the study of various classification systems and classification theories. The observation sheet for this study was based on a differentiation between activities involving indirect and direct patient contact In this study, the students engaged in the one‐to‐one nonparticipatory observation of HHC nurses’ n = 18) work, observing 2–3 work shifts per nurse. Nonparticipatory observation involves observing participants without active participation and is used to understand a phenomenon by accessing a setting while still maintaining detachment from the activities being observed 8 work, oThe data collected included students’ observations of HHC nurses’ activities and time management and some demographic patient data . The observation data (n = 196 observation sheets) were synthetised using quantitative descriptive methods , but due to small subsample sizes, no correlations or statistical significance tests were calculated.The ethical principles delineated by the Finnish National Board on Research Integrity The healthcare administration course part of the master’s‐level caring science programme was obligatory for those students seeking to minor in healthcare administration. Because the focus of the course was on healthcare administration research and development, those overseeing the degree programme sought a project whereby the students could gain practical research experience. This included students following a research process from start to finish: from plan (written by the research leader) to published results (written by the research team). The students’ were tasked with collecting data. While one can consider this project to be more of a didactical exploration than an ordinary research project, it nonetheless yielded useful information for the various stakeholders involved, that is the university offering the degree programme and the municipalities providing the HHC services.The HHC nurses received a study information sheet from their respective nurse managers and were given an informed consent letter to fill in, providing agreement to participate in the study. The information sheet contained information about the aim of the study, quality improvement process, data collection procedures, informants’ right to self‐determination and aspects of confidentiality. The HHC nurses also received information about who to contact for additional study information. All of those given the study information sheet agreed to participate in the study.The course teacher for the healthcare administration course, two members of the study research team and the HHC nurses’ nurse manager together created a schedule for the observations. The observation sheet was pilot‐tested when one volunteer HHC nurse was followed and observed by the course teacher during a workday. Following this pilot test, the observation sheet was revised, because the original, precise separation of nursing tasks was seen to be problematic. During the pilot test, for example, it was observed that an HHC nurse could provide emotional support (through a caring conversation) while simultaneously taking care of wounds or be interrupted by a telephone call while dispensing medication.The course teacher and the HHC nurses’ nurse manager together paired the students and HHC nurses. The participating HHC nurses were guaranteed anonymity, and all information relating to their identity was coded in the data analysis and removed from the research report.While the students did not participate in any nursing activities, the HHC patients were nonetheless asked whether they consented to the students’ presence during an HHC visit (informed consent).The observation sheets were collected in separate boxes. All data were collected and are safely stored in a locked filing cabinet at the university where the researchers are employed. The data will not be used for any other purposes other than what was agreed upon with the informants prior to data collection.Altogether, 18 HHC nurses were observed during 2–3 work shifts per nurse, and the observation data consisted of 196 observation sheets. The HHC nurses’ background data are presented in Table All of the HHC nurses had a professional nursing education, and the majority (56%) also had one or more specialisations, such as public health nurse, midwife, internal medicine and surgery, or acute care. The HHC nurses received their nursing degrees between 1987 and 2017, with the majority (85%) receiving degrees between 1997 and 2014. Their HHC work experience varied from 1.5 months to 21 years. Due to small subsample sizes, it was not possible to analyse any correlations between the demographic data and other variables.The observation material consisted of one observation sheet per home visit, and patients can be visited several times during the data collection phase. The majority of HHC patients seen here Table  were femDuring eight‐hour shifts, the HHC nurses in this sample (n = 196 observation sheets) spent from 75 to 410 minutes  on indirect patient contact activities  per patient per visit on direct patient contact activities. On the majority of observation sheets, the only information recorded was categorised under the main categories , with nothing under the subcategories . This, however, was not seen to be a detriment, because the subcategories were mainly used to exemplify the main categories and facilitate the students’ observations. About 15 minutes (M) was spent on Nursing care, 17 minutes (M) on Medication and 10 minutes (M) on Caring discussion (could include patient education). Explicit patient education was offered during only 3.5% of home visit. Information recorded under Other activities included the following: waiting for the patient to come and open the door (3–5 minutes), documentation during home visit (3–15 minutes), further situation analysis (5–10 minutes) and acute care situation . It was observed that the data for direct patient contact activities represent nurses’ time management during one home visit and should therefore be multiplied by the average number of home visits per nurse during a work shift, that is 3–6 home visits Table .From the data, one sees that the HHC nurses spent 50% of their time on indirect patient contact activities and 38% on direct patient contact activities. Of the direct patient contact activities, the majority were illness‐centred and included a focus on clinical symptoms or medication. Altogether, 12% of activities were characterised as unclear (neither indirect nor direct), possibly because the students only recorded activities under the main categories in the observation sheet. It is also possible that this was related to methodical difficulties; the students may have been uncertain about how to record what they observed, for example if many activities occurred simultaneously. Prior to the start of the observations, the students were instructed to record any activities that they perceived as being unclear under the category Other activities in the observation sheet, along with a brief explanation.The aim of this study was to describe HHC nurses’ activities and time management from the perspective of master’s‐level nursing students. With reference to Benner’s The majority of the patients in this sample received home visits because of a long‐term illness  or multimorbidity. Also, the majority of activities underlying the home visits could, to some degree, be linked to long‐term illnesses: medication (57%), blood samples (23%), wound care 17%) or measurement of blood pressure (14%). Only a few observations of acute care activities were seen . The sample corresponds well with long‐term illness prevalence statistics in Finland. Consequently, it can be considered relevant and comparable to other HHC populations (see also Ref. 7% or meaPatient education was observed during only 3.5% of home visits. Still, the nurses may have also given emotional support, engaged in caring conversations, encouraged patients’ physical activity or conducted rehabilitative acts while performing other nursing activities. As noted previously, the simultaneous performance of nursing activities could be problematic with regard to characterisation, and the students were instructed to record any activities considered to be unclear under the Other activities category. Despite 12% of the patient sample having cancer and 2.5% having pain, there were no observations of palliative care as such. Based on the findings, we maintain that HHC is quite illness‐centred (see also Ref. In this sample, about half of each eight‐hour work shift was used on indirect patient contact activities In comparison, the time spent on direct patient contact activities We still note the possibility that missed care or care left undone due to unrealistic nurse‐to‐patient ratios, as seen by Aiken et al. in a hospital context for the patient, to promote continuous intra‐ and interprofessional patient care (see also Ref. with the patient. Observation data on person‐centeredness as shared decision‐making and/or in meaningful activities in a personalised environment were not available (see also Refs The aim of periodic or continuous HHC is the provision of holistic medical and nursing care. The patients here had different long‐ or short‐term health problems, and diverse nursing activities were required. As seen in the data, there were a number of activities conducted The accuracy of the students’ observations is related to their individual capacity to objectively and selectively observe, which is a limitation. Also, the structure of the observation sheet, which was based on a differentiation between activities involving indirect and direct patient contact Older and/or multimorbid clientele require integrated care skills, which at a minimum necessitates the further education and training of HHC staff or even standardised certification. To ensure integrated, person‐centred, safe patient care, these vital reforms should be immediately implemented alongside the reorganisation of HHC nurses’ work duties, that is HHC structures and processes. Performance effectiveness is related to the training and quality of individual nurses and the way care is organised.In the observation data, 50% of the care provided by nurses during each eight‐hour work shift was spent on indirect patient contact activities and only 38% on direct patient contact activities. While the indirect patient contact activities did promote continuous intra‐ and interprofessional patient care and patient safety, such a difference could weaken person‐centeredness and rehabilitation. The appropriate balance between indirect and direct patient contact activities should be discussed intra‐ and interprofessionally, delineated and made explicit in nurses’ work plans and nursing documentation, alongside discussions pertaining to relevant resource allocation.During an eight‐hour work shift in an HHC setting, nurses spend more time on indirect than direct patient contact activities.Health issues related to long‐term illnesses underlie the majority of HHC visits. Thus, one can conclude that HHC is at present quite illness‐centred, with a focus on clinical symptoms and medication instead of person‐centred care.To ensure person‐centred, safe patient care in an HHC setting, vital reforms should be immediately implemented. These include standardised certification policies and the delineation of the balance between indirect and direct patient contact activities in nurses’ work plans and nursing documentation, in parallel with relevant resource allocation.What does this paper contribute to the wider global clinical community?The authors have no conflicts of interests.LF was responsible for the pilot study design and the observation sheet structure, and has participated the manuscript writing with critical appraisal. YN was responsible for the leadership course during which the data collection was organised, tested the observation sheet, instructed the master's students in use of it, and participated the manuscript writing. HVR was responsible for the data analysis and had responsibility over the manuscript, submission and correspondence.We have followed the journal’s authorship policy in the Editorial Policies and Ethical Considerations section on eligibility for author listing.This manuscript is part of a research project funded by Eschnerska Foundation, Turku, Finland.


