The role of climate in the Coronavirus disease 2019 (COVID-19) transmission appears to be controversial, as reported in earlier studies. In Africa, the subject is poorly documented. In this study, over the period from January 1st, 2020 to September 31, 2022, the daily variations in cumulative confirmed cases of COVID-19 for each African country (54 countries) are modelled through time-series-based approaches and using meteorological factors as covariates. It is suggested from the findings that climate plays a role in COVID-19 transmission since at least one meteorological factor is found to be significant in 32 countries. In decreasing order, the most often occurring meteorological factors are dewpoint temperature, relative and absolute humidity, average temperature and solar radiation. Most of these factors show a lagged effect with confirmed cases (between 0 and 28 days). Also, some meteorological factors exhibit contrasting effects on COVID-19 transmission, resulting in both positive and negative association with cumulative cases, therefore highlighting the complex nature of the interplay between climate and COVID-19 transmission. Sars-CoV-21. Initially called 2019-nCOV acute respiratory disease, later renamed COVID-19 disease, it was declared a pandemic by the World Health Organization (WHO) on March 11, 2020, and further acknowledged as a Public Health Emergency of International Concern (PHEIC)2. The disease quickly spread throughout the world, starting in January 2020. Despite the wide array of restrictive measures largely promoted by governments worldwide4, the outbreak of the pandemic has been largely unprecedented: a year later, on December 31, 2020, a total of 83,638,090 cumulative confirmed cases and 1,880,710 deaths were reported globally, hence a case-fatality rate of 2.25%5.In December 2019, a transmissible disease emerged in the city of Wuhan . The disease was found to be caused by a new coronavirus, the 5. These estimates seem low compared to those from America, Europe and Asia, which reported respectively 44.6%, 28.6% and 24.8% of the global count of confirmed cases6. Yet, the case-fatality rate of the disease appears to be almost twice as high in Africa  as compared to the global level (1.08%), indicating the higher lethality of the disease in Africa7.Even though at the global scale, the outbreak of the COVID-19 disease has been exponential, the African continent emerges as the least affected in the World, according to the numbers of confirmed cases and deaths reported. The first confirmed case in Africa was reported in Egypt on February 14, 2020. On December 31, 2020, a total of 2,760,450 cumulative confirmed cases and 65,458 deaths  were reported. As of September 30, 2022, the total cumulative confirmed cases in Africa rose to 12,355,709 , while the number of deaths reached 256,764 in decreasing order of severity: South Africa, Morocco, Tunisia, Egypt and Libya) reported 60.3% and 69.7% of the total confirmed cases and deaths (respectively)5. These figures are thought to be due to specific traits of the African context, including the low rate of urbanization, the limited transport network hindering the mobility of people, and the young age of the population9. Also, the lower case fatality rate in Africa of non-communicable diseases such as cancer, cardiovascular accidents and diabetes  has been often put forward10.A typical trait regarding the spatial patterns of the spread of the pandemic is that, at the scale of the African continent, large discrepancies are observed among countries. As of September 30, 2022, for example, South Africa alone reported 32.5% and 39.8% of the total confirmed cases and deaths (respectively) in Africa. Meanwhile, the top five hard-hit countries  have also been identified as significant in explaining COVID-19 deaths13. Moreover, the relationship between climate and COVID-19 transmission is thought to be complex because weather patterns in a year affect human behaviour, therefore affecting the observation of lifting of containment measures. For example, Ganslmeier et al.21 reported that weather substantially affects the likelihood of social gatherings, therefore increasing the spread of the disease. Also, previous research indicates that including human behaviour and climate is critical in modelling the spread of a disease outbreak22.Among the factors affecting the transmissibility of COVID-19, the role of climate conditions has been early investigated and is still a trending and active topic23. The modelling methods often used range from generalized additive models24, generalized linear models24, compartmental epidemiologic approaches based on Susceptible, Infectious or Recovered (SIR) models27, and artificial neural networks29. Among these methods, time series-based modelling methods such as Autoregressive Integrated Moving Average (ARIMA) have been largely used for COVID-19 modelling and to explore the potential effect of external regressors such as meteorological variables on COVID-19 transmission32.Previous modelling studies attempted to analyse the spread of COVID-19 in different contexts, mainly to forecast the pandemic prevalence or assess the potential effect of meteorological conditions (as covariates) on COVID-1936. The question is of importance to African countries, especially in building effective, well-informed and adapted coping strategies for the ongoing pandemic37.However, despite the huge body of available literature, still, few studies addressed the case of Africa as a whole, especially regarding the specific role of meteorological conditions on COVID-19 transmission. There is still a need to assess which and to what extent climate factors influence the transmission of COVID-19In this study, we aimed to provide a continental scale assessment of the potential isolated effect of meteorological conditions on COVID-19 prevalence in the specific context of Africa. Our objectives are twofold: (i) identify the climatic factors which significantly affect COVID-19 transmission in African countries; (ii) assess the isolated level of association of these climatic factors to COVID-19 and their relative importance across African countries. In this scope, the study uses publicly available data on COVID-19 prevalence accumulated over 33 months, from January 1, 2020, to September 30, 2022, which is deemed appropriate to investigate the potential long-term effects of meteorological conditions on COVID-19 transmission.6, the first confirmed case of COVID-19 was reported in Egypt (EGY) on February 14, 2020; it was shortly followed by countries mostly from Northern Africa (NAf) region, especially Algeria (DZA), Tunisia (TUN) and Morocco (MAR)9. Over time, East Africa (EAf) and Southern Africa (SAf) emerged as the regions where the incidence of the pandemic is the largest. These regions witnessed three waves of increasing magnitudes: (i) in January 2021, 500–750 daily new confirmed cases per million; (ii) in May–July 2021, 1500–1700 daily new confirmed cases per million; and (iii) in January 2022, 2000–3000 new daily confirmed cases per million). West Africa (WAf) and Northern Africa (NAf) are the second largest regions affected, with waves occurring at the same periods, although roughly similar in magnitude, with 700–900 new daily confirmed cases per million. Central Africa (CAf) is the least affected region in the continent  is observed for the NAf region (202.3 mm), whereas it increases to 2580.7–4564.7 mm in other regions. NAf region also shows the lowest median dew point temperature (tdew = 5.1 °C), which increases to 12.1 °C (SAf region) and 21.0 °C (CAf region). The highest minimum (tmin), average (tmoy) and maximum (tmax) median temperatures are observed in the WAf region , whereas the lowest values are reported in the SAf region . The NAf region also shows the lowest relative (rh) and absolute (ah) median humidity (38.7°% and 7.3% respectively), but the highest median wind speed (3.2 m/s). In contrast, the median relative (rh) and absolute (ah) humidity in the other regions range between 63.2% (EAf region)-81.3% (CAf region) and 11.6% (SAf region)-18.4% (CAf region). Wind speed (wspd) is also generally lower in WAf (median of 2.2 m/s), EAf (median of 2.1 m/s), SAf (median of 2.7 m/s) and CAf (median of 1.0 m/s). Finally, solar radiation (insol) shows the highest values in the NAf region (median of 22.0 MJ/m2/day) and the lowest values in the CAf region (median of 16.9 MJ/m2/day). The correspondence between countries and regions is given as Supplementary Material in Table The spatial patterns of meteorological conditions in Africa are presented in Fig. tdew), tmax, tmin and tmoy variables are positively associated in NAf, EAf and SAf regions, whereas tdew appears to be negatively associated with tmoy and tmax in the WAf region and only with tmax in the CAf region. Also, wspd is always negatively correlated with tdew and pr in NAf, WAf and CAf regions, negatively correlated with pr in EAf and SAf, but positively associated with tdew in EAf and SAf regions. ah appears to be positively associated with all climate variables in EAf and SAf regions, but shows negative association with wspd (in NAf region), wspd, tmax and tmoy (in WAf region), wspd and tmax (in CAf region). In all regions, however, rh and ah variables are positively associated with tdew and pr.The correlation between climate variables is presented in Fig. These inter-correlations shed light that climate variables show different forms of associations depending on the region. However, these correlations are influenced by seasonal variations (forced by the Earth’s rotation around the Sun), and therefore, do not consider the unique properties of intra-annual variability of the considered climate variable over the period 2020–2022. In this regard, we complement the previous analysis with the assessment of correlations on anomalies of climate variables, estimated from climate normals  and presented in Fig. tmoy, tmin and tmax , and also rh, ah and tdew . A moderately positive association is observed between insol, tmoy and tmax in all regions except NAf. A moderately negative association is reported between tmax-tmoy and rh-ah pairs in almost all regions, and also between rh-ah pair and insol. These observations reveal consistent patterns of relationship between the climate variables across the different regions in Africa, despite the seasonal patterns which can be specific to each region43.The analysis of correlations between anomalies reveals similar patterns across all regions. The highest positively correlated sets are RegARIMA model with meteorological factors as covariates on the COVID-19 time series of cumulative cases results in 156 candidate models in which the climate variable included is significant  