Breast cancer (BC) is the most common cancer in the world, and is associated with significant economic costs for patients and communities. Therefore, the information on the costs of the disease and the identification of its underlying factors will provide insights into designing effective interventions and reducing the costs. Thus, the present study aimed to identify the factors affecting the economic burden of breast cancer from all medical centers providing diagnostic and treatment services in southern Iran.A list of factors affecting the economic burden of breast cancer was obtained based on the effective factors searched in the databases, including PubMed, ProQuest, Scopus, ISI Web of Science, SID, and Magiran, and the opinions of BC cancer specialists. Then, the data on 460 breast cancer patients was collected from March 2020 to March 2022. The relationship between the factors affecting Breast Cancer costs was analyzed using SPSS 13.0 software by the use of multiple regression analysis.The results of the multiple regression analysis showed that stages , being an extreme user (p = 0.025), type of treatment center , income , chemotherapy side effects , and distance to the nearest health center  were important factors affecting the costs of breast cancer patients.According to the results, encouraging people to undergo annual screenings, increasing insurance coverage, assuring the patients about the desirability and adequacy of the provided medical services, deploying specialists in chemotherapy centers  to recommend special diets, and establishing cancer diagnostic and treatment centers in high-population cities could help reduce the costs of breast cancer patients.The online version contains supplementary material available at 10.1186/s12913-023-10346-5. Breast cancer (BC) is the most common cancer worldwide , and is Along with the increase in the number of cancer cases, the costs associated with cancer have also significantly increased worldwide. In most developed countries, cancer results in a significant increase in national economic burden –13 and iConsidering the fact that the data used to develop medical guidelines in high-income countries  are ofteEffectively and reasonably controlling the growth of medical costs is of great significance in reducing the economic burden of disease on society. However, the management of breast cancer in Iran is currently too extensive, which is not conducive to the reasonable control of expenses. Therefore, it has become an urgent and realistic research topic to explore the important factors that affect the costs of breast cancer patients and provide a scientific basis for establishing a reasonable reimbursement mechanism and standard for the expenses of breast cancer patients. The researchers did not find any study that comprehensively addressed the factors affecting the direct and indirect costs of breast cancer, especially in Iran. Therefore, the present research aimed to investigate the factors affecting the economic burden of breast cancer in Iran. It is hoped that the results of this research will help healthcare providers identify these factors and plan interventions to reduce the economic burden of breast cancer in the future.To identify the factors influencing the costs of BC, the researchers first conducted a scoping review of previous studies and consulted with BC specialists to identify the most influential factors. Then, they determined the relationship between these factors and the costs of the disease.This part of the study was conducted in six stages based on the scoping review method of Joanna Briggs Institute (JBI) as a framework. In the first stage, a question was raised based on the Population (or participants)/Concept/Context (PCC) elements was raised. All the patients with BC (population), the factors affecting BC costs (concept), and all countries of the world (context) were included in the question. The target population included all studies on the “factors affecting BC costs” in various countries. This part of the study was a scoping review, based on the method of Joanna Briggs Institute (JBI) as a framework. Scoping reviews can determine the main components and related aspects of a specific concept, and thus, help to draw a thematic map based on the collected evidence and identify the knowledge gaps in the scope. Thus, determining the factors affecting economic burden of BC was performed in the following six stages: In the first stage, a specific question was asked based on the PCC elements  as follows: All the patients with BC (population), the factors affecting BC economic burden (concept), and all countries of the world (context). The research question was “What are the factors affecting BC patients economic burden in various countries?https://www.strobe-statement.org/).In the second stage, all relevant studies conducted until 2021 were retrieved through the search strategy , d = tolerated margin of error, and s = standard deviation.In order to select the samples, breast cancer patients from all medical centers providing diagnostic and treatment services in southern Iran were selected using the list of patients provided by the Cancer Registry Center. These centers included hospitals, clinics, laboratories and offices in the public and private sectors. It should be noted that prevalence-based and bottom-up approaches were respectively used to prepare the cost data and calculate the costs from the societal perspective. The data on direct medical costs (DMC) were collected using the information in the patients’ medical and financial records. On the other hand, the data on direct non-medical (DNMC) and indirect costs (IC) were obtained using self-reports by the patients or their companions. Table The collected data were then entered into the SPSS 13.0 software. The Independent sample T-test and ANOVA were used to investigate the difference in the factors affecting the costs of BC, and the Mann-Whitney test was also used for the variables of undergoing surgery and tumor recurrence, which did not have a normal distribution. The Kolmogorov-Smirnov test was used to check normality. In order to find out the correlation between some continuous variables and the cost of the healthcare, Pearson or Spearman correlations were applied; in the way that if normality was established, Pearson correlation was used and Spearman correlation was used otherwise. The correlation coefficients were also tested to assess if there was a significant correlation between covariates. Furthermore, simple and multiple analyzes were used to investigate the relationship between the factors affecting the costs of the disease. The simultaneous effect of independent variables on the disease costs was determined using the multiple linear regression model through the stepwise method. At each step, the independent variable not yet included in the regression equation with the smallest p-value was added if its p-value was smaller than 0.05. Variables already in the regression equation were removed if their p-values were larger than 0.10. It should be noted that tolerance was also checked for all predictors and if the tolerance of a variable was more than 0.0001, the variable would be a candidate for entering the model through the stepwise method. Based on the stepwise approach, the final set of predictors was selected, and a full model including all two-way interaction effects was fitted. The significance of the interaction effects was then examined. Finally, for other analyses except for multiple regression, the significance level was considered lower than 0.05.The cost of each patient was calculated by adding up his/her DMC, DNMC, and IC. The data collection form included four sections as follows:Demographic information of the patients were collected by reviewing the patients’ medical records.The DMC of each patient were collected using a researcher-made checklist and referring to the medical centers under study. which were collected using the patients’ medical and financial records.The total annual DMC of each patient = (average number of visits per year × visit tariff) + (average number of diagnostic-therapeutic services per year × tariff for each service) +  + (the number of medications and drugs prescribed in a treatment period × the cost of each medication and drug unit).To estimate the DNMC during the study period, in addition to the reports from patients or their companions, the approved government tariffs for the costs of accommodation, food, gas, and transportation expenses were used.Average cost per patient = number of visits to receive medical services per year × cost of each visit.The data on the IC were collected through telephone interviews with the patients or their companions. The IC included the costs of productivity loss due to the disease (morbidity costs) and due to premature death . To calculate the IC, the human capital method was used, which estimates the economic value of lost productivity due to