Soil organic matter (SOM) is abundant in the environment and plays an important role in several biogeochemical processes, including microbial activity, soil aggregation, plant growth and carbon storage. One of its key functions is the retention and release of various chemical compounds, primarily governed by the sorption process, which strongly affects the environmental fate of nutrients and pollutants. Sorption largely depends on the composition of SOM, as well as its structure, dynamics and the thermodynamic conditions. Although several approaches are available, experimental characterization of sorption mechanisms is not easy. Computational models for predicting sorption coefficients often require a wealth of experimental data for training and are only applicable to compounds and conditions related to the training dataset. Here, we use molecular dynamics (MD) simulations to study the sorption of a range of small organic compounds. As a model SOM system we use the standard Leonardite humic acid (LHA) sample, which physicochemical properties have recently been characterized computationally in detail. This model allowed us to estimate sorption propensities of the systems at two different hydration levels (water activities close to 0 and 1), showing a remarkable correlation with experimental data. Importantly, this molecular modelling approach based on perturbation free‐energy calculations is rigorously derived from statistical thermodynamics and requires no experimental sorption data for training. It is therefore in principle applicable to any SOM model or thermodynamic condition. Moreover, the power of MD simulations to provide high‐resolution insight into atomistic and molecular interactions was employed to explore how sorbate molecules associate with the LHA matrix and which contacts they form. The heteroatoms of both sorbate and sorbent play an important role and water molecules are identified as further key players in facilitating the sorption process.Modelling of the sorption processes in soil organic matter at atomistic level.Rigorous, physics‐based approach applicable to a range of SOM systems and conditions.Remarkable level of matching with experimental data with additional insight into the molecular mechanism.Interactions between the sorbate and local environment strongly affects the sorption process. However, QM methods are computationally rather expensive and, therefore, limited in the number of atoms and tractable timescales. On the other hand, classical modelling methods, including molecular dynamics (MD) simulations, approximate the interactions with a force field . Associated empirical parameters are typically derived by fitting atomic or molecular properties of small molecules against calculated quantum‐mechanical or experimentally measured data. So far, different approaches have been employed to model SOM systems , a sample readily available from the International Humic Substances Society. It is one of the richest known sources of humic acids and its isolation, preparation and chemical composition have been documented in detail  from the free‐energy difference of transferring a water molecule from bulk water to the system of interest (ΔGwater → LHA)  and at water activity equal to 1 (hydrated system with 0.3 M fraction of water) were taken from Petrov et al. . Briefly−4 (kJ mol−1 nm−3)−1. A molecular pair‐list was generated using a triple‐range cut‐off  is obtained, whereas at λ = 1, the interactions between the sorbate and its surroundings have been switched off. A soft‐core potential was used for perturbations of non‐bonded interactions  and growing (λ = 1 → λ = 0) a sorbate molecule within 1.6 ns simulation was repeated 25 times for three independent models for a total of 150 perturbation simulations and 240 ns per sorbate. Equilibrated systems were used as initial configurations with a sorbate molecule placed and oriented randomly within the simulation box. To obtain statistically robust results, we have resampled the non‐equilibrium work distributions 1,000 times. Reported free‐energy differences and their error estimates were calculated using the Crooks Gaussian intersection method as the averages and the standard deviations over the resampled distributions of free energies. The free energy of sorption was calculated as:ΔGLHA is the free energy of decoupling of the sorbate in the standard Leonardite HA and ΔGvac is the free energy of decoupling in a vacuum. Importantly, this property directly relates to the logarithm of the experimentally measured humic acid/air partition coefficients KiHA,air (up to an elusive constant c)  of the studied set of compounds, together with two additional groups of compounds chemically similar to dimethyl succinate and 1‐undecene (Table λ points. The free energy of this process (ΔGwater) is computed by integrating the ensemble average of ∂H/∂λ over λ, which was numerically calculated using trapezoidal integration. The hydration free energy (ΔGhyd) is then obtained as:Non‐equilibrium free energy calculations were carried out to compute the sorption free energies for a set of 18 small organic molecules  and GAB for Kirkwood‐Buff integrals that were calculated from the radial distribution functions with an upper boundary of 1.5 nm. xA is the molar fraction of species A in the system, calculated as the normalized number of heavy atoms. Moreover, Kirkwood‐Buff integrals were also evaluated with shorter upper boundaries of 0.3, 0.4 and 0.5 nm to characterize the local environment surrounding sorbate molecules. Note that non‐normalized Kirkwood‐Buff integrals (multiplied with xA and xB) are marked with a star.Coordinates of the simulations were stored to disk every 5 ps. Simulated trajectories were analyzed primarily using gromos++ analysis tools . In particular, potential energy and its two components  and the number of hydrogen bonds were monitored between a sorbate and LHA molecules, water and calcium ions, and between LHA molecules and water, respectively. The occurrence of a hydrogen bond was determined using a geometric criterion considering the acceptor‐hydrogen distance (at most 0.25 nm) and the donor‐acceptor angle (at least 135°). The solvent‐accessible surface area (SASA)  of the sorbate was calculated together with the carbon and heteroatom fractions. Kirkwood‐Buff integrals, which quantify the amount of one type of molecule or particle surrounded by another type, were calculated between a sorbate and constituents of the Leonardite HA models and their subparts, including carbon and heteroatoms of the sorbate on the one hand, and carbon and heteroatoms of LHA molecules, water and calcium on the other.33.1We have used molecular dynamics simulations to study sorption of a set of small organic compounds Table , which w−1) than for the corresponding group of additional compounds bearing only one.To the best of our knowledge, experimental hydration free energies are not available for dimethyl succinate and 1‐undecene, for which reason additional, chemically similar compounds with available experimental data were added to the set Table , with a ΔGLHA and ΔGLHA depicted in Figure The set of compounds was subjected to calculations of sorption free energies. In particular, we performed 150 independent non‐equilibrium perturbation simulations of growing and removing a sorbate in the dry and hydrated LHA models, corresponding to the perturbation process of ‐ΔΔGsorbexp. Even with some level of disagreement, these correlations are remarkable given that the calculation approach applied is exclusively based on statistical‐mechanics principles and does not require prior calibration of the model against experimental sorption data. Several potential sources of observed discrepancies can be identified, including uncertainty in experimental measurements and calculations (estimated averages of 1.6 and 1.3 kJ mol−1 for the dry and hydrated LHA) or differences in modelled and experimental conditions to name a few (see Discussion for more detail). Interestingly, sorption free energies calculated in the dry Leonardite HA show a similar level of matching to experimental data measured in hydrated LHA samples  with a correlation coefficient of 0.77, whereas the opposite comparison yields a weaker correlation (r = 0.67). Furthermore, calculated free energies of hydration are almost identical to the sorption in hydrated LHA, to