and the residuals are similar to white noise . However, within this total, some meteorological factors often show multiple significant lags for the same country. Most of the time, these multiple significant lags are not consecutive, but separated by lags without significance. This could be further explained by the recurrence time scale, as shown by the plots of the Autocorrelation Function (ACF) provided as a Supplementary Material (pages 10–63). There is also no apparent direct relationship between the number of significant lags and the decorrelation time scale.The fitting of a true’ models, the ‘duplicate’ models are filtered to retain the model showing the highest association  and Seychelles , closely followed by Gabon (GAB), Guinea-Bissau (GNB), Liberia (LBR), South Sudan (SSD) and Togo (TGO).Overall, it appears that in 32 African countries (out of 54), at least one of the 9 meteorological factors considered in this study appears to be significant in COVID-19 cumulative cases. Interestingly, some countries were found to have the largest numbers of climate variables significantly related to COVID-19 cumulative cases. These countries include Côte d’Ivoire (CIV: tdew (in 10 countries), followed by rh and ah (both in 9 countries). They are followed by insol and tmoy (both in 8 countries). Variables such as pr, tmin and tmax are both reported as significant in 4 countries and wspd in 3 countries.The meteorological factors most often occurring are RegARIMA models retained while separating positive and negative association.Figure rh and insol (median lags of 18.0 and 13.0 days respectively), followed by pr (median lag of 10.0 days), wspd (median lag of 7.0 days) and finally ah (median lag of 4.0 days).Some variables show a positive delayed association with COVID-19 Fig. a, meanininsol and pr have the highest negative association lags (medians of 25.5 and 24.5 days respectively), followed by tmin (median lags of 15.5 days), then tmoy, ah, rh and tdew at a similar level . tmax shows the shorter lag in terms of negative association (median of 3.5 days).The majority of the climate variables considered in this study show a negative delayed association with COVID-19 Fig. b, meaninah, insol, pr and rh show both positive and negative associations, but in different countries. However, the negative associations are less dominant, in comparison with the positive ones.It should be noted that some variables such as rh) is reported significant for Gabon (GAB) in CAf, Guinea-Bissau (GNB) in WAf, but also Eswatini (SWZ) and Malawi (MWI) in SAf. Solar radiation (insol) is significant for Sierra Leone (SLE) and Liberia (LBR), while absolute humidity (ah) appears significant for Senegal (SEN) and South Africa (ZAF). Wind speed (wspd) is reported for Côte d’Ivoire (CIV), Kenya (KEN) and Egypt (EGY), which are mostly coastal countries.The spatial distribution of countries where a positive association between a meteorological variable and COVID-19 is detected is shown in Fig. tdew) is reported significant for countries mostly in WAf, EAf and SAf (to a lesser extent). Average temperature (tmoy) is also negatively associated with COVID-19 in mostly EAf countries and also the WAf region. Absolute (ah) and relative (rh) humidity are found significant mostly in WAf and EAf, while maximum (tmax) and minimum (tmin) temperature are reported significant mostly in the EAf region.The spatial distributions of countries where a negative association between meteorological variables and COVID-19 is observed are presented in Fig. 8). Also, some other factors include the low rate of urbanization, the reduced mobility rate due to the limited means of swift transportation and the low volume of international transit with other continents26. More recent studies even suggested the possibility of immune formation endemic to developing countries44, where interestingly the previous occurrence of diseases such as malaria, and tuberculosis have been associated with a lower prevalence of COVID-1946.In this study, the potential effect of meteorological factors on COVID-19 transmission is evaluated in the context of African countries. The global pandemic figures show that Africa as a whole remains largely less affected by COVID-19 in comparison to Europe, America and Asia. Previous studies have suggested that this apparent resilience from Africa can be explained by the youthfulness of its population . The prominent factor appears to be dewpoint temperature (in 10 countries), for which negative associations have been observed in this study but also reported in the literature50. Relative and absolute humidity closely follow, (both occurring in 9 countries), in line with earlier studies52. To a similar extent, solar radiation and average temperature are both reported in 8 countries in this study but also in previous research, for both positive54 and negative52 associations. Finally, to a lesser extent, variables such as rainfall, minimum and maximum temperature appear as the less often occurring factors (in 4 countries)55, and wind speed (in 3 countries), as already observed in previous research56.The role of meteorological conditions of COVID-19 has been investigated in previous research58. Yet, an interesting finding highlighted in this study is the fact that some of the meteorological factors show significant positive and negative associations with COVID-19, in line with the findings of previous studies59. In this study, such variables include rainfall, relative and absolute humidity and solar radiation. In the case of solar radiation, previous research suggests that increased solar radiation reduces the likelihood of airborne persistence of the virus in outdoor environments, decreasing its transmission13; Yet, the positive association of high solar radiation could be explained by the fact that high temperature increases human mobility, resulting in people gathering outside, breaking lockdown measures, therefore increasing the likelihood of transmission60. As for rainfall, relative and humidity, regarding the negative association highlighted in this study, previous research suggests that it can be partly explained by the fact that most people stay home on rainy days, hence decreasing the likelihood of the spread of the disease61. Also, rainfall causes the washout of aerosols, which is known to decrease the residence time of the virus in the atmosphere12. Other studies however explain that at specific ranges of humidity, the virus can remain active for up to 4–5 days on outdoor surfaces, increasing the likelihood of transmission and resulting in positive association to COVID-1963. Overall, the findings in this study shed light on the complex and contrasting effect of meteorological factors on COVID-19 prevalence in Africa, but also that the climate sensitivity of the disease varies greatly in space and is not consistent across all countries. Also, it should be acknowledged that other major factors, such as socio-economic features and immunity of the populations might have a stronger influence on the spread of the pandemic62.Some previous studies also highlighted the major role of average temperature and relative humidity on COVID-19 transmission, which was primarily considered an airborne disease whose transmission might be amplified in humid environments, with low temperatures, less solar radiation and higher wind speed58. We should also indicate that this study focused on the individual effect of climate variables on COVID-19, yet the synergistic effect of all climate variables altogether was not considered, leaving out interaction effects64. Finally, some other shortcomings are the non-consideration of socio-economic factors, healthcare system and other development country-level indicators, and population immunity, which could explain the variation in specific sensitivities of countries to COVID-199. However, in our understanding, such factors are less likely to explain day-to-day variations, which is the target of this study. In this regard, our findings appear to be of importance as they shed light on the contribution of climate to the spread of the pandemic. This, in turn, might help refine further modelling and forecasting attempts, sustain the preparedness of healthcare systems and foster informed management policies.This study highlighted major findings regarding the pandemic spread in Africa: first, the relationship between meteorological conditions and COVID-19 and their time-dependence structure have been explored. The substantial geographical differences in the prevalence have also been highlighted, especially towards the end of the study period, which resulted in a clear clustering in the severity of the disease. However, there are also some limitations which should be acknowledged. First, we should be well aware that all models are as perfect as the data used. Especially in the case of African countries, COVID-19 daily reports tend to be fraught with inaccuracies, especially when testing policies are different or not heavily promoted. Second, the analysis framework used in this study relies on time-series-based modelling, in which case time-dependency structural behaviour can sometimes result in spurious correlations, which should often be treated with caution. It should also be noted that some specific factors were not included in our analysis such as air quality due to the lack of accurate data in the case of Africa. Air quality, especially the concentration of fine particulate matter (PM2.5) has been previously highly associated with COVID-19 in previous large-scale studiesThe data used in this study, regarding both COVID-19, stringency index and meteorological factors, are all available from public databases. Therefore, an ethical review was not required.COVID-196. The time series were treated for inconsistencies, such as decreasing values in cumulative confirmed cases from 1 day to the next (occurring for example for Benin—BEN).In this study, COVID-19 cumulative confirmed cases data were gathered for the study period covering January 1, 2020, to September 30, 2022. The data were automatically collected at the daily timestep and for each African country , using the R package pr), dewpoint temperature (tdew), minimum (tmin), mean (tmoy) and maximum (tmax) temperatures, wind speed (wspd), relative humidity (rh), absolute humidity (ah) and solar radiation (insol), both at the daily timescale. The data for these variables were collected from the so-called “Modern-Era Retrospective Analysis for Research and Applications” (MERRA-265), which is a global climate reanalysis , accessible through the NASA POWER Data Access Viewer (https://power.larc.nasa.gov/data-access-viewer/). The data were automatically collected using the nasapower R package66. The time