The rosemary plant, Rosmarinus officinalis L., one of the main members of the Lamiaceae family, is currently one of the most promising herbal medicines due to its pharmaceutical properties. This research aimed to evaluate the antioxidant role of Rosmarinus officinalis and its bioactive compounds on the skin, with a focus on the newly emerging molecular mechanisms involved, providing extensive scientific evidence of its anti-inflammatory, antimicrobial, wound-healing and anticancer activity in dermatological practice. The search was conducted on articles concerning in vitro and in vivo studies in both animals and humans. The results obtained confirm the antioxidant role of R. officinalis. This assumption derives the possibility of using R. officinalis or its bioactive elements for the treatment of inflammatory and infectious skin pathologies. However, although the use of rosemary in the treatment of skin diseases represents a fascinating line of research, future perspectives still require large and controlled clinical trials in order to definitively elucidate the real impact of this plant and its components in clinical practice. Rosmarinus officinalis L., one of the main members of the Lamiaceae family, cultivated in the Mediterranean basin for culinary use [Rosmarinus officinalis owes its clinical notoriety to its anti-inflammatory potential [Rosmarinus officinalis, investigating their therapeutic potential in various neurological disorders, including neurodegenerative diseases [Rosmarinus officinalis L. and, more specifically, of the wide range of its bioactive constituents on various dermatological diseases, with a special focus on its promising antioxidant role and the ambitious attempts to elucidate the pathogenetic molecular pathways involved.Phytotherapy, to take its most classic meaning, is the branch of medicine that uses plants in their entirety or their components for medical purposes to treat or prevent a plethora of diseases. A cornerstone of various medical traditions over the centuries, above all Ayurvedic medicine, traditional Chinese medicine, allopathic and naturopathic medicine , it is, nary use , is listnary use  supportenary use . Rosemarnary use ,21; phennary use ,23,24; fnary use ; and rosnary use ,27. Rosmnary use . The EO otential , as wellotential . Carnosiotential ,31. An idiseases ,33, priodiseases , cerebradiseases , neuropadiseases  and encediseases . Along tRosmarinus officinalis and its bioactive constituents has been extensively investigated in both in vitro and in vivo studies, especially for its promising therapeutic effects on UV-induced photoaging, atopic dermatitis (AD) and pollution-induced skin aging. Relative to the aforementioned time frame, one of the first in vitro studies on this topic highlighted the interesting proportionality between protein glycation-inhibiting activity and antioxidant activity [Rosmarinus officinalis, paving the way for their prospective therapeutic use in diabetic complications and aging. Further confirmation of the antioxidant potential of this plant came from Ezzat et al., who emphasized the anti-wrinkle action of the defatted rosemary extract (DER), an effect attributable largely to rosmarinic acid, the main phenolic compound, but also to the diterpenes carnosic acid, carnosol and rosmanol [Rosmarinus officinalis, which showed both the highest antioxidant activity and the most pronounced anti-elastase, anti-tyrosinase and anti-collagenase activity [Oxidative stress is the pathogenic primum movens of most cutaneous disorders, as the skin is the organ most widely and severely exposed to oxidative stress, despite the extensive endogenous and exogenous antioxidant system at its disposal . For desactivity . This furosmanol . Furtheractivity .Rosmarinus officinalis was first investigated in vivo by Mengoni et al., who evaluated how these bio-active compounds could modify the expression of the inflammation-associated genes cyclooxygenase-1/2 , interleukin 1β (IL-1β), intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor-α (TNF-α) and fibronectin, thus revealing a downregulation of IL-1β and TNF-α, leucocyte migration reduction and, most interestingly, selective COX-2 inhibitory activity [Rosmarinus officinalis in atopic dermatitis, beyond the first study that more generally attributed an ameliorative role in skin lesions to nerve growth factor (NGF) inhibition, a more recent and detailed molecular characterization of carnosol’s intracellular action partially recalled the already known molecular targets and brought to light new ones involved in the implementation of its antiphlogistic action [Very recent is the interest in the curative potential of rosemary in skin oxidative damage from pollution. In a randomized, double-blind, placebo-controlled study, Nobile et al. evaluated the antioxidant efficacy of the oral supplementation of four phenol-rich plants, including R. officinalis, in one hundred Caucasian and Asian women living in the polluted urban area of Milan . It was activity . Regardic action . The mosc action . Furtherc action .Rosmarinus officinalis and its bioactive elements in UVR-induced skin aging. Martin et al. identified the photoprotective role of a water-soluble extract of Rosmarinus officinalis which downregulates both the basal levels of matrix metalloproteinase-1 (MMP-1) and the transcription of UVA/UVB-induced MMP-1 in dermal fibroblasts. Moreover, in a reconstructed skin model, the MMP-1 downregulatory action was also demonstrated further upstream, through the decrease in the UV-induced cytokines IL1- α and IL-6 [A much more widely represented topic in the literature is the photoprotective role of and IL-6 .Rosmarinus officinalis, but also involves compounds from other plants, such as citrus flavonoids, in a synergic action that is even stronger than the therapeutic efficacy of the plants taken individually. To this end, Pérez-Sánchez et al., in their clinical trial, highlighted the advantageous effects of combinations of these extracts in human HaCaT keratinocytes, a spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin, and in human volunteers after oral supplementation. A consistent reduction in the UVB-induced formation of ROS and prevention of DNA damage was demonstrated in HaCaT cells, with consequent higher survival. In human volunteers taking 250 mg of combined citrus and rosemary extracts daily, a significant and progressive increase in minimal erythema dose (MED) was detected, thus suggesting that oral supplementation could improve UVB protection [Rosmarinus officinalis and Citrus paradisi. These effects are probably attributable to the inhibition of UVR-induced ROS formation, as well as proinflammatory cytokines, coupled with the downregulatory action of intracellular matrix metalloproteinase-activating pathways [In the wake of the above-mentioned work, Park et al. deeply evaluated the molecular mechanisms underlying the anti-photoaging activity of carnosic acid, identifying its ability to downregulate the UV-induced expression of MMP-1, MMP-3 and MMP-9 in human fibroblasts and keratinocytes. In addition, its UVB-induced MMP expression inhibitory activity would recognize the carnosic acid-mediated suppression of MEK/ERK/AP-1 pathways as an upstream causative agent . The phootection . Furtherpathways .Rosmarinus officinalis extract. The antioxidant, antiaging and healing potential of rosemary hexane extract was evaluated both in vitro and in a UVB-irradiated mouse model. Ibrahim et al. demonstrated the photoprotective potential of rosemary extract, the permeability and bioavailability of which improved when topically conveyed into lipid nanocapsule-based gel [Rosmarinus officinalis and its antioxidant functions are summarized in Rosmarinus officinalis against UV-induced and pollution-induced skin aging and against cutaneous inflammation are shown in The recent literature is teeming with works confirming the photoprotective role of various plant extracts, of which rosemary, with its bioactive elements, is an increasingly consistent member. Hyuck Auh et al. pioneered the investigation of the anti-photoaging potential of combined extracts of marigold and rosemary, finding in a mouse model that the oral supplementation of these extracts suppressed UV-induced dermal–epidermal thickening in a dose-dependent manner; this histological finding was supported by reductions in various photoaging-related biomarkers observed in the lab . A new mased gel . In the ased gel . The maiStaphylococcus aureus, Streptococcus oralis and Pseudomonas aeruginosa. De Macedo et al. concluded by asserting that this topical formulation based on Rosmarinus officinalis could be a natural therapeutic novelty against microorganisms, which are becoming increasingly resistant to conventional drugs [Rosmarinus officinalis can be successfully used as a matrix component and active ingredient of nanostructured lipid carriers (NLCs), it was subsequently demonstrated that the nanoparticles ensured a prolonged in vitro release of clotrimazole, thus increasing the antifungal activity. This confirmed that NLCs containing Mediterranean EOs represent a promising strategy to improve efficacy against topical candidiasis [Rosmarinus officinalis and Tetradenia riparia contain antifungal bioactive compounds. Hydro-alcoholic extracts from these leaves seem to be effective against dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum gypseum, with fungal growth inhibition and morphological alterations in the hyphae [Rosmarinus officinalis were analyzed to evaluate its ability to inhibit AhR, confirming its dose-dependent antimicrobial activity against Malassezia furfur [Rosmarinus officinalis, and plant extracts, including carnosol and carnosic acid, showing that Rosmarinus officinalis extract inhibited the growth of both aerobic and anaerobic bacteria and yeasts. Furthermore, the Rosmarinus extract was able to inhibit both Candida strains, further showing its antifungal action [Sporothrix, increasingly affecting humans and cats [Sporothrix schenckii [Sporothrix brasiliensis [Sporothrix brasiliensis was inoculated into 30 Wistar mice, which were randomly treated with itraconazole, rosemary oil or saline as the control population. In mice treated with rosemary oil, the remission of skin lesions was noted, with mild to absent yeast cells. Furthermore, rosemary oil has also shown a protective effect on systemic organs, such as the liver and spleen, delaying the spread of infection [Staphylococcus aureus, a common cause of skin and soft tissue infection (SSTI), has generated increasing concern due to drug resistance. Staphylococcus aureus is an opportunistic Gram-positive bacterium, whose virulence mechanisms involve the activation of the quorum-sensing accessor gene regulator (agr) operon. The diterpene carnosic acid and carnosol, found in Rosmarinus officinalis L. leaves, have been demonstrated to have a specific inhibitory effect on Staphylococcus aureus agr expression, thus suppressing the cell–cell communication system and, consequently, its pathogenicity [Escherichia coli. The results show that both essential oils tested were active against all clinical strains of Escherichia coli, including broad-spectrum β-lactamase-positive bacteria [Rosmarinus officinalis can be used both as an important therapeutic tool and as an adjuvant within cosmetological formulations for its broad-spectrum antioxidant and antimicrobial capacities. Rosmarinus officinalis.In recent times, the scientific literature has provided ever-increasing knowledge on the antimicrobial activities of essential oils, which are finding use in both medical and cosmetic fields. Secondary plant metabolites have a pharmacological effect on the treatment of skin disorders, for which they are used within topical formulations. In this regard, rosemary extract has shown antimicrobial activity in several cases ,60,61,62al drugs . Anotheral drugs ,65, inclal drugs ,67, thusal drugs ,69. Theial drugs . The phaal drugs . Howeverdidiasis . Specifie hyphae . Moreovea furfur . Anotherl action . Sporotrand cats . Despitechenckii  and itrailiensis ,77. The nfection . Finallynfection . By specnfection . Staphylgenicity . Finallybacteria . All of Rosmarinus officinalis in wound healing, as