Fasciola hepatica) was collated by members of the European COST Action “COMBAR” (Combatting Anthelmintic Resistance in Ruminants), and combined with data from a previous systematic review of AR in GIN. A total of 197 publications on AR in GIN were available for analysis, representing 535 studies in 22 countries and spanning the period 1980–2020. Reports of AR were present throughout the European continent and some reports indicated high within-country prevalence. Heuristic sample size-weighted estimates of European AR prevalence over the whole study period, stratified by anthelmintic class, varied between 0 and 48%. Estimated regional (country) prevalence was highly heterogeneous, ranging between 0% and 100% depending on livestock sector and anthelmintic class, and generally increased with increasing research effort in a country. In the few countries with adequate longitudinal data, there was a tendency towards increasing AR over time for all anthelmintic classes in GIN: aggregated results in sheep and goats since 2010 reveal an average prevalence of resistance to benzimidazoles (BZ) of 86%, macrocyclic lactones except moxidectin (ML) 52%, levamisole (LEV) 48%, and moxidectin (MOX) 21%. All major GIN genera survived treatment in various studies. In cattle, prevalence of AR varied between anthelmintic classes from 0–100% (BZ and ML), 0–17% (LEV) and 0–73% (MOX), and both Cooperia and Ostertagia survived treatment. Suspected AR in F. hepatica was reported in 21 studies spanning 6 countries. For GIN and particularly F. hepatica, there was a bias towards preferential sampling of individual farms with suspected AR, and research effort was biased towards Western Europe and particularly the United Kingdom. Ongoing capture of future results in the live database, efforts to avoid bias in farm recruitment, more accurate tests for AR, and stronger appreciation of the importance of AR among the agricultural industry and policy makers, will support more sophisticated analyses of factors contributing to AR and effective strategies to slow its spread.Helminth infections are ubiquitous in grazing ruminant production systems, and are responsible for significant costs and production losses. Anthelmintic Resistance (AR) in parasites is now widespread throughout Europe, although there are still gaps in our knowledge in some regions and countries. AR is a major threat to the sustainability of modern ruminant livestock production, resulting in reduced productivity, compromised animal health and welfare, and increased greenhouse gas emissions through increased parasitism and farm inputs. A better understanding of the extent of AR in Europe is needed to develop and advocate more sustainable parasite control approaches. A database of European published and unpublished AR research on gastrointestinal nematodes (GIN) and liver fluke ( Fasciola hepatica) threatens the profitability and sustainability of livestock production. Helminths affect growth [Livestock production is estimated to contribute on average 40% of agricultural production value worldwide  . The inft growth , productt growth  and reprt growth , and thrt growth . Furthert growth  and GIN t growth , 29, 47.F. hepatica) may also be widespread , levamisoles (LEV) and macrocyclic lactones  to maintain infections below levels that can cause clinical and sub-clinical disease. However, Anthelmintic Resistance (AR) in GIN has been reported worldwide in multiple nematode species, against most anthelmintic classes and sometimes simultaneously multiple different classes , 42, 49 ad e.g. , 18, 25), 25F. hehttps://www.scops.org.uk) and Control of Worms Sustainably (https://www.cattleparasites.org.uk), yet farmers continue to implement AR-selective practices, such as moving sheep to low challenge or “clean” pastures immediately after treatment and treating ewes and lambs more frequently than necessary [Newer, more sustainable, approaches to helminth control, which reduce the frequency of anthelmintic treatments  while maintaining high productivity levels are available. These approaches include Targeted Selective Treatment (TST), based on individual animal health or production parameters , 34, or ecessary . Confirmecessary . Similarecessary . This suhttps://www.combar-ca.eu) established a consortium of researchers from 26 countries across Europe. The consortium aims to advance research on the prevention of AR in helminth parasites of ruminants and disseminate current knowledge among all relevant stakeholders through improving diagnosis, understanding the socio-economic aspects of infection and decision making, and developing innovative, sustainable control methods. As part of this, and to encourage the uptake of COMBAR outputs and recommendations for sustainable control of helminth parasites, an up-to-date synthesis of current AR research is needed.A systematic review of reports of AR in European ruminant livestock confirmed that AR is spatially widespread, but also highlighted limitations in the available data, due to sample selection bias, a lack of georeferenced data to allow robust spatial analyses, and a number of countries for which no data existed . In 2017In this study, we draw on the collective expertise and data held by the COMBAR consortium to address the limitations of AR research identified previously, by collating published and unpublished data on AR in Europe that can be used to support advocacy for sustainable control programmes and to target future research efforts where they are needed most.This review was performed and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) : (1) preA standardised spreadsheet model was populated with data from the previous systematic review . MembersEach publication or unpublished dataset, hereafter referred to as “publication”, was given a unique identifying number. Within each publication, multiple anthelmintic classes and livestock classes tested were entered as separate entries, hereafter referred to as “studies”. Therefore, one “publication” may contain several “studies”. When a publication presented separate data for different regions within the same country, these data were split into separate rows (studies) in the database (e.g. ). When aFor GIN, data were stratified primarily by host species and anthelmintic class, with the exception of the ML, which were divided into avermectins (e.g. ivermectin) and milbemycins . Hereafter, MOX is analysed separately to the other ML. Other classes were benzimidazoles (BZ), imidazothiazoles, i.e. levamisole (LEV), amino-acetonitrile derivatives, i.e. monepantel (MPTL), and salicylanilides, i.e. closantel (CLOS). Studies testing more than one anthelmintic simultaneously in the same animals were entered as combination treatments (COMB), except where the combination involved MOX and ivermectin; in this case the anthelmintic class was entered as MOX due to its relatively high efficacy against some ivermectin-resistant populations of GIN, and observations that the extent of cross-resistance is greater in ivermectin than MOX-resistant populations (reviewed by ).F. hepatica, data were stratified by anthelmintic compound, rather than class, in order to differentiate between the activity of triclabendazole (TBZ) and albendazole (ALB), which have different efficacy profiles depending on the age of the fluke [F. hepatica are genetically similar between host species [For he fluke . Data fo species .in vivo; Faecal Egg Count Reduction Test (FECRT) and Controlled Efficacy Test (CET), in vitro, and molecular methods) is unavailable, therefore increasing the timeliness of the analysis and potentially reducing limitations such as regional publication bias. Some misclassification of resistance is consequently expected in both directions, but the increased number of studies adds power to analysis of trends.Due to significant upcoming changes in protocols for detecting AR , inclusiData analysis was completed in R v3.6.1 . Figuresx = the proportion of farms with AR, w = weights :GIN AR prevalence for each anthelmintic class and ruminant species were estimated from the reported prevalences and were weighted by sample size (number of farms in each study) to give a weighted mean (I2 statistic [−7) to allow variance to be calculated as input for Cochran’s Q statistic when estimated prevalence was zero. Negative I2 values were set to zero [I2 values were not estimated where only one study existed. Higher I2 values indicate higher levels of heterogeneity.Heterogeneity in AR prevalence estimates between studies (aggregated by anthelmintic class and host species) was estimated using the tatistic , calculatatistic , with th to zero , as wellI2 were also estimated using only studies investigating 10 or more farms.To evaluate the impact of sample selection bias in studies with small sample sizes , sample size-weighted mean prevalences, standard deviations and F. hepatica due to insufficient studies.Similar analyses were not completed for ” function in R) and estimates for the cost of helminth infections and research budget for projects starting after 01/01/2008 and ending before 31/12/2017 [Qualitative assessment of spatial bias in AR research was made by mapping the number of publications per ruminant species per country. Quantitative assessment of spatial bias in AR research (GIN only) was made by relating the number of studies per country and the research budget or cost of helminth infection per country using Spearman rank correlation  for each active compound, and na is the number of actives to which resistance was documented to date. For GIN, prevalence for up to four actives was included: BZ, LEV, ML, and MOX separately from other MLs as a special case (as detailed above). MPTL was not included in the prevalence part of the equation as it has been tested only rarely to date, and the same applies for the narrow-spectrum