a much greater extent than experimentally observed . However, this water‐like behaviour in terms of sorption strength might also arise as a bias of non‐equilibrium simulations, where the sorbate localizes preferentially to water patches due to low diffusion coefficients of LHA molecules. This is further corroborated by the analysis of preferential solvation, showing that sorbate molecules indeed preferentially interact with water in hydrated LHA and with LHA molecules in the dry systems , and how they relate to the sorption free energy. For example, we observed a strong anticorrelation between the sorption free energy and the number of hydrogen bonds the sorbate forms with water molecules Figure a. Simila4This study presents the first‐ever attempt to study sorption properties of a range of small organic molecules in standard Leonardite HA as a model SOM system, using perturbation free‐energy calculations in combination with MD simulations. In contrast to several approaches applied so far  is needed. Intrinsically, the interactions that govern atomic and molecular motions are of a quantum nature, and by using a force field they are approximated with classical potential energy terms. These approximations notwithstanding, force field methods have been successfully employed for decades to study various molecular systems  are connected with vertical dotted lines. Note that the effect of reparameterization of dimethyl succinate bearing two ester groups is much more pronounced (approximately 8 kJ mol−1) than is the case for additional similar compounds as they bear one ester group. Compounds (Table 1) are separated into groups based on their chemical composition. The correlation is captured with the black regression line and Pearson coefficient , while the identity line is shown in green.Figure S2. Sorption free energy in the hydrated Leonardite HA compared to experimental data from dry Leonardite HA and the other way around. Compounds (Table 1) are separated into groups based on their chemical composition. The correlation is captured with the black regression line and Pearson coefficient, while the identity line is shown in green.Figure S3. Comparison between sorption free energy in hydrated Leonardite HA and hydration free energy for calculated (left) and experimental (right) data. Compounds (Table 1) are separated into groups based on their chemical composition. The correlation is captured with the black regression line and Pearson coefficient, while the best fitting line with slope 1 is shown in green. Nota that the same comparison of the hydration to sorption free energy in the dry LHA systems shows weaker agreement, with the correlation coefficients of 0.8 and 0.72 for the calculated and experimental data, respectively (data not shown).Figure S4. Selected microscopic properties calculated from observed interactions in simulated trajectories between sorbate compounds and Leonardite HA and their relation to sorption free energy in the dry Leonardite HA. The correlation between a given property and the sorption free energy for the 18 studied compounds (Table 1) is captured with the black regression line and Pearson coefficient. Similar to Figure 6, properties showing a strong anti‐correlation A‐C, a strong anti‐correlation D and E, and no correlation F–H.Table S1. List of microscopic properties calculated from observed interactions in simulated trajectories between sorbate compounds and the Leonardite HA and their relation to sorption propensity, expressed in terms of the correlation coefficients to the calculated sorption free energy. Analyzed properties include potential energy (E) and different components thereof , hydrogen bonds (H‐bonds), and Kirkwood‐Buff integrals (G)  with the limit of 0.3, 0.4 and 0.5 nm between the Leonardite HA and the sorbate and their subparts , as well as solvent‐accessible surface area (SASA) of the sorbate with the carbon and heteroatom fractions.Click here for additional data file.


Pseudacris brachyphona), an understudied anuran, in Appalachian Virginia, USA, prior to and during the SARS‐CoV‐2 pandemic. A transition to virtual training in this initiative did not lead to a decrease in scientific output and led to unexpected natural history insight about our focal taxon; however, a reliance on virtual instruction did decrease overall participation by local residents, particularly for rural K‐12 students. We discuss the trade‐offs exhibited by the adaptation of our initiative to a virtual format and provide recommendations for other citizen science initiatives facing similar restrictions in the face of current and future public health crises.Citizen science approaches provide adaptable methodologies for enhancing the natural history knowledge of understudied taxa and engaging underserved populations with biodiversity. However, transitions to remote, virtual training, and participant recruitment in response to public health crises like the SARS‐CoV‐2 pandemic have the potential to disrupt citizen science projects. We present a comparison of outputs from a citizen science initiative built around call surveys for the Mountain Chorus Frog ( Pseudacris brachyphona), an understudied anuran, in Appalachian Virginia, USA, prior to and during the SARS‐CoV‐2 pandemic.Citizen science approaches provide adaptable methodologies for enhancing the natural history knowledge of understudied taxa and engaging underserved populations with biodiversity. However, transitions to remote, virtual training, and participant recruitment in response to public health crises like the SARS‐CoV‐2 pandemic have the potential to disrupt citizen science projects. We present a comparison of outputs from a citizen science initiative built around call surveys for the Mountain Chorus Frog ( This is particularly true for easy‐to‐identify taxa that are located across undersurveyed areas and/or regions dominated by privately owned lands that are inaccessible to biologists , an easily identified yet understudied anuran with high regional conservation priority  is a small member of Hylidae adapted to forests across portions of the eastern United States, primarily centered across the southern and central Appalachian Mountains  increase the distributional knowledge of Mountain Chorus Frogs across the study area and (b) engage rural residents from historically underserved communities, particularly K‐12 students and undergraduates, with anuran biodiversity and associated monitoring approaches. We initially trained 486 individuals  through in‐person programs from February–May 2019, corresponding to the period just prior to and during the species’ local breeding season. The locations of in‐person training modules were chosen to overlap with the known distribution of Mountain Chorus Frogs in Virginia.https://www.mtchorusfrog.fishwild.vt.edu/). Samples of content used during training modules  can be viewed under the “Learn” and “Report Observations” tabs at the aforementioned website. All approved institutional protocols involving the use of human subjects were followed during the design and implementation of training and data collection procedures.Training modules consisted of presentations by the coauthors on regional anuran diversity, characteristics of Mountain Chorus Frogs, the purposes of the monitoring effort, and how to identify the species’ advertisement call and distinguish it from other regional taxa. When possible, we accompanied participants to local wetland habitats on public lands following training events to model field protocols. All participants were trained to record samples of advertisement calls as audio or video files using their smartphone's native applications or a digital recorder provided to each participating classroom, along with data on the context of the observation . Participants then sent observations to the investigators via email. Training information, along with links to online audio samples, was also housed on a website created to allow participants to review training content following the delivery of in‐person modules  to recruit interested participants. Participants were encouraged to only participate in sampling if it was possible to meet social distancing requirements . For both years of the project, we accepted submissions from citizen observers throughout the entirety of the species’ local breeding season (roughly 1 March to 1 June), with participants encouraged to sample accessible public lands and only those private lands that participants either owned or had permission to sample. 