illness or death. The individuals’ wages were used to calculate lost income.The references used to value tariffs, wages, etc. were extracted from the Ministry of Cooperatives Labor and Social Welfare and tariffs for diagnostic and treatment services in the public and private sectors , 32. TheThis study was approved by the Ethics Committee of Shiraz University of Medical Sciences (Code: IR.SUMS.REC.1400.052). The patients were free to choose to participate in the study, and once the objectives of the research were explained to them, their written informed consent was obtained. The questionnaires and checklists were completed anonymously and the patients were assured of the confidentiality of their answers to the questions. It should be noted that in order to comply with ethical considerations and the confidentiality of patient information, the patients were distinguished by the codes at the top of the data collection form.The results of the search for articles in databases showed that there were 6,758 articles in the field of study purpose, of which 1,834 were duplicates. After reviewing the titles and abstracts of the remaining 3,780 English-language articles, 3,458 and 217 articles were removed from the list, respectively. A total of 105 articles were selected for full-text review. Finally, the research team selected 27 articles that answered the research question , married (78%), without academic education (67%), overweight or obese (73%), diagnosed with the disease on time (95%), underwent surgery (94%), and experienced chemotherapy side effects (59%). Additionally, most of the patients (73%) visited both private and public centers simultaneously to receive diagnostic and treatment services. Although all the patients had basic insurance coverage (100%), only 49% of them were covered by supplementary insurance organizations. A majority of the patients had no comorbidities (60%), no history of smoking (91%), no history of tumor recurrence (94%), low physical activity (46%), stage III of the disease (51%), and an income level of $1,428.57-$1,904.76 (48%). It is worth noting that the average distance from each patient’s residence to the medical centers receiving services was estimated at 100.36 ± 112 km , being an extreme user of services , type of medical center , having supplementary insurance coverage , undergoing surgery , household income level , and chemotherapy side effects  and the costs of BC patients. Additionally, the Spearman correlation test results in Table The results of the simple regression analysis in Table The results of the simple regression analysis in Table The results of the multiple regression analysis showed a significant relationship between disease stage and disease costs. An increase in the stage of the disease significantly increased the costs of BC by $2,081 . Being an extreme user, referring to both private and public centers, increased income level, and chemotherapy side effects also increased the costs of the patients by $4,312 , $3,720, $2,936, and $3,032, respectively . As observed in Table It is worth mentioning that the overall significance of the multiple regression model was also assessed and found to be significant . Moreover, the normality of the residuals, which indicated whether they followed a normal distribution, was also confirmed .Overall, the results of the Independent sample T-test, ANOVA, Mann-Whitney U test, and simple and multiple regression analyses were almost consistent in terms of significance of affecting variables including: disease stage, being an extreme user, visiting both private and public centers, increased income level, and chemotherapy side effects.The results of Table The incidence and prevalence of BC have increased in recent decades due to the progressive nature of this disease and the aging of the population . The impBased on the simple regression analysis, the results showed that having academic degrees, an increase in disease stage, being an extreme user, receiving care from both private and public service providers, having supplementary insurance coverage, undergoing surgery, experiencing chemotherapy side effects, and having higher household income led to an increase in the costs of BC patients.The results of the multiple regression analysis in this study revealed a significant relationship between disease stage and disease costs so that higher stages of the disease significantly increased the costs. This suggests that the overall average cost was higher in higher stages of BC due to the use of more resources, longer hospitalization, more visits to cancer clinics, and the need for more care at home. In fact, the disease stage at diagnosis was an important predictor of treatment costs. Treatment for the more advanced and higher-stage disease was often more complex or invasive than treatment for earlier stages. However, higher stages not only required the use of more financial and non-financial resources but also usually had poorer health outcomes . Hence, Being an extreme user was another effective factor found to affect the costs of BC patients in this study. Self-referred patients who visited diagnostic and treatment centers outside of the times set by physicians and specialists within a year had higher payments and, consequently, greater costs compared to other patients. The reason for being an extreme user of health services could be attributed to factors such as older age, having supplementary insurance coverage, higher education level, higher income, urbanization and shorter distance to diagnostic and treatment centers –41. AccoThe results of the present study also showed that referring to both private and public centers led to an increase in the costs of the patients. Patients who went to private centers to receive diagnostic or treatment services had higher costs than those who received all necessary services only in public centers. This may be due to the higher service tariffs in private centers and the lack of insurance coverage for some services in these centers. Additionally, having supplementary insurance coverage may increase the probability of selecting private service providers, further contributing to the higher costs.Slavova et al. (2020) conducted a study on cancer patients in Australia  and AfkaAccording to the findings of this study, household income level could be another important factor contributing to the increased costs of illness. As the income level of the patient’s family increased, the costs of the disease also increased. This may be due to the fact that as household income and purchasing power increased, patients were more likely to seek care at private medical centers and use more expensive transportation and accommodation, leading to higher costs. The results of this study are similar to those of other studies, including those by Adanu et al. (2022) in Ghana , Sun et The results of this study showed that chemotherapy side effects may increase the costs of patients. Patients in this study reported suffering from complications such as anemia, itchy and dry skin and nails, hair loss, dizziness, physical weakness, and sometimes nausea during their chemotherapy process. Therefore, they had to consult specialists such as dermatologists and hematologists, take medication to alleviate the side effects, or be absent from work for a short period of time, all of which incurred costs. Consequently, the costs of patients who experienced chemotherapy side effects were significantly higher than those who did not. These findings are consistent with those of other studies, including Rashid et al. (2016) , HurvitzThe results of the multiple regression analysis revealed that the cost of the disease increased as the distance from the patient’s residence to the medical center increased. This may be due to travel costs, accommodation costs, and the increased need for patient and companions’ absenteeism. Other studies, including Bona et al. (2021) , SlavovaThe present research has some limitations, including the reliance on self-reports of patients or their companions regarding direct non-medical and indirect costs which may be subject to recall bias and imprecision. Additionally, incomplete information in some patients’ medical records and non-cooperation from some patients in providing detailed information on costs may have affected the accuracy of the data. Also, we only examined the factors that were based on the review of previous studies and derived from the opinions of breast cancer experts. Therefore, there may be other effective factors that were not included in our research. Despite these limitations, the present study provides valuable insights into the various factors that contribute to the costs of BC patients, which can help inform efforts required to improve the affordability and accessibility of cancer care.The results of this study identified several factors that were found to be influential in affecting the costs of BC. These factors included higher