Poisoning among children in Malaysia: A 10-years retrospective study.

BACKGROUND: Poisoning commonly occurs among children due to their curiosity, where they tend to explore and investigate their surroundings. They frequently put what they find into their mouths as they do not understand the danger and probably cannot read the warning label. As this issue has not been extensively studied in Malaysia; hence, a retrospective analysis of records was carried out to determine the profile of phone call enquiries regarding poisoning among children at the National Poison Centre (NPC). METHODOLOGY: The records of all cases of poisoning among children below the age of 18 years were retrospectively reviewed over a period of 10 years from 2006 to 2015. The data on the cases were analysed according to age group and gender, the circumstances and the toxic agent implicated in the poisoning. RESULTS: During the 10-year study period, 13,583 calls that met the criteria for this study were referred to the NPC. Of these calls, 62.2% involved children between the age of 0 to 5 years, 9% were children aged between 6 to 12 years, and 28.8% were children between 13 to 18 years. Unintentional poisoning accounted for 96.7% of the incidents involving children between the age of 0 to 5 years, although among the children who were between the age of 13 to 18 years, 76% of the cases were intentional. In all the cases involving children, pharmaceutical agents were the most frequent source of the poisoning. More than 95% of the cases were exposed to poisoning through the oral route. CONCLUSION: Poisoning in children between the age of 0 to 5 years was mainly unintentional, while poisoning in children between the age of 13 to 18 years was mainly intentional, where pharmaceutical and household agents were responsible for more than two-thirds of the poisoning cases. Most of these incidents could have been prevented if protective measures, such as child-resistant enclosures, had been implemented and if the parents and guardians had been educated about preventive measures, such as keeping poisoning agents out of the reach of children.

Exposure and risk assessment of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) for primiparous mothers and breastfed infants in Penang, Malaysia.

An average 50 ml breast milk samples were collected from 21 lactating primiparous mothers (range 25 to 45 years, mean 33 years), 4-8 weeks after delivery in Penang Island, Malaysia. The geometric mean concentration of the most toxic congeners, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) was 0.14 pg WHO2005-TEQ g-1 zlipid. The most abundant congeners of PCDD/Fs were octachlorodibenzo-p-dioxin (OCDD) (5.9-75.4%), followed by 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (1,2,3,4,6,7,8-HpCDD) (1.1-30.7%). The geometric mean level of total dioxins and dl-PCBs was 2.2 pg WHO2005-TEQ g-1 lipid, significantly lower than those in developed countries or highly contaminated areas. The total dioxins and dl-PCBs in pg WHO2005-TEQ levels in breast milk were significantly correlated with years of residence at potential contaminated site. The average daily intake of 11.8 pg WHO2005-TEQ kg-1 body weight was estimated for a breastfed infant at 6 months of age. This demonstrates the exposure risk to infants, especially from Penang region, to these pollutants from human milk intake are potentially high during the lactation period.

Docetaxel-Loaded Poly(3HB-co-4HB) Biodegradable Nanoparticles: Impact of Copolymer Composition.

Polyhydroxyalkanoate (PHA) copolymers show a relatively higher in vivo degradation rate compared to other PHAs, thus, they receive a great deal of attention for a wide range of medical applications. Nanoparticles (NPs) loaded with poorly water-soluble anticancer drug docetaxel (DCX) were produced using poly(3-hydroxybutyrate-co-4-hydroxybutyrate), P(3HB-co-4HB), copolymers biosynthesised from Cupriavidus malaysiensis USMAA1020 isolated from the Malaysian environment. Three copolymers with different molar proportions of 4-hydroxybutirate (4HB) were used: 16% (PHB16), 30% (PHB30) and 70% (PHB70) 4HB-containing P(3HB-co-4HB). Blank and DCX-loaded nanoparticles were then characterized for their size and size distribution, surface charge, encapsulation efficiency and drug release. Preformulation studies showed that an optimised formulation could be achieved through the emulsification/solvent evaporation method using PHB70 with the addition of 1.0% PVA, as stabilizer and 0.03% VitE-TPGS, as surfactant. DCX-loaded PHB70 nanoparticles (DCX-PHB70) gave the desired particle size distribution in terms of average particle size around 150 nm and narrow particle size distribution (polydispersity index (PDI) below 0.100). The encapsulation efficiency result showed that at 30% w/w drug-to-polymer ratio: DCX- PHB16 NPs were able to encapsulate up to 42% of DCX; DCX-PHB30 NPs encapsulated up to 46% of DCX and DCX-PHB70 NPs encapsulated up to 50% of DCX within the nanoparticle system. Approximately 60% of DCX was released from the DCX-PHB70 NPs within 7 days for 5%, 10% and 20% of drug-to-polymer ratio while for the 30% and 40% drug-to-polymer ratios, an almost complete drug release (98%) after 7 days of incubation was observed.

