A study on selected responses and immune structures of broiler chickens with experimental colibacillosis with or without florfenicol administration.

BACKGROUND: Colibacillosis in broiler chickens is associated with economic loss and localized or systemic infection. Usually, the last resort is antibacterial therapy. Insight into the disease pathogenesis, host responses and plausible immunomodulatory effects of the antibacterials is important in choosing antibacterial agent and optimization of the treatment. Selected responses of broiler chickens experimentally infected with Escherichia coli (E. coli) and also those treated with florfenicol are evaluated in this study. Chickens (n = 70, 5 weeks old) were randomly assigned to four groups. The control groups included normal control (NC) and intratracheal infection control (ITC) (received sterile bacterial medium). The experimental groups consisted of intratracheal infection (IT) that received bacterial suspension and intratracheal infection with florfenicol administration (ITF) group. RESULTS: Florfenicol reversed the decreased albumin/globulin ratio to the level of control groups (p > 0.05). Serum interleukin 10 (IL-10) and interferon-gamma (IFN-γ) concentrations decreased in IT birds as compared to NC group. Florfenicol decreased the serum interleukin 6 (IL-6) concentration as compared to IT group. Milder signs of inflammation, septicemia, and left shift were observed in the leukogram of the ITF group. Florfenicol decreased the severity of histopathological lesions in lungs and liver. Depletion of lymphoid tissue was detected in spleen, thymus and bursa of IT group but was absent in ITF birds. The number of colony forming units of E. coli in liver samples of ITF group was only slightly lower than IT birds. CONCLUSIONS: Experimental E. coli infection of chickens by intratracheal route is associated with remarkable inflammatory responses as shown by changes in biochemical and hematological parameters. Histopathological lesions in lymphoid organs (especially in the spleen) were also prominent. Florfenicol has positive immunomodulatory effects and improves many of the lesions before the full manifestation of its antibacterial effects. These effects of florfenicol should be considered in pharmacotherapy decision-making process.

The Effects of Resveratrol, Gallic Acid, and Piperine on the Expression of miR-17, miR-92b, miR-181a, miR-222, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA in Human Acute Myeloid Leukemia Cells and Their Roles in Apoptosis.

MicroRNAs (miRs) play a crucial role in the leukemogenesis and the prognosis of acute myeloid leukemia (AML). This study investigated the therapeutic effects of resveratrol, gallic acid, and piperine as natural anticancer agents on the HL-60 cell line and their roles in apoptosis. In this experimental study, quantitative analysis of miRs, including miR-17, miR-92b, miR-181a, and miR-222, were performed in 150 newly diagnosed patients with AML by real-time PCR assay. HL-60 cell viability as well as the expression of miRs, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA, were also assessed after transfection with the LNA-miRs and treatment with resveratrol, gallic acid, and piperine. The expression of miR-17 and miR-181a decreased significantly in LNA-anti-miRs. Although HL-60 cell viability decreased in LNA-anti-miR-222, miR-17, and miR-92b, blockade of miR-181a increased the cell viability. Besides, the cell viability increased merely in the piperine-treated group. Compared to untreated cells, miR-17 and miR-92b expression significantly increased in gallic acid- and resveratrol-treated cells. In HL-60 cells treated with resveratrol, gallic acid, and piperine, the expression of miR-181a was also increased significantly. The expression of BAX was also increased in resveratrol and piperine-treated groups. Compared to untreated cells, the expression of c-Kit increased significantly in the piperine-treated group; however, it decreased in the resveratrol-treated group. LNA-anti-miRs may be a promising agent for the treatment of AML. All three compounds used in this study showed anticancer effects, which can exert the desired outcome in patients with AML.

Incidence and pattern of traumatic spine injury in a single level I trauma center of southern Iran.