disease stages, being an extreme user, seeking care at both private and public health centers, experiencing chemotherapy side effects, higher levels of household income, and greater distance to medical centers. Based on the results of this study, promoting and training individuals to undergo monthly self-examinations and annual screenings before menopause could aid in the early detection of masses in lower stages, ultimately leading to reduced costs associated with BC. Furthermore, increasing basic and supplementary insurance coverage and educating patients about the quality and availability of services provided in diagnostic and treatment centers could help reduce the frequency of patients’ visits to these centers, thereby controlling costs. Moreover, the deployment of specialists, particularly nutritionists, in chemotherapy centers to provide dietary recommendations could help prevent chemotherapy side effects and reduce subsequent costs. In addition, the construction of cancer diagnosis and treatment centers in higher-population cities throughout provinces could facilitate access to services and prevent patients from having to travel long distances, thereby reducing costs associated with travel and accommodation.Below is the link to the electronic supplementary material.Supplementary Material 1: Detailed information on selected studies & Average direct medical, direct non-medical, and indirect costs per studied breast cancer patient (USD)


Multiplex-PCR for the diagnosis of acute gastroenteritis (AGE) has allowed for rapid detection of multiple pathogens simultaneously but poses challenges in distinguishing between shedding and disease-causing pathogens. We aimed to evaluate the epidemiology of viral AGE and compare clinical characteristics among the 5 most common viruses..SUMC is the only hospital in southern Israel serves a population of ∼97,500 children < 5 years. Rotavirus vaccine was added to the national immunization program in 2010 and vaccine coverage (3 doses) reached 70% in 2 years. All rectal swabs for multiplex-PCR targeting; rotavirus, norovirus, adenovirus 40,41, astrovirus and sapovirus collected from diarrheic children < 5 years, December 2017 - March 2022, were included. Detection of the same virus within 2 months was considered a single episode. The clinical analysis included all episodes with single-virus detection and negative stool bacterial PCR . No clear seasonality was observed for AGE viruses in 2018-19. However, during the 2nd year of the COVID-19 pandemic, an unusual surge in warm months was observed, first attributed to rotavirus and later to norovirus . Of the single-virus AGE episodes with negative bacterial PCR, 34.6% and 5.9% presented with mucus and bloody stool, respectively, and 29.3% were treated with antibiotics. No significant differences in rotavirus vaccination rates were found between rotavirus and other viruses. Children infected with astrovirus and sapovirus had higher rates of hospital-acquired AGE and immunodeficiency (P< 0.05) (Table), while children with rotavirus had higher dehydration severity and metabolic acidosis (P< 0.05) .Of the 5,151 rectal swabs collected, 1,934 (37.5%) were positive for at least one virus, with 245 (12.6%) showing multiple virus detection. Norovirus and rotavirus were the most prevalent 37.5% of all rectal swabs from diarrheic hospitalized children < 5 years were positive for enteric virus, 12.6% with multiple detection. Rotavirus remained significant and the most severe despite vaccination efforts. Our findings highlight the importance of continuous surveillance in the context of multiplex PCR testing for accurate management and future prevention methods.Dana Danino, Dr. MD, Pfizer: Grant/Research Support David Greenberg, Professor MD, GSK: Advisor/Consultant|GSK: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria


We report a case involving a young male patient without a significant medical history who exhibited symptoms of fatigue, shortness of breath, chest and back pain, and syncope with vomiting. He was found to have adrenal insufficiency and cardiac tamponade requiring pericardiocentesis. Further inpatient workup revealed the patient had positive IgM and IgG antibody titers for the coxsackie B virus, which we believe caused his presentation. The coxsackie B virus strain can cause mild gastrointestinal to more severe cardiac and neurological complications, including meningitis and myocarditis. On rare occasions, the virus can appear in an unexpected fashion, such as in cardiac tamponade or hormonal disruption. This case raises attention to the broad manifestations of the virus and recognizing its more uncommon presentations. Enterovirus in the Picornaviridae family that is typically spread through the fecal-oral route. Within the virus, there are 29 recognized serotypes belonging to either group A or group B [The coxsackievirus is a form of  group B . With thStrains of the coxsackie B virus have been observed to target the pancreas, resulting in conditions such as acute pancreatitis or type 1 diabetes mellitus . Other cOur patient showcases a unique scenario of the coxsackie B virus causing both cardiac tamponade and adrenal insufficiency. This case highlights the importance of awareness in identifying the virus and the need for further research regarding pathophysiology and treatment.This 30-year-old male without significant medical history arrived with complaints of chest pain and shortness of breath for the past three days. He was sitting up as he could not tolerate being supine. Just prior to arrival, his spouse noted a syncopal episode with some non-bloody, non-bilious vomiting.Vitals on admission include a heart rate of 122 beats per minute, respiratory rate of 27 beats per minute, blood pressure of 63/48 mmHg, SpO2 of 90% requiring 4 L of oxygen, and a temperature of 96.8°F. On physical examination, the patient was alert and oriented ×3 with no focal deficits but was noted to be very lethargic. His heart sounds displayed a regular rhythm but were tachycardic and diminished. The patient was tachypneic on lung auscultation but had normal breath sounds. His chest X-ray demonstrated no acute cardiopulmonary abnormalities, and his electrocardiogram (EKG) showed sinus tachycardia, left posterior fascicular block, borderline low voltage  revealed a large pericardial effusion with tamponade. Given hypotension and hypoglycemia, he was provided dextrose with fluid boluses and started on a norepinephrine drip. Cardiology was consulted, and computed tomography (CT) angiogram ruled out aortic dissection but again showed pericardial effusions and concerns for tamponade Figure .Once pressures improved, the patient went to the catheter laboratory for pericardiocentesis where 450 cc of fluid was removed Table .Post-procedure, vitals quickly stabilized. Blood work revealed the patient had 1:320 positive antibody titers for the coxsackie B virus and had adrenal insufficiency with low cortisol levels. Treatment with colchicine and steroids was initiated, and 48 hours later, transthoracic echocardiogram was negative for pericardial effusion. He was discharged the following day with recommendations for follow-up with endocrinology and his primary care physician.The coxsackie B virus traditionally affects adults with a benign and uneventful course. This case functions as a demonstration that the virus can sometimes present in a unique fashion. The coxsackie B virus knowingly causes pericarditis, but the pathophysiology for tamponade is unclear with only a handful of reported cases. One case involving a 58-year-old male with hemorrhagic pericardial effusions and tamponade from the coxsackie B virus postulated that since the virus has been shown to cause chronic infection, the long-term damage to the myocardium could in theory result in fluid buildup . There aHowever, what sets this report apart is the additional component of virus-mediated adrenal insufficiency. There are examples of the coxsackie virus affecting different aspects of the endocrine system. Acute pancreatitis is a well-known complication seen from coxsackie virus infections . UnfortuA second process by which the virus causes adrenal disruption is through transient suppression of the hypothalamic-pituitary system. There are instances of temporary hypogonadism seen in coxsackie virus-mediated encephalitis that resolves shortly after the resolution of infectious symptoms . AlthougThe coxsackie virus clearly manifests in various and hard-to-predict ways. Most of the presentations are benign and ultimately harmless. However, we cannot be complacent when confronted with the disease. The virus on occasion can be challenging and sometimes fatal for the patient, such as in cardiac tamponade or adrenal insufficiency. The pathophysiology of these conditions and the coxsackie B virus is unclear and not extensively researched. This case brings awareness to better understand the virus when dealing with these uncommon findings.