Epidemiology and risk factors of pesticide poisoning in Malaysia: a retrospective analysis by the National Poison Centre (NPC) from 2006 to 2015.

OBJECTIVE: Pesticide poisoning is a global health problem, and its progressive deterioration is a major cause of concern. The objective of this study is to assess epidemiological characteristics and identify risk factors of pesticide poisoning in Malaysia. SETTING: Pesticide poisoning database of Malaysia National Poison Centre (NPC) from 2006 to 2015. PARTICIPANTS: Telephone enquiries regarding pesticide poisoning were made by healthcare professionals. Information received by the NPC was entered into a retrievable database of standardised Poison Case Report Form, as adapted from the World Health Organization (WHO). OUTCOMES: The outcome of the study is to provide an overview of national epidemiological profile of pesticide poisoning. High-risk groups of people and their circumstances were also identified to ensure that appropriate measures are strategised. RESULTS: Within the study period, a total of 11 087 pesticide poisoning cases were recorded. Sixty per cent of these cases were intentional in nature and most were found among male individuals (57%) of the Indian race (36.4%) aged between 20 and 29 years (25.5%), which occurred at home (90%) through the route of ingestion (94%). The highest number of poisoning was due to herbicides (44%) followed by agricultural insecticides (34%), rodenticides (9.9%), household insecticides (9.5%) and fungicides (0.5%). In addition, 93.6% of intentional pesticide poisoning cases were caused by suicide attempts. The results of this study show that there was an increasing trend in pesticide poisoning incidents over the 10-year duration. This indicates that pesticide poisoning is a prevalent public health problem in Malaysia, resulting in an average incidence rate of 3.8 per 100 000 population. CONCLUSIONS: Deliberate pesticide ingestion as a method of suicide has become a disturbing trend among Malaysians. Therefore, regulation of highly hazardous pesticides must be enforced to ensure controlled and limited access to these chemicals by the public.

Predicting healthcare professionals' intention to use poison information system in a Malaysian public hospital.

PURPOSE: The main objective of this paper is to determine the predicting factors that influence the intention to use Poison Information System (PIS) among healthcare professionals. METHODS: A quantitative approach was applied, using a five-point Likert scale questionnaire, adapted from previous studies. Data were collected from 167 healthcare professionals working for Malaysian Public Hospitals in Penang. Smart Partial Least Square (PLS) version 3.2.7 were used to analyse the proposed relationships. RESULTS: The results indicated that attitude and computer anxiety had a significant positive relation to the intention to use PIS among healthcare professionals wherein computer knowledge was found to have had a significant relationship with attitude and computer habit. Apart from that, technical support and training had a positive relationship with perceived ease of use. Surprisingly, computer habit, perceived usefulness, perceived ease of use, compatibility and facilitating condition did not significantly influence intention to use PIS. CONCLUSION: The results of this study provided useful insights for healthcare agencies to understand the underlying elements that could improve the poison information management. The results proved that attitude and computer anxiety were critical factors among healthcare professionals managing poisoning cases in a highly stressful and unpredictable work environment. These factors must, therefore, be considered before implementing PIS in managing poisoning cases. The study also provided an understanding of how to improve system development by utilising the end user's expectation on the implementation of the system.

Pharmaceuticals Poisoning: Reported by the National Poison Centre in Malaysia between 2010 and 2015.