well as in promoting the survival of skin flaps. Concerning the wound-healing process, beyond some in vivo evidence of the regenerative potential of Rosmarinus officinalis in the treatment of acute wounds, especially burn wounds, much of the scientific evidence instead concerns the therapeutic potential of rosemary in chronic wounds, primarily diabetic wounds [In the past decade, a new and interesting strand of phytotherapeutic research has become increasingly popular, which aims to evaluate the curative potential of c wounds ,83.Rosmarinus officinalis in healing diabetic wounds by pointing out the greater healing efficacy of the essential oil over the aqueous extract [First, Abu-Al-Basal, in an in vivo study conducted on BALB/c mice, demonstrated the efficacy of both aqueous extract and essential oil of  extract . In the  extract . Additio extract . Similar extract . The mos extract .Rosmarinus officinalis in improving skin flap survival in relatively recent times, Ince et al. topically tested this ability in vivo with encouraging results [Rosmarinus officinalis oil. The resulting increased blood flow to the flap averted the dreaded necrotic complication, suggesting a systemic use of rosemary, especially in patients with circulatory disorders such as chronic obliterative artery disease [Rosmarinus officinalis, alpha-pinene and cineole, as the main systemic contributors to the increased flap survival [Rosmarinus officinalis in wound healing and skin flap survival.Regarding the potential use of  results . These l disease . In linesurvival . Table 3Rosemary has been shown to have not only antioxidant and antimicrobial properties, but also a beneficial role in the treatment of various skin diseases.Rosmarinus officinalis managed to improve microcirculation surrounding the hair follicle [Rosmarinus officinalis. Moreover, scalp irritation was more frequent in the minoxidil 2% solution group, confirming the relatively few side effects of natural compound therapies [Rosmarinus officinalis has also been evaluated in systemic sclerosis-related Raynaud’s. Additionally, in this connective tissue disorder, the high levels of ROS contribute to the development of fibrotic processes and closely correlate with the severity of skin fibrosis [Rosmarinus officinalis L., highlighting that warmth perception in patients with Raynaud’s phenomenon was ameliorated by topical rosemary EO application [Rosmarinus officinalis, was shown to reduce lipid accumulation, platelet aggregation and inflammation, thus ameliorating microcirculation through a dose-dependent inhibition of free radical formation. This evidence suggests the potential topical use of rosemary, combined with other extracts, and also in the aesthetic field, taking advantage of its anti-inflammatory and antioxidant properties [In the treatment of alopecia aerate, an autoimmune disease affecting the follicles with subsequent hair loss, the essential oil of follicle . Moreoveherapies . Among therapies . Combinefibrosis ,96. In alication . The potoperties . As alreoperties ,100. ROSoperties . In receoperties .On this topic, the potential role of carnosol in the chemoprevention of UVB light-induced non-melanoma skin cancer has been evaluated in an HaCat cell study, highlighting that carnosol leads to a partial reduction in UVB-induced ROS and subsequently in a reduction in DNA damage. This ability consists of the absorption of UVB radiation, which in turn could decrease the UVB-induced formation of cyclobutane pyrimidine dimers (CDP) in keratinocytes, further inhibiting the UVB-induced activation of NFκB and UVB-induced mutation .Rosmarinus officinalis were studied by evaluating the skin tumor mean latency period, incidence, burden, yield, weight and diameter. Mouse skin carcinogenesis, evaluated by the formation of papillomas, was induced by topical application on the dorsal skin of 7,12-dimethlybenz(a)anthracene (DMBA) and promoted by croton oil. The results of the study conducted by Sancheti et al. suggest that Rosmarinus officinalis leaf extract could postpone the onset of papillomas and their latency period. Furthermore, confirming its antioxidant action, it was observed that serum levels of lipid peroxidation, an index of cellular oxidation, were significantly reduced in mice treated with Rosmarinus officinalis [In a mouse model, the modulatory effects of icinalis . Rosmarinus officinalis, in a dose- and time-proportional way through cytotoxic and cytostatic effects on the cell cycle. Through the compositional characterization, the individual pure components of the extract were tested. The observations led researchers to hypothesize that the antiproliferative activity was a property of the entire extract, most likely deriving from multifactorial effects involving the majority of its elements [A growing body of evidence indicates that specific compounds of rosemary, including carnosol, carnosic acid and rosmarinic acid, exert antiproliferative activity in several cancer cell lines ,107,108.elements . All of Rosmarinus officinalis and cutaneous lymphomas are rather limited, in vitro studies would seem to confirm the antineoplastic activity of this substance. Visanji et al. studied the antiproliferative effects of carnosol and carnosic acid on Caco-2 cells, demonstrating that after incubation with these components, the cells increased their doubling time, i.e., the time required to double their population. This was estimated to be due to G2/M phase cell cycle arrest. Furthermore, carnosic acid and carnosol were observed to arrest the cell cycle at different times. While carnosic acid arrested cells before prometaphase by reducing cyclin A levels, carnosol exerted its major impact on the cell cycle after prometaphase [Other skin disorders, including lymphomas, may benefit from the antioxidant properties of rosemary. A rare and frequently severe T-cell lymphoma, which can develop in the blood, lymph nodes or skin, is known as adult T-cell leukemia/lymphoma (ATLL). Human T-cell lymphotropic virus type 1 (HTLV-1) infection has been related to ATLL onset; however, less than 5% of HTLV-1 infected-patients develop ATLL. The Caribbean, some regions of South and Central America, and some portions of Africa are the areas where the HTLV-1 virus is most prevalent. To date, we are unable to predict which infected patients will develop ATLL. Through their crucial functions in accelerating cell proliferation and preventing cell death, the viral genes tax and HTLV-1 bZIP factor (HBZ) supports the growth of infected cells. An ATL clone emerged as a result of the persistence of infected clones in vivo and the accumulation of genetic mutations and abnormal epigenetic alterations in host genes . Accordietaphase . All of This research was carried out on the PubMed database, using the keywords “Rosmarinus officinalis” and “skin”. The preliminary research excluded previous reviews and systematic reviews, along with articles not in the English language. The results were screened and selected in the following order: title, abstract and content. Double results were screened and removed from the final article count. Rosmarinus officinalis L., a medicinal plant native to the Mediterranean region, already well-known and thoroughly investigated for its anti-cancer potential, is increasingly showing promising results for its antioxidant and anti-inflammatory activity due to the interaction between the bioactive elements of the plant and the molecular pathways governing inflammatory processes, as well as the pro-oxidative/antioxidant balance. Among the organs that would benefit from such healing effects, according to the evidence, the skin stands out. In light of the promising and well-documented in vitro effects and in vivo results in animals, the future goals of phytotherapeutic research should be geared towards an expansion of clinical trials, especially aimed at investigating in more depth the single bioactive elements of the plant and characterizing new ones, as well as assessing their therapeutic efficacy when combined with other plant extracts. Another pursuable goal, with a view to systemic use, concerns the need for more studies to establish therapeutic dosages of this plant or its bioactive elements. For the latter, the development of innovative technologies directed at their targeted extraction should be encouraged in order to meet the growing future demand for phytotherapy. A further critical issue to be investigated considering the increasingly confirmed recognition of phytodermatitis as a clinical entity [Ever-increasing scientific attention is being paid to phytotherapeutics, plants with potential therapeutic activities. Among these, l entity  is the n


Adult patients with OHCA from cardiac causes in the province of Limburg (the Netherlands) were included. The time horizon was from OHCA occurrence up to one year after hospital discharge. First, the total average healthcare costs of OHCA patients were analysed as well as the yearly operating costs of the CRS. Second, an early modelling was conducted to compare from the healthcare perspective the healthcare costs of OHCA patients with the CRS being activated but no responders attended (CRS-NV) versus the CRS being activated with attendance of ≥1 responder(s) (CRS-V).The total average healthcare costs per patient are €42,533. The yearly operating costs for the CRS are approximately €1.5 million per year in the Netherlands. The early modelling of costs and effects showed that the incremental healthcare costs per patient thus were €4,131 in the CRS-V versus the CRS-NV group . Incremental quality-adjusted life years (QALYs) was 5 per 100 patients (16 per 100 patients in the CRS-V group versus 11 per 100 patients in the CRS-NV group). The incremental cost-effectiveness ratio (ICER) was €79,662 per QALY for the CRS-V group.This study shows that patients in the CSR-V group had additional health care costs of €4,131 per patient compared to patients in the CRS-NV group. This increase is caused by patients surviving more often, who then continue to utilise health services, which results in a (logic) increase in healthcare costs. For future research, accurate and up-to-date data on effectiveness and costs of the CRS needs to be collected. Out-of-hospital cardiac arrest (OHCA) is one of the most common causes of mortality worldwide , 2. The In the Netherlands, when the dispatch centre is notified of a patient with suspected OHCA, two ambulances  are dispatched, each staffed with a paramedic and a driver with CPR skills. Simultaneously, the police and fire brigade are alerted, as they also are trained to start CPR and perform defibrillation (if they carry an AED in their vehicle) should they arrive first. In that case they would start resuscitation and continue until the ambulances arrive; when the ambulance is to arrive first, the police and fire brigade staff assist the ambulance staff as needed.To reduce the time to CPR and/or defibrillation, an early intervention program was set up in 2008. A citizen-rescuer system (CRS) was implemented in the Netherlands that activates volunteers who have signed up for the CRS by means of an app or text-messaging. The CRS alerts citizen-rescuers close by the victim, who generally arrive faster at the scene than the EMS and start CPR and defibrillation with an AED, thereby increasing survival chances . This syNext to identifying the system´s effectiveness, it is important to analyse the costs and calculate the returns associated with a CRS. As data required for a full economic evaluation are still scarce, the objectives of this study were to 1) analyse the total healthcare costs of a patient with an OHCA up to one year after hospital discharge, as well as estimating the operational costs of the CRS; and 2) to conduct an early modelling of the effects and healthcare costs of the Dutch CRS in comparison to no CRS with a one-year time horizon from a healthcare perspective.A health economic modelling study has been conducted. First, we analysed the healthcare costs of OHCA patients up to one year after hospital discharge, as well as the yearly costs for operating the CRS. Second, we conducted an early modelling to compare the healthcare costs of OHCA patients with the CRS being activated but no responders attended (CRS-NV) versus the CRS being activated with attendance of ≥1 responder(s) (CRS-V) from the healthcare system perspective. The patient group consisted of adult patients with witnessed OHCA of cardiac origin in the province of Limburg (the Netherlands). A ’witness’ was described as an individual who observed, heard, or monitored the incident, while the term ’bystander’ was used for those individuals who were not present during the event but arrived at the location afterward.The healthcare costs were analysed with a time horizon from occurrence of the OHCA up to one year after hospital discharge.The main data sources on costs were scientific literature –22, repoFirst, the healthcare costs associated with the OHCA were determined. These included costs for the EMS, hospital care (consisting of emergency room (ER) treatment, hospital stay, diagnostics, and treatment), costs incurred during the first year after hospital discharge, and end-of life costs. In Healthcare costs after discharge were based on Moulaert et al.  