434 individuals viewed our virtual training video during the 2020 field season, providing a similar scope of trainees across both years of the initiative.We hypothesized that a switch to virtual, asynchronous training and social distancing restrictions imposed on participants as a result of the SARS‐CoV‐2 outbreak would: (a) result in fewer overall citizen submissions, (b) reduce the proportion of reports submitted from public lands, relative to those recorded on participants’ private property, and (c) increase the rate of misidentified advertisement calls due to limited training and a lack of field‐based engagement with the project investigators. We assessed these differences following the completion of the species’ peak local breeding season in June 2020.3N = 14; Figure Citizen observers across both years reported a total of 83 confirmed observations of Mountain Chorus Frogs backed by verifiable sound recordings or photographs, which accounted for nearly six times the number of historic observations recorded by biologists from the late 1800s to 2019 across the study area , and several state‐managed multi‐use trail systems. By contrast, observations in 2020 were primarily reported from privately owned lands  and Upland Chorus Frogs , as well as Cope's Gray Treefrog .False positives, or reports of species other than Mountain Chorus Frogs, were minimal both prior to and during the SARS‐CoV‐2 outbreak . Misidentified observations were primarily constrained to congeners that are common and abundant in the study region, including Spring Peepers ; Formal analysis (lead); Funding acquisition (supporting); Methodology ; Writing‐original draft (lead); Writing‐review & editing . M. Kevin Hamed: Data curation ; Formal analysis (supporting); Funding acquisition (lead); Methodology ; Writing‐original draft (supporting); Writing‐review & editing .


Radiofrequency catheter ablation has become an established treatment for ventricular tachycardia. The exponential increase in procedures has provided further insights into mechanisms causing arrhythmias and identification of ablation targets with the development of new mapping strategies. Since the definition of criteria to identify myocardial dense scar, borderzone and normal myocardium, and the description of isolated late potentials, local abnormal ventricular activity and decrementing evoked potential mapping, substrate‐guided ablation has progressively become the method of choice to guide procedures. Accordingly, a wide range of ablation strategies have been developed from scar homogenization to scar dechanneling or core isolation using increasingly complex and precise tools such as multipolar or omnipolar mapping catheters. Despite these advances long‐term success rates for VT ablation have remained static and lower in nonischemic than ischemic heart disease because of the more patchy distribution of myocardial scar. Ablation aims to deliver an irreversible loss of cellular excitability by myocardial heating to a temperatures exceeding 50°C. Many indicators of ablation efficacy have been developed such as contact force, impedance drop, force‐time integral and ablation index, mostly validated in atrial fibrillation ablation. In ventricular procedures there is limited data and ablation lesion parameters have been scarcely investigated. Since VT arrhythmia recurrence can be related to inadequate RF lesion formation, it seems reasonable to establish robust markers of ablation efficacy. New mapping strategies for radiofrequency ablation of ventricular tachycardia have been developed so substrate‐guided ablation has become the method of choice to guide procedures. Also, many ablation strategies have been developed using increasingly complex and precise tools. However long‐term success rates for VT ablation have remained static. Many indicators of ablation efficacy have been developed but in ventricular procedures ablation lesion parameters have been scarcely investigated. Since VT arrhythmia recurrence can be related to inadequate RF lesion formation, it seems reasonable to establish robust markers of ablation efficacy. The recent international consensus report supports RFCA as a first‐line therapy for VA in normal heart Ventricular Tachycardia (VT) and in structural heart VT after ineffective anti‐arrhythmic drug (AAD) therapy.The exponential increase in the treatment of VAs with RFCA in clinical practice has provided further insight into the mechanisms of these arrhythmias, improved identification of ablation targets with the development of new mapping strategies supported by mapping and ablation technological advances. Much of this growth in the field of VT RFCA has been focused on identification of the VT critical isthmus and localizing the site of origin of the arrhythmias.Traditionally, the 12 lead ECG has been a useful tool in defining the location of arrhythmia origin and this should not be neglected despite the subsequent development of highly specific complex mapping technologies. These technologies have helped to further define the VT site of origin from conventional entrainment and pacing maneuvers during triggered VT, towards substrate mapping during sinus or paced rhythmAfter the first description by Marchlinsky et al, the electrical criteria for the characterization during substrate mapping of myocardial dense scar, BZ and normal myocardium have been universally adopted and more recently adapted by the EP community.Technological advances for VT mapping has been another field that has undergone exponential development. EGM amplitude for normal and abnormal tissue were described using the standard ablation and mapping catheters with 4‐mm tip electrodes, 1‐mm ring electrodes and 2‐mm interelectrode spacing. However, EGMs detected are strictly dependent on electrode size and orientation respective to wavefront propagation, which rapidly changes directions resulting in a changeable recording according to the vector line of assessment. As a result, these catheters may not identify low‐voltage EGMs propagating orthogonal to their orientation potentially missing critical arrhythmic substrate. More recently, multipolar electrode catheters with 1mm electrodes and variable interspacing have been introduced facilitating high‐density map construction. This enables an increase in the near‐field voltage detected and reduces far‐field signals providing a better definition of substrate. Furthermore, omnipolar mapping catheters also provide a wavefront directional assessment.Indeed, an accurate, detailed substrate map plays a crucial role in short‐ and long‐term ablation efficacy as critical isthmus and slow conduction region identification is facilitated. These regions provide the substrate for reentrant circuits and are often characterized by the presence of isolated LPsAmong the varying substrates for structural heart diseases an important determinant in ablation efficacy is the underlying cardiomyopathy: for instance the scar region in most ischemic cardiomyopathy (ICM) patients is endocardialThe experience in ablation treatment of ventricular arrhythmias in normal hearts and more specifically in treatment of premature ventricular complexes (PVCs) has also advanced. It has been demonstrated that an ablative approach is more efficacious than conservative medical therapy with anti‐arrhythmic drugs (AADs).2Embracing RFCA as an effective therapy for the treatment of VAs is based on the fundamental principle that the intervention delivers solid and durable ablation lesions in the human myocardium. RFCA utilises electromagnetic energy that once delivered at the myocardial tissue interface is transformed into heating that irreversible damages the viable myocytes causing the loss of cellular excitability. Heating to a critical temperature directly destroys the myocardium in contact with the catheter bipolar electrode delivering energy; this process is known as resistive heating.Prior to the increasing application of RFCA in the ventricles, ablation therapy has been widely applied and studied in the atria and more specifically in the complex setting of atrial fibrillation (AF). There is a wealth of literature that has explored optimizing ablation lesions in AF to define the fine