Background: Autosomal dominant polycystic kidney disease (ADPKD), a hereditary nephropathy, eventually leads to end-stage renal disease (ESRD), typically by mid-life.Objectives: The objective of this study was to assess real-world healthcare resource utilization and cost among commercially insured (COM) and Medicare Advantage (MAPD) ADPKD patients in addition to the cost profile by chronic kidney disease (CKD) stage.Methods: Patients diagnosed with ADPKD (two or more claims) with ≥30 days of continuous medical and pharmacy benefits and no evidence of autosomal recessive polycystic kidney disease were selected . Plan and patient paid healthcare costs and resource utilization per patient per month (PPPM) were described in total and by insurance type. CKD stage was established based on serum creatinine laboratory values or dialysis-related codes. Adjusted, CKD stage-specific costs were predicted for 4 years using regression models.Results: Of the 36,253,096 patients in the databases (1/1/06-8/31/12), 5,051 had evidence of ADPKD. Following exclusion criteria, 4,356 COM and 468 MAPD ADPKD patients remained. Total healthcare resource utilization and costs were high, and costs increased substantially from CKD stage 1–5. PPPM healthcare costs were 37% for ADPKD management and 52% for dialysis services. Predicted 4-year healthcare costs by CKD stage were $40,164 (stage 1), $33,397 (stage 2), $42,686 (stage 3), $148,402 (stage 4), and $207,548 (stage 5).Conclusions: Healthcare resource utilization and costs associated with ADPKD were substantial, irrespective of payer type, and primarily driven by CKD stage. Of the total healthcare costs, 88% were ADPKD- and dialysis-related. Most impactful was the spike in predicted cost when patients progressed from CKD stage 3 to stage 4 (by 348%) after multivariate adjustment. These stage 4–associated costs are primarily due to ultimate progression into stage 5 and ESRD within the 4-year time frame.


Thus, we have obtained comprehensive multiplex PCR test results and analyzed the nasal colonization status of respiratory viruses in patients during the COVID-19 epidemic period.Few reports have comprehensively investigated the frequency of respiratory virus nasal colonization in both children and adults. Since the coronavirus disease 2019 (COVID-19) pandemic in 2020, St. Marianna University Hospital has used the multiplex polymerase chain reaction (PCR) test , 20–59 years , and ≥60 years . The positivity rates for severe acute respiratory syndrome coronavirus 2 were 14.8%, 10.2%, and 6.0%, respectively; rhinovirus or enterovirus 26.2%, 1.9%, and 0.7%, respectively; respiratory syncytial virus 7.1%, 0.4%, and 0.3%, respectively; parainfluenza virus type 3 3.6%, 0.3%, and 0.2%, respectively; and adenovirus 3.1%, 0.3%, and 0.1%, respectively, were detected significantly in children, and to some extent in adults.Despite various restrictions during the COVID-19 pandemic period, children as well as adults had a certain degree of respiratory virus colonization in the nasal cavity. This result suggests that asymptomatic or mildly symptomatic adults may be spreaders of some viral infections to children.All Authors: No reported disclosures


Adeno-associated virus (AAV) differs from most other viruses, as it requires the simultaneous presence of a helper virus for an active infection. Up to 80% of the human population is seropositive for AAV antibodies. AAV has been known to be a non-pathogenic virus and an inhibitor of carcinogenesis caused by coinfecting viruses. However, the recent reports associating AAV infection with hepatocellular carcinoma development and the mysterious cases of acute severe hepatitis in children have challenged the idea that AAV is a harmless virus. Herein, we explore the usefulness of AAV in gene therapy and the importance of AAV as a protector or perpetrator in human carcinogenesis, ultimately reflecting on the dual role of AAV in human health. Dependoparvovirus genus within the Parvoviridae family [Discovered as an adenovirus stock contaminant in the mid-1960s, adeno-associated virus (AAV) is a non-enveloped mono-stranded DNA virus that belongs to the e family , 3. The e family . Unlike e family .The most visible and popular application of AAV is in gene therapy, where it offers the unique capacity of recombinant AAV (rAAV) vectors to transduce dividing and non-dividing cells with high efficiency to yield long-term transgene expression, relatively low immunogenicity, and selective tissue tropism . Gene thGiven that AAV is endemic in the human population, it is remarkable that many questions on its natural infection remain unresolved. There have been few research addressing the influence of AAV infection on human health, and the findings are inconsistent (reviewed in ). In genSurprisingly, the idea that AAV is a non-pathogenic virus has been challenged by recent reports. These studies found that clonal wild-type AAV (wtAAV) insertions in human cancer-driver genes were associated with rare cases of hepatocellular carcinoma (HCC) in a non-cirrhotic liver background –21. In pNature demonstrating that infection with AAV serotype 2 (AAV2) was linked to recent clusters of unexplained acute severe hepatitis in children [Nature studies, Gates and colleagues (2023) [Also surprising were the three independent studies published in the March 2023 issue of children –27. The children . Based ochildren , the U.Schildren , respectchildren . Intereschildren . Consistchildren , 26. Thechildren , 31. Of s (2023)  investigClearly, the recent studies associating AAV infection with HCC development and acute hepatitis in children are paving the way for renewed interest in wtAAV biology. Further research is needed to determine the impact of AAV infection and the frequency of insertional mutagenesis in additional cohorts of patients. Moreover, to evaluate whether AAV2 infection can cause, or contribute to, acute hepatitis in children, prospective and well-controlled follow-up studies are necessary. The existing literature on AAV shows us that the virus-host relationship is complex and the viruses can be useful in several healthcare contexts.