series were also treated for missing values using spline interpolation. The daily values of absolute humidity (ah) were calculated from the Clausius Clapeyron approximation, as shown in Eq. , defined as a composite mean score of nine pandemic response measures  is systematically considered as a potential covariate for each country’s COVID-19 confirmed cases time series. The si index takes a value between 0 and 100, with a higher score indicating a stricter mitigation response67. The si time series data were collected from Ritchie et al.68.Over the study period, various and different policy responses to COVID-19 have been adopted by countries to contain and mitigate the spread of the pandemic. In this study, as the analysis of the potential effect of climate variables is carried out on a cross-sectional basis, it is critical to isolate the potential effect of such different policy responses from that of the climate variables considered. Therefore, a stringency index  are assessed through the non-parametric Spearman’s rank correlation test  is given by 70. The evaluation of Moran’s I was carried out in this study through the ape R package71 using the inverse Euclidean distance on all pairs of countries’ centroid coordinates to compute the spatial matrix weights.Furthermore, to evaluate the spatial clustering of the pandemic spread at the level of the continent, the spatial autocorrelation in cumulative cases (per million people) at different time points selected within the study period is assessed through Global Moran’s s in Eq. :2\documeThe general workflow of the methodology used to detect the potential association between meteorological variables and COVID-19 is presented in Fig. min–max method, in the 0–1 range  model, which is a common approach used in time series modelling, resulting in the backshift notation presented in Eq.  test  model, which includes exogenous explanatory variables. Previous studies indicate that the effect of climate is not necessarily immediate on COVID-19 transmission, but can typically be lagged by up to 28 days73. Therefore, in this study, for each of the 9 climate variables considered , the time series data collected over the study period is initially screened to filter significant lags (between 0 to 28 days) through pre-whitening. Pre-whitening helps in evaluating at which specific lag a covariate (independent variable) affects a dependent variable74. The steps in the pre-whitening procedure include:i.ARIMA  model to the dependent variable time series and saving the residuals  is true. Here, to account for the length of the time series, which could deflate the reported p-value75 and to provide better estimates , the correlation was assessed through screening of the distribution of 1000 sieve random bootstrap simulations, carried out using the ‘ccf_boot’ command in the R funtimes package77.analyzing the cross-correlation function between the residuals The potential effect of climate variables on COVID-19 confirmed cases is assessed through a variation of the 79.Another major advantage in working with the residuals (from the pre-whitening procedure) is that such residuals are assumed to be independent, while the original meteorological variables are unlikely, since weather systems could persist for many days, therefore reducing the number of degrees of freedom of the time series. This effect is further amplified by seasonal fluctuations, which should be thoroughly addressed when assessing for statistical significance to avoid the detection of spurious correlationsmin–max method  errors is developed using simultaneously the stringency si index time series  and the considered climate covariate. The regression model obtained, hereafter referred to as RegARIMA , is defined as in the backshift notation given in Eq.  model parameters p and q are obtained through maximum likelihood fitting using the auto.arima function provided with the forecast R package72. The Bayesian Information Criterion (BIC) is used to select the optimal model, defined as the one minimizing the BIC72. The definitive optimal and meaningful models are retained based on the following conditions:i.the model residuals are typically similar to white noise: this condition further ensures that the model has captured the maximum variance in the dependent variable . This is assessed through the application of the Ljung-Box Q test (at 80.ii.the climate variable coefficient is significant in the model: this condition is assessed through the Wald t-test of coefficients at lmtest R package81.iii.the climate variable with its actual lag is significantly correlated to COVID-19 cumulative cases: this condition is assessed using the non-parametric Spearman rank correlation test at Further, a regression model with n in Eq. :5\documeSupplementary Information.


In animals, the endocannabinoid system regulates multiple physiological functions. Like humans, animals respond to preparations containing phytocannabinoids for treating several conditions. In Argentina, laws 27350 and 27669 have expanded the possibility of studying beneficial and adverse effects.We conducted a web-based survey of Argentinian Cannabis Veterinarians to make a situational diagnosis on the number of veterinary medicine professionals currently developing treatments with cannabinoids focusing on dogs and cats. Among the species treated, 77% corresponded to dogs, while 21% were cats. Pain, seizures, and behavior disorders are the most prevalent conditions in dogs. Seven conditions and combinations were treated in cats. Full-spectrum cannabis extract derived from three different chemotypes was administered alone or with standard medication. Response to cannabis treatment was characterized based on improvement categorized according to clinical assessment. Both dogs and cats showed different improvement grades in clinical signs.This analysis provides promising results regarding the medicinal use of cannabis in dogs and cats. Based on this analysis, we propose to expand the training of professionals, obtain quality preparations, and initiate controlled trials to reinforce knowledge of the use of cannabinoids in veterinary medicine.The online version contains supplementary material available at 10.1186/s42238-023-00209-5. The endocannabinoid system (ECS), composed of endogen ligands, receptors, and enzymes responsible for their synthesis and degradation, is present in numerous animal species Silver, . The ECSThe ECS plays a role in pathologies that affect other organs and systems, trying to restore homeostasis. Moreover, the ECS can also be dysregulated. Using phytocannabinoids in veterinary medicine may help alleviate symptoms and modify subcellular mechanisms associated with different animal disorders , the use of cannabis and its derivatives for veterinary purposes is not currently regulated. However, in some EU countries, veterinarians may use cannabis products authorized for human use “off-label” in animals. In the United States of America (USA), medical and recreational cannabis is still illegal under federal law, and veterinarians cannot legally prescribe cannabis for animals. Still, they can guide pet owners who consider using it or potentially could test cannabis products authorized for human use “off-label” in animals, following regulations and guidelines. In Canada, cannabis for medical and recreational use was legalized in 2018. Like in the USA, veterinarians cannot legally prescribe cannabis. The Canadian Veterinary Medical Association (CVMA) has issued guidelines for veterinarians on the use of cannabis in animals. In Japan, cannabis and its derivatives are strictly prohibited, and possession or use can result in severe penalties, including imprisonment. The use of cannabis and its derivatives in veterinary medicine is not allowed  and Santa Fe (16%), followed by the Autonomous City of Buenos Aires (CABA) (9.30%) and the rest of the provinces (23.10%) , 21% to cats (n = 24), and 2% to other species (one horse and one turtle). Following, we focused on dogs and cats. In the group of dogs, the most frequent breeds were German Shepherd, Labrador, Dachshund, French Bulldog, Beagle, Cocker, and mixed breeds. In the group of cats, the European Shorthair cat and the Persian and Siamese breeds were the most treated. Both dogs and cats were grouped according to age and the conditions they had. Diseases/conditions were identified through a precise diagnosis based on correct anamnesis and additional tests such as x-rays, laboratory tests, magnetic resonance imaging, and cytology.Figure n = 47) corresponded to animals between 9 and 14 years old. In this group, pain was the most prevalent symptom treated with phytocannabinoids (31 cases). Following that, behavioral disorders (12 cases) and seizures (n = 11) were the most frequent conditions. The remaining disorders/diseases included sequelae of distemper, cancer, senile cognitive dysfunction, dermatopathies, and combinations of two or more conditions. The term “other” included not listed pathologies/conditions in the structured question like obesity, arthrosis, tracheal collapse, intrahepatic shunt and metabolic disorder, and nervous and articular signs of leishmania infection.The upper graph in Fig. Cats received in consultation 24 animals) were distributed over a wide age range similar to dogs  , chemotype 2 was characterized by a similar concentration of both cannabinoids ([THC] = [CBD]), and chemotype 3 presented more CBD than THC ([THC] < [CBD]). Figure n = 14 and 52%, n = 16, respectively), while chemotype 3 was less used . Doses were adjusted throughout treatment in order to observe improvement in clinical signs. The dose range was between 1 and 18 drops/day for chemotype 1, with average values between 6 and 7 drops from the beginning of treatment to 60 days. For chemotype 2, the dose range was between 1 and 12 drops/day, with mean values between 3 and 6 drops. On the other hand, 58% of dogs (n = 7) with behavioral disorders received chemotype 3. Chemotype 1 was used in 33% (n = 4) and chemotype 2 in 8% of patients (n = 1) with this condition. Chemotype 3 was also utilized in 54% of patients with seizures (n = 6). The dose range of chemotype 3 was between 2 and 10 drops/day with mean values of 4 to 6 drops. In cats, chemotypes 1 and 2 were used for various conditions. Behavioral disorders (n = 2) and dermatopathies (n = 2) were preferentially treated with chemotype 3. The dose range for all chemotypes was between one and four drops/day with mean values of two drops.In dogs, 97% of patients with pain were treated with chemotypes 1 and 2  showed mild, 27% (n = 3) moderate, and 37% (n = 4) significant improvement at 15 days of treatment. At 30 days, 50% (n = 4) showed moderate, and at 60 days, 80% (n = 4) exhibited significant