active sulphonamide, CLOS. Both, however, were added to na in countries in which cases of resistance had been confirmed. Thus, for instance, a country with reports of AR involving BZ and ML with sample-size weighted prevalence of 0.5 and 0.1, would score (0.5 + 0.1 + 2 = 2.6), while another reporting resistance to BZ, LEV, ML, MOX and MPTL with prevalence, respectively of 1, 0.7, 0.8, 0.4 and 0.1, would score (1 + 0.7 + 0.8 + 0.4 + 5 = 7.9). For liver fluke, seven actives were included in both p and na (see Results).To compare the estimated level of AR between countries alongside the relative confidence that can be placed in that estimate, an index was compiled for each, as follows:S is the number of separate publications (or unpublished reports) in the database, F the total number of farms included, and A the total number of anthelmintic classes investigated. F is the sum of the total number of farms used per study, regardless of how many anthelmintics were assessed on each, to prevent double counting. Both S and F were log10-transformed to stabilise variance, and scaled to the maximum value across countries , to provide a measure of the relative research effort among countries in the database at the time of the analysis. One publication from Ireland included data from 4211 farms but used pooled faecal samples collected by farmers: for this case, the number of farms was divided by an arbitrary value of 10 before entry into the equation, to avoid unfair comparison with studies using full FECRT. The confidence index itself is arbitrary, but standardised across countries, and aims to assess the relative extent to which AR has been thoroughly investigated, to aid interpretation and prioritisation of future research.Confidence was not estimated from prevalence; rather, it is an index of research effort, taking into account the depth and breadth of investigation into the AR situation nationally:Level versus Confidence (= Research effort) were plotted for each country: separately for GIN in either sheep, goats or cattle, and for fluke for all host species combined. Data manipulation and analysis were completed using Excel .Results of Anthelmintic Resistance is a dynamic process, evolving as helminth populations experience repeated treatment, and as farmers change to more effective anthelmintics when treatment failure is recognised. Research on AR is also dynamic, often responding initially to reports of treatment failure on particular farms, before expanding to prospective surveys, with highly variable selection criteria, and assessing additional anthelmintic groups as they become available or fall under suspicion of failure. Because of this, prevalence data averaged over a long period are unlikely to accurately capture the current situation in any given country, or trends in AR over time.To address these confounders, change in prevalence was evaluated over time. Reports of AR on single farms were excluded, since these are often conducted in response to suspected treatment failure. Prevalence was transformed to arcsine of the square root of prevalence in order to stabilise the variance around values close to 0 or 1. The relationship between year and prevalence was then tested using Pearson and Spearman rank correlation.Nematodirus battus was also excluded. Initially, average prevalence was plotted for each anthelmintic group for each decade, to visualise trends in AR over time. The database was then searched separately for each anthelmintic group in GIN in sheep, goats and cattle, and fluke in all hosts. For each country meeting these criteria , correlation between prevalence and year was assessed as above. Where a significant correlation was confirmed, linear regression was conducted to evaluate the rate of change in AR prevalence over time.In a second stage analysis, the data set was reduced to countries that reported at least three studies in different years, to further decrease the influence of responsive investigations and to capture change over time within countries. Sample-size adjusted prevalence, while arguably giving the fairest indication of how common AR is among farms in a given sample set, can result in bias: for example, if larger surveys are conducted as concern over resistance rises over time, more recent data will dominate overall prevalence estimates. For this reason, prevalence from individual studies was averaged over each decade without adjusting for sample size. Studies in sheep and goats were combined to increase power, given that helminth species are largely shared between these hosts. Italy was excluded because its combination of low AR prevalence and high level of reporting in recent years (19/20 reports in sheep and goats coming after 2007) strongly affected the overall trajectory across countries, and a single large study in the UK focusing only on The main relevant influences that might affect research on AR were identified by SWOT  analysis, to inform further AR research. The SWOT template was drafted by the lead authors and circulated for input by all co-authors.Supplementary Material. A live version of the database is also freely available on the Open Science Framework [https://www.gnu.org/licenses/gpl-3.0.html).The database used in these analyses is provided as ramework  and submramework . This vehttps://www.parasite-journal.org/10.1051/parasite/2020062">Fig. S1). The majority of studies investigated AR in GIN on single farms . 23.4% (n = 47) of the “publications” were unpublished.In all, 197 publications were available for analysis, representing 535 studies, 22 countries and spanning the period 1980–2020 (p = 0.49) but was positively correlated with the economic cost of helminth infections estimated in the same study .There was a regional research bias towards Western Europe and especially the UK, while Eastern European countries were relatively underrepresented in the body of AR research . AR was most widely reported in sheep, whereas AR in cattle and goats was understudied in many regions, indicated by the number of countries with no data available .Reports of AR were widespread throughout Europe, particularly to BZ . However, there was considerable heterogeneity between studies . TBZ resistance was reported in the UK, Ireland, Spain and the Netherlands. ALB resistance was reported in Sweden and Spain. CLOS resistance was reported in Sweden, and clorsulon resistance was reported in Spain. No resistance was observed in Italy. The majority of publications investigated AR on individual farms, with the exception of two larger studies. Kamaludeen et al. [F. hepatica originated from the Netherlands and were reported on 94 farms by the Royal Animal Health Service between 1998 and 2003 (https://www.gddiergezondheid.nl).Anthelmintic Resistance in n et al.  identifin et al.  identifiρ18 = 0.75, p = 0.001; and ρ15 = 0.79, p < 0.001, respectively), but this relationship was not apparent for studies of GIN in cattle (p = 0.46), or for fluke across host species .For GIN in sheep and goats, the observed level of treatment failure correlated with research effort  and in the UK for BZ  and ML . Correlation in other countries was mostly positive but not significant. Linear regression of prevalence against year ) produced similar slopes for the rate of increase in BZ in Switzerland and the UK, equating to approximately 20% increase in prevalence per decade, and a faster rate of increase of 33% per decade for ML.For GIN in sheep, six countries reported at least three studies in different years, excluding single-farm case reports: France (BZ), Italy , the Netherlands , Slovakia (BZ) Switzerland (BZ), and the United Kingdom . No countries met this criterion for GIN in goats or cattle, or fluke. Further analysis of these 11 country-anthelmintic group combinations for GIN in sheep, on arcsine-transformed prevalence and with a Bonferroni-adjusted critical The main relevant influences that might affect research on AR that were identified by SWOT analysis . Prevalence of AR in GIN against BZ, LEV, ML and MOX ranged between 0% and 48% when averaged over the entire database, but confidence intervals were wide and there was a high level of heterogeneity between studies. There was also considerable variation within and between regions depending on host species and anthelmintic class. Ten studies were largely in agreement that AR against MPTL in sheep is currently rare in Europe, although these studies were focussed on only six countries. AR in https://www.parasite-journal.org/10.1051/parasite/2020062">Fig. S4) is reflected in the spatial distribution of publications per country , and implementing looser inclusion criteria, allowed the inclusion of data from more countries than in previous reviews , publica country . FailingThe relationship between research effort and observed AR was investigated semi-quantitatively using composite indices of level of AR across anthelmintic groups and research effort or confidence, per country. Level of AR included the number of anthelmintic groups to which AR was reported and observed prevalence of resistance to each (i.e. proportion of farms with AR). Research effort, indicative of relative confidence in the levels of AR, comprised the number of studies in the database, the total number of farms investigated, and the number of anthelmintic groups tested. The positive relationship between level of AR and research effort in the better-studied systems  is to be expected for two main reasons. Firstly, as more studies are conducted and more anthelmintic groups tested, the chance of finding AR increases. Secondly, a perceived problem with anthelmintic efficacy is often the stimulus for investigations, and finding AR will provide justification for further and larger studies, fuelling a cycle of perceived and observed AR. To some extent, therefore, differences between