balance between the creation of durable ablation lesions versus the avoidance of lesion formation complications such as pulmonary vein stenosis, cardiac tamponade and collateral damage to adjacent structures such as the phrenic nerve and oesophagus. Due to the challenging nature of visualizing lesion formation in real time and ensuring an effective transmural lesion, different surrogate measures of lesion quality have been utilized. The fall in local impedance during ablation is considered as a marker of the direct effect of ablation in cardiac tissue.One of the major determinants of lesion formation is an adequate contact between the tip of the catheter and the myocardial surface. A major technological advancement in ablation catheters was the development of sensors at the distal tip capable of monitoring contact, contact force (CF). While the bulk of evidence has investigated the correlation between CF and outcome of pulmonary vein isolation (PVI) in AF, very limited data are available regarding VT ablation. Elsokkari et al reported the only experience so far showing that in a small cohort of patients with ischemic heart disease, a mean contact force of 10 g within the scar zone has the best correlation with effective lesion formation.A more recent ablation marker is the Force‐Time Integral (FTI), which multiplies CF by radiofrequency application duration; it has been demonstrated that it is predictive of PVI segment reconnection at repeat electrophysiology study.In order to overcome some of these important limitations the Ablation Index (AI) (Biosense Webster Inc) variable evolved which is calculated by incorporating power delivery in its formula and combining it with CF and time in a weighted equation. It has been shown to be a more precise estimation of lesion depth in a canine model.Since its validation as a reliable marker of short‐ and long‐term ablation efficacy, increasing emphasis has been placed on AI, the feasibility in settings other than AF, and the pursuit to determine optimal cutoffs. In a recently published paper, Casella et al retrospectively investigated this topic in a multicenter observational study evaluating AI reliability in patients who underwent RFCA of idiopathic outflow tract PVCs performed using the CARTO electroanatomic mapping system. They investigated 1226 lesions and found that both maximum and mean AI values were significantly higher in patients without PVC recurrence even when stratified for anatomical areas. Lesions were analyzed according to acute and long time success and accordingly the AI values were lower both in patients with acute  and long‐term (6 months) failure; in this second case occasionally acute success was reached suppressing PVCs, but as a result of induced edema, recurrences manifested once the edema had resolved. Authors concluded that AI seems to be a reliable index to evaluate RFCA in PVC ablationUnlike the field of AF ablation, where the AI algorithm has been studied extensively in the atrium,There is an ongoing clinical trial led by Ullah et al to assess the value of LPs and AI in VT ablation . This is a small (n = 15) open label study which aims to collect ventricular substrate maps  in patients undergoing ablation for VT. During ablation, impedance and AI data will be collected. Thus, the only experience investigating radiofrequency (RF) lesion depth and width in normal voltage myocardium (NVM), LVM and IVM defined by electroanatomical maps (EAM) and their association with AI and impedance drop is limited to basic science studies.P < .001). In addition, the RF lesion depth and width were smaller in LVM compared with IVM (P < .001). The RF lesion depth and width correlated with CF, AI and impedance drop in NVM and IVM: The RF lesion depth and width correlated stronger with AI in NVM than in IVM  while the impedance drop during ablation was higher in NVM (27 ± 10Ω) compared with IVM  and LVM  but this did not differ between IVM and LVM. Tofig et al also utilized native contrast magnetic resonance imaging (ncMRI) to correlate the RF lesion depth and width with that of gross anatomical evaluation. They found that the RF lesion depth and width as assessed by cnMRI correlated closely with that of gross anatomical evaluation in NVM, IVM (depth and width P < 0.001 in both NVM and IVM) and LVM (depth and width P < .05).Tofig et al performed in vivo EAM and endocardial RF ablation in 10 pigs at 12 weeks post‐myocardial infarction (MI) by left anterior descending artery (LAD) occlusion and reperfusion.The findings by Tofig et al suggest that IVM and LVM regions are less prone to conductive heating compared to NVM and this may be because of the higher degree of heterogeneity of myocardial composition in the IVM and LVM regions. In terms of the potential applicability in the clinical setting, the findings of this study could one day be used to guide the titration of RF delivery to ensure adequate lesion formation especially in the IVM and LVM regions.This was not the first study evaluating RFCA in MI models but it is the first one that utilizes the newer indices to evaluate RF efficacy and differences between areas of normal myocardium and scar. A similar study was performed by Kovoor et alSimilar to AI, Lesion Size Index (LSI) is a multi‐parametric ablation index that incorporates in a weighted formula the 3 components contact force, power and duration of radiofrequency delivery. In an in‐vitro model of radiofrequency ablation on porcine left ventricular myocardial slabs, LSI values were highly predictive of lesion width and depth, whereas power and CF did not In a study investigating tissue temperatures in porcine heart specimens during radiofrequency ablation at different power settings for fixed AI and LSI values, Takemoto et al showed that the maximum tissue temperature was significantly lower at 40 W compared to 20 W for a given LSI value, providing evidence for a safer LSI‐guided procedure at higher power RF settings. In comparison, an equivocal AI provided a similar tissue temperature at high and low power. Of note LSI‐guided lesion size was significantly larger with 20 W applications due to the longer duration of high temperature and enhanced heat distribution, whilst lesion size did not significantly alter with AI‐guided 20 W or 40 W applications for the same AI valueA few preliminary studies have assessed performance of LSI in clinical setting, showing better long‐term free survival from AF recurrence in PVI procedures guided by LSI compared contact force monitoring The potential advantage of LI DIRECTSENSE in respect to AI and LSI is that it facilitates a substrate map based on tissue impedance defining areas of scar and normal myocardium as well areas of impedance drop after ablation. Indeed the data reported by Münkler et al in patients with NIDCM suggests a potential preference for LI guided procedure for VT ablation in this cohort of patients. Indeed it is in the context of NIDCM where VT ablation presents the most unsatisfactory outcomes due to the already described characteristics and distribution of myocardial scar. Recently, Della Bella and colleagues reported on the feasibility and efficacy of bipolar ablation in patients with NIDCM VT originating from the deep inter‐ventricular septum. Of note, the authors regulated the delivery of bipolar radiofrequency pulses on the basis of a drop in impedance of 20‐40 Ω as per prior ex vivo study protocols.Increasing insights regarding radiofrequency lesions and their anatomical characteristics have come from the expanding use of cardiac MRI (CMR). Initial observations have emerged from animal models In conclusion, RFCA has become a mainstream therapy for the treatment of VT. The procedure has evolved focusing on the accurate identification of targets for ablation, improving and defining substrate mapping. In addition, there has been a technological advancement in the monitoring and titration of energy delivered to yield effective RF lesion formation. However, the application of these tools have been scarcely investigated and implemented in the practice of VT ablation. Since VT recurrence in patients treated with RFCA can be related, at least partly, to inadequate RF lesion formation, it is imperative that we continue to explore the need for robust, transferrable markers of ablation efficacy.The authors declare that there is no conflict of interest.