improvement  of patients showed significant improvement after 15 days of treatment  showed marked improvement at 15 days  at 15 days and 75% (n = 3) at 30 days  = 3.4862, p = 0.061. Therefore, both chemotypes relieved the symptoms.In order to evaluate whether chemotype 1 or chemotype 2 was the most appropriate for the treatment of pain, we compared the number of animals that showed significant improvement to those that showed mild/moderate improvement after 15 days treated with chemotypes 1 or 2. The relationship between these variables was not significant, The adverse effects reported in dogs were sedation and a case of a paranoid state in a poly-medicated patient with a behavioral disorder. The veterinarian replaced the oil with another one of the same chemotype, and the adverse effect was reversed.Ten cats received cannabis as a single therapy. Diseases included gingivostomatitis, dermatopathies, oncologic disease, pain, asthma, and signs and symptoms produced by two pathologies. Data are shown in Fig. Χ2  = 3.2527, p = 0.3542 for dogs, and Χ2  = 2.7563, p = 0.4307 for cats. According to these data, feeding is not associated with the response during the treatment.Then, we analyzed whether the type of food influenced the improvement in clinical conditions in both groups. Supplemental Table In Argentina, recent regulation of Law 27669 allows the production of medical cannabis and hemp  reduced seizures’ frequency, duration, and intensity in epileptic conditions and minimized behavioral disorders , respectively. Other studies have evaluated the clinical efficacy of CBD-based preparations at doses from 1 to 10 mg/kg/day administered orally. In this survey, doses in the order of micrograms result in an improvement in clinical signs. The positive effect of microdoses has not been reported in veterinary medicine. However, its effectiveness has been observed in humans  and one case of a paranoid state with chemotype 1 (THC-predominant oil); both cases were reported in dogs. Both were reversed by dose adjustment and provision of new preparation. Studies analyzing different doses and preparations with different THC:CBD ratios in dogs indicated that CBD-predominant oils are better tolerated than formulations with higher THC concentrations  education of veterinarians about the function and dysregulation of ECS as medicinal properties of cannabinoids; (2) knowing the origin and composition of the preparations, as well as the relative content of the main cannabinoids and other compounds such as terpenes, flavonoids, and heavy metals, before being applied on patients; (3) initiate treatments with the lowest possible doses, according to scientifically based studies, mainly because the distribution and density of cannabinoid receptors are different in dogs and cats compared to humans; and (4) document beneficial and adverse effects, through rigorous clinical trials testing cannabinoids and placebo, as well as individual case reports. Part of these actions are underway, allowing cannabinoid treatments to be safely applied on a case-by-case basis to improve patients’ quality of life.This survey is the first one conducted in Argentina, and it is exploratory. Possibly, a higher proportion of veterinarians who treat dogs and cats with cannabinoids did not access the online survey. Such restriction might underestimate the number of cases documented. Analysis of cats requires an incremented number of cases to elaborate a robust analysis of the effectiveness of cannabinoids in treatments of the mentioned conditions. This survey presents a situational diagnosis and is not a placebo-controlled study. Analysis of clinical signs not always was standardized for all practitioners. Future studies are needed to analyze specific races and conditions.Additional file 1 : Supplemental Table 1. Doses of main cannabinoids of chemotypes 1 and 2 administered to dogs with pain. Supplemental Table 2. Doses of main cannabinoids of chemotype 3 administered to dogs with behavioral disorders. Supplemental Table 3. Doses of main cannabinoids of chemotypes 1, 2, and 3 administered to cats. Supplemental Table 4. Incidence of food on the response to cannabinoids treatment.


BackgroundThe gold standard management for symptomatic gallstone disease is elective laparoscopic cholecystectomy, which has replaced open cholecystectomy. The wall thickness of the gallbladder is an indicator of cholecystitis in patients who have presented with symptoms of gallstone disease. The aim of this study was to evaluate preoperative gall bladder wall thickness by ultrasonography and assess its impact on the outcome of laparoscopic cholecystectomy, including conversion rate, complications, operative time, and postoperative hospital stay.MethodThis prospective study was conducted on 350 patients with symptomatic gallstone disease, those who had undergone laparoscopic cholecystectomy in Dr. Sampurnanand Medical College, Jodhpur, and attached hospitals from July 2019 to November 2021. On the basis of ultrasonography findings of gallbladder wall thickness, patients were divided into four groups: normal thickness - up to 2 mm, mild thickness - 3-4mm, moderate thickness - 5-6mm, and severe wall thickness - more than 6mm). Up to 2 millimeters thickness was considered as normal.ResultsThe incidence of conversion rate, as well as intra or postoperative complications, were higher in moderate and severe wall thickness groups. The maximum incidence of complication rate is seen in moderately thickened group (33.33%). In severely thickened group, complication was seen in 100% of patients. Operative time, as well as postoperative hospital stay, were more in higher thickness groups. There was a statistically significant correlation between gallbladder wall thickness and conversion rate, complications operative time, and postoperative length of stay.ConclusionIncreased gallbladder wall thickness causes increased intra as well as postoperative complications, more conversion to open procedure rate, increased operative time, and enhanced postoperative hospital stay. Among the total study population, 29.71% of patients had increased gallbladder wall thickness. In our study, a positive correlation was seen among gallbladder wall thickness, complication rate, conversion rate, intraoperative time, and postoperative hospital stay. The gold standard management for symptomatic gallstone disease is elective laparoscopic cholecystectomy, which has replaced open cholecystectomy . The walThis prospective observational study was conducted at Mathura Das Mathur Hospital and Mahatma Gandhi Hospital attached to Dr. Sampurnanand Medical College (SNMC), Jodhpur, Rajasthan, India, from 1 July 2019 to November 2021. This study comprises of a total of 350 cases. This study started after taking permission from the College Institutional Ethical Committee (IEC) (SNMC/IEC/2019/1383-1385 ). Dr. SNMC IEC have access to any information or data of this study.All diagnosed cases of symptomatic gallbladder disease  planned for laparoscopic cholecystectomy were included in this study. The exclusion criteria included deranged coagulation profile (prothrombin time), acute biliary pancreatitis, carcinoma gallbladder, all types of gallbladder polyps, cholangitis, perforated gallbladder, biliary enteric fistula, portal hypertension, peritonitis, and pregnancy. The data was collected as general details of patients, including their name, age, sex, registration number, date of admission, date of operation, and date of discharge. A detailed history of the patient with special emphasis on symptoms of biliary colic, history of previous attacks of colic, jaundice, history suggestive of pancreatitis, etc. History of comorbid conditions, including diabetes mellitus (DM), hypertension (HT), significant illnesses and previous symptoms, general physical examination, and abdominal examination. All patients presented with symptoms suggestive of uncomplicated or complicated gallstone disease - having pain in the epigastrium or right hypochondrium and increased severity after taking food, flatulence, and fever. All patients were thoroughly examined and further evaluated with abdominal ultrasonography by a sonologist. The gallbladder wall thickness was measured at the level of the fundus of the gallbladder along with other parameters of gallstone disease. On the basis of ultrasonography findings of gallbladder wall thickness, patients were divided into four groups: normal thickness - up to 2 mm, mild thickness - 3-4mm, moderate thickness - 5-6mm, and severe wall thickness - more than 6mm). Up to 2 millimeters thickness was considered as normal.Patients who were diagnosed with gallstone disease were advised to undergo laparoscopic cholecystectomy. Those willing to undergo surgery were then divided into four groups on the basis of gallbladder wall thickness. Patients were then planned for laparoscopic cholecystectomy either during the same sitting or different according to patient presentation and preference. Their intraoperative findings, duration of surgery, rate of conversion to open procedure, and length of hospital stay were recorded. Intraoperative and postoperative complications were recorded, and they have been broadly categorized as intraoperative and postoperative complications as adhesions, hemorrhage, common bile duct (CBD) injury, postoperative bile leak, and surgical site infection. Patients were followed up till suture removal or till postoperative day 12. Late complications were not included.In our study, the youngest patient was 18 years of age, and the oldest was 90 years of age. The majority of the patients, 92 (26.29%), were present in the age group of 41-50 years. Forty-one (11.71%) patients were >60 years of age. Maximum complications were present in seven (17.07%) in the >60 age group. The mean age of presentation was 45.01 years. The mean age of males was 46.64 years with a standard deviation of 12.64 years, and the mean age of females was 45.01 years with a standard deviation of 13.97 years.In our study, of the patients who underwent laparoscopic cholecystectomy, 90 (25.71%) were male, and 260 (74.29 %) were female, with a male-to-female ratio of 1:2.8. Complications were present in nine (10%) male and in 12 (4.61%) of female patients.The incidence of conversion seen in the moderately thickened group was 40%. The conversion rate was 100% in the severely thickened group, whereas it was 6.67% in the normal gall bladder wall thickness group. The correlation between gallbladder wall thickness and conversion rate is statistically significant , and the association is positive.Table Complications were seen in a total of 21 patients out of 350 patients (6%), either intra or postoperatively. The incidence of complication rates was 100% in