Zoonotic viral infections that cause severe disease or even death in some people may be asymptomatic or mild in reservoir hosts. Comparison of the pathogenesis of these two host categories may potentially explain the difference in disease. However, infections in reservoir hosts are often neglected. Therefore, we compared the pathogenesis of rabies virus, macacine alphaherpesvirus, West Nile virus, Puumala orthohantavirus, monkeypox virus, Lassa mammarenavirus, H5N1 highly pathogenic avian influenza, Marburg virus, Nipah virus, Middle East respiratory syndrome, and simian/human immunodeficiency viruses in both humans and reservoir hosts. We showed that most aspects of the pathogeneses were remarkably similar. The remaining differences lead to the identification of tipping points in the pathogeneses that are important for explaining the disease outcome in severe human cases. Further elucidating these tipping points by studying zoonotic viral infections in their reservoir hosts may teach us how to reduce the severity of zoonotic viral diseases in humans. This haA key question after a spillover of a virus from an animal reservoir is whether it is able to transmit between humans, thus leading to expanding outbreaks. A second key question is what the potential impact will be, which is related to the virus’s ability to cause disease in humans . The comIn general, the pathogenesis of a viral infection can be split into different parts according to the pathway the virus follows in its host. From the perspective of a pathologist, using light microscopy, we can split them into (1) attachment to receptors on exposed host cells, (2) replication in host cells at the entry site, (3) release from host cells with subsequent dissemination within the host to other replication sites, (4) replication in host cells at sites that are important for virus amplification, and (5) excretion from the host to enable transmission to a new host. Together, these processes determine cellular, tissue, and immune responses, which in turn contribute to the clinical outcome of infection and the ability to spread viruses to the environment and new hosts. Because of ethical and practical reasons, we often cannot study the pathogenesis of an emerging viral disease directly in patients and instead use laboratory animal models. Researchers tend to focus on finding the best animal models, which are those in which the pathogenesis in the laboratory animal closely reflects that in the human host, i.e., in which parapathogenesis mirrors neopathogenesis.Relative to neo- and parapathogenesis, orthopathogenesis is often ignored  virus attachment site, (2) primary replication site or entry (cell types or tissue at the start of infection), (3) route of dissemination within the host, (4) virus amplification (cell types or tissues), and (5) cell types or tissues responsible for virus excretion. We also reviewed the outcome of infection, which can be seen as the end result of these virus-host interactions. Virus attachment site and entry were assessed separately because virus attachment is such a critical step, and they can be studied separately. For example, virus attachment sites can be studied on formalin-fixed paraffin-embedded tissue sections with virus histochemistry or receptor-specific immunohistochemistry of uninfected, healthy individuals, while entry can be studied by the examination of tissues from infected individuals.For these selected zoonotic viral infections, we outlined some basic virus-host interactions at the tissue level, following the natural course of a viral infection . We focuThe selected zoonotic viral infections belong to 11 different virus genera and 8 different virus orders: rabies virus , macacine alphaherpesvirus 1 , West Nile virus , Puumula orthohantavirus , Marburg virus , Lassa virus , highly pathogenic avian influenza virus H5N1 , monkeypox virus , Nipah virus , Middle East respiratory syndrome (MERS) coronavirus , Simian/Human immunodeficiency virus-1  . They arThe severity of disease can differ within subpopulations of a host species, e.g., obese male adults may have more severe disease than children. Thus, we needed to make a choice about which subpopulation we wanted to study. We chose differently for the reservoir host and the human host as we were interested in what the orthopathogenesis could teach us about how viruses and hosts have adapted to each other. Therefore, if known, for reservoir hosts, we chose the pathogenesis of the infections in the subpopulation within the reservoir host that is most important for the maintenance of the virus in the species (often mild disease) . With re3.Several trends in similarities and differences could be identified from the comparison between orthopathogenesis and neopathogenesis for each of these 11 examples of zoonotic viral infections. Details on assigning rates of similarity are available in the Camelus dromedarius) and humans. Second, the entry was generally the same as well; this was assessed to be (likely) the same in 7 of the 10 examples for which we had information. Of note, even in two of the three examples in which entry was different (Middle East respiratory syndrome [MERS] and highly pathogenic avian influenza [HPAI] H5N1), the entry was still in the same organ system: the respiratory tract. However, the specific entry cell type was different: upper respiratory tract epithelial cells in reservoir hosts and lower respiratory tract epithelial cells in hospitalized humans. Third, dissemination of the virus was also well conserved, with 10 of the 11 examples being similar. When dissemination via blood or neurons was typical in the orthopathogenesis, this was also the case in the neopathogenesis. The exception was HPAI H5N1 in poultry, which can disseminate via blood abundantly because the virus can replicate well in galliform endothelial cells. In humans, however, endothelial cell infection and dissemination via blood occur less frequently, likely because of the lack of virus to replicate (well) in human endothelial cells in vivo. Thus, three of the five virus-host interactions were similar for the reservoir hosts and the human hosts for the majority (7 of 10 to 11 of 11) of our examples.The first three virus-host interactions – virus attachment site, entry, and dissemination – were the most similar. First, the virus attachment site was generally the same for the reservoir host and humans. For example, the MERS virus attaches to dipeptidyl peptidase 4 (DPP4) and alpha-2,3-linked sialic acids in both dromedaries  site of infection. In all three cases, this resulted in humans rarely or not excreting virus, and reservoir hosts excreting virus frequently via multiple routes.The two remaining interactions – amplification and exit – showed more differences between the reservoir host and human host: they were more frequently assessed to be (somewhat) different rather than (somewhat) similar. For amplification, 7 of the 11 infections were assessed as somewhat different. For four of those , the differences arose not from the cell types themselves but rather from the number of infected cells, so it was a quantitative rather than a qualitative difference. The differences in the number of infected cells were inferred from reviewed literature in which quantities of cells were usually categorized, e.g., ‘few’ or ‘abundant’. In these four examples, humans showed infection in a larger proportion of cells than reservoir hosts. For the remaining three , the main cell type involved in the amplification phase in the reservoir host was also frequently important in the human host, but in the human host, the amplification also extended to other cell types. For exit, 5 of the 11 infections were assessed as (somewhat) different. For two of those (West Nile virus and Puumula orthohanta virus infections), the same cell types were likely involved in both reservoir hosts and humans, but this resulted in detectable excretion of infectious virus only in the reservoir hosts, suggesting, again, a quantitative rather than a qualitative difference. For the remaining three , the main cell type involved in virus exit was different, for instance, Despite the many similarities in the selected characteristics of