From thiThe costs of the CRS for the Netherlands were obtained during an interview with a board member of the national organisation in charge of the CRS. The costs of the CRS were considered societal costs. They were thus assessed for the purpose of placing them in perspective, but not in the early modelling below. The costs for running and maintaining the system were considered to be similar to the costs for keeping the fire brigade or ambulance services in place.Total average healthcare costs per patient was the main outcome measure. These were calculated by multiplying volumes of healthcare resources with the unit costs.An early modelling study was conducted of the effects and healthcare costs of patients with an OHCA when the CRS is activated and when at least one volunteer shows up compared to when the CRS is activated and no volunteers show up. The healthcare costs, survival, and quality adjusted life years (QALYs) per patient were analysed using a decision-tree model programmed in Microsoft Excel . The QALY was calculated by multiplying the 1-year survival rate after hospital discharge with the utility scores. The analysis was conducted from a healthcare system perspective over a time horizon from the OHCA to one year after hospital discharge, in the Dutch setting.The decision-tree is presented in The main data sources were scientific literature , 31–35, The healthcare costs of OHCA patients up to one year after hospital discharge determined in the first objective of this study were included in the early modelling.For each pathway in the decision-tree, the probability of following that pathway was multiplied with the costs incurred along the way, leading to the total healthcare costs per patient per intervention. For the incremental costs, the cost of no CRS in place were subtracted from the CRS. Incremental effects are determined by subtracting the QALYs of the CSR-NV group from the CRS-V group.A one-way sensitivity analysis (OWSA) was performed to assess the model results’ robustness and to identify the key drivers of the analysis. Each individual parameter was varied by +/-20% while other parameters remained at their base case value.Several scenario analyses were conducted. The first two scenarios concerned increasing the survival of the CRS-V group by an absolute by 5% (scenario 1) and 10% (scenario 2) , as improvement of the CRS may have further reduced the time to CPR/AED since 2016. The third scenario includes the use of extracorporeal membrane oxygenation (ECMO) treatment  in both The main outcome measures were incremental costs per patient, incremental quality adjusted life-years (QALYs) per patient, and the incremental cost-effectiveness ratio (ICER).As this study did not involve patients or study participants, an ethical research approval was not needed according to Article 1b of the Dutch Medical Research in Human Subjects Act . NotwithThe average healthcare costs per patient are shown in The costs for the CRS are approximately €1.5 million per year for the Netherlands. These costs consist of management of the platform; support and management of trained volunteers, AED-administrators, and local partner organizations; relationship management; functioning of the application; policy and legal duties; follow-up care for volunteers who attended a patient; and costs of communication, partner days and support (activities aimed at retaining volunteers and AED-administrators). The costs related to the recruitment of the volunteers was stated to be negligible.The average total healthcare costs per patient with an OHCA were €25,184 in the CRS-V group and €21,053 in the CRS-NV group, resulting in additional costs of €4,131 per patient in group CRS-V versus CRS-NV . The aveWhen varying the input meters by +/- 20% one by one, the most influential parameters were: (1) percentage of patients alive at EMS departure, CRS-V group, (2) percentage of patients alive at EMS departure, CRS-NV group, (3) percentage of patients alive at ER arrival, CRS-V group, and (4) percentage of patients alive at hospital discharge, CRS-V group. The tornado diagram  shows thIn In this study we analysed the average healthcare costs of a patient with an OHCA surviving up to one year after hospital discharge and conducted an early modelling of the healthcare costs and effects of the Dutch CRS with a one-year time horizon. The total average healthcare costs per OHCA-patient over the complete time horizon were €42,533. The early modelling of costs and effects showed that the incremental healthcare costs per patient thus were €4,131 in the CRS-V versus the CRS-NV group and the incremental QALY was 5 per 100 patients. The ICER was €79,662 per QALY for the CRS-V group.The sensitivity analysis showed that the most influential input parameters were: (1) percentage of patients alive at EMS departure, CRS-V group, (2) percentage of patients alive at EMS departure, CRS-NV group, (3) percentage of patients alive at ER arrival, CRS-V group, and (4) percentage of patients alive at hospital discharge, CRS-V group. The scenario analysis demonstrated that an increase of survival in CRS-V group by an absolute 5% and 10% resulted in an incremental costs per patient of €6,287 and €8,493 respectively, and incremental QALYs of 7 per 100 patients and 10 per 100 patients respectively.The increased costs in the CRS-V group compared to the CRS-NV group are caused by more patients surviving in that group. The treatment costs when surviving are identical per group. As in the CRS-V group more patients survive and make use of these costs, their healthcare costs increase. When a person survives or lives longer thanks to a healthcare intervention, it is very likely that this person will consume medical care during treatment and in his/her extra years of life. The inclusion of (related and unrelated) medical costs due to life years gained in economic evaluations of life-prolonging healthcare interventions remains a point of discussion .In previous literature, Danish studies have reported on the activation of citizen responders to arrival at OHCA location and the association with bystander interventions –41, alsoTo the best of our knowledge, this is the first study that investigated the total healthcare costs of an OHCA up to one year after hospital discharge and the costs of the CRS and conducted an early modelling of the costs and effects of the Dutch CRS. As our study was a first and early attempt to determine the costs related to an OHCA and to model the system´s cost-effectiveness, limitations need to be considered. The main limitation of our study is the limited availability of data on the CRS. Ideally, the comparison would include either a pre-post comparison of survival rates before and after the introduction of the CRS, or a comparison of regions in which one region used the CRS and the other would not. Also, the total number of QALYs gained in relation to the incremental costs can seem rather low, however, this is caused by the short time horizon of our analysis (one year), due to the scarcity of data on long-term effects. Patients who survive up to one year after hospital discharge are expected to have a survival averaging many more years. Thus, the increased healthcare costs in the CRS-V group need to be seen as desirable, as these reflect the higher survival after the introduction of the CRS.In this study data were based on the Pijls-study which compares getting no response from trained volunteers versus getting a response from trained volunteers when the CRS is activated. This had the disadvantage that it is not the same as having no CRS versus having a CRS. In addition, the effectiveness data of Pijls et al. (2016)  used in Regarding future research, more recent data and a more extensive and long-term cost-effectiveness analysis can be conducted to capture the healthcare costs and outcomes beyond the one-year time horizon. This could involve tracking patients’ health and healthcare costs for several years post-discharge to get a comprehensive understanding of the CRS’s impact on long-term survival and quality of life. As mentioned earlier, the CRS is continually being improved since the study’s data in 2016. The impact of these ongoing improvements can be investigated, such as improved GPS tracking system, on the CRS’s effectiveness and cost-effectiveness. Moreover, challenges regarding adoption and implementation to the widespread adoption and successful implementation of the CRS in different healthcare settings can be investigated. This can help develop strategies to overcome obstacles and ensure efficient utilization. Also, the societal perspective could be adopted in the early-modelling, in which the costs of the CRS, productivity costs, costs associated with time off work for volunteers, costs related to additional care next to the intervention, and costs of the patient and the informal carers are taken into account. We had assessed the costs of the CRS system but did not include them in the modelling from the healthcare system perspective. We considered these societal costs and found it inappropriate to divide the costs among the patients experiencing an OHCA, as this is a system that was put in place as the society considers it desirable to increase survival chances after an OHCA. The costs of the CRS were analysed to be approximately €1.5 million per year. This may sound high, but must also be considered in light of costs spent on other societal provisions that may not be used by all citizens regularly, but society values these services to be in place . In the Netherlands, there is broad understanding and desire to have AEDs available in strategic places, such as train stations, and for the CRS. Due to the ongoing adaptions to improve the CRS, it is expected that the number of survivors with good neurological outcome will increase, implicating that the incremental QALYs increase while incremental costs will also increase. It can also be explored how the CRS affect healthcare costs and outcomes in different regions in the Netherlands. Similar systems in Europe with varying levels of healthcare infrastructure can be compared, which may help to identify contextual factors that influence the CRS’s effectiveness and cost-effectiveness. Furthermore, examining patient-centred outcomes, such as quality of life, patient satisfaction, may help understand how the CRS affects these aspects, which is crucial for comprehensive evaluation.This study showed that over the time horizon of up to one year after hospital discharge patients in the CSR-V group had additional health care costs of €4,131 per patient compared to patients in the CSR-NV group. This increase is caused by patients surviving more often, who then continue to utilise health services, which results in a (logic) increase in healthcare costs. The patients in the CRS-V group had 5 incremental QALYs per 100 patients compared to CRS-NV. The ICER was €79,662 per QALY for the CRS-V group. The additional costs for the CRS will increase as the number of OHCA survivors will also increase. For future research, accurate and real world data on effectiveness and costs of the CRS needs to be collected.S1 File(PDF)Click here for additional data file.