the severely thickened group, whereas it was 33.33% in the moderately thickened group. In the severely thickened group, complications were seen in all patients. The correlation between gallbladder wall thickness and intra and postoperative complications is statistically significant  , followed by the moderately thickened group (89 minutes), and the shortest operative time was seen in the normal group (52.97 minutes). The correlation between gallbladder wall thickness and mean operative time is statistically significant.Maximum postoperative hospital stay was seen in the severely thickened group , followed by the moderately thickened group (4.8 days), and the shortest mean postoperative hospital stay was seen in the normal gallbladder wall thickness group . The correlation between gallbladder wall thickness and mean postoperative hospital stay is statistically significant .Table Currently, laparoscopic cholecystectomy is the gold-standard surgical procedure for gallstone disease. Although a minority of them still convert to open procedures due to impaired visualization of surgical anatomy due to inflammation, dense adhesions, abnormal anatomy, or any other region. Few of them have intra or postoperative complications. Identification of predictive factors of conversion and complications can be beneficial to both surgeon as well as for patient outcomes. As far as demographics were concerned, the male-to-female ratio (M:F) in our study was 1:2.8, which is similar to an Indian study by Chandra et al. in which the sex ratio was 1:1.64 . This isMany preoperative factors have been identified in the literature for the prediction of impact on laparoscopic cholecystectomy, but gallbladder wall thickness is a very important factor for laparoscopic cholecystectomy. The cutoff value for gallbladder wall thickness is 2 millimeters which is measured by ultrasonography by an expert radiologist.As per the results of the present study, the thicker the gallbladder wall, the greater the risk of conversion to open procedure and increased risk of intra as well as postoperative complications. Similarly, it increases operative time as well as the total duration of hospital stay.The overall conversion rate to open procedure was 4.28%. It is slightly less than the reported literature; 5-10%  and simiThe overall complication rate in the present study was 6%, which included both intra and postoperative complications. Postoperative complications were more prevalent than intraoperative complications. The incidence of postoperative complications was 4%, which is slightly less than the available literature . The mosOperative time and postoperative length of stay were more criteria that were included in the present study. The lowest mean operative time was seen in the normal wall thickness group; 52.97 minutes with SD of 9.27 minutes. The mean operative time increased with increasing gallbladder wall thickness; this is similar to the literature .Another criterion that was included in this study was the postoperative length of stay as a measurement of outcome after surgery. The mean postoperative time was the lowest in the normal gallbladder wall thickness group, 2.8 days with SD of 1.45 days, and the highest in severely thickened group, 11 days with SD of 10.12 days. The contributory factors for increasing length of stay were postoperative bile leak, postoperative pain, and surgical site infection. The postoperative length of stay is slightly higher than the reported literature .There were a few limitations of this study; one of them was the timing of ultrasonography (USG). In some patients, USG was done in an elective setting, and in some, it was done in an acute setting in an emergency when the patient presented with acute abdominal pain in case of cholecystitis. Ultrasonography itself is a highly subjective investigation, although it was done by a single expert radiologist.There can be discrepancies in acute settings about the line of management; it could be prudent to wait for surgery in case of acute cholecystitis to avoid complications, but no proven study is yet available for this; it depends on the operating surgeon's experience.Increased gallbladder wall thickness increases intra as well as postoperative complications, more conversion to open procedure rate, and increases operative time as well as the postoperative hospital stay. Among the total study population, 29.71% of patients had increased gallbladder wall thickness. In our study, a positive correlation was seen among gallbladder wall thickness, complication rate, conversion rate, intraoperative time, and postoperative hospital stay. An accurate preoperative or intraoperative diagnostic tool is mandatory for planned gallbladder surgery to provide information and to predict the outcome of laparoscopic cholecystectomy.Ultrasonography is a highly subjective imaging modality, but with the availability of an expert radiologist, an assessment of gallbladder wall thickness was done at an accurate level. More than 2 mm gallbladder wall thickness was considered significant, and all findings were significantly high in these groups. It appears that gallbladder wall thickening is the best predictor for outcome following laparoscopic cholecystectomy.


The Bradost and Chinara mountains are two well-known geomorphic features in the Iraqi Kurdistan Region (IKR), forming two anticlines, besides Shireen and Sare Musa anticlines, which are located north of the Bradost anticline, all four anticlines trend NW – SE. The four anticlines are dissected by the Greater Zab River that swings along its course within the anticlines due to tens of very old landslides and/or plunges. The four studied anticlines are dissected by different thrust faults, which extend for a few kilometers. The thrust faults trend NW – SE; however, locally they deflect from the main trend. The Lower Jurassic rocks are the oldest exposed rocks in the studied area, whereas the rocks of the Bekhme Formation form the carapace of the Bradost and Chinara anticlines. Different structural and geomorphological features were interpreted from satellite images and those which are accessible were checked in the field, all of them indicate the four anticlines exhibit lateral growth. We have measured different aspects to elucidate the type of folds. The four anticlines are Detachment folds, with shallow decollement, which ranges in depth between (100–250) m. The IKRApart from the Chinara anticline, the other three anticlines have very anomalous shapes, which fairly resemble the normal anticlinal shape, the Chinara anticline; however, also exhibit anomalous shapes but are not extensive as the other three anticlines. The anomalous shapes are attributed to: 1) intensive thrusting of an anticline over an adjacent anticline leading to the disappearance of the syncline in between them, or even one limb over the other leading to the disappearance of the axial part of the anticline, 2) presence of rock with various competencies, 3) en-echelon plunging, 4) extensive erosional and karst forms, 5) development of different valley shapes, 6) development of very deep water and wind gaps, 7) development of steep and high ridges, and 8) different mass movement phenomena along the limbs of the anticlines. According to Burbank and Anderson ; Blanc e2, and it can be reached via Erbil and Duhok cities.The studied area is located in the central northern part of the Iraqi Kurdistan Region . The stuThis study aims to deduce the structural and geomorphological status of the Bradost, Chinara, Shireen, and Sare Musa anticlines. Moreover, to update the structural forms of the concerned anticlines.2We have interpreted satellite images, used geological maps , and revWe also have added some uncommon symbols directly on some images to clarify the used symbols; like karstified area, old landslide, hanging syncline … etc. Moreover, we have conducted field visits to the accessible parts to check the interpreted data. The studied area is characterized by a very steep and rugged topography, which makes a large obstacle for field checks, besides the presence of thousands of mines, which were haphazardly distributed during many past decades and form a true challenge for fieldwork.From the reviewed published articles and books, we have adopted the opinions of different researchers when we recognized significant structural and geomorphological forms and features based on ,, We havThe dip amount was calculated by equation  A and B , D is thThe IFS is calculated by Ref.  equationThe AR is calculated by Ref.  Fig. 3)Fig. 3) eThe Smf is calculated by Ref.  equatione length . Table , whereas the lowest point is at the merging point of the Rawandouz River with the Greater Zab River, which is about 402 m (a.s.l.) . The stuHogbacks are developed locally; for example, within the rocks of the Shiranish Formation along the northeastern limb of the Bradost anticline . KarstifFor the location, refer to A very special case is recognized, where the slid mass has moved up to the southwestern limb of the Shireen anticline crossing the Greater Zab River, which flows now in the opposite direction of the slid mass . Some ro3.2The studied area is within the High Folded Zone (HFZ) which is part of the Zagros Fold – Thrust Belt and the HFZ covers the northeastern part of the Arabian Plate . All antThe four folds are formed like those in the competent group of the Zagros Simply Folded Belt (HFZ in Iraq), they are formed by buckling and developed by a combination of flexural-slip and neutral-surface . In the The four studied anticlines show many thrust faults , Fig. 9,Normal faults also occur along the Bradost anticline and the plunge area of the existing syncline between the Chinara and Pirat anticlines . Domes w3.3The exposed formations in the studied area are presented in the geological map , whereas4From the interpretation of satellite images, reviewing geological maps, and field investigation, we have acquired the following data about the four studied anticlines.4.1The Bradost anticline is a double plunging anticline trending NW – SE with a length of 47.8 km and width of 9.39 km, it is worth mentioning that the true width can be measured only in one locality , Fig. 12According to Burberry et al. , the AspDifferent geomorphological forms were interpreted along the Bradost anticline and some of them were checked during field investigations, like: Water gaps, wind gaps, flat irons, abandoned alluvial fans, inclined valleys, radial valleys, cross-shaped valleys, fork-shaped valleys , Fig. 144.2The Chinara anticline is a double plunging anticline with an NW – SE trend, a length of 53.1 km, and a width of 5.84 km . The souDifferent geomorphological features were interpreted along the Chinara anticline and some of