PURPOSE: Spine injury is one of the leading causes of death and mortality worldwide. The objective of this study was to determine the incidence, pattern and outcome of trauma patients with spine injury referred to the largest trauma center in southern Iran during the last 3 years. METHODS: This is a cross-sectional study conducted between March 2018 and June 2021 in the largest trauma center in the southern Iran. The data collection form included the age, sex, injury location (cervical, thoracic, and lumbar), cause of injury (traffic accidents, falls, and assaults), length of hospital stay, injured segment of spine injury, severity of injury, and outcome. Statistical analyzes were performed using SPSS software version 24. RESULTS: Totally 776 cases of spine injury were identified. The spine injury rate was 17.0%, and the mortality rate was 15.5%. Cervical spine injury (20.4%) more often occulted in motorcycle accident, and thoracic spine injury (20.1%) occulted in falls. The highest and lowest rates of spine injurys were related to lumbar spine injury (30.2%) and cervical spine injury (21.5%), respectively. There was a statistically significant relationship between the mechanism of injury and the location of spine injury (p < 0.001). And patients with lumbar spine injury had the highest mortality rate (16.7%). Injury severity score (OR= 1.041, p < 0.001) and length of stay (OR = 1.018, p < 0.001) were strong predictors of mortality in trauma patients with spine injury. CONCLUSION: The results of the study showed that the incidence of traumatic spine injury rate was approximately 17.0% in southern of Iran. Road traffic injury and falls are the common mechanism of injury to spine. It is important to improve the safety of roads, and passengers, as well as work environment, and improve the quality of cars. Also, paying attention to the pattern of spine injury may assist to prevent the missing diagnosis of spine injury in multiple trauma patients.

Do clinical and paraclinical findings have the power to predict critical conditions of injured patients after traumatic injury resuscitation? Using data mining artificial intelligence.

PURPOSE: The triage and initial care of injured patients and a subsequent right level of care is paramount for an overall outcome after traumatic injury. Early recognition of patients is an important case of such decision-making with risk of worse prognosis. This article is to answer if clinical and paraclinical signs can predict the critical conditions of injured patients after traumatic injury resuscitation. METHODS: The study included 1107 trauma patients, 16 years and older. The patients were trauma victims of Levels I and II triage and admitted to the Rajaee (Emtiaz) Trauma Hospital, Shiraz, in 2014-2015. The cross-industry process for data mining methodology and modeling was used for assessing the best early clinical and paraclinical variables to predict the patients' prognosis. Five modeling methods including the support vector machine, K-nearest neighbor algorithms, Bagging and Adaboost, and the neural network were compared by some evaluation criteria. RESULTS: Learning algorithms can predict the deterioration of injured patients by monitoring the Bagging and SVM models with 99% accuracy. The most-fitted variables were Glasgow Coma Scale score, base deficit, and diastolic blood pressure especially after initial resuscitation in the algorithms for overall outcome predictions. CONCLUSION: Data mining could help in triage, initial treatment, and further decision-making for outcome measures in trauma patients. Clinical and paraclinical variables after resuscitation could predict short-term outcomes much better than variables on arrival. With artificial intelligence modeling system, diastolic blood pressure after resuscitation has a greater association with predicting early mortality rather than systolic blood pressure after resuscitation. Artificial intelligence monitoring may have a role in trauma care and should be further investigated.

Should we change our approach to resuscitating victims of femoral fracture? A clinical experience in a busy trauma hospital in Shiraz, Iran.