Treatment numbers of various cardiovascular diseases were reduced throughout the early phase of the ongoing COVID‐19 pandemic. Aim of this study was to (a) expand previous study periods to examine the long‐term course of hospital admission numbers, (b) provide data for in‐ and outpatient care pathways, and (c) illustrate changes of numbers of cardiovascular procedures.Administrative data of patients with ICD‐10‐encoded primary diagnoses of cardiovascular diseases  and in‐ or outpatient treatment between March, 13th 2020 and September, 10th 2020 were analyzed and compared with 2019 data. Numbers of cardiovascular procedures were calculated using OPS‐codes. The cumulative hospital admission deficit (CumAD) was computed as the difference between expected and observed admissions for every week in 2020. In total, 80 hospitals contributed 294 361 patient cases to the database without relevant differences in baseline characteristics between the studied periods. There was a CumAD of −10% to −16% at the end of the study interval in 2020 for all disease groups driven to varying degrees by both reductions of in‐ and outpatient case numbers. The number of performed interventions was significantly reduced for all examined procedures .This study provides data on the long‐term development of cardiovascular patient care during the COVID‐19 pandemic demonstrating a significant CumAD for several cardiovascular diseases and a concomitant performance deficit of cardiovascular interventions. Consecutive patient cases with an in‐ or outpatient hospital admission date between March 13th 2020  and September 10th 2020 were analyzed and compared with the corresponding period in 2019 . Cause‐specific hospitalizations were defined based on the encoded primary diagnosis at hospital discharge according to the International Statistical Classification of Diseases and Related Health Problems (ICD‐10‐GM [German Modification]). Patients with primary discharge diagnosis of specific cardiovascular diseases were further studied. Numbers of cardiovascular interventions were calculated using the Operations and Procedures‐codes  within hospital discharge data. Comorbidities were identified from encoded secondary diagnoses at hospital discharge according to the Charlson Comorbidity Index (CCI), which has been calculated with minor adjustments according to previous publications.2.22 test for the last week of the period. The p‐values were adjusted for multiple comparisons using a Bonferroni correction. For all tests we apply a two‐tailed 5% error criterion for significance.Administrative data were extracted from QlikView . We calculated the total number of monthly and weekly admissions, with weeks defined so that the first day of the national protection phase  corresponds to the beginning of the investigated week. The cumulative hospital admission deficit (CumAD) was computed as the difference between the expected and observed cumulative admission number for every week in 2020, expressed as a percentage  of the cumulative expected number, which is defined as the weekly average across the time interval in 2019. The difference between the expected and observed cumulative admission number was assessed using a χ33.1A total of 80 hospitals contributed 294 361 patient cases to the database  for the years 2019 and 2020 . There were no differences in the distribution of baseline characteristics between the control period in 2019 and each of the studied months in 2020 with respect to gender, age groups, CCI or the treatment in areas with different COVID‐19 case volumes  for heart failure, −13% for cardiac arrhythmias , −11% for ischemic heart disease ; −13% for valvular heart disease , −16% for arterial hypertension‐related hospital admissions , and −14% for admissions of patients with peripheral vascular disease . The total reduction in hospital admissions was driven in all disease groups by a decline in both in‐ and outpatient treatment numbers with a greater reduction in inpatient cases in heart failure (inpatient −17% vs. outpatient −7%), cardiac arrhythmias (inpatient −16% vs. outpatient −7%), arterial hypertension (inpatient −21% vs. outpatient −11%), and peripheral vascular disease (inpatient −17% vs. outpatient −6%), a similar reduction of in‐ and outpatient treatment numbers in the group of ischemic heart disease (inpatient −11% vs. outpatient −12%) and a pronounced reduction of outpatient cases in valvular heart disease (inpatient −10% vs. outpatient −18%). All results of the CumAD analysis are shown in Table 3.3In total, 117 782 interventions were counted . Baseline characteristics were not different in the subgroup of patients who underwent any prespecified cardiovascular procedure comparing 2019 and each of the studied months in 2020 , this should only affect our findings to a minor extend. Factors being discussed to potentially truly reduce the necessity of in‐ our outpatient hospital treatment are an improved air quality during the lockdown phase and the reduction of seasonal infections as a consequence of restricted social contacts since both of them are triggers for an acute deterioration of pre‐existing heart diseases.Further studies are needed to confirm our findings and identify causes for the observations being made. Whether those changes in healthcare utilization during the COVID‐19 pandemic imply consequences for future treatment of patients with cardiovascular diseases cannot yet be foreseen.5This study analyzed administrative data, which were not stored for research interests, but for remuneration reasons, which potentially could affect the encoded information. Quality of the results depends to a large extent on the correct encoding of procedures and diagnoses at hospital discharge.6Our study is the first to show the development of hospital admission numbers during the course of the COVID‐19 pandemic for several cardiovascular disease groups demonstrating both a decrease in case numbers within the in‐ and outpatient setting. Although increasing after the early pandemic phase from March to May, a significant CumAD remained for all disease groups. Moreover, a significant performance deficit for all studied cardiovascular interventions was found. Consequences of these findings cannot be foreseen and deserve further research.Gerhard Hindricks is receiving grants through the Leipzig Heart Institute from Boston Scientific , and Abbott/St. Jude Medical , no personal payments are to declare. All other authors state that there is nothing to declare.CCICharlson comorbidity indexCIconfidence intervalCumHDcumulative hospital admission deficitGLMMgeneralized linear mixed modelsICD‐10‐GMInternational Statistical Classification of Diseases and Related Health Problems (German Modification)OPSoperations and proceduresAppendixS1. Supporting information.Click here for additional data file.