Vigna mungo (L.) Hepper) causing distinct symptoms that often result in serious yield losses. It has been known to occur for more than five decades and is considered to be of viral etiology. The identity of the causal agent, often referred to as the urdbean leaf crinkle virus, is not unequivocally proved. There are few attempts to characterize the causal agent of ULCD; however, there is no unanimity in the results. Recent attempts to characterize the causal agent of ULCD using next-generation sequencing of the virome of ULCD-affected urdbean plants indicated the involvement of cowpea mild mottle virus; however, without conforming through Koch’s postulates, the etiology of ULCD remains inconclusive. Claims of different insect vectors involved in the transmission of ULCD make this disease even more mysterious. The information available so far indicates that either two different viruses are causing ULCD or a mixture of viruses is involved. The identity of the virus/es causing ULCD still remains to be unambiguously ascertained. In this review, we attempt to analyze information on the various aspects of ULCD.Urdbean leaf crinkle disease (ULCD) affects mainly the urdbean or blackgram ( Vigna mungo (L.) Hepper, also known as blackgram, is an important pulse crop of the Indian sub-continent. In India, it is mainly grown during the kharif (rainy) season in the northern and central parts. Additionally, it is also grown after paddies as a rice fallow crop in large tracts of the southern states during the rabi (winter) season and is also a catch crop during the spring season in the northern plains. The urdbean was cultivated in over 4.63 m of hectares, with a total production of 2.78 million tonnes and a productivity of 600 kg/hectare in India in 2020–2021 [Urdbean  , workingA review of early publications on ULCD indicates contradictions in regards to mechanical and vector transmission. Presently, the mechanical and seed transmission of ULCD is unequivocally proved but there is no unanimity on the vector.Initially, attempts to transmit ULCD through mechanical sap inoculations were met with negative results . It was,Seed transmission of ULCD has been proven conclusively ,54,55,57Bemisia tabaci), which transmits the ULCD without any incubation period. An incubation period of 20–23 days is, however, required for symptom appearance [Aphis craccivora Koch, A. gossypii Glov., Acyrthosiphon pisum and Myzus persicae [Transmission of ULCD by the insect vector has been the most baffling issue, as different insects have been shown to be the vector of ULCD. It was shown to be transmitted by whitefly , whiteflies (Bemisia tabaci) and leaf hoppers (Circulifer tennellus) [Aphis craccivora, A. gossypii, Rhopalosiphum maidis), whiteflies (Bemisia tabaci), jassids (Empoasca motti) and beetles (Henosepilachna dodecastigma). Nevertheless, reports of ULCD being transmitted by different vectors point to the possibility of involvement of different viruses in causing ULCD. A comparatively recent study [Aphis craccivora) in a non-persistent manner and also by whiteflies (Bemisia tabaci). Other species of aphids, melon aphids (Aphis gossypii), cabbage aphids (Brevicoryne brassicae) and hadda beetles (Epilachna vignitioctopuntata and Epilacna dodecastigma) failed to transmit ULCD. On the other hand, Golluru et al. (2017) [Aphis craccivora, transmitted the causal agent of ULCD in non-persistent manner, unlike the whitefly, Bemisia tabaci. Issue of vector transmission became further confounded when the Pantnagar isolate of the causal agent of ULCD was shown to be transmitted by a beetle, nnellus) . Adding nnellus) ,16, basent study  on the t. (2017)  showed tVigna radiata, V. sinensis and V. aconitifolia) developed crinkle symptoms. In another study involving 60 plant species of 9 families, two cucurbitaceous plants viz., the cucumber and bottle gourd, were found to be the host of the causal agent of ULCD [Convolvulus arvensis as a host with systemic symptoms and four species of Datura viz., D. metel, D. stramonium, D. metaloides, and D. incrimis as susceptible hosts with local symptoms while studying the host range of ULCD in most commonly found weeds., Seventeen weed species, namely Amaranthus spp., Achyranthes spp., Cannabis sativa (L), punarnava (Boerhavia diffusa), tree spinach (Chenopodium giganteum), quinoa (Chenopodium quinoa), silver cock’s comb (Celosia argentea), nut grass (Cyperus rotundus), asthma-plant (Euphorbia hitra), Philippine tea tree (Euphorbia microphylla), Forsk (Digera arvensis), tex-Mex tobacco (Nicotiana plumbaginifolia), gale of the wind (Phyllanthus niruri), common Purslane (Portulaca oleracea), Indian milkwort , giant pigweed (Trianthema monogyna) and rough cocklebur (Xanthium strumarium) did not exhibit any symptoms [Many workers have worked out the host range of the causal agent of ULCD. Using mechanical sap inoculation, Kolte and Nene 1975)  inoculat of ULCD . Kadian 75  inocukharif season. The mixed infection of crinkle with yellow mosaic disease and leaf curl (GBNV) in the urdbean also occurs in certain field conditions [Several researchers have reported the reaction of mungbean and urdbean genotypes against ULCD under field conditions. Sravika et al. (2019)  found thnditions . Godara nditions  screenednditions . Kumar enditions  screenednditions . Chaudhrnditions  screenednditions  screenednditions , in Pakinditions . A blacknditions . A high nditions . Researchers have shown that viral infections can lead to alterations in chlorophyll and sugar levels, resulting in a decline in photosynthetic activity ,78. Decr2O2 was reported in abundance as compared to the susceptible cultivar [Mungbean yellow mosaic India virus (MYMIV) [Tobacco mosaic virus (TMV) [The first line of defense comprising lignin and suberin prevents the entry of invading pathogens by strengthening the cell walls of the host plant. Since both are derivatives of phenolic compounds, varied levels of these phenolic compounds can be observed in resistant and susceptible hosts ,88. It icultivar . A simil (MYMIV)  and Tobaus (TMV) . Enzymesus (TMV) ,95. The us (TMV) . VmJAR1, VmAOC, VmWRKY, VmNPR1VmAP2/ERF and VmSAM), exhibiting reduced symptoms as compared to the susceptible cultivar [WRKY and NPR1 accompanied by a burst of H2O2 [JAR1 and AOC were observed in ULCD infection and concluded to be the responsible factor for the susceptibility reaction in the urdbean [AP2/ERF and SAM) [Another physiochemical change that generally occurs in plants on experiencing biotic stress as a part of a defense mechanism is the production of phytohormones such as salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) ,97. ULCDcultivar . These lcultivar . Of thescultivar . A resis of H2O2 . The SA  of H2O2 , which w of H2O2  against  of H2O2 . The lat urdbean . The tim urdbean , SA path urdbean . The resand SAM) ,104. Colc. 28 nm in diameter in the leaf dip preparations from the ULCD-affected leaves. They found that the antiserum of Blackgram mottle virus trapped a large number of particles in immunosorbent electron microscopy tests. Using ELISA, Patel et al. (1999) [Cowpea mild mosaic virus (Carlavirus), Mungbean yellow mosaic India virus (Begomovirus) and Groundnut bud necrosis virus (Orthospovirus). The latter two viruses are known to affect the urdbean and may be excluded as mere contaminants since the diseased samples were taken from the field. The role of the cowpea mild mosaic virus (CpMMV) in causing crinkle disease needs to be investigated using biological and molecular assays. The interference caused by asymptomatic viruses present as contaminants in field samples during the etiological identification of uncharacterized disease through NGS could be resolved by maintaining a pure inoculum under vector proof-controlled conditions. For this, in a recent study, an inoculation by the sprout seed abrasive method was developed and validated in different genotypes of the urdbean [Pea enation mosaic virus [From the early investigations ULCD is believed to be of virus etiology. Bhaktavatsalam et al. (1983)  in their. (1999)  found an. (1999)  employed urdbean . Earlieric virus . In ultric virus . Dubey eic virus  purifiedTrichoderma virens-based formulation), foliar sprays of imidacloprid and spinosad between 30 and 45 days after sowing (DAS), respectively, and a combination of seed treatment and foliar spray, all resulted in the reduced incidence of ULCD and increased grain yield in the urdbean [M. jalapa and B. spectabilis applied as a foliar spray before the inoculation of blackgram plants reduced ULCD. The reduction in disease was attributed to the induced resistance by the accumulation of phenols and enhanced activities of peroxidase, phenylalanine ammonia lyase and polyphenol oxidase in treated plants [Zingeber officinalis, Prosopis juliflora and Piper longum were found to inhibit an incidence of ULCD, and the inhibition was attributed to the induced resistance by the plant extracts [Azadirachta indica) and garlic  extract were found effective in reducing ULCD severity [Attempts have been made to manage the ULCD using chemicals. Seed treatment with a combination of Imidacloprid, carboxin + tetramethylthiuram disulfide (TMTD), Pusa 5SD  against the causal agent of ULCD in blackgram (Vigna mungo), resulting in reduced ULCD infection [The pre-inoculation application of two strains of the plant-growth-promoting rhizobacterium (PGPR), nfection . Karthiknfection  found thnfection ,112,116.nfection ,117,118.Viruses as disease-causing agents in plants have been known for more than a century. Since the discovery of the tobacco mosaic virus, which was the first plant virus to be characterized, about 1000 plant viruses have been identified ,119. DesOf late, next generation sequencing (NGS) is being studied as an effective tool to decipher the identity of, not only an unknown virus, but of the whole virome of a plant in a short span of time ,122,123.