pathogenesis in reservoir hosts and human hosts, the outcomes of infection were different for 10 of the 11 infections. For 9 of these 10 infections, the outcome was more severe for the human host, as one would expect due to our selection bias . The exception was HPAI H5N1, for which infection in chickens causes more severe disease and higher mortality than in humans. For 1 of the 11 infections, rabies virus infection, the disease outcome was similar for carnivores and humans.Explanations for the differences in the outcome of infection appeared to have three patterns, based on quantitative and qualitative descriptions observed by microscopic examinations in the reviewed literature. First, differences could arise due to higher numbers of cells becoming infected during the amplification phase in the neopathogenesis, while the cell types were generally the same; here, the difference was quantitative. This was the case for infections with Marburg virus, macacine alphaherpesvirus 1, Nipah virus, HIV-1, and possibly also monkeypox virus and Lassa virus, in which the higher number of cells infected in humans compared to reservoir hosts was associated with more severe disease. Second, differences could arise from differences in cell type tropism during the start of the infection; here, the difference was qualitative. This was the case for the HPAI H5N1 virus, which infects endothelial cells in chickens, and, thus, enables the virus to spread systemically. Conversely, the lack of endothelial cell infection in humans enables the host to contain the viral infection mainly within the respiratory system. It was also the case for MERS coronavirus, which infects the upper airways and, thus, causes an upper respiratory tract infection in dromedaries. Conversely, MERS coronavirus in humans infects the deeper airways and, thus, causes a lung infection, which leads to more severe disease. Third, differences could arise due to an increased immune response associated with the same or even smaller numbers of cells infected in the neopathogenesis compared to the orthopathogenesis, e.g., in West Nile virus and Puumula hantavirus infections. In these infections, the higher number of infiltrated immune cells observed in humans compared to reservoir hosts was associated with more severe disease.Though sufficient information was available for our comparison, significant knowledge gaps relating to basic parts of orthopathogenesis were revealed. When there were gaps, our comparison was based on assumptions and was, therefore, less confident (‘likely’). Most of the gaps . TK was supported by European Union Horizon 2020 program grant agreement DELTA-FLU no. 727922. DVR is supported by a fellowship from the Netherlands Organization for Scientific Research (VIDI contract 91718308) and an EUR fellowship. MK is supported by NWO Stevin Prize.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Lassa fever, caused by Lassa virus (LASV), is endemic to West Africa, where ≈300,000 illnesses and ≈5,000 deaths occur annually. LASV is primarily spread by infected multimammate rats via urine and fomites, highlighting the need to understand the environmental fate of LASV. We evaluated persistence of LASV Josiah and Sauerwald strains on surfaces, in aqueous solutions, and with sodium hypochlorite disinfection. Tested strains were more stable in deionized water  than primary influent wastewater . Both strains had similar decay rates on high-density polyethylene  and stainless steel . Sodium hypochlorite was highly effective at inactivating both strains. Our findings can inform future risk assessment and management efforts for Lassa fever. Arenaviridae family , an enveloped RNA virus of the Mastomys natalensis, which is found in 50%–98% of households in West Africa and puts ≈58 million persons at risk for infection  of either Josiah or Sauerwald LASV isolates in the cell-free medium on the disks, and allowed the plates to air dry at 20°C. At each time point, we placed 450 µL of Dulbecco’s Modified Eagle Medium , supplemented with heat-inactivated fetal bovine serum  and 2% Pen/Strep (GIBCO) to a final concentration of 50 U/mL penicillin and 50 µg/mL streptomycin, onto the surface and gently agitated to free the surface-bound virus. Then we added L-glutamine (GIBCO) to a final concentration of 2 mmol in an appropriately labeled 2 mL screw top vial and froze at −80°C. We then determined viral titers for each surface.We conducted solid surface persistence experiments similar to those previously described   Test Kit .We analyzed the decay of infectious LASV strains for all experiments by using a first-order decay model and excluded data points below the limit of detection for the assay, as previously described (Stainless steel and high-density polyethylene (HDPE) are commonly used nonporous materials for hospital equipment. In addition, HDPE is a component of common full-body personal protective coveralls and gowns worn in hospitals . ConversWe spiked LASV strains into deionized water and raw municipal wastewater and monitored persistence for 5 days. The decay rate was significantly higher in wastewater than deionized water (p<0.002), which can be attributed to multiple factors . Sodium hypochlorite is a widely available disinfectant is used for wastewater disinfection .Neither strain was removed at 0 mg/L sodium hypochlorite over the experimental timeframe. Increased sodium hypochlorite concentrations resulted in significantly higher decay rates for Josiah (p = 0.001–0.3) and Sauerwald (p = 0.001–0.007) strains of LASV. The Sauerwald strain showed faster inactivation than the Josiah strain for both 5 mg/L and 10 mg/L (p = 0.04). Those results indicate that sodium hypochlorite effectively inactivates the LASV strains analyzed in this study.In general, we found LASV persisted longer in aqueous solution than on surfaces. Josiah strain persistence was significantly longer in wastewater than on HDPE and stainless steel (p<0.01). Both Josiah and Sauerwald strains had significantly lower decay rates in deionized water than on HDPE and stainless steel (p<0.01–0.02), indicating higher stability in deionized water than on either surface . Ebola virus and SARS-CoV-2 persisted in wastewater similarly to LASV under the same experimental conditions (Previous research analyzed the persistence of other priority pathogens, including Ebola virus, SARS-CoV-2, and Nipah virus, on representative surfaces or solutions (Bacteriophage Phi6 and murine hepatitis virus are commonly used as surrogates for enveloped viruses of concern, such as Ebola and SARS-CoV-2, and potentially LASV. Bacteriophage Phi6 and murine hepatitis virus decay rates were previously assessed in wastewater (Given the differences in stability between the surrogates and LASV, the differences in stability and susceptibility to chlorine disinfection between the LASV strains were not predicted here. The 2 strains evaluated displayed strain-dependent behavior, suggesting that the potential for environmental transmission might vary by strain. Those differences could have ramifications that affect virus transmission between the zoonotic reservoir and humans, as well as influencing human-to-human transmission. Future transmission studies should incorporate potential differences in stability between lineages into the study design. Additional investigations into the mechanistic basis of those differences could help elucidate potential regional differences of spillover risk in human populations.In conclusion, LASV is a World Health Organization priority pathogen with pandemic potential. Our findings supply data for the environmental persistence of LASV on representative surfaces, in aqueous solutions, and with sodium hypochlorite disinfection. LASV showed shorter persistence on surfaces than previously assessed enveloped virus surrogates and priority pathogens, and longer persistence in aqueous solution. LASV was rapidly disinfected in the presence of free chlorine from the addition of sodium hypochlorite. The data we provide on the stability and control of LASV in the environment could be used to further LASV management and mitigation efforts.Additional information on environmental persistence and disinfection of Lassa virus.