countries in both observed level of treatment failure and research effort represent different positions on a trajectory of learning about existing AR problems, as well as between-country heterogeneity in true levels of AR. Nevertheless, the fact that low research effort is invariably associated with low apparent levels of treatment failure should stimulate further studies, especially in those countries positioned towards the lower left in Overall confidence in AR status in GIN in cattle, and in fluke in both sheep and cattle, was very low, and further studies should also be prioritised to address these knowledge gaps in all countries. In sheep and goats, high confidence can be placed in high levels of AR in several countries  and limited time range, as well as potential bias in farm selection. However, with the notable exception of LEV, for which some surveys gave inaccurate results before the mid-90s , successIncreasing AR is less obvious after 2009 for LEV, although sample sizes are low and there is no robust evidence of a decrease in prevalence. Studies in New Zealand have suggested that a change to less intensive treatment regimens might be successful in slowing or even reversing anthelmintic resistance in GIN populations . The relThe analyses of AR revealed several sources of bias, which can confound interpretation and impede solutions-oriented research. Thus, bias makes it very difficult to identify risk factors for rapid development of AR, and to determine whether differences in observed levels of treatment failure between countries, and between farms, can be used to guide future strategies. While removal of bias in studies of AR is difficult and perhaps impossible, greater efforts to reduce or account for it could support more refined analyses and better understanding of regional patterns and risk factors on which to base advice to farmers and policy makers.SWOT analysis also identified potential biases, and within-country variation that could affect current and future AR research. Although data protection legislation  may limit the resolution of location data that can be published, there is now an opportunity to improve reporting of AR research to facilitate future geostatistical analyses. Future studies should strive to publish the location of farms in a way that protects farmer anonymity e.g. publishing latitudes and longitudes to one decimal place would give an indicative spatial accuracy of ±10 km at the equator.https://cordis.europa.eu/project/id/22851) GLOWORM , DELIVER  and PARAGONE . As a result, AR is now considered part of the broader antimicrobial resistance problem and stakeholders have recently recognised the emerging risk and agreed that it is now time to take concrete actions to ensure the responsible use of all veterinary medicines, including anthelmintics in livestock species [During past decades, European research and investment tended to focus on resistance to antibiotics, but AR research effort accelerated after the turn of the millennium, coinciding with investment by the European Commission in several AR research consortia: PARASOL  was lower than on non-randomly selected farms . Similarly, small sample sizes  may inflate uncertainty. Study design includes the active compounds to be tested and whether or not to include an untreated control group, which are also subject to farmer consent: FECRT with all five licensed groups for sheep (including an avermectin and moxidectin) and a control group, with 15 animals in each, would require 105 animals, which is often unrealistic on commercial farms due to the time and cost of sampling; consequently, most studies test only a limited range of anthelmintics. The conditions for inclusion of animals in the test, such as pre-treatment Faecal Egg Count (FEC) varies between studies, as does the detection limit of the FEC method used, and the extent of species identification. The gold standard for assessing AR, the CET, requires slaughter of both control animals and treated animals, and is not suitable for monitoring on commercial farms. Each FECRT or in vitro method is open to error, e.g. FECs are an indirect measure of anthelmintic efficacy against adult helminths. Sample size within the existing database was not sufficiently high to compare AR prevalence across countries while taking account of variation in method and would be further undermined by concealed variation and bias.Non-random sampling, for example, due to researchers selecting farms with suspected AR, or farmers self-selecting to participate (possibly because they suspect they have AR on their farm) may inflate estimated prevalence. This is supported by a survey of both randomly selected and non-randomly selected sheep flocks in Norway  where thFrequent anthelmintic treatment is held as one of the major reasons for the genesis of resistant GIN populations, and a number of approaches are advocated to slow the development of AR . ExtensiIn Switzerland, a programme was established in 1999 by the Small Ruminant Health Service to provide an annual service for sheep and goat farmers based on quantitative faecal examination. The programme, now including about 1400 farms, is partially subsidized by the government, covering about one third of the costs. Pooled samples are analysed from different groups of animals and, based on the results, veterinary advice is given with respect to anthelmintic treatment and further sampling. An evaluation performed five years after establishment of the program revealed that, on 73% of the farms, GIN were controlled successfully, with a mean annual treatment frequency of 2.0 compared with 3.4 on farms that did not participate in the programme. Participation in faecal monitoring also strengthened collaboration with the veterinarian – according to the farmers, the support of the veterinarian was “good” or “very good” in 86% of cases (unpublished data).In Italy, the Regional Centre for Monitoring Parasitic Infections  has been established since 2000 by the Department of Agriculture and Livestock Production of the Campania region and is economically supported by the farmers’ associations of Campania and other Italian regions. The strategies for the management of livestock infections caused by GIN, liver flukes and other parasites are based on promoting: best practice for diagnosis, regular monitoring on-farm (at least three FEC per year), best practice for treatment, monitoring the efficacy of treatments through the FECRT, and tailored advice to farm veterinarians on sustainable parasite control. These recommendations and activities are now well integrated into routine farm management of large ruminants  and small ruminants (sheep and goats). The programme includes over 1000 farms per year. A survey performed for the last decade revealed that, on 88% of the farms, GIN were controlled successfully, with a lower mean annual treatment frequency of 2.0 compared with 3.1 on farms that did not participate in the programme. Participation in faecal monitoring also strengthened collaboration with the veterinarian – according to the farmers the support of veterinarian was “very good” in 94% of cases.Recent studies suggest that improving awareness of helminth control and AR may improve the uptake of sustainable parasite control practices . Jack etF. hepatica are increasing, confirming AR presence on small numbers of farms may no longer be necessary. The introduction of more rigorous methods for detecting AR is an opportunity to shift focus to employing robust randomised sampling methods that would allow more detailed epidemiological investigations, including improved estimates of regional prevalence and risk factor analysis.AR is present across the European continent and despite the limitations of the current body of AR research, the analyses presented here provide useful indicators of the potential scale and potential future trajectory of the problem of AR in Europe, and may help improve the uptake of sustainable control practices. As the presence of AR in GIN is now widespread globally, and reports of AR in The authors have no conflicts of interest to declare.supplementary data files.LR, ERM and HRV conceived the project. HRV and LR collated data. HRV, ERM and LR conducted analyses and drafted the manuscript. All authors developed the database by contributing data and participating in quality control, assisted with technical editing of the manuscript, and approved the final manuscript and https://www.parasite-journal.org/10.1051/parasite/2020062The supplementary material of this article is available at Figure S1. Number of publications (peer-reviewed papers or theses) investigating AR in GIN in ruminants.Figure S2. Estimated prevalence of resistance against the benzimidazoles (BZ), levamisole (LEV), avermectins , and moxidectin (MOX) in gastrointestinal nematodes in goats.Figure S3. Estimated prevalence of resistance against the benzimidazoles (BZ), levamisole (LEV), avermectins , and moxidectin (MOX) in gastrointestinal nematodes in cattle.Figure S4. Countries reporting at least one case of anthelmintic resistance in gastrointestinal nematodes infecting sheep, goats and cattle in Europe.Table S1. Mean (SD in brackets) sample size weighted prevalence of anthelmintic resistance in sheep stratified by country and anthelmintic class.Table S2. Mean (SD in brackets) sample size weighted prevalence of anthelmintic resistance in cattle stratified by country and anthelmintic class.Table S3. Mean (SD in brackets) sample size weighted prevalence of anthelmintic resistance in goats stratified by country and anthelmintic class.Table S4. Regression analysis results for prevalence of anthelmintic failure over time.Table S4a. Benzimidazole efficacy in sheep in Switzerland.Table S4b. Benzimidazole efficacy in sheep in the UK.Table S4c. Ivermectin efficacy in sheep in the UK.