them were checked during field investigations, like: Water gaps, wind gaps, flat irons, abandoned alluvial fans, inclined valleys, radial valleys, fork-shaped valleys , Fig. 104.3The Shireen anticline is a double plunging anticline trending NW – SE with a length of 37.7 km and a width of 5.46 km . The souDifferent geomorphological features were interpreted along the Shireen anticline and some of them were confirmed during field investigations, among them are: Water gaps, wine glass form, hogbacks, inclined valleys, and fork-shaped valleys , Fig. 8,4.4The Sare Musa anticline was not named in all existing geological maps; therefore, we used this name based on the highest peak's name on the top of the anticline. The Sare Musa anticline is a double plunging anticline with an NW – SE trend, a length of 32.2 km, and a width of 3.24 km . The souDifferent geomorphological features were interpreted along the Sare Musa anticline, among them are: Water gaps, and fork-shaped valleys , Fig. 8,5The Bradost, Chinara, Shireen, and Sare Musa anticlines were studied using satellite images to interpret and deduce the structural and geomorphological characteristics, some of the interpreted forms (which are accessible) were checked in the field. Accordingly, we have found a lot of data that were not shown in the geological map . This isThe four studied anticlines are Detachment Folds a, as theThe four studied anticlines exhibit thrust faults , Fig. 14The presence of water gaps, wind gaps, differently shaped valleys, and domes are all good indications that the four studied anticlines are exhibiting lateral growth . AbandonAccording to Sepehr and Cosgrove , the geoMoreover, the sinuosity index (Smf) can be used to indicate the relative ages of folds, a higher sinuosity measurement implies a heavily incised fold front and thus an older fold structure . The reLandslides were recognized at different parts of the four studied anticlines , Fig. 17Other geomorphological forms which were recognized are hogbacks and whaleback anticline, like in a part of the Bradost anticline , Fig. 8,The values of the Smf index are divided into three classes: Class 1) High, Smf = 1.0 to 1.5, Class 2) Moderate, Smf = 1.5 to 2.5, and Class 3) Low, Smf > 2.5 . Therefo6The studied Bradost, Chinara, Shireen and Sare Musa anticlines are Detachment folds; as indicated by their measured aspect ratio, fold symmetry index, hinge length, length, and width of the anticlines. The measured Smf values indicate that the Chinara and Shireen anticlines exhibit High tectonic activity, whereas the Bradost and Sare Musa anticlines exhibit Moderate tectonic activity. The recognized geomorphological forms  and structural forms (domes and en-echelon plunges) indicate that all four studied anticlines are laterally growing, and the stream incision rates are larger than the fold growth rates. Different mass movement phenomena have recognized majority are very old; however, recent, and active mud flows were recognized in the southeastern plunge area of the Chinara anticline. Other phenomena are old landslides, rock fall, and mud flow. Severely karstified large areas were recognized on the top of Shireen and Sare Musa anticlines.Varoujan K. Sissakian; Ala A. Gahfur; Nadhir Al-Ansari: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Hassan O. Omer; Hawkar A. Abdulhaq: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.10.13039/501100007781UKH to perform the field work, no other fund was received by the authors to perform this research work.Apart from the provided logistics by Data will be made available on request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE.A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test.p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61).Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban. Venous thromboembolism (VTE) is characterized by the obstruction of venous blood flow due to the formation of a thrombus, either in the lungs, known as pulmonary embolism (PE), or in the lower or upper extremities, referred to as deep vein thrombosis (DVT) . VTE hasVitamin K antagonists, such as warfarin, were once widely used for VTE treatment . HoweverClinical trials have demonstrated a superior profile of efficacy and safety in terms of mortality and the risk of bleeding events for DOACs compared to warfarin , 8, inclAn observational analytical study was conducted at a single center, using propensity score matching analysis, involving patients with VTE who were treated with warfarin or rivaroxaban at Clínica Universidad de La Sabana in Chía, Colombia, between August 2009 and January 2020.Male and female individuals over 18 years of age who were prescribed warfarin or rivaroxaban for the treatment of DVT or PE were included. Patients with aortic aneurysms, suspected vascular lesions, non-traumatic aortic pathology, acute aortic syndrome, or pregnancy were excluded. Additionally, patients who received concurrent treatment with both warfarin and rivaroxaban and lacked medical history information, inaccessible radiology reports, or telephone follow-up were also excluded.VTE was defined as a confirmed diagnosis of PE through a positive radiological report of pulmonary artery computed tomography angiography, patients with a high probability report of ventilation/perfusion scintigraphy for PE, or a confirmed diagnosis of DVT through a positive report of lower extremity venous doppler performed by a radiologist.The study included variables such as age, gender, comorbidities, symptoms, physical examination findings, D-dimer levels, troponin levels, echocardiogram results, chest X-ray, pulmonary artery computed tomography, venous doppler ultrasound of the lower extremities, need for mechanical ventilation, and admission to the intensive care unit. The primary outcome was measuring survival at 6 and 12 months through investigator-conducted telephone follow-up. Secondary outcomes included the occurrence of major bleeding at 12 months and the appearance of a new episode of VTE during follow-up, determined according to the previously mentioned VTE definition.Major bleeding was defined based on the criteria set by the International Society on Thrombosis and Haemostasis (ISTH): clinically evident bleeding with a decrease in hemoglobin of > 2 g/dL within a 24-hour period, transfusion of 2 or more units of packed red blood cells, fatal bleeding, and bleeding occurring in any of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, and retroperitoneal .Patients were followed from the initiation of anticoagulant therapy until the occurrence of the primary outcome, loss to follow-up, or completion of the study. Those patients who did not complete the 12-month follow-up were not excluded from the overall analysis but were censored in the survival analysis. Data collection from medical records was conducted by trained pairs of researchers. The researcher responsible for data analysis was not involved in data collection, and propensity score matching was used to reduce confounding bias.We determined the sample size based on the results of the study by Dennis et al. , which rp-value < 0.05 was considered [Data from medical records were collected using the electronic data capture software RedCap , 14 and nsidered .p-value was < 0.05.We selected independent variables with biological plausibility and statistically significant differences in both intervention groups for propensity score matching. A model was created using logistic regression with the intervention variable as the dependent variable and the predefined variables as the independent ones . Using tp = 0.02); inconsistent data were observed in the matched population. General characteristics are presented in Table From an initial group of 2193 patients with suspected VTE who were potentially eligible, 505 patients were included in the analysis. Of these, 285 patients received Warfarin treatment, while 220 patients were anticoagulated with Rivaroxaban. In the unmatched population, the average age was 59.9 years (SD: 19.41), and 56.0% (283/505) were males. Similar data were observed in the matched group, with an average age of 60.8 (SD: 19.21) and 57.9% (242/418) males. In the unmatched population, dementia occurred in 3.6% (8/220) of patients on Rivaroxaban compared to 0.7% (2/285) in the Warfarin group (p = 0.11) Table Chest pain was reported by 27.7% (61/220) of patients receiving Rivaroxaban, compared to 34.3% (98/285) of patients receiving Warfarin in the unmatched population (p = 0.001) Table p = 0.001).In terms of clinical outcomes, major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.76)   in patients treated with rivaroxaban compared to those treated with warfarin . SimilarA strong causal association between the use of Rivaroxaban and the development of dementia has not been established , 22. LinThe relationship between the use of anticoagulants like Rivaroxaban and dementia may be associated with the risk of significant intracranial bleeding, which, in turn, could lead to a negative impact on cognitive function, especially in elderly patients –24. In oAmong the limitations of the study, the exclusive inclusion of patients from a single hospital stands out, which limits the generalization of the results to other populations. The quality of information in an observational study relies on the contents of the medical records and the competence of the research team in extracting this data. However, the researchers are adequately medically trained to ensure precise data interpretation and collection.The study was conducted in a highly complex institution, which carried a substantial risk of selection and prevalence bias. This is because patients with severe thromboembolic diseases might pass away prior to receiving oral anticoagulation therapy, which would exclude them from the study. This could, in turn, increase the inclusion of subjects with milder diseases, significantly affecting the mortality rate in a biased manner. Nonetheless, the study boasts a sufficient sample size for comparative analysis. Another limitation was the lack of monitoring of prothrombin time and international normalized ratio (PT/INR) values for patients in the warfarin group, which is a crucial covariate for measuring the risk of bleeding. Additionally, deaths occurring during enoxaparin bridging therapy in patients on warfarin were not considered, leading to an immortal time bias. To mitigate this bias, the start date of follow-up was chosen as the commencement of anticoagulant treatment.Our findings suggest the possibility of future studies assessing the economic implications of rivaroxaban compared to warfarin in VTE patients in the Colombian population.In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban compared to warfarin.