Altering the relationship via a phase shift between the trained visual sequence and auditory metre slowed reaction times. Sensitivity to rhythm was predictive of reaction times over all. In an exploratory analysis, we, moreover, found that approximately half of participants made systematically different responses to visual cues on the basis of the cues’ position within the auditory metre. We demonstrate the influence of auditory temporal structures on visuomotor sequential learning in a widely used task where metre and timing are rarely considered. The current results indicate sensitivity to metre as a possible latent factor underpinning individual differences in SRTT performance.The ability to learn and reproduce sequences is fundamental to every-day life, and deficits in sequential learning are associated with developmental disorders such as specific language impairment. Individual differences in sequential learning are usually investigated using the serial reaction time task (SRTT), wherein a participant responds to a series of regularly timed, seemingly random visual cues that in fact follow a repeating deterministic structure. Although manipulating inter-cue interval timing has been shown to adversely affect sequential learning, the role of metre  remains unexplored within the regularly timed, visual SRTT. The current experiment consists of an SRTT adapted to include task-irrelevant auditory rhythms conferring a sense of metre. We predicted that (1) participants’ (The online version contains supplementary material available at 10.1007/s00426-022-01690-y. From humans to songbirds  gradually decrease. To dissociate sequence learning from more general motor practice effects, a test block containing an unfamiliar order of cues is presented in later stages of the experiment. The abrupt increase in RT that usually follows the introduction of the novel sequence is taken to index a participant’s implicit procedural knowledge of the learned sequence.In addition to content learning, the SRTT can also be thought to have a temporal component. For example, the presentation of a new cue is usually timed relative to the previous stimulus . In this case, the participant’s actions trigger the upcoming cue, but a fixed stimulus rate or inter-stimulus interval (ISI) can also be implemented , which are achieved in sign language by analogously longer, more vigorous, or higher positioned movements  with their two index and middle fingers on a regular computer keyboard. The cue locations were deterministic, as probabilistic sequences substantially complicate the interpretation of temporal structure in SRTT responses  were compared with RT from the immediately preceding late learning blocks . We confirmed with piloting  that the transition from learning into phase-shifted metre was subtle, and unlikely to be consciously noticed by participants. In comparison, the New Metre block was obvious, even to musically untrained individuals. To preserve the low profile of phase-shifting the auditory metre, we therefore held the block order constant.Prior to beginning the SRTT proper, participants completed a practice session, which consisted of a visual sequence that was common to all conditions and paired to only unaccented drum sounds without any background subdivision sound. Participants received automatic text feedback on their accuracy and speed, with a prompt encouraging them to respond as quickly as possible for the rest of the task. Each block of the SRTT began at a different cue position within the auditory metre and visual sequence, and consisted of ten cycles equating to 120 cues per block, followed by a self-paced resting period before beginning the next round. The block structure was formally organised as follows: n = 120). Responses from this check were compared to RT from pooled from Blocks 8 and 10 in the main task. A subset of participants who performed the main task  were further tested for explicit knowledge of the learned SRTT sequence to confirm that our modified version of the task did not inadvertently encourage explicit learning strategies using a sequence completion task. Details of these checks are given in Online Appendix C.1.5.After completing the main SRTT, to ensure that the basic premise of visual sequential learning had been achieved, participants were presented with an unfamiliar visual sequence paired with the familiar auditory metre . No test trial feedback was provided. For “different” trials, the level of difficulty was varied by pairing rhythms that were more or less similar in terms of their pattern of inter-onset intervals, as determined by the first author, who is a professionally trained jazz musician and educator. For example, a “different” trial would be considered to be relatively difficult if both rhythms started with the same pattern of inter-onset intervals, but deviated by a slightly differing order of intervals within the second parts of the two rhythms. The task started with mostly easier “different” trials, before finishing with mostly harder “different” trials, with the intended goal of easing in participants who might feel less confident with such a task. Trials were equally distributed between “same”/“different” categories, and “different” trials were also equally distributed across “easier”/“more difficult”. The task consisted of forty trials with two self-paced rest periods. All participants heard the same trial order. The resultant dependent variable Rhythm Score was percent correct “same”/“different” responses, from a maximum score of 40. & Kraus , origina & Kraus , which wMusical Experience Participants were asked to report, on a five-point Likert scale with 1 being “no experience” and 5 being “expert experience”, whether they currently, or had ever, played a musical instrument . In a subset of the participants who also performed the SRTT (n = 16), we also collected the Goldsmiths Musical Sophistication Index (Gold-MSI), a psychometric tool for the measurement of musical attitudes, behaviours, and skills . Only correct SRTT trials > 50 ms were retained for further analysis. Raw or untransformed RT formed the dependent variable, but RT is generally plotted as mean-centred reaction times, which are calculated by removing each participant’s mean RT from their data points. Similarly, performance in the Rhythm Discrimination Task, hereafter termed Rhythm Score, was modelled as a continuous variable, but is sometimes also summarised as a binary low/high Rhythm Score group membership for plotting and descriptive analysis. These groups were calculated by taking the median Rhythm Score split. For the SRTT analysis, we identified the following main contrasts of interest: Accented versus Unaccented responses during learning (Blocks 1–8).Phase-Shifted Metre (Block 9) versus late learning (Block 8).New Metre (Block 11) versus late learning (Block 10).In the case of Contrast 1, predictors of interest included: Metre and Accent as factors; and Rhythm Score and Block (Blocks 1 - 8) as continuous variables. For Contrasts 2 and 3, predictors of interest included: Metre and Block; and Rhythm Score as a continuous variable. Random intercepts and slopes were estimated within Participant. Statistical tests were carried out using linear mixed models [LMM; lmer from the lme4 package  or Mann-Whitney U-tests (ranksum in MATLAB), and linear trends were inspected with Pearson’s linear correlation coefficient or Spearman’s rank coefficient (both corr in MATLAB). The threshold for statistical significance was 0.05 and multiple comparison corrections were applied to post hoc contrasts using the Bonferroni method. The false discovery rate  was used to correct correlations and the permutation analyses in the exploratory section. In all cases, adjusted p-values are reported. Descriptive statistics  reported at the group level are first aggregated within Participant.N3/4 mN4/4 mn of 41 = – 2.71, pRpt= – 3.91, pRt= 4.79, pRt= – 3.05, pRpt= -1.96, pRWe hypothesised that, over the learning period (Blocks 1–8), visual cues associated with Accented auditory stimuli in the auditory Metre would elicit shorter RT. As a main effect, higher Rhythm Score was significantly predictive of faster RT = – 4.88, pt= – 1.79, pPost hoc contrasts revealed that responses significantly differed on the basis of Accent for participants in the 4/4 m condition  for visual and descriptive parsimony. For participants who heard the 3/4 m, their RT significantly decreased by Block for both Accented . Hence, although participants heard the same auditory Metre and saw the same visual cues as in earlier blocks, the sequences no longer corresponded in the same way. We predicted that this would lead to a slowing of RT in comparison to learning blocks, particularly for participants who scored higher in the Rhythm Discrimination Task.t= 2.33, pRpt= – 2.69, pRThere was a significant main effect of Block = -2.33, pt= – 1.69, pppppPost hoc analyses revealed that, holding Rhythm Score