PURPOSE: Traumatic hemorrhagic shock is a life-threatening event worldwide. Severe brain trauma accompanying femoral fractures can trigger inflammatory responses in the body and increase pre-inflammatory cytokines such as TNF-α, IL-1. The primary treatment in these cases is hydration with crystalloids, which has both benefits and complications. The purpose of this study was to investigate the effects of fluid therapy on the hemodynamics, coagulation profiles, and blood gases in such patients. METHODS: In this cross-sectional study, patients were divided into two groups: femoral fracture group and non-femoral group. The hemodynamic status, coagulation profile, and blood gases of patients in both groups were evaluated upon arrival at the hospital and again 2 h later. Data were analyzed by t-test and ANOVA with repeated data and paired samples t-test. RESULTS: A total of 681 trauma patients (605 men and 76 women) participated in this study, including 69 (86.3%) men and 11 (13.8%) women in femoral fracture group and 536 men (89.2%) and 65 women (10.8%) in non-femoral group. The laboratory parameters were evaluated in response to the equal amount of crystalloid fluid given upon arrival and 2 h later. Blood gases decreased in the fracture group despite fluid therapy (p < 0.003), and the coagulation profile worsened although the change was not statistically significant. CONCLUSION: The treatment of multiple-trauma patients with femoral bone fractures should be more concerned with the need for the infusion of vasopressors such as norepinephrine. If there is evidence of clinical shock, excessive crystalloid infusion (limited to 1 L) should be avoided, and blood and blood products should be started as soon as possible.

Effect of different periods of chronic heat stress with or without vitamin C supplementation on bone and selected serum parameters of broiler chickens.

This study evaluates the effect of different periods of chronic heat stress (CHS) on selected bone and serum parameters of broiler chickens with or without vitamin C administration. Ninety 23-day-old chickens were randomly allocated into seven groups: (1) control, (2) short-term CHS (5 days), (3) short-term CHS + vitamin C (12 g/100 l drinking water of a 50% product), (4) medium-term CHS (10 days), (5) medium-term CHS + vitamin C, (6) long-term CHS (20 days) and (7) long-term CHS + vitamin C. In heat-stressed groups the temperature was increased to 39 ± 1°C for 8 h/day. At the end of the experiment, blood samples were collected and shank, keel and tibia bones were removed. CHS was not associated with a drastic change in serum Ca and corticosterone, or bone characteristics (both cortical and trabecular bones in radiographical and histological evaluation), or birds' performance. Oxidative stress was present especially with short-term CHS. CHS, especially for short or medium periods, showed a tendency to increase serum vitamin C and administration of this vitamin did not make a significant change in its serum levels although it ameliorated oxidative stress. In conclusion, it seems that CHS is not associated with an appreciable change in broiler performance, bone characteristics, or selected serum parameters; and simultaneous vitamin C administration at the dosage of 12 g/100 l in drinking water has no beneficial effect apart from reducing oxidative stress especially in short-term chronically heat-stressed birds.

Balancing immune responses: regulatory cells in eosinophilic gastrointestinal disorders.

Eosinophilic gastrointestinal disorders (EGIDs) are a group of conditions characterized by an abnormal accumulation of eosinophils in the gastrointestinal tract, leading to inflammation and tissue damage. Regulatory cells are a subset of immune cells that are crucial in maintaining the balance of the immune system and preventing the occurrence of autoimmune diseases. In EGIDs, regulatory cells are believed to play a key role in controlling the immune response and overseeing the growth and activation of eosinophils in the gastrointestinal tract. There is evidence indicating that regulatory T cells (Tregs) and regulatory eosinophils may play a role in suppressing the inflammatory response in EGIDs. Regulatory eosinophils are a subgroup of eosinophils that possess an anti-inflammatory role. Recent studies have shown that enhancing the number or effectiveness of regulatory eosinophils can reduce the severity of EGIDs. Regulatory eosinophils dampen inflammation through their regulatory mediators, such as galectin-10 and growth factor beta (TGF-ß), which promote Treg expansion and inhibit effector T cell function. Further research on regulatory cells in EGIDs may have significant implications for the advancement of novel therapies for these uncommon and intricate disorders. The aim of this review is to provide complete view of the immune responses connected to EGIDs, examine the regulatory cells that control these responses, and evaluate their potential as therapeutic targets for EGID treatment.

Evidence-based practice in traditional persian medicine (TPM): a stakeholder and social network analysis.