BACKGROUND AND PURPOSE: The wide availability of medications has led to an increased exposure of humans to the possibility of poisoning. An unavoidable effect due to the availability of these medications has also led to a rising increment in the number of poisoning cases. All drugs, especially when administered in large doses or overextended periods, can initiate a toxic condition. Therefore, the objective of this study was to examine nationwide, the patterns attributed to poisoning, and to describe the sociodemographic, and geographic distribution of poisoning, by identifying the category of substances implicated in these cases. DATA SOURCES AND METHODS: A retrospective study based on telephone calls reported on poisoning caused by pharmaceutical products undertaken by the National Poisoning Centre (NPC) in Penang (Malaysia) was used as the basis of this study covering the period between 2010 and 2015. The study included the mode and type of poisoning, exposure routes as well as the incidence locations. RESULTS: A total of 10,998 cases were examined, finding that females represented 5,899 cases (53.6%) being intoxicated more frequently compared to the number of males, 3,839 (34.9%). The age group of poisoning cases ranged between 20 and 29 years representing 2,579 (23.4%) of reported cases. The common mode of poisoning was attributed to suicide 5,203 (47.3%) from among the 10,998 cases and the highest poisoning agents reported were from the psychiatric group of pharmaceutical products of 2,287 (21%). CONCLUSION AND IMPLICATIONS: These findings indicate a rising trend of suicidal poisoning attempts between 2013 and 2015, which emphasizes the need for more stringent and effective enforcement protocols to limit the rising incidence of poisoning. As such, analyzing the trends in poisoning in a particular zone periodically could help health policy-makers to develop management policies and prevention strategies.

Paraquat poisoning calls to the Malaysia National Poison Centre following its ban and subsequent restriction of the herbicide from 2004 to 2015.

This study analyses the incidences and patterns of paraquat poisoning from calls received at the Malaysia National Poison Centre (NPC) since 2004 following the ban of the herbicide (2004-2006) and subsequent restriction up to year 2015. Related reported cases to the centre over twelve years (2004-2015) were retrieved and studied in respect to socio-demographic characteristics, mode and type of poisonings, exposure routes and location of incident. Ages of poisoned victims range from 10 months old to 98 years with males being intoxicated more frequently than females (ratio male to female = 2.7). The age group mainly involved in the poisoning was 20-39 years. The most common mode was intentional (62.8%) followed by unintentional (36.9%). Among the 1232 reported cases, suicidal poisoning was the highest (57.2%); accidental poisoning (30.8%) and occupational poisoning (3.3%). The findings showed an upward trend of suicidal poisoning over the years, clearly emphasizing the need for more stringent and effective enforcement to ensure the safe use of paraquat.

Acute and repeated dose 28-day oral toxicity of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) nanoparticles in Sprague-Dawley rats.

This study aimed to investigate the oral acute and subacute toxicity of Poly [3-hydroxybutyrate-co-4-hydroxybutyrate], P(3HB-co-4HB) in the form of nanoparticles in Sprague-Dawley rats. Acute oral administration of P(3HB-co-4HB) nanoparticles was performed as a single dose up to 2000 mg/kg in six female rats for 14 days. Subacute toxicity study via oral administration for 28 days at doses of 0 (control), 500, 1000 and 2000 mg/kg in rats (10 rats in each group, female:male = 1:1) was conducted. The estimated lethal dose (LD50) of P(3HB-co-4HB) nanoparticles was >2000 mg/kg. No mortality, unusual changes in behaviour, adverse clinical signs, abnormal changes in body weights or food consumption were observed on all animals treated with P(3HB-co-4HB) nanoparticles during 14 days of the acute toxicity study. In the subacute test, there was no mortality and toxicologically significant changes in clinical signs, body weights, food consumption, hematology, clinical biochemistry, urinalysis, macroscopic findings, organ weights as well as histopathological examination were observed.

Evaluation of types of poisoning exposure calls managed by the Malaysia National Poison Centre (2006-2015): A retrospective review.