We present the case of an 82-year-old woman diagnosed with monoclonal gammopathy of renal significance (MGRS) with the presence of different and peculiar kidney lesions, who began treatment with bortezomib and dexamethasone, presenting during her evolution a relapse. Although the bone marrow biopsy in this case showed plasma cells as pathologic clone and there was also a reduction after chemotherapeutic treatment, rituximab was proposed as a second line. We suspected that the relapse was possibly due to another precursor as B-cell or lymphoplasmacytic cell clone. We review the literature and suggest that the treatment for MGRS should be patient-tailored, preferably by consulting a multidisciplinary team. Future research is needed to better understand the disease course and establish the efficacy and safety of the therapeutic approach for the relapse of MGRS. The monoclonal gammopathy of renal significance (MGRS) is pathogenically characterized by the proliferation of B lymphocyte clones or plasma cell clones that synthesize and secrete a monoclonal immunoglobulin (Ig) or its components (light or heavy chains), with the ability to cause damage at the tubular, glomerular, vascular, and interstitial compartments through direct (deposition) or indirect  mechanisms, constituting a heterogeneous group of entities. It is unusual to find more than two forms of monoclonal immunoglobulin lesions as well as different injury mechanisms in the same biopsy, as in the case of our patient.Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS-associated lesions where M-protein is deposited in the glomerulus. According to the classification scheme proposed by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) , it beloOn the other hand, thrombotic microangiopathy (TMA) is a syndrome physiologically characterized by endothelial injury. TMA may be hereditary or acquired, including a variety of disorders, such as complement-mediated TMA ) and other associated conditions . TMA, acThe optimal treatment for most subtypes of MGRS is not known, but there is recent consensus among experts that treatment should be specific for the underlying clone . This isOur patient was an 82-year-old female with a past medical history of arterial hypertension (AHT) and dyslipidemia. Her medication included angiotensin II receptor blockers (ARBs) and statin. The patient presented with asthenia, fatigue, and uncontrolled AHT for a one-month duration. On admission, physical examination revealed a blood pressure of 250/130 mmHg, a respiratory rate of 24 breaths/min, an oxygen saturation of 90% while breathing room air, pulmonary rales, and peripheral edema. Furthermore, the patient presented with fever and low level of consciousness. Her laboratory values indicated a creatinine (Cr) level of 1.93 mg/dl, hypoalbuminemia without hypercholesterolemia, a massive proteinuria of 4.9 g/gCr, and blood smear with schistocytes <1%. Other laboratory test results are shown in Thus, a kidney biopsy was performed; 14 glomeruli could be analyzed. Three of the glomeruli were globally sclerotic. Under light microscopy, all of the remaining 11 glomeruli showed mesangial proliferation and endocapillary hypercellularity without crescent formation. 60% of the glomeruli had mesangial expansion and basement membrane duplication (Jones methenamine silver stain). Congo red and thioflavin staining were negative. One glomerulus showed mesangiolysis and a thrombus at the vascular pole (silver methenamine-stained section) with capillary wall remodeling, multiple layering, and double-contour formation in the section stained with periodic acid-Schiff- (PAS-) positive. The arteries and arterioles showed intimal fibrosis that decreased the light by approximately 25%. In only one of the arterioles, a luminal thrombus with phenomena of hematic extravasation and fragmentation of red blood cells could be seen. Immunohistochemical staining for CD61 was positive in the arteriole described histologically, as well as in some of the glomeruli. There were mild tubular atrophy and interstitial fibrosis as estimated at 15–20% (as shown in Bone marrow (BM) biopsy revealed <3% plasma cells, with negative Congo red staining. The immunophenotypic study showed that 2.1% of the total cellularity were plasma cells and, of these, 97% had an abnormal phenotype with monoclonality for the kappa light chain. IdentiClone assay was not performed. A PET/CT (positron emission tomography-computed tomography) scan revealed the absence of data on lymphoproliferative syndrome, solitary plasmacytoma, and other extramedullary affectations.Given the diagnosis of MGRS with lesions of PGNMID (IgG-kappa), glomerular TMA, and light-chain deposits of peculiar morphology (DNAJB9 negative) seen in EM, treatment with cycles of bortezomib and dexamethasone (BordD) chemotherapy was initiated and well tolerated. After receiving three cycles, a partial renal response  and a partial hematological response (reduction >50% of kappa light chain) were achieved. Nevertheless, after the sixth cycle, the patient presented a worsening of kidney function with creatinine increasing to 2.4 mg/dl, proteinuria to 2.7 g/day, and kappa light chain (26.6 mg/d) in an immunophenotypic study that showed a slight decrease in abnormal cellularity .For this reason, and given the evidence of relapse, different therapeutic options were evaluated . Treatment with intravenous rituximab  and prednisone (0.8 mg/kg/day) tapered to 10 mg/d over 3–6 weeks followed by a gradual discontinuation after 3 months, was initiated. Four months later, our patient presented improvement in renal function with a Cr of 1.7 mg/dl and a proteinuria of 1.43 g/day. The following controls were delayed due to the onset of the COVID-19 pandemic and the patient died 3 months later of COVID-19 pneumonia.The spectrum of renal involvement in MGRS is wide. Most of the cases are due to M-protein deposits, while in other occasions it occurs indirectly through the dysregulation of the alternative complement pathway that leads to C3 glomerulopathy (GNC3) or more rarely to an aHUS , 5. The n = 28, 43.8%); PGNMID was the second most common lesion , followed by light-chain proximal tubulopathy (LCPT) , light-chain deposition disease , and type I cryoglobulinemic GN . 96 patients (60%) had a kidney lesion that was unrelated to the monoclonal protein (non-MGRS group). The authors identified the following clinical predictors for the increase of odds of finding an MGRS lesion: proteinuria ≥1.6 g/d, hematuria, low serum C3 levels, abnormal FLC, and abnormal bone marrow biopsy specimen. Our case presented 4 of the 5 parameters described according to the study of the Mayo Clinic group.Klomjit et al.  recentlyIn our case, the renal biopsy showed an MPGN pattern of glomerular injury by light microscopy. In routine IF, it presented a false-negative staining for monoclonal immunoglobulins, which was unmasked by performing IF-P. These paraffin rescue techniques are used when a valid kidney tissue is not available in IF-F. It has a high probability of success for the immunohistochemical detection of light chains . FurtherThe lesions of glomerular TMA associated with MG were also observed in our patient, without presence in the clinical setting of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, and with normal levels of factor H autoantibody, the diagnosis of aHUS (complement-mediated TMA) was ruled out. Ravindran et al.  observedThe most striking finding was the presence of electron-dense deposits with fibrils of 10–15 nm in the EM. These images are not typically observed in FGN or amyloidosis . Therefore, these images could correspond to a special way of crystallizing light-chain deposits or are unique features of this biopsy, demonstrating the unusual appearances that abnormal light chains can display. The fibrillar deposits are easy to confuse with each other since we only have the diameter, structure, and organization to differentiate them in EM. For this reason, it is necessary to perform amyloid stains and DNJB9 immunostaining for their better classification. In our case, the immunohistochemistry technique for DNAJB9 was negative. This is in line with a recent study published by Said et al.  althoughMGRS treatment strategies are based on chemotherapy that must be adapted to the nature of the cell clone, both lymphocytic or plasma, renal function, and the presence or absence of extrarenal involvement. The evaluation of hematological response is crucial because the reduction of monoclonal Ig components is associated with the best renal outcomes. However, renal response is not contingent on the resolution of the M-protein in PGNMID . RecentlIn our case, the flow cytometric immunophenotyping of bone marrow showed the presence of plasma cells with abnormal kappa. Therefore, treatment with cycles of BordD chemotherapy was initiated, with good outcomes at the beginning. However, at the end of the sixth cycle, both renal and hematological relapse was evident, despite observing a 26.8% reduction in plasma cells with an abnormal phenotype for kappa. Given the heterogeneity of multiple kidney lesions associated with MGRS, and even more so in cases of relapse, to date, there is little experience regarding the optimal treatment of these complex forms . DiffereNew diagnostic tools need to be investigated in cases where the M-protein is little or not detected since clonal identification is even more difficult . DespiteIn conclusion, we recommend that the treatment for MGRS should be patient-tailored, preferably by consulting a multidisciplinary team. Future larger, prospective, and multicenter studies on pathophysiology are needed to better understand the disease course and to establish the efficacy and safety of therapy in the relapse of MGRS.