ACTB, IL6), training AE , PI (EZH2), acute AE combined with PI (DDIT3), and training AE combined with PI (MYC). Both FOS and MYC were upregulated in response to acute AE, and they were, respectively, downregulated by higher PI and a combination of AE and PI. COL1A1 was upregulated by training AE but was downregulated by higher PI. Results from the gene set enrichment analysis (p < 0.05 and FDR < 25%) showed that AE and PI delivered their impacts on human skeletal muscle in analogous pathways, including aerobic respiration, mitochondrial complexes, extracellular matrix (ECM) remodeling, metabolic process, and immune/inflammatory responses, whereas, PI may attenuate the response of immune/inflammation and ECM remodeling which would be promoted by AE, irrespective of its types. Compared to PI alone, acute AE combined with PI would further promote protein turnover and synthesis, but suppress skeletal muscle contraction and movement.This study aimed to provide a more comprehensive molecular insight into the effects of aerobic exercise (AE), protein intake (PI), and AE combined with PI on human skeletal muscle by comparing their transcriptomic profiles. Fourteen published datasets obtained from the Gene Expression Omnibus (GEO) database were used. The hub genes were identified in response to acute AE ( Muscle metabolism plays an essential role in the genesis of many pathologic conditions and chronic diseases . SarcopeExercise could help preclude the pathophysiological processes of muscle mass and function, and prevent or delay the development of sarcopenia ,7,8. Con2max, and stimulation of lean mass accretion have also been reported [Nutritional interventions have also been recommended as a non-negligible option to preserve muscle mass and function ,29,30,31reported ,40,41. Hreported ,43,44,45NR4A3) and SMAD Family Member 3 (SMAD3) were identified as two of the most exercise- and inactivity- and acute- and training-responsive genes, respectively [More evidence is needed to identify whether AE or and its combination with PI could also be effective interventions for improving human skeletal muscle health. Understanding the key molecular signature characteristics underlying responses to these interventions may bring some new hints. Transcriptomic analysis can provide a unique microscopic insight to access the directions of adaptive changes and predict the underlying mechanisms. Previous studies have used transcriptomic analysis to summarize the overlap and the difference of human skeletal muscle in response to RE, AE, acute exercise, training exercise, and inactivity/disuse ,40,41. Nectively ,41. The Thus, the present study aimed to highlight the divergent transcriptomic responses of human skeletal muscle to AE, PI and their combinations, and to provide more molecular evidence of these interventions for maintaining muscle health and alleviating sarcopenia.The Gene Expression Omnibus (GEO) database  was searTo minimize the heterogeneity across the multiple microarray platforms, quantile normalization and log 2 transformations were used for each microarray expression matrix data. If more than one probe was used for the gene detection, the probe with the maximal average expression would be taken. Whereas, if a probe was used for more than one gene, the probe would be discarded due to its low specificity. If multiple categories were used to assess the degree of PI, the category with the highest degree would be chosen to compare with the one with the lowest degree.p value less than 0.05 in DEA were identified as the DEGs. These DEGs with a threshold of log2 Fold Change (log2FC) above 0 were considered to be upregulated, while those with log2FC less than 0 were downregulated.Differential expression analysis (DEA) was performed using the Benjamini–Hochberg (BH) correction for paired samples using the limma package in R (version 4.2.0) . The genThose DEGs which were identified in two or more datasets were labeled as co-differentially expressed genes (co-DEGs). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify the biological functions and potential pathways of the co-DEGs. The bioconductor package “org.Hs.eg.db” and the “cluster profiler” package  were usehttps://cn.string-db.org/, accessed on 26 December 2022, version: 11.5). The gene with the top degree value calculated by CytoHubba plugin [Subsequently, all the co-DEGs were used to construct a gene expression network to find the interactions among these genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) Database  less than 25%.GSEA among different interventions was further performed to explore genome-wide expression profiles within each dataset, without setting up an arbitrary threshold. This would provide an alternative way to screen out obvious differential biological functions induced by varied interventions within each dataset. GSEA was performed using the “cluster profiler” package. The number of permutations was set up at 10,000. Gene set was considered to be significantly enriched when the absolute value of normalized enrichment score (NES) was more than 1 with a There were fourteen datasets included in the present study . Those wThe details of the number of DEGs from each dataset and co-DEGs among different populations across interventions were summarized . CompareNR4A3), Pyruvate Dehydrogenase Kinase 4 (PDK4), PPARG Coactivator 1 Alpha (PPARGC1A) were consistently upregulated in response to acute AE (MIR206), and Circadian-Associated Repressor of Transcription (CIART) were the most downregulated co-DEG in response to acute AE in the YM and the OM, respectively (The top five up- and down-regulated DEGs within each dataset and co-DEGs within each intervention among different populations in response to varied interventions were summarized . Nuclearacute AE . These gectively .SCD), Rho GTPase Activating Protein 12 (ARHGAP12), and Asporin (ASPN) were the most upregulated genes in response to training AE in the YM, the OM, and the older female (OF), respectively (ANKRD2), G Protein-Coupled Receptor 37 (GPR37), and Establishment of Sister Chromatid Cohesion N-Acetyltransferase 1 (ESCO1) were the most downregulated co-DEGs in response to training AE in the the YM, the OM, and the OF, respectively (Stearoyl-CoA Desaturase (ectively . Ankyrinectively .C10orf126), Secretoglobin Family 2A Member 2 (SCGB2A2), and EPH Receptor A2 (EPHA2) were the most upregulated co-DEGs in response to PI in the YM, the OM, and the OF, respectively (LOC654780), Adhesion G Protein-Coupled Receptor G2 (ADGRG2), and Mannose Binding Lectin 2 (MBL2) were the most downregulated genes in response to PI in the three groups, respectively (FOS was significantly downregulated in response to PI but was upregulated in response to acute AE.Chromosome 10 Open Reading Frame 126 (ectively . Splicinectively . NoteworIFRD1) and DNA Damage Inducible Transcript 3 (DDIT3), were consistently upregulated in response to acute AE combined with PI. Protein Phosphatase 1 Regulatory Subunit 15A (PPP1R15A) was the most downregulated co-DEG in response to acute AE combined with PI. What is noteworthy is that some immune/inflammation-related genes such as C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Receptor 7 (CXCR7) were downregulated in response to acute AE combined with PI (COL1A1) and Collagen Type III Alpha 1 Chain (COL3A1), were downregulated both in response to PI and acute AE combined with PI  and Solute Carrier Family 13 Member 2 (SLC13A2), respectively. They were reported to be related to the negative regulation of cell proliferation and the formation of kidney stones, respectively (The top upregulated and downregulated genes in response to training AE combined with PI were CCR4-NOT Transcription Complex Subunit 7 (ectively .ACTB) and Interleukin 6 (IL6) were the hub genes in response to acute AE in the YM and the OM, respectively. Ubiquitin B (UBB) and COL1A1 were the hub genes in response to training AE in the YM and the OF, respectively. The enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), DDIT3, and MYC Proto-Oncogene (MYC) were the hub genes in response to PI, acute AE combined with PI, and training AE combined with PI in the YM, respectively (A minimum interaction score of 0.4 was set up for the gene expression network construction in the STRING database using the identified co-DEGs. The degree value was calculated and the top five genes were summarized for each network . Actin Bectively .FOS, MYC, and COL1A1 identified above were upregulated by acute AE and training AE, but were downregulated by PI and acute AE combined with PI (FOS, MYC, and COL1A1 were higher in acute AE and training AE but lower in the PI-related studies, although statistical significance was not shown in all comparisons ( with PI . Subsequparisons .GO terms and KEGG pathways enrichment analysis were conducted to explore the biological functions of the co-DEGs. For acute AE studies, co-DEGs were mainly enriched in the