BACKGROUND: The utilization of complementary and alternative medicine (CAM) is experiencing a global surge, accompanied by the adoption of national CAM policies in numerous countries. Traditional Persian medicine (TPM) is highly used as CAM in Iran, and the ongoing scientific evaluation of its interventions and the implementation of evidence-based medicine (EBM) encounters various barriers. Therefore, comprehending the characteristics and interactions of stakeholders is pivotal in advancing EBM within TPM policies. In this study, we utilized both classical stakeholder analysis and social network analysis to identify key stakeholders and potential communication patterns, thereby promoting EBM in TPM policy-making. METHODS: A cross-sectional nationwide stakeholder analysis was conducted in 2023 using snowball sampling. The interviews were carried out using a customized version of the six building blocks of health. Data were collected through semi-structured interviews. Stakeholders were assessed based on five factors (power, interest, influence, position, and competency). The connections and structure of the network were analyzed using degree, betweenness, closeness centrality, and modularity index to detect clusters of smaller networks. RESULTS: Among twenty-three identified stakeholders, the Ministry of Health and Medical Education (MOHME) and the Public were the most powerful and influential. The Iranian Academy of Medical Sciences was the most competent stakeholder. Social network analysis revealed a low density of connections among stakeholders. Pharmaceutical companies were identified as key connectors in the network, while the Public, supreme governmental bodies, and guilds acted as gatekeepers or brokers. The MOHME and Maraji were found to be high-ranking stakeholders based on four different centrality measures. CONCLUSION: This study identifies powerful stakeholders in the network and emphasizes the need to engage uninterested yet significant stakeholders. Recommendations include improving competence through education, strengthening international relations, and fostering stronger relationships. Engaging key connectors and gatekeepers is essential for bridging gaps in the network.

How Similar Are Drug Data and Disease Self-report? Estimating the Prevalence of Chronic Diseases in Less Developed Settings.

BACKGROUND: Drug data has been used to estimate the prevalence of chronic diseases. Disease registries and annual surveys are lacking, especially in less-developed regions. At the same time, insurance drug data and self-reports of medications are easily accessible and inexpensive. We aim to investigate the similarity of prevalence estimation between self-report data of some chronic diseases and drug data in a less developed setting in southwestern Iran. METHODS: Baseline data from the Pars Cohort Study (PCS) was re-analyzed. The use of disease-related drugs were compared against self-report of each disease (hypertension [HTN], diabetes mellitus [DM], heart disease, stroke, chronic obstructive pulmonary disease [COPD], sleep disorder, anxiety, depression, gastroesophageal reflux disease [GERD], irritable bowel syndrome [IBS], and functional constipation [FC]). We used sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the Jaccard similarity index. RESULTS: The top five similarities were observed in DM (54%), HTN (53%), heart disease (32%), COPD (30%), and GERD (15%). The similarity between drug use and self-report was found to be low in IBS (2%), stroke (5%), depression (9%), sleep disorders (10%), and anxiety disorders (11%). CONCLUSION: Self-reports of diseases and the drug data show a different picture of most diseases' prevalence in our setting. It seems that drug data alone cannot estimate the prevalence of diseases in settings similar to ours. We recommend using drug data in combination with self-report data for epidemiological investigation in the less-developed setting.

Immune checkpoint molecules in prevention and development of asthma.

Allergic asthma is a respiratory disease initiated by type-2 immune responses characterized by secretion of alarmins, interleukin-4 (IL-4), IL-5, and IL-13, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Immune checkpoints (ICPs) are inhibitory or stimulatory molecules expressed on different immune cells, tumor cells, or other cell types that regulate immune system activation and maintain immune homeostasis. Compelling evidence indicates a key role for ICPs in both the progression and prevention of asthma. There is also evidence of asthma development or exacerbation in some cancer patients receiving ICP therapy. The aim of this review is to provide an updated overview of ICPs and their roles in asthma pathogenesis, and to assess their implications as therapeutic targets in asthma.

miR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required. METHODS: In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided. RESULTS: After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (*P = 0.002-*P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL (P = 0.01-P = 0.004, respectively), CMV seropositivity, and aGVHD. CONCLUSION: Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.