OBJECTIVE: Accidental or intentional poisoning is a public health concern requiring intervention. The current study designs to evaluate the types of poisoning exposure calls received by the Malaysia National Poison Centre (NPC) over a 10-year period. SETTINGS AND DATA SOURCES: The poisoning enquiries database (2006-2015) from the Malaysia NPC was used for the analysis. PARTICIPANTS: The NPC records all telephone calls that it manages using a validated and standardised form. Demographics and types of the poisoning exposure calls were extracted and descriptive analysis was applied. PRIMARY AND SECONDARY OUTCOMES: The primary outcome of this study is to evaluate NPC data for trends in the poisoning exposure calls based on the types and modes of poisoning over a 10-year period. The secondary outcome is to evaluate the characteristics of human exposure cases based on the calls received by the NPC. RESULTS: There was a notable increase in the number of poisoning exposure calls noticed during the 10-year period but dropped significantly in 2012. The highest number of poisoning exposure calls came from Selangor (21.0%), Perak (18.0%) and Negeri Sembilan (9.8%). More than half of the exposure was intentional (53.8%) involving more women (50.3%) as compared with men (41.9%), and in the 20-29 years age group category (33.5%). Exposure mostly occurred at home (96%) through the ingestion route (94.1%). Pharmaceutical products (40.5%), pesticides (31.7%) and household products (20.1%) were the common agents implicated for intentional exposure. CONCLUSIONS: There is an increasing trend in enquiries on poisoning exposure calls made to the NPC. Most of the intentional poisoning exposures occurred among younger women and involved pharmaceuticals, pesticides or household products. Poisoning safety education and other interventions are needed to curb poisoning incidents.

Present status and future concerns of expanded newborn screening in malaysia: sustainability, challenges and perspectives.

Newborn screening (NBS) program is an important tool for the early diagnosis and preventive treatment of life-long impairments. NBS is one of the strategies recommended by the World Health Organization to promote the primary prevention of congenital anomalies and the health of children with these conditions. However, NBS initiation and implementation in developing countries, especially South-East Asian and North African regions, are slow and challenging. Expanded NBS is not mandatory and has not yet been incorporated into the public healthcare system in our country. Limited funding, manpower shortages, inadequate support services, low public awareness, and uncertain commitment from healthcare practitioners are the main challenges in establishing this program at the national level. Involvement and support from policy makers are very important to the success of the program and the benefit of the entire population.

Dioxin-like polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans in seafood samples from Malaysia: estimated human intake and associated risks.

A total of 127 and 177 seafood samples from Malaysia were analyzed for polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs), respectively. The World Health Organization-toxic-equivalency quotients (WHO-TEQ) of PCDD/Fs varied from 0.13 to 1.03 pg TEQ g(-1), whereas dl-PCBs ranged from 0.33 to 1.32 pg TEQ g(-1). Based on food-consumption data from the global environment monitoring system-food contamination monitoring and assessment programme, calculated dietary exposures to PCDD/Fs and dl-PCBs from seafood for the general population in Malaysia were 0.042 and 0.098 pg TEQ kg(-1) body weight day(-1), respectively. These estimations were quite different from the values calculated using the Malaysian food-consumption statistics (average of 0.313 and 0.676 pg TEQ kg(-1) body weight day(-1) for PCDD/Fs and PCBs, respectively). However, both of the dietary exposure estimations were lower than the tolerable daily intake recommended by WHO. Thus, it is suggested that seafood from Malaysia does not pose a notable risk to the health of the average consumer.

Contamination of food samples from Malaysia with polychlorinated dibenzo-p-dioxins and dibenzofurans and estimation of human intake.