Background: Patients with chronic kidney disease undergo various stages of therapeutic adaptation which involve lifestyle modifications, physical changes, and adjustment to renal replacement therapy. This process produces adaptive stress. Objective: To identify how resilience, health- related quality of life, and sociodemographic, clinical, and hemodialysis routine-related variables are related to perceived stress in patients with chronic kidney disease receiving hemodialysis for more than six months. Methods: This was a multicenter and cross-sectional study involving 144 patients from the Valencian Community (Spain). The assessment scales used for the study were the Perceived Stress Scale 10, the Kidney Disease Quality of Life 36, and the Connors–Davidson Resilience Scale. To identify variables with predictive power over Perceived Stress Scale 10 scores, multiple regression analyses were performed. Results: Employment status (p = 0.003), resilience (p < 0.001), and quality of life (p < 0.001) were shown to be significantly related to perceived stress. The regression models determined that health-related quality of life and resilience explained up to 27.1% of the variance of total PSS10 scores. Conclusions: Resilience was identified as one of the most important predictors of Perceived Stress Scale 10 scores. Thus, the development of interventions to promote resilience may have a positive impact on perceived stress in patients with chronic kidney disease. Chronic kidney disease (CKD) is a public health issue that affects over 10% of the global population . The worTherapeutic management of the HD patient is based on pharmacological measures as well as lifestyle modifications or changes in routine that include healthy habits, visits to the health center for HD, and vascular access care . HD patiPerceived stress occurs when the individual considers their relationship with the environment to be threatening or overwhelming in a way which can affect well-being . The HD Resilience is defined as a coping style that allows for positive progress in adverse situations . The resAmong the models aimed at understanding the fundamental elements of resilience is the Systematic Self-Reflection (SSR) model. This model differentiates three basics concepts for coping: (a) resilient resources, (b) their use and emotional regulation, and (c) resilient beliefs . ResilieFinally, in HD patients, quality of life can be affected by symptoms related to the end stage of CKD. HRQoL refers to how well a person functions in life and his or her perceived well-being in the physical, mental, and social domains of health . HRQoL hOne way of delaying the evolution of the disease and reducing the risk of these complications is the use of tools to reach a consensus in decision-making between the medical team and the patient. This interaction between patients and health professionals improves risk perception, reduces the levels of conflict in decision-making, and increases the sense of control perceived by the patient . The eduIn this sense, HRQOL refers to how well a person functions in their life and his or her perceived well-being in physical, mental, and social domains of health . HRQoL hThe HD patient experiences three periods of great psychological stress during the progression of the disease: (1) at the time of diagnosis of CKD, (2) at the time of diagnosis of ACKD and (3) when to start the RRT, and consequent adaptation of lifestyle ,14. AdapControversy currently exists surrounding the relationship between psychological stress and HRQoL in adaptation to chronic illness. Some authors have shown how adaptation to the disease and its treatment reduces stress levels and increases HRQoL ,18, whilFor the aforesaid reasons, this study aimed to identify how resilience, health-related quality of life, and sociodemographic, clinical, and hemodialysis routine-related variables are related to perceived stress in patients with chronic kidney disease undergoing hemodialysis for more than six months. A secondary objective was to identify how the studied variables could predict perceived stress in these patients. Multicenter and cross-sectional study carried out in the Valencian Community (Spain) in 2016.The sample population was selected from all ACKD patients in the Valencian Community receiving hospital-based hemodialysis from the renal care service provider Diaverum. Five of the eight hemodialysis clinics in the area managed by Diaverum agreed to participate in the study. These five clinics provided treatment to a total of 407 patients. All patients meeting the inclusion criteria were asked to participate. Of the 407 patients treated at the Diaverum clinics, 60 patients were treated in three small clinics that chose not to participate in the study, 54 had received treatment for less than six months, 42 presented with cognitive problems, and 28 had problems with reading and writing in Spanish. As a result, 223 potential participants for the study remained. To achieve a representative sample of the five clinics with a 95% confidence level, a 5% of error rate, and assuming the greatest possible heterogeneity (50%), a minimum sample size of 142 patients was calculated. Data collection took place in January 2016.To be included in the study, participants were required to be CKD patients aged over 18 who had received HD for over six months. Patients with literacy or cognitive problems that limited self-completion of the questionnaires were excluded.Sociodemographic, HD Routine-Related, and Clinical Data: An ad hoc questionnaire was created to collect data. The sociodemographic variables included age, sex, level of education, employment situation, home setting, and living arrangement, whereas the HD routine-related variables included means of transport and accessibility to the clinic. Data on clinical variables were recovered from patient files and included information on diabetic status, type of vascular access used for treatment , and comorbidity. Perceived Stress: The Perceived Stress Scale 10 (PSS10) is composed of 10 items, with scores ranging between 0 (lower stress level) and 40 points (maximum stress level). The Spanish version of the PSS10 has a Cronbach’s alpha of 0.82 .Resilience: The Connor–Davidson Resilience Scale (CD-RISC) questionnaire features 25 items and has a score range between 0 (lower resilience level) and 100 (maximum resilience level). The Spanish version of the CD-RISC has a Cronbach’s alpha of 0.89 . Health-Related Quality of Life: The Spanish version of the Kidney Disease Quality of Life 36 (KDQOL-36) was used (36 items) . This asTo present descriptive information on the sample, the mean (M), the standard deviation (SD), the median, and the interquartile range of the quantitative variables were used, as well as the frequencies and percentages of the qualitative variables. The internal consistency for the PSS10, the CD-RISC, and the KDQoL-36 was assessed using the Cronbach’s alpha coefficient. t-test was used, and ANOVA was employed for polytomous variables. The Bonferroni post hoc test was implemented in the case of significant differences in the ANOVA. Given the non-normal distribution of all variables except age, correlations were determined using Spearman’s rho.The normality analysis of the quantitative variables was performed using the Kolmogorov–Smirnov and Shapiro–Wilk normality tests. For the bivariate analysis with dichotomous variables the independent samples Finally, multiple regression analysis was performed using the forward stepwise method. Only normally distributed variables were used as dependent variables. Among the models obtained, the parsimony principle was applied . Given op = 0.05).Statistical analysis was performed using SPSS v23   and was conducted in accordance with Spanish regulations for the protection of personal data.In total, 223 patients were invited to participate in the study. Of these, 64.6% completed all the assessment scales, resulting in a final study sample of only 144 patients.SD = 12.32). Of the participants, 68.8% were male, 29% were diabetic, and 83.2% had undergone arteriovenous vascular access placement. A significant difference was observed between the groups with regard to employment status and perceived level of stress (p = 0.003) (p = 0.025) or the incapacitated/retired (p = 0.012). No significant difference in perceived stress was found between actively employed participants and the incapacitated or retired (p = 0.276).The mean age of patients was 67.31 years old (= 0.003) . BonferrStress (as per the PSS10) correlated negatively with resilience (ρ = –0.404) and HRQoL (ρ = –0.368). Age (ρ = 0.022) and comorbidity (ρ = −0.003) were not significantly correlated with stress . We developed different linear regression models to determine which variables had predictive power over PSS10 scores . In thes2 = 0.271) of the variance of PSS10. After testing the normality of the residues in the regression analysis, a normalized distribution was observed (p = 0.200).The regression model for the PSS10  showed hThe main objective of this study was to identify variables affecting perceived stress in HD patients with ACKD. It was found that HRQoL and resilience constituted the main predictors of perceived stress at this stage of the disease. The finding that HRQoL and resilience are the main predictors of perceived stress is in line with previous studies, which argue that resilience is key to adjusting to stressful situations in chronic disease ,21. ThusAlterations in risk and protective factors occur during stressful circumstances related to the disease . This prThe SSR model helps to explain the relationship between perceived stress, health-related quality of life, and resilience. Resilient resources, emotional regulation strategies (which modulate perceived stress), and resilient beliefs  aid in the management of stressful situations. Once the stressful event has been overcome, in the short term the use of resources and new emotional regulation strategies can modify perceived quality of life. In the medium term and after a period of self-reflection, resilient resources, their use, and resilient values are redefined, ultimately modifying resilience . FinallyOf the socioeconomic, clinical, and HD routine-related factors studied in our sample of HD patients with ACKD, only patient employment status was found to be significantly related to perceived stress. Seventy-eight percent of patients depended on financial resources such as retirement or unemployment benefits. This figure is higher than that reported for patients undergoing other types of RRT such as ambulatory peritoneal dialysis, where 60% of individuals were found to be professionally inactive . In thisNo significant differences were found with regard to adaptation to changes in daily routines, the need for personal support, and transport to the clinic, in line with the proposed adaptation period of 66 days .In addition, no significant differences were found for the analyzed clinical variables in relation to perceived stress, unlike other studies where it has been suggested that people with greater comorbidity or poorer clinical conditions tend to present with higher stress levels ,40,41. NIn summary, the absence of sociodemographic, clinical, and HD routine-related factors associated with perceived stress within the framework of the dynamic model of resilience ,21 couldThis study provides support for patient involvement strategies in educative processes for therapeutic decision-making, as well as multidisciplinary and group-based education for CKD patients ,43 to inThere is a clear need for the development of studies with new designs to clarify the problem and provide stronger evidence on how resilience and adaptation are associated with stress through cohort studies. If this relationship is confirmed, the effectiveness of interventions should be assessed through clinical trials, either with the expert patient model or the advanced practice nursing model in specialized CKD practice.Limitations: Several limitations must be acknowledged in this study. Our study included a larger number of participants as compared to other studies involving ACKD patients . Howeve [n = 37 . Resilience and HRQoL were found to be the main predictors of perceived stress among patients undergoing HD for more than six months. Among the sociodemographic factors analyzed in this study, only employment status was found to be related, with greater perceived stress being observed in the unemployed and in those engaged in domestic work. The remaining sociodemographic, HD routine-related, and clinical variables were not shown to be related to perceived stress in this population.