SCN1A is one of the most important epilepsy‐related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A‐related phenotypes. We investigate the presence of rare and more common variants in epilepsy‐related genes as potential modifiers of SCN1A‐related disease severity.SCN1A‐related epilepsy were investigated. Whole‐exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database.87 patients with Statistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of <0.05. Patients with extreme phenotypes showed much greater excesses of epilepsy gene variants than patients with intermediate phenotypes.SCN1A phenotypes. They may modify the phenotypes of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients.Our results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic, may play a large role in modulating  SCN1A‐related phenotypes. They may modify the phenotypes of both severely and mildly affected patients.Relatively common variants in epilepsy genes may play a large role in modulating  Patients were either part of families with multiple SCN1A variant that was predicted to cause a loss of function (LoF), or a variant that has been described before in Dravet syndrome patients. This limits the influence of the different pathogenic SCN1A variants itself on the phenotypes and creates a group of patients for which we can be relatively certain that ameliorating modifiers play a role. The “severe” and “intermediate” groups included patients with all mutation types.To compare subgroups, we then excluded “mild” patients that did not carry an 2.32.3.1Whole‐exome sequencing was performed on DNA from lymphocytes in all patients by the Beijing Genomics Institute (BGI), using the Agilent V5 50M exome kit enrichment, followed by paired‐end sequencing on an Illumina Hiseq. The resulting data was processed using an in‐house developed pipeline , previous literature and the KEGG pathway database  , and in genes associated with ID , based on genes included in diagnostic gene panels of the University Medical Center Utrecht  . These analyses were performed for the ratio between epilepsy gene variants and variants in all four sets of control genes, for all three frequency thresholds  and for different groups of patients . We hypothesized that patients with a phenotype on both the severe and mild ends of the disease spectrum would carry more variants in epilepsy genes than intermediate patients, as both groups are likely to have a modified phenotype.We investigated whether groups of patients carry an excess of variants in our selection of epilepsy genes, as compared to the number of variants in the different sets of control genes (1–4). Since these control sets contain different numbers of genes than the set of epilepsy genes, with different lengths and mutation rates, we first investigated a healthy control population to establish the normal ratios of variants between the epilepsy genes and the different control sets. For this, we extracted variants in the same genes from the ExAC database . The total number of alleles per group was calculated . The number of found variants per group was then divided by the total number of alleles per group, to obtain a percentage of variants corrected for group size and for male/female ratio . Differences between groups were calculated using Fishers' exact test. Analyses were performed 5 times, once for each category of variants (type A–E). For each of these categories, we furthermore identified in which genes severe patients carried most variants compared to mild patients, and vice versa .2.4.3In families with multiple affected family members with different disease severities, we report variants that were present in only severe patients and not in their milder family member(s) (=possible negative modifiers that could aggravate the phenotype) and variants that were present in mild patients but not in their severe family member(s) (=possible positive modifiers that could ameliorate the phenotype). Only the most predicted deleterious variants are described (type A), as it is difficult to prove the influence of more common and milder variants.We furthermore report the most predicted deleterious variants in the patients with the most extreme phenotypes from the mild and severe groups . For each patient, the predicted most deleterious variant in an established epilepsy gene and the predicted most deleterious variant in a candidate gene is reported, based on the highest CADD score. When the variant with the highest CADD score was present in a recessive gene, the highest CADD score in a dominant gene was reported, if these were present.3SCN1A pathogenic variants and clinical data). Coverage values of the analyzed gene sets differed between cohorts (ExAC and the described cohort), but was similar for sets within the same cohort , meaning no samples swaps had occurred.For 87 participants whole‐exome data were obtained (see Table ort Data  and S4. Varying phenotypes were observed in six families Data . For 69 3.1p < .0003). A statistically significant overrepresentation of type D epilepsy gene variants was furthermore observed for extreme patients in relation to the control gene sets combined . Overall, extreme patients showed a two‐ to fourfold (type E) and five‐ to sevenfold (type D) greater excess of epilepsy gene variants than intermediate patients , no statistically significant differences were observed Table . This is3.3Family 1 consists of a severely affected 10 year old proband with Dravet syndrome, and a father with mild epilepsy and normal cognitive functioning. Family 2 is a large GEFS+ family in which exome sequencing was performed in two mildly affected family members  and in one severely affected family member . Family 3 consists of two brothers with Dravet syndrome, one of whom is more severely affected than the other. Family 4 consists of a proband with a phenotype on the border of Dravet syndrome and GEFS+, with regression over the years. His father has never had any seizures. Family 5 consists of two brothers of whom the oldest has severe Dravet syndrome and the youngest has a much milder phenotype. Family 6 consists of a proband with mild Dravet syndrome, a father with a milder epilepsy‐ and better cognitive functioning but with many social‐ and behavioral problems, and a grandmother who only experienced three seizures in her life.Detailed clinical data on the phenotypes of participants from the six families with varying phenotypes are described in Data Type A variants that were only present in either the mild or the severe family members of each family are depicted in Table 3.4We further investigated type A variants in patients with the most extreme phenotypes in this cohort (IQ at the age of six <30 or >70): this comprised all 10 “mild” patients, and seven of the “severe” patients. For each patient, their most predicted deleterious variant in both an established epilepsy gene and in an epilepsy candidate gene is depicted in Table 3.5SCN1A‐related epilepsy is shown in Data A list of all previously implicated modifier genes for 4SCN1A mutations. More insight in modifying factors is essential for understanding genotype–phenotype relations and for accurate counselling of patients. Besides factors such as mosaicism, variants in regulatory regions, and clinical management, variants in modifier genes are suggested to modify phenotypes. We hypothesized that phenotypes of both severely and mildly affected patients are influenced by modifier genes, as both are on the most extreme ends of the disease spectrum. However, different hypotheses are possible as to which kinds of variants can modify these phenotypes: rare variants with large effects, or multiple more common variants with smaller effects. Previously, rare and/or pathogenic variants in genes involved in neuronal excitability and other known epilepsy genes were suggested to be modifiers  that were detected in the most extremely mild and severe patients, and those that were only present in either the mild or the severe members of affected families, in a descriptive way. Studying families in which the same SCN1A mutations of which the effect can reliably be predicted, which consequently leads to low detection power. Our study may suffer from this. Furthermore, the variety of different possible modifier genes that may act simultaneously makes it difficult to attribute effects to specific variants. In addition, since some genes can carry both LoF and gain of function (GoF) variants, and also variants that cause no relevant effect at all, they may be incorrectly dismissed as modifier genes when variants are present in both severe, mild, and intermediate patients. Functional testing is required to conclusively prove or disprove any modifying effects of single variants, which is not feasible for all variants detected in this study. However, by presenting the most significant genes in each category of variants , strengthening those associations ; several GABA receptor genes have already been suggested as potential SCN1A modifiers , was previously shown to decrease epileptic activity . Both