A total of 126 food samples, categorised into three groups (seafood and seafood products, meat and meat products, as well as milk and dairy products) from Malaysia were analysed for polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The concentration of PCDD/Fs that ranged from 0.16 to 0.25 pg WHO05-TEQ g(-1) fw was found in these samples. According to the food consumption data from the Global Environment Monitoring System (GEMS) of the World Health Organization (WHO), the dietary exposures to PCDD/F from seafood and seafood products, meat and meat products, as well as milk and dairy products for the general population in Malaysia were 0.064, 0.183 and 0.736 pg WHO05-TEQ kg(-1) bw day(-1), respectively. However, the exposure was higher in seafood and seafood products (0.415 pg WHO05-TEQ kg(-1) bw day(-1)) and meat and meat products (0.317 pg WHO05-TEQ kg(-1) bw day(-1)) when the data were estimated using the Malaysian food consumption statistics. The lower exposure was observed in dairy products with an estimation of 0.365 pg WHO05-TEQ kg(-1) bw day(-1). Overall, these dietary exposure estimates were much lower than the tolerable daily intake (TDI) as recommended by WHO. Thus, it is suggested that the dietary exposure to PCDD/F does not represent a risk for human health in Malaysia.

Bioassay-guided isolation of a sesquiterpene lactone of deoxyelephantopin from Elephantopus scaber Linn. active on Trypanosome brucei rhodesience.

Methanolic extracts of 70 Malaysia plants were screened for their in vitro antitrypanosomal activity using Trypanosome brucei rhodesience, strain STIB 900 and mouse skeletal cell (L-6) in cytotoxicity activity assay. Results indicated that methanol extract from Elephantopus scaber Linn. (E. scaber) possessed the highest value of antitrypanosomal activity with good selectivity index (antitrypanosomal IC50 of 0.22±0.02 µg/ml, SI value of 204.55). Based on these results, E. scaber was chosen for further study by applying bioassay guided fractionation to isolate its antiprotozoal principle. The antiprotozoal principle was isolated from the ethyl acetate partition through solvent fractionation and crystallization process. The isolated active compound 1 was identified as deoxyelephantopin on the basis of its spectral analysis (FTIR, MS, 1D and 2D NMR).

The effect of mitragynine on cAMP formation and mRNA expression of mu-opioid receptors mediated by chronic morphine treatment in SK-N-SH neuroblastoma cell.

ETHNOPHARMACOLOGICAL RELEVANCE: [corrected] Mitragynine is an indole alkaloid compound of Mitragyna speciosa (M. speciosa) Korth. (Rubiaceae). This plant is native to the southern regions of Thailand and northern regions of Malaysia and is frequently used to manage the withdrawal symptoms in both countries. AIM OF STUDY: To investigate the effect of mitragynine after chronic morphine treatment on cyclic AMP (cAMP) level and mRNA expression of mu-opioid receptor (MOR) in human neuroblastoma SK-N-SH cell. METHOD AND MATERIALS: Mitragynine was isolated from the Mitragyna speciosa plant using the acid-base extraction method. The cAMP level upon forskolin stimulation in the cells was determined using the Calbiochem(®) Direct Immunoassay Kit. The mRNA expression of the MOR was carried out using quantitative RT-PCR. RESULT: Cotreatment and pretreatment of morphine and mitragynine significantly reduced the production of cAMP level at a lower concentration of mitragynine while the higher concentration of this compound could lead to the development of tolerance and dependence as shown by the increase of the cAMP level production in foskolin stimulation. In MOR mRNA expression study, cotreatment of morphine with mitragynine significantly reduced the down-regulation of MOR mRNA expression as compared to morphine treatment only. CONCLUSION: These finding suggest that mitragynine could possibly avoid the tolerance and dependence on chronic morphine treatment by reducing the up-regulation of cAMP level as well as reducing the down-regulation of MOR at a lower concentration of mitragynine.

In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid.

CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis. CYP1A2 and CYP3A4 enzyme activities were evaluated using P450-Glo™ assays. The effects of mitragynine on human CYP3A4 protein expression were determined using an optimized hCYP3A4-HepG2 cell-based assay. An in silico computational method to predict the binding conformation of mitragynine to the active site of the CYP3A4 enzyme was performed and further validated using in vitro CYP3A4 inhibition assays. Mitragynine was found to induce mRNA and protein expression of CYP1A2. For the highest concentration of 25 µM, induction of mRNA was approximately 70% that of the positive control and was consistent with the increased CYP1A2 enzymatic activity. Thus, mitragynine is a significant in vitro CYP1A2 inducer. However, it appeared to be a weak CYP3A4 inducer at the transcriptional level and a weak CYP3A4 enzyme inhibitor. It is therefore, unlikely to have any significant clinical effects on CYP3A4 activity.