The language environment is important for the development of early communication and language. In the current study, we describe the natural home language environment of 9-month-old infants in Sweden and its concurrent association with language development. Eighty-eight families took part in the study. The home language environment was measured using the Language ENvironment Analysis (LENA) system, and language development was assessed using Swedish Early Communicative Development Inventory (SECDI), a parent questionnaire. LENA measures showed dramatic variation between individuals but were comparable to and showed overlapping variance with previous studies conducted in English-speaking households. Nonetheless, there were significantly more infant vocalizations and conversational turns in the present study than in one previous study. Adult word count correlated significantly and positively with infants’ Use of gestures and the subscale of that section Communicative gestures. These together with another four non-significant associations formed a consistent overall pattern that suggested a link between infants’ language environment and language development. Although the direction of causality cannot be determined from the current data, future studies should examine children longitudinally to assess the directionality or the bidirectionality of the reported associations between infant’s language environment and language development. The language environment of young children  varies considerably, both quantitatively and qualitatively e.g., . The lanThe preverbal infant communicates by using sounds and body language . Infant Individual differences in early communication and language development are large . Early cExposure to adult speech is an important part of the infant’s language environment and varies considerably . For exaApart from adult speech as such, interaction with adults is another important part of the infant’s language environment. Families differ in how much parents and children interact with each other e.g., . Parent-A newer element in infants’ language environment is digital media. Today’s infants are born into a digital media world, and many are exposed to digital media from a very young age . The SweInconsistency in reports may be due to mediating factors. Specifically, researchers have emphasized the importance of adult-child interaction as the mediator between digital media and language development e.g., . For exaTools to measure language environment have advanced from field notes to include a variety of options. In the pioneering study conducted by A small-scale study used 12 h LENA recordings to investigate the language environment of 30 North American infants aged 12–20 months, and found dramatic variation between individuals in AWC , while variation within individuals over repeated measures was small . AWC didN = 329) from the United States used LENA to investigate natural language environment in typically developing children between 2 and 48 months . All families in a selected region of Sweden with an infant aged 9 months during one of two data collection periods in 2017 received an invitation to participate in the study. In total, 1,324 invitations were sent.SD = 0.26, Min = 9.04, Max = 10.22). Three of the participants were 10 months old. All but one of the participants were full-term , and parents reported normal Apgar score at 5 min for all but one of the participants. Mean birth weight was 3,564 g (SD = 470 g), and mean birth length was 50.9 cm (SD = 2.02 cm). All parents reported that their infant was typically developing and had no known medical issues. Among the participants, 53 were the only child in their family, while 26 had one older sibling and nine had two. None of the participants had begun childcare. All families reported Swedish as main language at home . The families were highly educated; and 83% of mothers and 66% of fathers had a university degree.Among those families who responded to the invitation to participate, 88 were included in the current dataset. This was after 13 were excluded, four of these declined to participate, and datasets for nine were lost due to data storage failure. The sample included 40 girls and 48 boys. Mean age on the LENA recording day was 9.51 months . Parents were given the option of deleting the recorded data afterward if they felt it compromised their privacy (without the research team listening), but no parent chose to delete data. The collected audio recordings were downloaded into, analyzed in, and extracted from the LENA software advanced data extractor (ADEX). ADEX categorizes the data into different variables and time intervals . The minLanguage development was measured through the SECDIs-words and gestures (SECDI-w&g), which is a Swedish adaptation of the established and well-validated MB-CDIs . The SECa priori that if we found a statistically significant correlation between any of the LENA variables and Use of gestures, we would also perform an explorative analysis of the correlation between that LENA variable and the Use of gestures’ subscale Communicative gestures. This subscale has been shown to provide valid data during the first year of life and to be strongly predictive of the emergence of meaningful speech . As regards the specific directional correlation predictions, we computed one-tailed correlations. Non-predicted correlations were tested using two-tailed tests.We computed mean values and standard deviations for the four LENA variables and the three SECDI sections. LENA mean values were compared to published data using independent samples SD = 18:37). However, two infants were around ES for 1 h or more, and indeed, median ES was only 10:02 min. There was no evidence that number of siblings, sex, or SES influenced any of the LENA variables.The 88 9-month-old infants enrolled in the current study heard an average of 15,152 AWC during the 12 h LENA recording in a natural home setting see . One infp < 0.001) and between CVC and CTC (p < 0.001). t(134) = 2.02, p = 0.045, standardized effect size = 0.33, and CTC, t(133) = 2.63, p = 0.010, standardized effect size = 0.43, but no significant difference regarding AWC, t(122) = 1.33, p = 0.185, standardized effect size = 0.23. It was not possible to make a similar statistical comparison with any previous study for the ES variable , and the average number of words produced for the Word production section was 0.62 . The average score for Use of gestures was 11.60 . Within the section Use of gestures, the average score on the subscale Communicative gestures was 6.18 . These results are in line with previous work . The average number of words comprehended for Word comprehension section was 22.08  and between Word comprehension and the subscale named Communicative gestures . There was also a correlation between the section Use of gestures and the subscale Communicative gestures . These correlations were two-tailed and uncorrected for multiple comparisons.Regarding the different sections in SECDI, there was a significant Pearson’s correlation between Word comprehension and Use of gestures . There were no other statistically significant correlations between LENA variables and SECDI section scores. However, close inspection of ps ≤ 0.10) between SECDI scores for the section Word comprehension and three of the LENA variables. This pattern is in line with our predictions. Specifically, there were positive, albeit non-significant, correlations with AWC (p = 0.064) and CTC (p = 0.099) as well as a negative, albeit non-significant, correlation with ES (p = 0.081). Further, there was a non-significant positive correlation between Use of gestures and CTC (p = 0.065), and was also in line with our predictions. Inspection of the scatterplot in t-test showed no significant difference in Word comprehension between these two subgroups. Inspection of scatterplots (not reproduced here) of the other non-significant associations that were consistent with our predictions provided no evidence of any kind of systematic relation other than that indicated by the non-significant correlation. Because of multicollinearity and the lack of statistical significance for all correlations except one, regression analyses could not be performed.As shown in r = 0.30, p = 0.008; see Since the correlation between the LENA variable AWC and the SECDI section Use of gestures was statistically significant, we further explored the association between AWC and the Use of gestures subscale Communicative gestures. The correlation between AWC and Communicative gestures was also statistically significant  in the present study, thus substantially less than we hypothesized . While AWC and CTC were positively associated with Word comprehension, ES was negatively associated with Word comprehension. Further, CTC was positively associated with Use of gestures. Although these findings did not meet conventional levels of statistical significance, this overall pattern of results was in line with our hypotheses. Thus, although we only have strong evidence that adult talk is associated with language development in infants aged 9 months, it would be wrong to ignore the indication that infant Word comprehension is also linked to factors in the child’s language environment.Previous studies have not studied the relation between LENA variables and language development at specifically 9 months. But, What the correlation between AWC and Use of gestures means is unclear. One probable explanation is that adult speech facilitates early communicative behavior, but it can also be in the opposite direction – that infants’ use of gestures itself encourages adults to speak more. The most reasonable explanation is probably that the relationship is bidirectional cf. . Future p = 0.099, p = 0.065, respectively). One aspect to be aware of is that LENA can only capture verbal interactions and that 9-months-old infants often use non-verbal communication to interact with others, for example, eye-contact, pointing, or raising their arms. Even though we do not have a broad picture of the adult-infant interaction, we can see non-significant tendencies toward more adult-infant interactions and better language development. With that said, it may still be the case as We expected a significant correlation between CTC and certain aspects of language development, namely Word comprehension and Use of gestures, but we only found non-significant associations (p = 0.081). Our sample was exposed to appreciably less ES than expected and the lack of significant associations might be a reflection of the fact that low levels of ES and language are not in fact related at the age of 9 months. That is, a threshold of exposure may be needed for interference with early communication to occur. It might also be the case that our measurement was simply not sensitive enough to detect the small variations our sample displayed. Additional data cross-validating the LENA, ES with other measures across a larger and more diverse sample is needed to address these questions.A non-significant tendency toward a negative correlation between ES and Word comprehension was observed  in the expected direction that together with the significant association might be interpreted as a link between infants’ language environment and language development. The direction of causality cannot be determined from the current data. Future studies should track associations between infant’s language environment and language development longitudinally to better assess directionality or bidirectionality of the associations.This manuscript provides the first description of the natural home language environment according to LENA in a sample of 9-month-old infants in Sweden. Both the amount of AWC, CVC, and CTC and the intra-individual variation were comparable to and showed overlapping variance with previous studies conducted in English-speaking households. Despite this, we identified significantly more CVC and CTC than in https://osf.io/c4vtd.The raw data supporting the conclusions of this manuscript are available on OSF at the following link The studies involving human participants were reviewed and approved by the Regional Ethical Board in Linköping, Sweden (2016/490-31). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.The study was conceived by MH, AS, RB, and F-SK. Data were collected by MH, AS, F-SK, and UB. Data were analyzed by F-SK and SN. The first draft of the manuscript was written by SN. MH, AS, F-SK, UBT, RB, SN, and MR contributed to the final version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