terms related to starvation, peptide hormones, protein turnover and synthesis, cellular response to external stimuli, and the circadian regulation of gene expression . The AGEFor PI in the OM, the most significant GO term was the positive regulation of vasoconstriction . No GO tConsistent results were shown across the studies of acute AE. The gene sets which were significantly upregulated in response to acute AE included the cellular response to external stimuli, regulation of fatty acid oxidation, energy metabolic process, ECM remodeling, vasculature development, skeletal muscle development, and immune/inflammation process .Compared to acute AE, more profound transcriptomic changes in the ECM remodeling and immune/inflammation process were observed in response to training AE in the older people. Gene sets related to extracellular stimuli, protein turnover and synthesis, and angiogenesis regulation were not significantly enriched in response to training AE . CompareGene sets in relation to aerobic respiration, mitochondrial complex, and electron transport complex were upregulated in response to PI in the older people . Notablyp > 0.05, FDR > 25%, Contrary to AE alone, gene sets associated with the immune/inflammation process, ECM remodeling, cellular response, muscle organ development, renal system development, and regulation of vasculature development were downregulated in response to acute AE combined with PI, which were opposite to their responses to AE alone . No geneKEGG gene sets’ enrichment analysis revealed that the oxidative phosphorylation pathway was consistently upregulated both in response to acute AE and PI . Pathwayp > 0.05, FDR > 25%, Gene sets concerning the olfactory transduction pathway were upregulated both in response to PI and acute AE combined with PI . Gene seACTB, IL6, UBB, COL1A1, EZH2, DDIT3, MYC was the hub gene in response to acute AE in the YM and the OM, training AE in the YM and the OF, PI in the YM, acute AE combined with PI in the YM, and training AE combined with PI in the YM, respectively. FOS was upregulated in response to acute AE but was downregulated in response to PI and acute AE combined with PI. MYC was upregulated in response to acute AE while it was downregulated in response to AE combined with PI. COL1A1 was upregulated in response to training AE while it was downregulated in response to PI.The transcriptional profiles of human skeletal muscle in response to AE, PI, and AE combined with PI were analyzed in the present study. AE and PI may deliver impacts on human skeletal muscle in several analogous pathways, which included aerobic respiration, mitochondrial complexes, ECM remodeling, energy metabolic process, and immune/inflammatory responses. However, compared to PI, AE have an opposite impact on ECM remodeling and immune/inflammation process. Compared to PI, acute AE combined with PI may have additional impact on upregulating protein turnover and synthesis and downregulating musculoskeletal movement and muscle contraction. Few gene set was enriched in response to training AE combined with PI, which suggested that the limited observed biological impact on skeletal muscle induced by additional PI based on training AE.The shared biological pathways and the overlap genes identified to acute AE and PI implied the molecular responses of muscle to them were not separate. The upregulated gene sets with both acute AE and PI alone were related to ATP synthesis and energy metabolic. AE could improve body metabolism by optimizing global energy expenditure and activating multiple neuroendocrine pathways , while mThe downregulation of immune/inflammation molecular process was identified both in response to PI and acute AE combined with PI in the present study, which was consistent with the reports in the previous RCTs ,66. AlthThe transcriptomic profile in response to acute AE combined with PI was comparable to PI alone, which may be due to the fact that the impact induced by acute AE had been offset in the combined intervention studies, where acute AE was always assigned to the control group. Meanwhile, the downregulation of skeletal muscle contraction, musculoskeletal movement, and muscle system development were found in response to acute AE combined with PI, which was contrary to the responses to AE alone. Thus, the additional impact may be induced by the combination of PI and AE. Postexercise PI, which may provide the most efficient gains in muscle plasticity and support myofibrillar protein synthesis as key components in defining contractile performance in response to AE . ProteinACTB are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling, which helps organize and maintain the cellular morphology by virtue of facilitating the processes of migration, division, growth, signaling and shaping the cytoskeleton [ACTB might participate in the mechanism of vascular remodeling and thrombogenesis [IL6 encodes a cytokine that functions in inflammation, maturation of B cells, tissue regeneration, and metabolism, which was consistent with the upregulation of the inflammation/immunity process in response to acute AE. FOS plays an important role in the gene interaction network of muscle in response to acute AE both in the YM and the OM, and it was the gene which was most upregulated in response to acute AE but was downregulated in response to PI and acute AE combined with PI. As a regulator of cell proliferation, differentiation, and transformation, FOS was involved in multiple inflammation pathways [DDIT3 is implicated in adipogenesis and erythropoiesis, is activated by endoplasmic reticulum stress, promotes apoptosis, and plays a crucial role in endoplasmic reticulum stress-induced apoptosis and autophagy, host innate immunity repression, and viral infection facilitation [skeleton . Meanwhiogenesis . As the pathways , which wlitation .Different from the response to acute AE, a cluster of ATP-metabolic-processes-, oxidative-phosphorylation-, aerobic-respiratory-, fatty-acid-oxidation-and-transport-, and mitochondrion-related complexes were downregulated in response to training AE in the YM but not in the elderly. The training volume may critically affect the changes in mitochondrial content, whereas exercise intensity may play a more important role in the changes of mitochondrial function . TraininInconsistent findings were reported for the response of protein turnover and protein synthesis rate to AE combined with PI ,37,45,85UBB encodes ubiquitin, which is involved in targeting cellular proteins for degradation by the 26S proteosome and the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Previous studies suggested AE training prevents oxidative stress and ubiquitin-proteasome system overactivity and reverse skeletal muscle atrophy [COL1A1, which was related to ECM collagen synthesis [MYC was significantly upregulated in response to acute AE in the younger male but downregulated in AE combined with PI, which has a widespread impact on the transcriptome including regulation of cell growth arrest and adhesion, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function [MYC was suggested to be associated with insulin sensitivity [ atrophy . Exercisynthesis . As the function . Moreovesitivity , which mThe strength of the present study was that this is the first study to compare the transcriptomic profiles of human skeletal muscle in response to AE, PI, and AE combined with PI. The findings provided the molecular evidence to support the positive role of PI in addition to acute AE, but limited molecular evidence was found for training AE combined with PI. This would help provide molecular hints for developing optimal measures to promote muscle health. The present study had some limitations. Firstly, there were heterogeneities among the five groups of intervention, such as the type and duration of AE, the dose and content of PI, which may had a profound impact on the transcriptomic changes and bias the comparisons. Secondly, demographic characteristics were not adjusted for in the comparison across varied interventions. Moreover, no blank control group was set in the studies of the intervention of AE combined with PI, which limited the power to assess the interaction effect of AE and PI.The present study suggested that human skeletal muscle may respond to AE and PI in analogous molecular pathways but the responses may differ in direction. PI and additional PI based on acute AE may attenuate the immune/inflammation response and ECM remodeling which would be promoted by AE, irrespective of the type of AE, age and gender. Compared to PI alone, acute AE combined with PI would further promote protein turnover and synthesis, but may suppress skeletal muscle contraction and movement. The molecular impact on human skeletal muscle delivered by training AE combined with PI was not significant. Further studies exploring on the optimal dose of PI in combination with AE for synergic effects are needed.