Effect of COVID-19 Pandemic on Incidence and Mortality Rate Due to Road Traffic Injury in Shiraz.

Objective: To evaluate the effect of COVID-19 pandemic on the incidence and mortality rate of road traffic injuries in Shiraz, Iran. Methods: This cross-sectional study was performed on the data of patients who admitted by road traffic accidents 18 months before the outbreak of COVID-19 and 18 months after COVID-19 in the largest provider of trauma level 1 care services in southern Iran. SPSS 19 software was used to analyze the data. Results: A significant decrease of 12.8% was observed in the number of patients admitted by road traffic accidents during the COVID-19 pandemic period compared to the same period before the pandemic (p<0.0001). But the death toll from road traffic accidents has increased significantly during the COVID-19 pandemic period compared to the same period before the pandemic (p=0.01). Conclusion: Due to the COVID-19 restrictions, it seems that factors such as restrictions on suburban travel, closure of public and recreational spaces, reduction of intra-city traffic, people staying at home and a significant reduction in injuries caused by traffic accidents, is reasonable. On the other hand, these restrictions, quarantines, and COVID disease itself can lead to confusion, anxiety, fear of infection, and thus avoid or delay the search for health care and increase mortality. Therefore, planning and policy-making is essential in order to prepare the correct guidance for seeking treatment.

An Update on Protective Effectiveness of Immune Responses After Recovery From COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits variable immunity responses among hosts based on symptom severity. Whether immunity in recovered individuals is effective for avoiding reinfection is poorly understood. Determination of immune memory status against SARS-CoV-2 helps identify reinfection risk and vaccine efficacy. Hence, after recovery from COVID-19, evaluation of protective effectiveness and durable immunity of prior disease could be significant. Recent reports described the dynamics of SARS-CoV-2 -specific humoral and cellular responses for more than six months in convalescent SARS-CoV-2 individuals. Given the current evidence, NK cell subpopulations, especially the memory-like NK cell subset, indicate a significant role in determining COVID-19 severity. Still, the information on the long-term NK cell immunity conferred by SARS-CoV-2 infection is scant. The evidence from vaccine clinical trials and observational studies indicates that hybrid natural/vaccine immunity to SARS-CoV-2 seems to be notably potent protection. We suggested the combination of plasma therapy from recovered donors and vaccination could be effective. This focused review aims to update the current information regarding immune correlates of COVID-19 recovery to understand better the probability of reinfection in COVID-19 infected cases that may serve as guides for ongoing vaccine strategy improvement.

In Silico Evaluation of Nonsynonymous SNPs in Human ADAM33: The Most Common Form of Genetic Association to Asthma Susceptibility.

ADAM33 is a zinc-dependent metalloprotease of the ADAM family, which plays a vital biological role as an activator of Th2 cytokines and growth factors. Moreover, this protein is crucial for the normal development of the lung in the fetus two months after gestation leading to determining lung functions all over life. In this regard, mutations in ADAM33 have been linked with asthma risk factors. Consequently, identifying ADAM33 pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) can be very important in asthma treatment. In the present study, 1055 nsSNPs of human ADAM33 were analyzed using biocomputational software, 31 of which were found to be detrimental mutations. Precise structural and stability analysis revealed D219V, C669G, and C606S as the most destabilizing SNPs. Furthermore, MD simulations disclosed higher overall fluctuation and alteration in intramolecular interactions compared with the wild-type structure. Overall, the results suggest D219V, C669G, and C606S detrimental mutations as a starting point for further case-control studies on the ADAM33 protein as well as an essential source for future targeted mechanisms.

Geoclimatic risk factors for childhood asthma hospitalization in southwest of Iran.