M = 40.63; SD = 15.67), who had been in a relationship for more than 6 months, was evaluated. In men, the highest sexual satisfaction levels were obtained in the egalitarian typology in the sexual freedom area. In women, no significant differences were found between the typologies of adherence to the SDS. Regression models showed that relationship satisfaction was the main predictor of sexual satisfaction in all the typologies in both men and women. In addition, the predictive relationship of personal variables with sexual satisfaction varied according to gender and the SDS adherence type. The results show the importance of studying sexual satisfaction by taking into account not only the differences between men and women. Furthermore, it is essential to consider other differences between people; for example, the difference that derives from the way of psychologically internalizing attitude toward the SDS.The sexual double standard (SDS) refers to the acceptance of different criteria to assess the same sexual behavior in men and women. To date, the few studies that have addressed the relationship between SDS and sexual satisfaction have obtained inconclusive results. In addition, no study has analyzed sexual satisfaction in people who maintain different forms of adherence to the SDS. This study establishes three SDS typologies of adherence  in two areas of sexual behavior  to examine the predictive capacity of personal variables , interpersonal variables (relationship satisfaction) and social variables  in sexual satisfaction. A sample of 1194 heterosexual adults  aged between 18 and 87 years ( One of the most relevant manifestations of sexual health is sexual satisfaction , which sA personal factor that has been associated with sexual satisfaction, albeit with inconsistent results to date, is the sexual double standard (SDS); that is, the attitude which involves a distinct evaluation of given sexual behaviors depending on if they are performed by a man or a woman, where men have more freedom and/or permissibility than women . Some stOn the other hand, we are interested in knowing if individual differences in SDS are related to sexual satisfaction. In accord with Moreover, in order to understand sexual satisfaction, the proposal of personal, interpersonal, and social factors could be considered in accordance with the Ecological Theory . In the Age stands out among the personal variables, which has been negatively associated with sexual satisfaction .Another personal factor that has not yet been considered to date is social dominance orientation. Social dominance orientation is an individual characteristic that predisposes someone to support and defend a social structure, where intergroup relations  are hierarchical and non-egalitarian . There iWe also considered the propensity for sexual excitation/inhibition, proposed with the Dual Control Model . What thOf the interpersonal factors, relationship satisfaction has been demonstrated to be the most important one as a determining factor of sexual satisfaction .Finally, it based on the assumption that social norms predict conduct , it was Therefore, based on the Ecological Theory of Human Development framework , this stWhen considering gender  and SDS adherence types in the SF and SS areas:RQ1:Would there be any differences in sexual satisfaction and related variables of personal , interpersonal (relationship satisfaction) and social ?RQ2:What predictive capacity would personal , interpersonal (relationship satisfaction), and social  variables have on sexual satisfaction?M = 40.63; SD = 15.67) and recruited by non-random sampling. The inclusion criteria included: (1) Spanish nationality; (2) heterosexual orientation; (3) being 18 years old or older; (4) being involved in a heterosexual relationship for at least 6 months. Significant gender differences were found in the sample. Men reported having more sexual partners  and younger partners . The sample was made up of 1194 adults  aged between 18 and 87 years  to 3 (strongly agree), and distributed into two factors: Acceptance of sexual freedom and Acceptance of sexual shyness. Each factor is formed by four pairs of parallel items: one refers to sexual behavior attributed to men, and the other to sexual behavior attributed to women. The responses to Acceptance of sexual freedom allow the Index of Double Standard for Sexual Freedom (IDS-SF) to be obtained, and the responses to the Acceptance of sexual shyness items allow the Index of Double Standard for Sexual Shyness (IDS-SS) to be acquired. Both indices represent a bipolar measurement (between −12 and +12). The man-favorable typology includes those people with positive scores in the index (between +1 and +12). The woman-favorable typology is obtained from the scores that take a negative value (between −1 and −12). Finally, the egalitarian typology includes those people whose score equals zero in either index and obtain a zero result in the subtractions between the pairs of parallel items of the index. The scale suitably evidenced internal consistency   . It was  factor) . So thes–completely disagree) to 7 (completely agree), and two factors: General opposition to equality and Support for group-based dominance  to 4 (strongly disagree). The items are distributed into three subscales: Sexual excitation, Inhibition due to threat of performance failure, Inhibition due to threat of performance consequences. Cronbach’s alpha coefficients range between 0.60 and 0.72. In this sample, the ordinal alpha values range fell between 0.73 and 0.79 for men and between 0.68 and 0.82 for women.The Spanish version of the Sexual Inhibition/Sexual Excitation Scales-Short Form  to 3 (strongly agree), and three factors: Acceptance of sexual shyness in men, Acceptance of sexual freedom in women, Acceptance of traditional gender role distribution. For each factor, the internal consistency obtained ordinal alpha values that equal 0.73, 0.70, and 0.90, respectively. In this sample and for each factor, the values were 0.72, 0.68, and 0.86 for men, and 0.75, 0.67, and 0.91 for women.The Spanish hetero-referred version of Sexual Double Standard Scale SDSS-H; . It eval–Very bad/Very good; Very unpleasant/Very pleasant; Very negative/Very positive; Very unsatisfying/Very satisfying; Very worthless/Very valuable. Its Cronbach’s alpha coefficients are 0.92 for men and 0.93 for women . The IP address was controlled and automatic responses were avoided by answering a security question consisting of a random arithmetic question. The participants accepted an informed consent form which specified the overall objective of the study. Anonymity and confidentiality were guaranteed, and their participation was voluntary without compensation.The study was previously approved by the Human Research Ethics Committee of the University of Granada. The target population was defined in the inclusion criteria of the study. Participants were recruited from the general Spanish population by incidental sampling to obtain a balanced proportion of men and women, and also across age groups , between March 2018 and February 2019. The evaluation in the paper-and-pencil format (86.6% of the sample) and the online format (13.4% of the sample) was used. Both procedures showed no differences in the responses in terms of information on general behaviors  or sexuat-test for two independent groups  were calculated for the scores of the SDS indices for Sexual Freedom (ID-SF) and Sexual Shyness (IDS-SS). The results revealed gender differences in both the IDS-SF  and the IDS-SS . Due to the found differences, we decided to divide the sample into men and women separately. According to the scores of the indices, the sample of men and women was distributed into the SDS adherence types  for the SF and SS areas. Second, by using an ANOVA for men and women, the differences for all the variables were calculated by typologies of adherence to SF and SS. Finally, we examined the degree to which sexual satisfaction could be explained by the different variables  with multiple linear regression using the stepwise method for each SDS typology of both sexual behavior areas. Independent variables were included in each step according to the significance of their correlation with sexual satisfaction. The degree of multicollinearity was assessed with the tolerance value and the variance inflation factor (VIF). When the tolerance value was >0.10 and the VIF was <10 for the predictor variables, there were no serious problems with multicollinearity , with higher scores for the egalitarian typology than for the man-favorable typology . For the personal variables, significant differences were observed between the typologies in general opposition to equality in SF , with higher scores for the man-favorable typology than for the egalitarian typology . Group-based dominance in SF  and in SS  was supported with higher scores for the man-favorable typology than for the egalitarian typology , and with higher scores for the man-favorable typology than for woman-favorable typology . No differences were found in relationship satisfaction as an interpersonal variable. Finally, regarding the social variables, differences were encountered in acceptance of sexual shyness in men in SF  with higher scores for the man-favorable typology than for the egalitarian typology , and in SS  with higher scores for the woman-favorable typology than for the egalitarian typology . See In men, significant differences were found in sexual satisfaction between the different SDS adherence types in SF  with higher scores for the man-favorable typology than for the egalitarian typology . Group-based dominance in SS  was supported with higher scores for the man-favorable typology than for the egalitarian typology , and with higher scores for the man-favorable typology than for the woman-favorable typology . For sexual excitation in SS , the man-favorable typology obtained higher scores than the egalitarian typology . No differences were found in relationship satisfaction as an interpersonal variable. Finally among the social variables, differences were encountered in acceptance of sexual shyness in men in the SS , with higher scores for the woman-favorable typology than for the egalitarian typology . See For women, no significant differences were found in sexual satisfaction between the different SDS adherence types in the sexual behavior areas . Differences appeared for personal