The prescribing of injectable end-of-life anticipatory medications ahead of possible need is recommended best practice. The financial costs of these medications have been little studied.To identify the costs of anticipatory medications prescribed, used and not used for patients approaching the end-of-life at home and in residential care.Retrospective observational study using general practitioner and community nursing clinical records.Data were collected from eleven general practitioner practices using the records of the 30 most recent deaths per practice. Patients were aged 18+ and died between 2017 and 2019 from any cause except trauma, sudden death or suicide.Anticipatory medications were prescribed to 167/329 patients, of which 164 were included in the analysis. Costs (GBP) were analysed both at patient-level and drug-level. Median anticipatory prescription cost was £43.17 . Median administered (used) drug cost was £2.16 . Median unused (wasted) drug cost was £41.47 . Prescription, administered and unused costs were significantly higher for the 59 patients prescribed an anticipatory syringe driver. There were wide variations in the unused costs of individual drugs; Haloperidol and Cyclizine contributed 49% of total unused costs.The costs of prescribed and unused anticipatory medications were higher than previously reported but remain modest. Usage of prescriptions was lower than previously documented. There may be scope to reduce the quantity of vials that are routinely prescribed without adversely affecting care; further research is needed to investigate this possibility. What is already known on this topic?The standardised prescribing of anticipatory medications is commonplace, often with a fixed number of vials issued.Previous calculations of anticipatory medications costs and usage have relied on incomplete data.What this paper adds?The median anticipatory prescription cost was £43.17, with a median administered drug cost of £2.16.Prescription, administered and unused costs were significantly higher for patients prescribed an anticipatory syringe driver.Cyclizine, Haloperidol and Glycopyrronium Bromide contributed to a majority of the total unused costs.Implications for practice, theory or policyCosts of prescribed and unused anticipatory medications were higher than previously reported but remain modest.There may be scope to reduce the quantity of vials that are routinely prescribed without adversely affecting care; prospective research with health economics components are needed to investigate this possibility.6 Two recent UK studies found community-based prescriptions of anticipatory medications for 51% to 65% of dying patients, with timing of prescriptions varying between 0 to 1212 days before death.8 Lower prescription rates have been reported in Australia. Practice and policy are based on healthcare professionals’ views and experiences that the intervention provides reassurance to all involved and optimises symptom control.10 Studies of nurses’ and family carers’ experiences suggest the intervention prevents delays in accessing prescriptions, especially during out of hours periods, and helps in relieving symptoms of pain and distress.14 However, patients and family carers also express ambivalence about the helpfulness of medications and have safety concerns;13 some families experience considerable delays in accessing timely visits from nurses and can find it difficult to persuade professionals to administer (use) injectable medications when needed.15 There remains limited robust evidence of the clinical and cost-effectiveness of anticipatory medications, and their impact on patient safety and crisis hospital admissions.16The anticipatory prescribing of injectable medication ahead of possible need for the management of distressing last-days-of-life symptoms is recommended practice in a number of countries.3 However, standardised anticipatory prescribing of four medications for pain, nausea and vomiting, agitation and respiratory secretions is commonplace19 which may lead to increased unused (wasted) medication costs. Medication that is returned unopened to pharmacies must generally be disposed of in most countries, including the UK, resulting in waste.21Guidance internationally recommends individualised prescribing, based on the patient’s likely symptom control needs.22 with unused medication costs estimated to be £10.00–£14.61. Our study addresses this gap in the knowledge base.Anticipatory medications are considered a low-cost intervention. Previous studies have relied on incomplete cost data: 2–3 days’ supply of four widely used medications have been calculated to be £22.12–£30.26 per patientTo identify the costs of anticipatory medications dispensed, administered and not used for patients approaching the end-of-life at home and in residential care.An observational study of deceased patient recorded care using general practitioner (GP) and community nursing electronic and paper clinical records. Examination of patient-level and drug-level prescribing, usage and wastage medication costs.Ethical approval was granted by the South Cambridgeshire Research Ethics Committee [Reference: 19/EE/0012]. The processing of confidential patient information without patient consent was approved by the Health Research Authority’s Confidentiality Advisory Group [19/CAG/0014]. Data were anonymised at the earliest opportunity to ensure confidentiality.Supplemental Document 1. Patient characteristics are reported in Bowers et al. Data was collected between May 2019 and March 2020. Eligible patients were aged 18+, lived in their own homes or in care homes for at least 1 day in the last month of life and died from any cause except trauma, sudden death or suicide. Patients died between 4 March 2017 and 25 September 2019 in any setting, including home, residental care, hospice or hospital.Patients were registered with eleven GP practices and two associated community nursing organisations in two English counties (the 30 most recent eligible deaths per practice). The sample size of 330 patients was calculated ahead to enable statistical analysis. Maximum diversity sampling of GP practices and data collection and are reported in ahead of need to be administered for last-days-of-life symptom control. The dataset included a mixture of anticipatory (in advance of symptoms arising) and reactionary (in response to presence of symptoms) prescribing. LM, SB and BB agreed on a priori inclusion and exclusion criteria ; LB and BB independently applied these to identify prescriptions that had been anticipatory: reactionary prescriptions were excluded.Anticipatory medications were defined as one or more injectable medication prescribed Prescription costs were calculated by multiplying the number of vials prescribed and dispensed by the cost of the vials. Usage costs were calculated by multiplying the number of vials administered to the patient by the cost of the vials. Wastage costs (medication costs that were dispensed and not used) were calculated by subtracting the usage cost from prescription cost. Non-medication costs such as community nursing visits and family carers’ input were not included. On that date, GBP to USD was £1 = $1.40 and GBP to EUR was £1 = €1.17.Drug costs in British pound sterling (GBP) were calculated using the British National Formulary online drug tariff price (20th April 2021).© version 27: p < 0.05 is considered statistically significant.Costs were analysed at both patient-level and drug-level using univariate and multivariate analysis. Costs in GBP are reported as median (interquartile range: IQR). Non-parametric tests  were used in the univariate analysis, as the data were not normally distributed; multivariate analysis used simple linear regression with bootstrapping. Data analysis was performed using SPSSInjectable anticipatory medications were prescribed to 167/329 patients; complete records were available for 164 who were included in the analysis. Costs per patient below reference the cost per patient prescribed anticipatory medications.The median anticipatory prescription cost per patient was £43.17 . It was standard practice to prescribe five vials of each medication; additional vials were issued when patients were prescribed an anticipatory syringe driver ; these were for the same drugs as accompanying anticipatory medication prescriptions, often with larger doses and dose ranges to be administered by continuous subcutaneous infusion if required.Anticipatory prescriptions were used (administered) for 97/164 (59%) of patients. The median usage cost per patient was £2.16 . The median wastage cost per patient was £41.47 . This unused medication would have been destroyed when returned to a pharmacy, rather than being repurposed, under UK legislation. In total, 85% of prescribed medication costs were wasted (assumed destroyed) . Haloperp < 0.05) and wastage costs (p < 0.05) for patients at different GP practices; there were statistically significant differences in prescription (p < 0.001) and usage costs (p < 0.001) but not wastage costs (p = 0.231) when comparing patients who were prescribed an anticipatory syringe driver with those who were not . This analysis identified that when adjusting for these variables, prescription costs were significantly higher for patients prescribed an anticipatory syringe driver (p < 0.001) and male patients (p < 0.05). Usage costs were significantly higher for patients prescribed an anticipatory syringe driver (p < 0.001). Wastage costs were significantly higher for patients prescribed an anticipatory syringe driver (p < 0.05) and patients who were not administered medications (p < 0.01).All statistically significant variables in the univariate analysis, along with gender, age and cause of death, were entered into multivariate regression analyses of prescription, usage and wastage costs  medication are often prescribed and infrequently administered as previously reported.Our study provides new, detailed insights into anticipatory prescription, usage and wastage costs. Prescription and wastage costs are considerably higher than previously estimated,7 Our study found a statistically significant difference between practices for median prescription and wastage costs, but not for median usage costs. However, prescriptions and wastage costs per patient at different GP practices were not statistically significant in the multivariate analysis. The presence of an anticipatory syringe driver prescription was associated with higher prescription, usage and wastage costs. The prescription of anticipatory syringe drivers is a contentious clinical intervention. Some clinicians see them as vital in ensuring timely symptom control24 while others view it as unsafe practice that may lead to medications and doses being initiated without a suitably skilled clinical assessment.25 Careful and timely individualised prescribing is required to minimise potential risks to patient safety.2426GP prescribing practices vary widely, with differences in the timing of prescriptions before death and in prescribing anticipatory syringe drivers.27 more research is needed to understand prevalent last-days-of-life symptom profiles and which medications are likely to be needed for various patient groups.16 Standardised anticipatory prescribing of four medications is commonplace in the UK;28 there is limited evidence of practices in other countries.16Haloperidol, Cyclizine and Glycopyrronium were particularly underused and accounted for nearly two-thirds of the total wastage cost . Guidanc30 However, current evidence does not support the standard use of antimuscarinic medications for the treatment of noisy breathing at end-of-life2931 and more high-quality clinical studies are needed to identify if and when