BACKGROUND: Asthma is a chronic respiratory disease resulting from a complex interaction between genetic and environmental factors. Among environmental factors, climatic and geographical variations have an important role in increasing asthma hospitalization. The current study aimed to investigate the effect of geoclimatic factors on the occurrence of childhood asthma hospitalization in Fars province, southwest Iran. METHOD: We mapped the addresses of 211 hospitalized patients with childhood asthma (2016-2019) and investigated the effects of different temperature models, mean annual rainfall and humidity, number of frosty and rainy days, evaporation, slope, and land covers on the occurrence of childhood asthma hospitalization using a geographical information system. The Kriging and Spline methods have been used for generating interpolated models. Data were analyzed using logistic regression. RESULTS: In the multivariate model, urban setting was recognized as the most important childhood asthma hospitalization predictor (p < 0.001, odds ration [OR] = 35.044, confidence interval [CI] = 9.096-135.018). The slope was considered the determinant of childhood asthma hospitalization when analyzed independently and its increase was associated with decreased childhood asthma hospitalization (p = 0.01, OR = 0.914, CI = 0.849-0.984). CONCLUSION: In the current study, the urban setting was the most important risk factor associated with increased childhood asthma hospitalization.

Diagnosing Myocardial Contusion after Blunt Chest Trauma.

A myocardial contusion refers to a bruise of the cardiac muscle, the severity of which can vary depending on the severity of the injury and when the injury occurs. It is a major cause of rapid death which happens after blunt chest trauma and should be suspected at triage in the emergency department. We demonstrated that suspected myocardial contusion patients who have normal electrocardiograms (ECGs) and biomarker tests can be safely discharged. However, if the test results are abnormal, the next steps should be echocardiography and more advanced measures. Diagnosing myocardial contusion is very difficult because of its nonspecific symptoms. If a myocardial contusion happens, cardiogenic shock or arrhythmia must be anticipated, and the patient must be carefully monitored.

Management of Deep Vein Thrombosis (DVT) Prophylaxis in Trauma Patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PTE) are known as venous thromboembolism (VTE). DVT occurs when a thrombus (a blood clot) forms in deep veins of the body, usually in the lower extremities. It can cause swelling or leg pain, but sometimes may occur with no symptoms. Awareness of DVT is the best way to prevent the VTE. Patients with trauma are at increased risk of DVT and subsequent PE because of coagulopathy in patients with multiple trauma, DVT prophylaxis is essential but the VTE prophylaxis strategy is controversial for the trauma patients. The risk factors for VTE includes pelvic and lower extremity fractures, and head injury.

Tube Thoracostomy (Chest Tube) Removal in Traumatic Patients: What Do We Know? What Can We Do?

Chest tube (CT) or tube thoracostomy placement is often indicated following traumatic injuries. Premature movement of the chest tube leads to increased hospital complications and costs for patients. Placement of a chest tube is indicated in drainage of blood, bile, pus, drain air, and other fluids. Although there is a general agreement for the placement of a chest tube, there is little consensus on the subsequent management. Chest tube removal in trauma patients increases morbidity and hospital expense if not done at the right time. A review of relevant literature showed that the best answers to some questions about time and decision-making have been long sought. Issues discussed in this manuscript include chest tube removal conditions, the need for chest radiography before and after chest tuberemoval, the need to clamp the chest tube prior to removal, and drainage rate and acceptability prior to removal.

Learning operational strategies in surgery training.

INTRODUCTION: Education and training in surgery is in the middle of apprenticeship style of learning especially in operating room with little importance of understanding on how trainees learn. METHODS: This training is one of the most difficult types of training. Medical training and expertise are the specialty of this education system. We can name these complex fields as "Operational Strategies". The strategies are includes of "what to do", "what to think" and "what to create". These strategies are good to test and train higher functions in persons who have professional's positions. RESULTS: Most of educational fields are complex. It means that the training is not limited in an area and includes of theory fields, areas of decision making and areas of handy and practical skills. These fields are the most relevant skills or expertise which individual must be informed of the performance of maintenance and repair or upgrade and make a new system. CONCLUSION:   The operational strategy is a new training strategy for surgery students. It is useful to train surgery students to modify and improve their practices and doing surgeries and treating patients in best conditions.