constant, the effect of the Phase-Shifted Metre test was statistically significant for the 3/4 m condition . In short, we compared the final two cycles of the sequence in Block 8, to the first two cycles of the sequence in Block 9, the test block. Summarising by median-split Rhythm Score group, there was a substantial overall increase in RT for participants in the High Rhythm group  but less so for the Low Rhythm group . Taken together, given that Rhythm Score is generally associated with faster RT throughout the task, and that the linear trend of Rhythm Score is overall reduced in Block 9 (Phase-shifted metre test) in the modelling, it appears that higher Rhythm Scoring participants were disproportionately affected by the change in association between the auditory metre and visual sequence. Full model details are given in Supplementary Materials in Appendix C, Table C4. An overview of the Metre Tests is depicted in Fig. .99, SD =In the following test block, the New Metre Test (Block 11), participants in the 3/4 m condition were exposed to a familiar visual sequence paired to the unfamiliar 4/4 auditory Metre, and vice versa. As with the previous Phase-Shifted Metre Test Block, we expected that disrupting the learned association between the familiar auditory Metre and visual sequence would result in relatively slower RT. We also predicted that we would see a more robust slowing in RT in comparison to the Phase-Shifted Metre Test block, because we expected that the effect of changing the Metre would be highly jarring, even for participants who had not integrated the auditory metre along with the visual sequence during learning.ppt= – 3.28, pRt= 2.18, pRt = – 0.48, pt = – 3.29, pt = – 2.87 pThere was no main effect of Block = 2.04, pRppppBecause we had incorrectly predicted that the effect of the New Metre Test would be more consistently negative and of a greater magnitude than the Phase-Shifted Metre Test, we did not experimentally vary Block order, meaning that the learning block (Block 10) to which we compare the New Metre Test Block (Block 11) could potentially be influenced by the earlier Phase-Shifted Metre Test (Block 9). We therefore modelled responses between Block 8 and Block 10. We saw no main effects of Metre nor of Block  than in Block 8 , and theoretically had more to lose, it seems less likely that this occurred. Alternatively, we could also speculate that participants were primed by the earlier test block, meaning that they were prepared for the New Metre Test. We cannot say for certain this did not occur, but during verbal debriefing, we found that no participants reported any notice or hint of the Phase-Shifted Metre test, despite most commenting on the New Metre Test. Hence, if any priming effect did occur, it was possibly unconscious. Taken together, although we cannot definitively establish that the Block order did not preclude the predicted effect of the New Metre Test, we can say that it was not because RT in the Learning Block 10 had yet to rebound from the Phase-Shifted Metre Test.After finishing the main SRTT, wherein the order of visual cues was held constant throughout both learning and the Metre test blocks, participants were exposed to an unfamiliar visual sequence, with auditory Metre held constant from the main task. Each participant’s RT from the new visual sequence test were compared with their RT from late learning (pooled Blocks 8 and 10) in the SRTT to verify that implicit learning of the visual sequence had indeed taken place.t= 9.24, pRpt= – 19.98, pt= – 9.24, pThere was a significant main effect of New Visual Sequence . There was no improvement to models fit with Metre condition, self-reported knowledge of the visual cue, nor whether or not the number of cues shown matched the participant’s own SRTT Metre condition, as guided by AIC (range 802–806). There was a marginal main effect of Rhythm Score .Rhythm Score positively correlated with self-reported musical activity levels , slowly to Accented cues, resulting in potentially qualitative individual differences.In our planned analysis of the SRTT, we established that participants in the 4/4 m condition responded more quickly to accented-visual cues during learning (blocks 1–8), and that participants in the 3/4 m condition showed a more reduced response in the opposite direction. Although these results were partly in line with our hypothesis, the effect was also subject to individual variability, especially during later Learning blocks. Visualising these individual differences, we became aware that, in the 4/4 condition, participants’ responses to Accent appeared to follow a bi-modal distribution Figs.  and 10. n iterations nnp values for the percentiles, is given in Supplementary Materials in Appendix D, Table D14. There was no statistical relationship between individuals’ Accent relative difference and their Rhythm Score, rpTo verify this unanticipated pattern of results, we first conducted a simulated permutation test = 4.60, pRpt= -4.08, pRppPrevious work investigating sensorimotor synchronisation to auditory Metre has suggested that actions performed during Accented cues are more temporally stable in comparison to Unaccented cues Madison, . Given tock Fig. . AccordiThe current study was motivated to understand how visual sequential learning may be influenced by exposure to two distinct, task-irrelevant auditory metres. Metres can be characterised as a pattern of accented and Unaccented elements or events, and previous behavioural and neural research suggests that these recurring structures dynamically tune attention, such that attentional peaks coincide with accents in time. We hypothesised that RT during visual sequential learning would vary according to accent, and that participants who demonstrated a heightened sensitivity to rhythm would also be more likely to reflect the metrical structure in their SRTT task performance, despite not having received any instruction to explicitly respond to or emulate the auditory rhythm. We devised two metre-specific test blocks that targeted the relationship between the auditory metre heard during training and the visual sequence, speculating that these breakdowns between cross-modal aspects of the learned task would lead to a disruption in RT, as would be expected following a change to the visual sequence itself.We expected to see faster responses according to auditory metric accent status. Instead, we found that response on the basis of accent was almost wholly concentrated in the 4/4 m, and the 3/4 m may have served as something of a control condition. For example, on the group level, we found that participants in the 4/4 m responded more quickly and less variably to accented than unaccented-visual cues. This difference was most pronounced during early learning, and unaccented responses had essentially “caught up” by later blocks. When we examined the magnitude, rather than absolute direction, of variation in response to accent, most participants in the 4/4 m revealed systematic differentiation between accented and unaccented responses. In contrast, just a few participants in the 3/4 m appeared to distinguish between accented and unaccented cues, and their responses to accented cues were associated with equal variability in comparison to unaccented cues.We suggest that this discrepancy between metre conditions is a strength, rather than a limitation, of the results, because if the accent effect was driven by some other factor, such as cross-modal associative learning  comparing the last 24 RT of Block 8 to the first 24 RT of Block 9 (the test block), however, suggests that participants in the 4/4 m initially slowed more consistently  than did those in the 3/4 m , before quickly regaining in speed. In any case, the  & Weiss  explored & Weiss . In the In comparison, the second metre test block, wherein participants heard a completely different metre, was very obvious to participants. The effect of the New Metre test on RT was noisy and prone to inter-individual variability. Looking at RT at the onset of the New Metre test Fig. , we can Participants who scored higher in the perceptual Rhythm Discrimination Task made faster responses in the SRTT, a trend that held in the subset of non-musicians. We had expected that participants with greater sensitivity to rhythm would be more likely to show metre-specific patterns in their RT, as musicians have been previously shown to have enhanced responses in auditory statistical learning  in assessing the overall influence of metre in the current experiment.In closing, we have shown that auditory metre can affect visual SRTT task performance, even when inter-stimulus intervals are held constant, as is typical for the standard SRTT. Although we explicitly induced a sense of metre using auditory stimuli, a consideration for any laboratory task is that rhythmic responses are planned and executed differently than non-rhythmic actions Below is the link to the electronic supplementary material.