antimuscarinics, including Glycopyrronium, are an appropriate clinical intervention for noisy respiratory secretions.Glycopyrronium was the most common anticipatory prescription and accounted for around one-sixth of total wastage costs in our study: 86% of all Glycopyrronium prescribed was not used. Cultural practice norms and clinical guidelines have made these medications part of routine management of noisy respiratory secretions.22 Evidence suggests that these may well be underutilised for the majority of patients.22 Research is needed to investigate if the current standard practice, at least in the UK, of prescribing five vials of relatively expensive antiemetics such as Haloperidol or Cyclizine could be reduced to three vials in cases where nausea and vomiting are not expected. This might lead to significant savings at a population level, providing it did not inhibit individualised prescribing and access to medications and timely further prescriptions when needed.Antiemetics were often prescribed in our study and others.22 it is important to keep in mind the costs of crisis hospital and hospice admissions, which may be undesired by patients and families. These may be precipitated by troublesome symptoms close to the end-of-life; although there is a lack of robust evidence that anticipatory medications reduce inpatient admissions.16 There are considerable emotional costs associated with unrelieved pain, suffering and inadequate symptom control at home, although access to anticipatory medications does not guarantee timely and effective symptom control. Patient and family experiences of this care require further investigation.28While wastage costs are higher than previously reported, This study was undertaken into two relatively affluent counties in England, limiting the generalisability to under-served and more diverse communities. While prescribing is routinely recorded in large-scale primary care datasets, medication usage is not;7 a strength of our study was using complete paper and electronic records. However, these did not provide adequate details to calculate associated service utilisation costs, including community nursing and GP time in prescribing and administering medications.We were only able to include the patients that had complete community-based records of anticipatory medication prescriptions and usage, and had to exclude just three patients from the analysis. The generalisability of the results is enhanced by the identification of a large number of sequential deaths and a purposive sample of eleven GP practices and two community nursing services, reflecting varied team cultures and practices.Tariff drug costs may vary at a local level due to negotiations with suppliers, although this price is unlikely to fluctuate greatly; the British National Formulary costs were used as the reference point in our study as these are the default costs and are often used as a cost reference point when prescribing. Patients in our cohort would in all likelihood not have had to pay anything for the prescriptions themselves, qualifying for free prescriptions under the National Health Service.Our study provides new and detailed insights into prescription, usage and wastage costs of anticipatory medications. Prescription and wastage costs are higher than previously estimated but remain modest. Anticipatory syringe driver prescriptions are associated with higher prescription, usage and wastage costs. There may be scope to reduce the number of vials of Haloperidol, Cyclizine and Glycopyrronium prescribed if they are thought less likely to be needed. Prospective research with health economics components is needed to investigate this possibility and its implications for patient safety and effective, timely symptom control.Click here for additional data file.Supplemental material, sj-docx-1-pmj-10.1177_02692163231198372 for The financial costs of anticipatory prescribing: A retrospective observational study of prescribed, administered and wasted medications using community clinical records by Lloyd Morgan, Stephen Barclay, Kristian Pollock, Efthalia Massou and Ben Bowers in Palliative Medicine


The BK virus is a polyomavirus known to particularly affect transplant recipients. An important complication caused by BK virus infection in bone marrow transplant patients is hemorrhagic cystitis. We present a 31-year-old male with a history of bone marrow transplantation complicated by graft-versus-host disease (GVHD) and was diagnosed with BK virus-related hemorrhagic cystitis. He presented with gross hematuria and suprapubic and penile pain for one week. He has a significant past medical history of acute B-cell lymphocytic leukemia for which he has successfully undergone allogenic bone marrow transplantation, which was complicated by GVHD. Imaging revealed significant bladder wall thickening which prompted an evaluation for BK virus-induced hemorrhagic cystitis. A urinary specimen was sent for BK virus polymerase chain reaction (PCR) which was strongly positive, confirming the infection. He was managed supportively throughout his hospitalization and improved with symptomatic management alone. Our case demonstrates one of the main complications caused by the BK virus in allogeneic bone marrow transplant patients in the setting of GVHD and is an important differential to keep in mind when treating patients presenting with hematuria after bone marrow transplantation. The BK virus, so named after the initials of the patient the virus was isolated from, is a polyomavirus known to particularly affect post-transplant patients . TransmiA 31-year-old male with a past medical history of allogeneic bone marrow transplantation for B-cell acute lymphoblastic leukemia 10 months ago complicated by GVHD presented to the emergency department complaining of worsening suprapubic and penile pain associated with bloody urine. He stated that his symptoms had been ongoing for eight days prior to the current presentation, and noted blood throughout the stream every time he urinates. He had been taking oxycodone 20 mg every two hours with minimal improvement in his pain. He did report one episode of fever on the day prior to the presentation. He denied feeling nauseous or having episodes of vomiting. He denied flank pain or tenderness. Examination revealed an uncomfortable-appearing male with normal vital signs. Cardiovascular and respiratory exams were unremarkable. An abdominal exam revealed some suprapubic tenderness and bloody urine was noted in his urine bag.Two years ago, the patient was diagnosed with Philadelphia chromosome-positive acute B-cell lymphocytic leukemia. He completed a course of eight cycles of hyper-cyclophosphamide, vincristine sulfate, adriamycin, and dexamethasone (CVAD) with successful remission induction. He was subsequently referred for haploidentical allogeneic bone marrow transplantation which he successfully underwent. An HLA-matched donor was unavailable as he was an undocumented immigrant. Post-transplant, the patient was maintained on sirolimus and imatinib as well as antimicrobial prophylaxis with acyclovir, fluconazole, and letermovir. His post-transplant course was complicated by the development of chronic GVHD five months after his transplant after he presented with mucosal lesions, odynophagia, and generalized swelling. His GVHD was deemed low grade and it was decided against treatment with immunosuppressive therapy.A urinalysis was obtained which showed turbid-appearing orange urine with 3+ blood and 3+ protein. Greater than 50 RBCs and 3-9 WBCs were also noted. No significant bacteriuria, crystals, or casts were appreciated. Basic serum chemistry and a complete blood count were within normal limits. A urine culture obtained for suspicion of infection did not reveal any significant growth.A CT urogram with contrast study revealed extensive thickening of the bladder wall Figure . No enhaAlthough the patient was empirically managed with IV ceftriaxone for suspicion of infection, his negative cultures prompted concern for possible BK virus infection. A urology consultation was obtained for cystoscopy and biopsy. Active bleeding from the right lateral wall of his bladder was noted during the procedure, and electrocautery was applied to these areas with good hemostasis being achieved. Microscopic and macroscopic descriptions from biopsy sections showed reactive fibroblastic tissue and acute and chronic inflammation with no overt evidence of viral inclusions with cytomegalovirus (CMV) stain. The viral culture was also negative from the biopsy specimen.A quantitative polymerase chain reaction (PCR) for the BK virus from his blood was sent and although BK viremia was detected, it was unable to be quantified owing to a low viral load below 390 copies per milliliter. Subsequently, a urinary specimen was sent for BK virus detection by PCR, which confirmed BK virus infection with 8,170,000 copies per mL being detected.In consultation with his transplant physicians, it was decided against specific therapy for his infection with cidofovir and to continue supportive care alone. For his pain, he was continued on oxycodone and high-strength Tylenol. He was given Ditropan and Pyridium to assist with symptomatic relief as well. Post-procedure, he continued to improve with respect to the hematuria and pain and was subsequently discharged the following day.The BK virus belongs to the polyomavirus family that is commonly acquired in childhood with a prevalence rate of up to 80% to 90% in adults . The virOur patient was diagnosed with B-cell acute lymphoblastic leukemia (ALL) for which he underwent a haploidentical bone marrow transplant. Annually, there are about 5000 patients diagnosed with ALL, and 1400 deaths are attributed to the disease. Despite their high remission rates of 80% to 90% for ALL, the overall survival rate is low in the adult population (30% to 40%) . The proIn a retrospective study looking at patients who received hematopoietic stem cell transplants between 2016 and 2020, risk factors for BK virus-induced hemorrhagic cystitis, acute graft-versus-host disease (aGVHD), and others were discussed . The stuThe incidence of aGVHD in patients with hematopoietic cell transplantation from HLA-matched siblings is 50% but the incidence is higher in unmatched donors . Our patThe European Conference on Infections in Leukemia (ECIL) provides a guideline for BK virus-related hemorrhagic cystitis. The diagnostic criteria include clinical features of cystitis, grade 2 or higher hematuria, and BK viral viruria ≥ 7log10/mL. Hematuria grades 2, 3 and 4 include macroscopic hematuria, macroscopic hematuria with clots, and macroscopic hematuria with clots and renal dysfunction due to urinary obstruction, respectively [The BK virus can be detected in both blood and urine. The BK viral viruria mostly precedes viremia and also resolves after the resolution of the viremia. Viral load in the urine is usually higher than in the blood making it a more sensitive protocol for detection . The posThere is currently no standard and approved treatment protocol for BK virus-related hemorrhagic cystitis . Most caThis case demonstrates one of the main complications caused by the BK virus in allogeneic bone marrow transplant patients in the setting of GVHD. It is important to keep this in mind when treating patients with GVHD after a bone marrow transplant since they are at increased risk for hemorrhagic cystitis. The overall management for patients with BK virus hemorrhagic cystitis depends on disease severity with mild cases only requiring conservative treatment. Although some studies report the use of cidofovir in the management of BK virus hemorrhagic cystitis, further studies are needed to determine the optimal treatment strategy for BK virus reactivation.