Swietenia macrophylla extract promotes the ability of Caenorhabditis elegans to survive Pseudomonas aeruginosa infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Swietenia macrophylla or commonly known as big leaf mahogany, has been traditionally used as an antibacterial and antifungal agent. AIM OF THE STUDY: The unwanted problem of antibiotic resistance in many bacterial species advocates the need for the discovery of the new anti-infective drugs. Here, we investigated the anti-infective properties of Swietenia macrophylla with an assay involving lethal infection of Caenorhabditis elegans with the opportunistic human pathogen Pseudomonas aeruginosa. MATERIALS AND METHODS: Using a slow killing assay, Caenorhabditis elegans was challenged with an infective strain of Pseudomonas aeruginosa (PA14). The ability of Swietenia macrophylla seed ethyl acetate extract to promote the survival of infected worms was assessed by comparing the percentage of survival between extract treated and non-treated worm populations. The effect of Swietenia macrophylla towards PA14 growth, Caenorhabditis elegans feeding rate and degree of PA14 colonization in the worm gut was also evaluated. Lastly, using a fluorescent transgenic Caenorhabditis elegans strain and real time PCR, the effect of Swietenia macrophylla on the expression of lys-7, an immune response gene was also investigated. RESULTS: Our results demonstrate the ability of Swietenia macrophylla seed ethyl acetate extract in rescuing Caenorhabditis elegans from fatal PA14 infection. Consequently, we showed that the extract promotes the survival without exhibiting any bactericidal effect or perturbation of Caenorhabditis elegans feeding rate. We also showed that Swietenia macrophylla was able to restore the initially repressed lys-7 level in PA14 infected Caenorhabditis elegans. CONCLUSION: Swietenia macrophylla extract is able to enhance the ability of Caenorhabditis elegans to survive PA14 infection without directly killing the pathogen. We further showed that the extract boosted the expression of a gene pivotal for innate immunity in Caenorhabditis elegans. Collectively, these findings strongly suggest the presence of compounds within Swietenia macrophylla seed that either reduces Pseudomonas aeruginosa virulence and/or enhance host resistance.

Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E2 production induced by lipopolysaccharide in RAW264.7 macrophage cells.

ETHNOPHARMACOLOGICAL RELEVANCE: [corrected] Mitragyna speciosa Korth (Rubiaceae) is one of the medicinal plants used traditionally to treat various types of diseases especially in Thailand and Malaysia. Its anti-inflammatory and analgesic properties in its crude form are well documented. In this study, the cellular mechanism involved in the anti-inflammatory effects of mitragynine, the major bioactive constituent, was investigated. MATERIALS AND METHODS: The effects of mitragynine on the mRNA and protein expression of COX-1 and COX-2 and the production of prostaglandin E(2) (PGE(2)) were investigated in LPS-treated RAW264.7 macrophage cells. Quantitative RT-PCR was used to assess the mRNA expression of COX-1 and COX-2. Protein expression of COX-1 and COX-2 were assessed using Western blot analysis and the level of PGE(2) production was quantified using Parameter™ PGE(2) Assay (R&D Systems). RESULTS: Mitragynine produced a significant inhibition on the mRNA expression of COX-2 induced by LPS, in a dose dependent manner and this was followed by the reduction of PGE(2) production. On the other hand, the effects of mitragynine on COX-1 mRNA expression were found to be insignificant as compared to the control cells. However, the effect of mitragynine on COX-1 protein expression is dependent on concentration, with higher concentration of mitragynine producing a further reduction of COX-1 expression in LPS-treated cells. CONCLUSIONS: These findings suggest that mitragynine suppressed PGE(2) production by inhibiting COX-2 expression in LPS-stimulated RAW264.7 macrophage cells. Mitragynine may be useful for the treatment of inflammatory conditions.