variables in general opposition to equality in SS . Those variables with predictive power were relationship satisfaction (β = 0.70) and age (β = −0.13). In the man-favorable typology, the model explained 60% of sexual satisfaction  with the variables relationship satisfaction (β = 0.71) and age (β = −0.23). Finally in the woman-favorable typology, the model explained 39% of sexual satisfaction , where relationship satisfaction was the only variable with predictive power (β = 0.62).F = 135.86; p < 0.001) by relationship satisfaction (β = 0.68) and age (β = −0.20). The man-favorable typology model explained 50% of sexual satisfaction , including relationship satisfaction (β = 0.65) and sexual inhibition due to threat of performance failure (β = 0.14). Finally, the woman-favorable typology model explained 54% of the variation of sexual satisfaction  with relationship satisfaction (β = 0.74) as the only predictor variable.In the SS area, the egalitarian typology model explained 53% of the variance of sexual satisfaction , with the predictor variable relationship satisfaction (β = 0.66). The man-favorable typology model accounted for 49%  with relationship satisfaction (β = 0.66) and age (β = −0.23). Lastly, the predictive model of the woman-favorable typology explained 55% of sexual satisfaction , including relationship satisfaction (β = 0.66) and age (β = −0.18).F = 156.03; p < 0.001) through relationship satisfaction (β = 0.71) and sexual inhibition due to threat of performance failure (β = 0.12). The man-favorable typology model accounted for 52% of sexual satisfaction  through relationship satisfaction (β = 0.65), general opposition to equality (β = −0.19), and age (β = −0.18). Finally in the woman-favorable typology, the predictive model explained 46% of sexual satisfaction  through relationship satisfaction (β = 0.61) and age (β = −0.21).In the SS area, the egalitarian typology model explained 54% of the variance of sexual satisfaction  to examine, according to the Ecological Theory , the relTo answer RQ1, differences were observed in sexual satisfaction, personal, and social variables by SDS adherence types in men and women and in both sexual behavior areas with a medium effect size. In sexual satisfaction, differences were found for SDS adherence types in men for the SF area, with higher scores for the egalitarian typology than for the man-favorable typology. It would support the notion that sexual satisfaction in men was less when they supported the man-favorable SDS , and wasDifferences were also found in some personal variables: general opposition to equality, support for group-based dominance, and sexual excitation. In the social dominance orientation dimensions, higher scores were obtained in the man-favorable typology in men for both sexual areas and in women in the SS area. These results corroborate that both the men and women who support the SDS that favors men  also agree more than egalitarian people with a hierarchical gender social structure . FurtherFinally in the social variables, it was found that people with different SDS adherence types differed as to how they perceived social gender norms about sexual behavior. Specifically, the acceptance of sexual shyness in men differs significantly among the SDS adherence typologies, with lower scores in the egalitarian typology in men in both areas, and in women in the SS area. The fact that egalitarian men and women (vs. man-favorable men and woman-favorable women) perceived that society does not support sexual shyness in men that much could work as a way to gain validation and support for their most democratic attitude toward the SDS . Future With RQ2, differences were observed in the predictive variables of sexual satisfaction according to SDS adherence types, the sexual behavior area (SF and SS) and gender. First of all, one of the personal variables that appeared more in the regression models was age, and for both men and women. Age negatively predicted sexual satisfaction, which coincided with the results reported in previous studies . Sexual Moreover, general opposition to equality also negatively predicted sexual satisfaction in women; specifically, those women with the man-favorable SDS adherence typology in SS area. Within the theory of system justification framework , the belUnlike previous evidence , sexual The interpersonal variable relationship satisfaction was the main predictor of sexual satisfaction in all the models, and was the only predictor in the woman-favorable typology in men in both sexual behavior areas and in the egalitarian typology in women in SF area, which confirms the results published in former studies . As relaNo predictive role was found in sexual satisfaction with gender norms about sexual behaviors. Systematic reviews performed to explain sexual satisfaction with the Ecological Theory Model have found that the predictive power of social variables is poor, and stressed that personal and interpersonal variables are the main predictors of sexual satisfaction . PreviouThis study has its limitations, which influence how its results are interpreted. Our sample was selected by performing non-probabilistic sampling of the Spanish population, which included individuals with a heterosexual orientation. So the extent to which these results can be generalized to the population and other sexual orientations must be taken into account. Given the use of explicit SDS measures, future studies could contemplate implicit measuring , as wellTo conclude, our results contribute to the study of sexual satisfaction for several reasons. We observed higher sexual satisfaction levels in the egalitarian typology to evaluate sexual behaviors, which means that the postures that defend the men or women hegemony would appear to make sexual satisfaction difficult. Particularly in the sexual freedom area, the men belonging to the man-favorable typology would experience less sexual satisfaction than the men of the egalitarian typology. It was found that the differences in sexual satisfaction and related variables  depended on both the person’s characteristics, such as gender and SDS adherence type, and also on the sexual behavior area  referred to by the attitude toward the SDS. Moreover, and once again, this study supports applying the Ecological Theory  to propoThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The Ethics Committee on Human Research of the University of Granada in Spain. The patients/participants provided their written informed consent to participate in this study.AÁ-M: data curation, formal analysis, methodology, software, resources, investigation, original draft preparation, writing, review, and editing. CG-B: conceptualization, formal analysis, project administration, resources, investigation, original draft preparation, writing, review, and editing. JS: conceptualization, funding acquisition, project administration, supervision, investigation, original draft preparation, writing, review, and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Echinococcus. CE can affect any organ with the liver and lungs being most commonly involved. The brain is involved in less than 2% of the cases. We report a case of a CE1 echinococcal cyst of the brain in an Iranian patient.Cystic echinococcosis (CE) is a neglected helminthic disease and major public health problem in several regions of the world. The zoonosis is caused by the larval stage of different cestode species belonging to the genus  Echinococcus. The zoonosis represents a formidable public health challenge given its global distribution, neglected status, and problems with the implementation of control programs [Cystic echinococcosis (CE) is caused by the larval stage of different cestode species of the genus programs –4. Approprograms . In Iranprograms . CE costprograms .Most patients have a single cystic lesion located in a single organ with the liver being affected most often, but the presentation can be highly variable , 8, 9. CA 39-year-old male was referred to the Khatamolanbia Hospital from the city of Gonbad-e Kavus in the province of Golestan with a two-week history of headache.9/L, normal eosinophil count, hemoglobin, and biochemical parameters. The patient was discharged and returned one month later with right hemisensory loss, severe headache, and loss of balance. A magnetic resonance imaging (MRI) of the brain showed a large cyst located on the left fronto-parieto-occipital region without surrounding edema, compressing the lateral ventricles and causing shift of the midline structures  count of 5.5 × 10ructures . An ultrructures –4. Histoructures .The patient was treated with albendazole at a dose of 15 mg/kg daily for four weeks postoperatively with no side effects. The patient is doing well approximately 14 months after discharge from the hospital.Cystic echinococcosis is a complex disease with many factors contributing to its morbidity and mortality; it is seen in the most impoverished areas of the planet. The cohabitation of humans and domestic animals is vital to the persistence of the disease in many regions of the world –16. The E. granulosus comprises 10 genotypes (G1 to G10) which have been assigned to different species. E. granulosus sensu stricto , E. equinus (G4), E. ortleppi (G5), and E. canadensis  [E. granulosus sensu stricto  being responsible for the bulk of cases worldwide [and G10) , 19. Allorldwide , 21. Theorldwide –24. GenoThe signs and symptoms of cerebral CE are those of a space occupying lesion, i.e., headache, nausea, vomiting, and papilledema. Focal neurological findings such as motor or sensory deficits, seizures, visual impairment, and gait and speech disturbances are also common , 25, 26.in vivo not just to diagnose the parasitic nature of the cyst in the brain but also, given that different cyst stages have different metabolic profiles [As with other anatomical locations, the diagnosis is suspected based on imaging. Computerized tomography (CT) and magnetic resonance imaging (MRI) are the modalities most commonly used to support diagnosis and therapeutic planning. Cerebral cystic echinococcosis in both imaging techniques frequently presents in the CE1 stage as a unilocular, smooth, thin-walled fluid filled spherical cystic lesion with the fluid of the same density as the cerebrospinal fluid . MRI usuprofiles , to moniprofiles .The differential diagnosis of cerebral CE in the CE1 stage includes arachnoid cysts, porencephaly, cystic astrocytoma, cystic primary and metastatic tumors, brain abscess, coenurosis, and neurocysticercosis , 27.All cyst stages have been shown to occur in the brain  althoughThe efficacy and safety of scolicidal agents such as hypertonic saline have not been prospectively studied although hypertonic saline has been used when intraoperative spillage occurs , 26, 32.Short or inexistent follow-up in case series and the differences in surgical interventions limit the risk assessment of recurrence after puncture or rupture of a cyst but a high risk of recurrence and mortality has been reported , 26, 32.Clinicians should include CE in the differential diagnosis of focal lesions of the brain in patients coming from or who have traveled to endemic areas, keeping in mind that all cyst stages are possible in the brain exactly as in the liver, although a stage-specific approach is limited by surgery being the best treatment. Use of albendazole in cysts that cannot be treated surgically should be encouraged and reported to make experience available to the medical community.