Small fiber neuropathy societal costs were estimated at €148 million with daily practice small fiber neuropathy patient data. Health-related quality of life was the key association on health care and societal costs. P < 0.001).Neuropathic pain is associated with substantial healthcare costs. However, cost-of-illness studies of small fiber neuropathy (SFN) are scarce. Our aim was to estimate the healthcare, patient and family, and productivity costs of patients with SFN in the Netherlands from a healthcare and societal perspective. In addition, the association of costs with age, pain impact on daily life, anxiety, depression, and quality of life (Qol) were examined. Cost questionnaires were completed by 156 patients with confirmed SFN. The average annual total health care and societal cost  was calculated at patient, SFN adult population, and societal level. The average annual healthcare, patient and family, and productivity costs per patient with a Pain Impact Numerical Rating Scale of 0 to 3 (mild), 4 to 6 (moderate), and 7 to 10 (severe) were calculated by using the cost questionnaire data. Quality of life was determined by the EuroQol 5D utility scores. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Associations of all costs were analyzed using linear regression analyses. At the patient level, the average annual SFN healthcare and societal cost of SFN was €3614  and €17,871 . At the SFN population level, the average healthcare costs were €29.8 (CI €26.4-€34.2) million, and on a societal level, these were €147.7 (CI 120.5-176.3) million. Severe pain was associated with significant lower Qol and higher depression scores, higher healthcare, patient and family, and productivity costs ( A cost of illness (COI) study of confirmed SFN has not yet been conducted. Therefore, the costs of SFN and the factors which influence healthcare consumption and productivity costs remain largely unknown. This COI study aims to examine the healthcare, patient and family, and productivity costs of patients with confirmed (by skin biopsy or QST proven) SFN in the Netherlands to estimate the annual SFN costs from a healthcare and a societal perspective. In addition, the associations of age, pain impact on daily life, anxiety, depression, and health-related Qol on these costs were investigated.The US annual total health care and patient and family costs of idiopathic painful neuropathy with SFN involvement since 2012 were estimated at $8055 (€7403) per patient.This COI study was conducted at the diagnostic SFN service of the SFN Center of the Maastricht University Medical Center+ in Maastricht, the Netherlands. The SFN Center is a tertiary referral center for patients with suspected SFN, evaluating approximately 500 patients yearly. The diagnostic SFN service is based on a 1-day stay at the neurological day care unit with time slots reserved for interviewing, examining, diagnostic tests, and analyzing and discussing the findings among a multidisciplinary team. Diagnostic tests include a skin biopsy for identifying abnormalities in IENFD, NCS, and QST.Using the waiting list registration, all patients with suspected SFN and ≥18 years of age, referred to the SFN Center between April 2017 and February 2020, were invited by e-mail to participate in this study. They were given access to an Internet-based electronic environment to complete the online questionnaires. For those patients not able to complete the online questionnaire, a paper version was provided. All questionnaires were completed before the patients' visit to the SFN Center, so while on the waiting list. Exclusion criteria were declining participation and significant language barrier. Only data of patients with confirmed SFN were analyzed. Between April 2017 and February 2020, 258 patients participated in the study. The flowchart of the waiting list up to and including their visit to the diagnostic SFN service is shown in Figure 35The study was approved by the Medical Ethics Committee of Maastricht UMC+ (15-4-004). Informed consent of all patients was obtained before participating in the study, according to the principles of the Declaration of Helsinki.Sociodemographic data  and data on clinical characteristics (duration of SFN complaints) and patient-related outcome measures  were obtained by the online survey and the electronic patient file.14Pain impact on daily life was measured using the 11-point Pain Impact Numerical Rating Scale .22Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS) questionnaire, disaggregated for anxiety (HADS-A) and depression (HADS-D). Each subscale consists of 7 questions with answers recorded on a 4-point Likert scale. Scores can range from 0 to 21. Higher scores indicate more symptoms of anxiety and depression.20 The EQ-5D-5L consists of a Visual Analog Scale (VAS), which ranges from worst (0) to the best imaginable health (100), and 5 additional questions, each representing a health-related QoL dimension. These 5 additional questions covered mobility, self-care, usual activity, pain/discomfort, and anxiety/depression.20 Each question has 5 response levels, classifying the severity of complaints for that specific dimension and allowing 3125 possible state-of-health combinations. These were converted into EQ-5D utility scores according to the Dutch tariff.33 Possible EQ-5D utility scores range from −0.446 to 1.00,33 with −0.446 being the worst imaginable state of health and 1.00 the best.The 5-level EuroQol 5D (EQ-5D-5L) was used to measure generic health-related QoL.4 The iMTA Medical Consumption Questionnaire includes questions on the utilization of general practitioner (GP) visits, medical specialist visits, other healthcare provider visits , emergency room (ER) visits, hospital outpatient visits, and hospitalizations and use of paramedical care, prescription medications, outpatient tests, and procedures. In addition, questions on out-of-pocket costs for medical care and nonmedical resources  related to SFN are also included.Healthcare and patient and family costs related to SFN were measured with the iMTA Medical Consumption Questionnaire. Participants were asked to only report resource use and costs related to neuropathic and autonomic complaints of SFN, within a 3-month recall period.5 Participants were asked to only report data on paid employment, reduced work schedule, absenteeism, unemployment, and the costs of productivity loss for unpaid employment activities as a result of neuropathic and autonomic complaints of SFN, using a 3-month recall period, in accordance with the Dutch guideline for cost research.19The iMTA Productivity Cost Questionnaire (iPCQ) was used to measure productivity costs.14Subjects were asked to score the pain impact on their working productivity of the last week on the Pain Impact NRS.36 Differences in demographics, pain impact on daily life, anxiety, depression, and health-related Qol among these groups were tested with an analysis of variance  where appropriate for the continuous variables, whereas a Chi-square test was used for the categorical variables. The continuous variables were tested for normality using a Kolmogorov-Smirnov test.Descriptive statistics were used to present sociodemographic, clinical characteristics, and PROMs data. The Pain Impact NRS scores on daily life were used to categorize subjects into 1 of 3 pain impact groups based on established cut-off points for neuropathic pain .30 Unit costs were converted to the reference year 2020 by means of index numbers.6 To acquire annual average overall costs per patient, the measured 3-month costs were multiplied by 4.Healthcare, patient, and family costs were calculated using per unit costs obtained from the Dutch guideline for cost research.19 The cost of an hour of productivity loss from paid employment was calculated by using the Dutch guideline for cost research based on the average hourly salary costs per paid worker.19The productivity costs of paid employment were quantified using the friction cost approach, in which productivity loss is restricted to 85 calendar days (12 weeks).19Productivity costs from unpaid employment were valued on the basis of replacement costs for household care. This was equated to a standard hourly rate for cleaning work, as used by the Dutch Central Administration Office (CAK).The total societal costs consist of the sum of healthcare, patient and family, and productivity costs. Average total societal costs per patient were multiplied by the prevalence of SFN for the general adult population to estimate the total COI of SFN for the Dutch society. In 2020, the Dutch adult population aged ≥20 years totaled 15,592,909 residents . By applying the prevalence rate of 53 cases per 100,000 inhabitants, it was calculated that approximately 8264 adults in the Netherlands have SFN.Usually, cost data are not normally distributed. Therefore, a nonparametric bootstrap resampling procedure with 1000 simulations was performed in SPSS to determine statistical uncertainty of the cost estimates per category. The differences in costs among the pain impact groups were established by calculating confidence intervals (CI) by the bootstrapping procedure.32 A backward stepwise method was used to test for interaction between the independent variables on all outcomes using an α of 0.05. For statistically significant interactions, results were presented with an interaction term whenever there was at least one continuous variable or stratified per category whenever there was at least one categorical variable. A log transformation was performed on the dependent variables to resemble normality. Where possible, the observed β′s were back transformed into a relative difference (in %) using the formula: (exp[β] − 1) × 100%. All analyses were performed using IBM Statistics SPSS version 25.0.Multivariate linear regression analyses were performed to estimate the association of age, pain impact on daily life, health-related Qol, anxiety and depression, with healthcare, patient and family, productivity, and societal costs. These variables were selected based on their relevance according to the literature.Demographics, clinical characteristics, and PROMs of the 156 patients with confirmed SFN are shown in Table P < 0.001). Furthermore, statistically