genes are associated with severe neurodevelopmental disorders (Carvill et al., SHANK3 variant resides in exon 11, which has previously been implicated to be absent from most or all SHANK3 transcripts (Kolevzon et al., SYNGAP1 variant is at the 3' end of the gene, which may lead to less severe effects. Nevertheless, it remains a possibility that some of the presented variants are sequencing or calling errors, since it was not feasible to confirm all variants by Sanger sequencing. We however do not expect such variants to influence our main results, since similar error rates are to be expected between different groups of patients and categories of variants.Despite a lack of statistical significance, some interesting results were observed in our study in relation to previous literature: a predicted deleterious In conclusion, our results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic by themselves, play a large role in modulating phenotypes, in both severely and mildly affected patients. Studies in larger cohorts, combined with functional assessments, will be necessary to confirm or disprove the modifying effects of the genes implicated in this study. Our results may be a first step towards meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients.None declared.Conceived and designed the study: EHB, BPCK; Data collection: IML, FM, RS, ACMS, MJAK, IJN, and FRE; Statistic analysis: IML; Wrote the paper: IML. All authors read and approved the final manuscript.We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Endoscopic submucosal dissection (ESD) for extensive esophageal cancer inevitably causes a post‐ESD stricture. It may be difficult to perform additional ESD if a new lesion develops on the anus side of the post‐ESD stricture. We sometimes perform balloon dilation of post‐ESD stricture in advance, so we could perform ESD using a transoral scope; however, there is a risk of balloon dilation causing severe tearing of the lesions if it is located near the stricture. A 68‐year‐old man who had undergone ESD for esophageal cancer several times was diagnosed with early esophageal cancer. The lesion was located near the anus side of the post‐ESD stricture. Unfortunately, the lesion was located on another post‐ESD scar. Although ESD using a transnasal scope was a useful option, it was expected to be challenging as the submucosal layer was thought to have severe fibrosis. We attempted to perform ESD with a transoral endoscope after stepwise scope bougienage of post‐ESD stricture. Endoscopic submucosal dissection (ESD) for extensive esophageal cancer inevitably causes a post‐ESD stricture. It may be difficult to perform additional ESD if a new lesion develops on the anus side of the post‐ESD stricture. We attempted to perform ESD with a transoral endoscope after stepwise scope bougienage of the post‐ESD stricture. Esophageal strictures are common after endoscopic submucosal dissection (ESD) of extensive tumors. Patients who have undergone ESD for such lesions often develop a post‐ESD stricture that a transoral scope cannot pass through. As metachronous esophageal cancer occurs frequently,A 68‐year‐old man who had undergone ESD for esophageal cancer several times was diagnosed with early esophageal cancer. The lesion was a superficially depressed lesion that occupied approximately half of the circumference and was located near the anus side of the post‐ESD stricture Fig. . UnfortuESD for extensive esophageal cancer inevitably causes a post‐ESD stricture. It has been reported that a mucosal defect involving more than three‐quarters of the esophageal circumference after endoscopic resection (ER) is a risk factor for post‐ESD stricture.Another important aspect in this case is the use of the handmade distal endoscope attachment instead of the commercially available one. Needless to say, the distal endoscope attachment is essential for endoscopic treatment.Interestingly, the mucosal defect subsequently became epithelialized without worsening of the stricture in this case. It should be noted that a new post‐ESD scar on the anus side led to traction of the stricture and a slight extension of the original lumen. As a result, the mild dysphagia the patient was feeling prior to treatment improved.In conclusion, we report a case of successful esophageal ESD with an oral endoscope after stepwise scope bougienage of post‐ESD stricture. If a patient with a post‐ESD stricture develops metachronous esophageal cancer only on the anus side of the stricture, this method offers an alternative for such cases.


Dear Editors,Thrombosis and Haemostasis, we investigated the effects of the novel bispecific antibody emicizumab on a variety of in vitro laboratory coagulation tests.In a recent study published in g, 15 minutes at room temperature) and the resulting plasma was transferred to another plastic tube for a second spin. Plasma was then aliquoted, immediately frozen (−70°C), and thawed in a water bath at 37°C immediately before testing. Analyses were performed in duplicate using the commercially available diagnostic kits according to manufacturer instructions; results presented are means of the two determinations. In each experiment, emicizumab was spiked into the samples to produce final plasma concentrations of 0, 50, 100, and 150 µg/mL.To this end, we used patient plasma samples to assess the effect of emicizumab therapy on three different LA detection assays. Frozen plasma samples were sourced as follows: two from persons with severe hemophilia A without FVIII inhibitors (Precision BioLogic Inc), two samples positive for LAs , and CRYOcheck™ pooled normal plasma (Precision Biologic Inc). In addition, individual samples from 12 healthy plasma donors were generated  via blood collection into plastic tubes containing 0.109 mol/L sodium citrate as an anticoagulant, centrifuged ; the Dilute Russel Viper Venom Time ; and the Taipan venom time .The aPTT assay is based on hexagonal phase phospholipid neutralization of LAs.Daboia russelii (Russell's viper) with the addition of a low (DRVV Screen) versus high (DRVV Confirm) concentration of phospholipids. The assay detects LAs by their ability to interfere with thrombin activation by the prothrombinase complex. By activating coagulation downstream of factors VIII and IX, the test is not subject to being affected by their deficiencies or specific inhibitors. Per the test manufacturer's recommendation, a DRVVT screen ratio of >1.2  was indicative of the presence of LAs.The DRVVT assay is based on the activation of FX and FV using the snake venom of Oxyuranus scutellatus (Taipan snake), which is dependent on the presence of phospholipids and free calcium ionsThe TVT assay is based on the activation of prothrombin to thrombin by the venom of The aPTT‐based and DRVVT LA assays were performed on the STA‐R Evolution analyzer (Stago), and the TVT assay was performed on the MC10 coagulometer (ABW Medizin und Technik GmbH). Investigations were performed at menal GmbH.Our results showed that emicizumab substantially shortened clotting times of the aPTT‐based LA assay, both with and without the presence of hexagonal phase phospholipids Figure . The preEmicizumab triggered a weak but detectable concentration‐dependent prolongation of DRVVT clotting times Figure A, and acTaken together, all three assays correctly discriminated the LA and non‐LA samples in the absence of emicizumab. However, emicizumab interfered with the Staclot LA assay to the extent that an LA‐positive sample would have been incorrectly classified as LA‐negative; this is not surprising given that emicizumab has a documented very strong shortening effect on the aPTT.Current guidelines for the detection of LAs recommend DRVVT followed by an LA‐sensitive aPTT‐based testThis exploratory study has a number of limitations: Plasma samples were derived from a small number of individual donors spiked with emicizumab, and not ex vivo samples from individuals receiving emicizumab therapy. Assay cutoffs from the literature or from manufacturers’ instructions were applied to the interpretation of the results, rather than locally generated reference ranges as recommended for clinical use.In conclusion, when analyzing samples from individuals receiving emicizumab therapy, all aPTT‐based assays should be avoided, including those for LAs, although it is acknowledged that a few patients who express their LA activity exclusively via aPTT‐based LA tests could be missed. Further studies on DRVVT and TVT in the presence of emicizumab are desirable to confirm the safe and accurate use and interpretation of these assays when testing for LAs in samples containing emicizumab.JIA is an employee of Genentech, Inc, and holds stock with F. Hoffmann‐La Roche Ltd. IPP is an employee of Genentech, Inc AK is an employee of and holds stock with F. Hoffmann‐La Roche Ltd.JIA designed the study, analyzed and interpreted data, and prepared the manuscript. AK and IPP interpreted data and edited the manuscript. All authors granted final approval of the manuscript for submission. Click here for additional data file.