significant higher depression scores were observed in the severe pain group compared with the mild pain impact group (P < 0.001). No statistically significant differences were seen between the 3 pain impact groups regarding age, sex, level of education, duration of SFN complaints, anxiety, and diagnostic tests.Between all 3 pain impact groups, statistically significant differences were seen in the Pain Impact NRS on daily life and health-related QoL utility scores  per patient  or full-time paid employment (22%), and 21% was disabled. The average SFN productivity costs are presented in Table The COI of patients with SFN €, 2020) in the Netherlands is presented in Figure 020 in thP < 0.01). An increase of 0.1 point on the EQ-5D utility score was associated with a 13.2% decrease (95% CI −20.8 to 4.9) in patient and family costs. No significant association with health-related QoL was observed in patients with severe anxiety symptoms . For the costs of productivity loss and societal costs, a significant interaction was observed between pain (pain impact NRS ≤ 6 vs pain impact NRS ≥ 7) and health-related QoL  (P < 0.05), and therefore, these results are presented separately by the pain group in Table P ≤ 0.001). An increase of 0.1 point on the EQ-5D utility score was associated with a 41.4% decrease (95% CI: −57.5 to −19.3) in productivity costs. No statistically significant association with health-related QoL was observed in patients with a pain impact NRS of ≥ 7 . Regarding the societal costs, health-related QoL was statistically significant inversely associated in the pain impact groups NRS ≤ 6 and NRS ≥ 7 . A 0.1 point increase on the EQ-5D utility score was associated with a decrease of 14.6% (−23.7% to −4.5%) in societal costs in the pain impact group NRS ≤ 6 and a decrease of 5.8% (−10.8% to −0.5%) in societal costs in the pain impact group NRS ≥ 7.There were no statistically significant associations found between age, pain impact on daily life, health-related Qol, anxiety and depression, and SFN healthcare costs Table . In the To the best of our knowledge, this is the first study examining the healthcare and societal costs of clinically referred patients with confirmed SFN in the Netherlands. The total healthcare costs to Dutch society for the SFN adult population is estimated to be almost €30 million annually, which is approximately 0.03% of the total healthcare expenditure in the Netherlands in 2020 . Overall, health-related QoL was statistically significant associated with SFN patient and family, productivity, and societal costs.27 which allows us to compare our results with previous research. Demographic and clinical characteristics of the 2 study populations were similar, but the study population in the previous study27 was insufficiently defined due to inadequate diagnosis of SFN. Therefore, the results may not be a representative for the SFN population. In addition, data in the previous study was collected over a period of 6 months, which is inconsistent with data collection guidelines for costs studies and may have led to an underestimation or overestimation of costs.28Previous COI of confirmed SFN has not been performed. A cost study of idiopathic painful neuropathy with SFN involvement has been conducted, however,27 only the direct costs of the mild and moderate pain severity groups were statistically significant higher.Total healthcare and patient and family costs (direct costs) of SFN in our study were lower (€5690), and severe pain was associated with statistically significant higher costs. In the previous study,27 In our SFN study, severe pain was associated with statistically significant higher costs of medical specialist care and active medical treatment, whereas in the previous study, no association was found.27The main contributors to the healthcare costs of SFN in our study were medical specialist care and active medical treatment and were different to main contributors identified in the previous study .27 and the costs of the severe pain group were significantly higher compared with the mild pain group. In the previous study, the indirect costs of the pain severity groups were not statistically significant higher.27The total productivity costs (indirect costs) of the 2 study populations were similar ,27The proportion of patients with SFN in paid employment (47%), who were retired (15%) or disabled (21%) in our study was different compared with the previous study .27The main contributor to the high costs of productivity loss of SFN in our study was the cost of lost hours due to being limited in performing daily household tasks, which was significantly higher in the severe pain group compared with the mild pain group. In the cost study of idiopathic painful neuropathy with SFN involvement was the main contributor costs of disability, with no association found.7 and the Dutch healthcare costs of fibromyalgia.34 Furthermore, the use of SFN pain treatments makes up 28% of the SFN healthcare costs, which is comparable with chronic neuropathic pain treatments in other academic pain centers.31 Neuropathic pain is associated with lower health utility scores, and the EQ-5D utility score of our SFN population (0.59) is comparable with diabetic neuropathy (0.61)13 and fibromyalgia (0.54).16 Comorbidities such as anxiety and depression have a negative effect on Qol in patients with chronic peripheral neuropathic pain,26 and our study results showed that severe pain was associated with higher depression scores. Health-related Qol is highly correlated with morbidity, mortality, healthcare, and societal costs,13 and in our study, we used the EQ-5D as a generic instrument to measure health-related Qol. The derived utility scores can also be used in a planned cost-effectiveness study.10Our average SFN healthcare costs are comparable with the UK healthcare costs of painful diabetic peripheral neuropathy24 and vitamin D23 are increasingly used1 and may play a role in neuropathic pain treatment, but more scientific evidence is needed on their effectiveness.Regarding the SFN patient and family costs, over-the-counter-medication  was often used in addition to the prescribed medications. Nutraceuticals, such as N-palmitoylethanolamide (PEA)19 Productivity costs in patients with a NRS ≤ 6 were associated with higher pain impact on daily life and lower health-related QoL. Our results observed a 41% reduction in productivity costs per 0.1 point increase on the EQ-5D utility score.The leading factor of SFN productivity costs was the limitation in performing daily household tasks due to painful SFN. Important for estimating the COI of SFN is including replacement costs for patients' not performed daily household activities. That is, valuing lost productivity hours from unpaid employment activities, which should not be limited to activities actually taken over by informal care givers.This study's contribution to the literature is in the detailed insight it provides into the societal COI of patients with confirmed SFN in the Netherlands. This study is based on daily practice data of patients with confirmed SFN, and we were able to investigate a number of associations between costs and patient characteristics.3 (2) the healthcare cost study from the US,27 and (3) the inclusion of a considerable number of patients with mild and moderate complaints (n = 69). Furthermore, because only older prevalence rates were available while rates are likely increasing due to increased global recognition,25 this could have led to an underestimation of COI in our study. Another issue may be that costs of absenteeism made in the quarter before registration on the waiting list can be prone to recall bias, because the optimum recall period for loss of productivity is 1 month.28 However, the optimal recall period for healthcare, patient, and family costs is different (3 months). Therefore, the recall period of all costs was equalized to 3 months. Finally, the use of the friction cost method for calculating costs of absenteeism may be considered conservative and leads to lower estimates than other methods, such as the human capital method.19 However, the friction cost method is in accordance with the Dutch cost guideline.A limitation of our study was that tertiary care patients were included, who may experience more severe SFN symptoms than patients seeking help in primary or secondary care. However, our sample is a representative for most of the total SFN prevalence figure for 3 reasons: Our study population is comparable with (1) the mean age, the percentage male–female ratio, duration of SFN complaints, and mean average pain of a Swiss study population with SFN,An actual cost estimation of patients with confirmed SFN from a Dutch healthcare and societal perspective was provided, with medical specialist care, active medical treatment, and productivity costs identified as the main contributors to these costs. Health-related QoL was the leading association on the high COI of patients with SFN. Future cost-effectiveness studies may explore the impact of therapeutic options for improving the health-related Qol of patients with SFN on the COI of the SFN population.MG, YVEH, LB, and CMLGB have nothing to disclose. JGJH reports a grant from the Prinses Beatrix Spierfonds (W.OK17-09 and W.TR22-01), outside the submitted work. ISJM reports grants from Talecris Talents Program/Perinoms study, grants from GBSjCIDP Foundation International, grants from Prinses Beatrix Fonds, grants from European Union seventh Framework Program, other grants from Steering committee members for various studies, outside the submitted work; serves on the editorial board of the Journal of Peripheral Nervous System, is a member of the Inflammatory Neuropathy Consortium (INC) and member of the Peripheral Nerve Society. MAJ reports grants from European Union's Horizon 2020 and ZonMw, other from participation in the research panel of the Medical Research Council in the United Kingdom. CGF reports grants from European Union's Horizon 2020 (grant no. 721841), grants from Prinses Beatrix Spierfonds, grants from Grifols and Lamepro, other from Steering committees/advisory board for studies of Biogen/Convergence and Vertex, outside the submitted work.