The average final weight of the fish was 346 ± 35.8 g. The ADCs of the dry matter, protein, lipid, chitin, ash, phosphorus, amino acids, fatty acids, and gross energy for the test ingredients and diets were calculated. A six-month storage test was carried out to evaluate the shelf life of the experimental diets, while the peroxidation and microbiological status of the diets were also assessed. The ADC values of the test diets differed significantly (p < 0.001) compared to those of the control for most of the nutrients. Altogether, the BSL diet was significantly more digestible for protein, fat, ash, and phosphorus than the control diet but less digestible for essential amino acids. Significant differences were found between the ADCs of the different insect meals evaluated (p < 0.001) for practically all nutritional fractions analyzed. The African catfish hybrids were able to digest BSL and BBF more efficiently than MW, and the calculated ADC values agreed with those of other fish species. The lower ADCs of the tested MW meal correlated (p < 0.05) with the markedly higher acid detergent fiber (ADF) levels present in the MW meal and MW diet. Microbiological evaluation of the feeds revealed that mesophilic aerobic bacteria in the BSL feed were 2–3 orders of magnitude more abundant than those in the other diets and their numbers significantly increased during storage. Overall, BSL and BBF proved to be potential feed ingredients for African catfish juveniles and the shelf life of the produced diets with 30% inclusion of insect meal retained the required quality during a six-month period of storage.A digestibility trial was conducted with African catfish hybrid juveniles in order to determine the apparent digestibility coefficients (ADCs) of different nutrients. The experimental diets contained defatted black soldier fly (BSL), yellow mealworm (MW), or fully fat blue bottle fly (BBF) meals, in a 70 : 30 ratio between the control diet and the tested insect meals. The indirect method for the digestibility study was performed using 0.1% yttrium oxide as an inert marker. Fish juveniles of 217.4 ± 9.5 g initial weight were distributed in 1 m Nevertheless, in non-EU countries, regulations are different and other insects are also considered useful for fish nutrition [Feed manufacturers show an increasing interest in insect-derived raw materials because of their potential as fish meal substituents. The ecological footprint of insect cultivation is much lower than that of field crops, which make up the vast majority of animal feeds. The development and reproduction cycle of insects requires a short period of time. They can be grown on biowaste, and being ectotherm organisms, they have high feed utilization rates . The neeThe chemical composition and nutritional value of insect larvae are variable and depend on many factors. The most important factors are the rearing substrate and processing methodology , an important and dominant aquaculture species in Hungary. Meals from insects such as shea caterpillar (Cirina butyrospermi), housefly, variegated grasshopper (Zonocerus variegatus L.), and black solider fly have previously been included in the diets of African catfish as alternative protein sources [Although insects have the potential as good protein and fat sources, less information is known about their utilization as feed ingredients for intensively reared African catfish ( sources –21. HoweOreochromis niloticus) and common carp (Cyprinus carpio) [Coleoptera, Orthoptera, and Blattodea species in Nile tilapia fingerlings [Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂), and ADC results for BSL are also available for Atlantic salmon  [The digestibility of feeds containing different proportions of insect meals has been examined, and the concerned studies were reviewed by Gasco et al. . The mos carpio)  and ADCsgerlings . Mohamadgerlings  presenteo salar) .Stratiomyidae family and is present on all major continents, predominantly in temperate and tropic regions. It can successfully develop on vertebrate remains, kitchen waste, fruits and vegetables, raw liver, fish offal, municipal and human waste, and dairy cattle manure. MW belongs to the order Coleoptera, and it has been produced in large quantities since the 1950s, initially for fishing bait and later for pet food and for the songbird feed market. Nowadays, thousands of tons of dry mealworm are produced and sold worldwide [Calliphora vicina, Calliphoridae, and Diptera), commonly referred to as “meat fly,” is used as bait or boilies ingredient for fishing or angling. However, its utilization in fish feeds is not yet authorized in EU countries (EU Regulation no. 2017/893) but it is present in several fishing products available in Europe, too.Black soldier fly and yellow mealworm (MW) are the most frequently utilized insects in fish nutrition. BSL belongs to the Diptera, orldwide –29. The orldwide , 31. BluSalmonella, Listeria, and E. coli [The microbiological composition of the fish feed has a high impact on the weight gain and fish health condition . A wide  E. coli . The ins E. coli , 35. How E. coli .Taking into consideration the abovementioned gaps in our knowledge, we aimed to determine the apparent digestibility coefficients (ADCs) of African catfish hybrid juveniles for BSL, MW, and BBF meals. Accordingly, the present study demonstrates a short-term digestibility trial conducted in a recirculating aquaculture system (RAS) using three experimental diets containing different insect meals. In addition, the stability and shelf life of these feeds were followed up during a six-month storage period.−1) of insect meals are summarized in −1 (for MW) to 25.64 MJ·kg−1 (for BBF). The essential amino acid content differed significantly in HIS between the meals. The highest level of LYS and MET and the lowest level of LEU have been observed in the BBF meal. Finally, the sum of essential amino acids (EAA) was the lowest in MW. The fatty acid profile of the meals differed in some cases. The lauric acid (12 : 0) content was the highest in BSL (43.12%) although the sample was defatted, while in MW and BBF, its level was very low . In BBF and MW, the oleic acid (18 : 1n − 9) and linoleic acid (18 : 2n − 6) levels were about two times higher than those in the BSL sample. Consequently, total monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acid levels were also high in the MW and BBF samples. Regarding the long chain n-3 polyunsaturated FAs (Lc-PUFAs), the insects do not contain them, thus depending on the rearing substrate, they can be detected only at trace levels in insects.The defatted black soldier fly meal was supplied by Agroloop Ltd., Netherlands; defatted yellow mealworm meal was imported from Berg and Schmidt Pte. Ltd., Singapore; while the fully fat blue bottle fly meal was produced by Csali Hungary Ltd. . The composition (% DM) and gross energy value  for 120 s according to Clarias gariepinus × Heterobranchus longifilis) juveniles. The experiments were conducted according to the European Union Directive 2010/63/EU regarding the protection of animals for scientific purposes. The animal experiments and related samplings were approved by the Ethical Committee of HAKI (license no. BE/25/4302-3/2017), which was established according to the Hungarian State law 9/1999 (I. 27.), and it is operated according to the relevant Hungarian legislation concerning animal experiments, transportation of animals, and their welfare (40/2013. II. 14).The research was carried out with African catfish hybrid (3 fiberglass tanks (75 fish per tank). Three experimental groups and one control group were set up and randomly distributed in tank triplicates. The water flow was adjusted to an average of 4.5 L/min per tank, the dissolved oxygen level was kept above 80% saturation, ammonia-N was below 0.1 mL/L, and pH varied between 7.8 and 8.4. The water temperature was set to 23 ± 1°C. During three days of acclimatization, the fish were fed with a commercial diet and thereafter switched to experimental diets. Fish were hand fed till apparent satiation with the experimental diets 3 times per day for 18 consecutive days. On the last day of feeding, 15 individuals from the fish stock per tank were sampled in order to collect faeces from the intestine [Nine hundred African catfish juveniles (average weight of 217.4 ± 9.5 g) originating from the institutional hatchery facility of HAKI were distributed in a RAS equipped with twelve 1 mntestine . The aventestine . The who2SO4 and 10 mL of 30% H2O2. Afterwards, the generated ammonium sulphate was distilled off by using 2% H3BO3. The CP was calculated as N × 4.75 in the case of insects and N × 6.25 for diets and faeces. The crude fat was determined from the 5 g dry sample according to the AOAC 945.16 Soxhlet method using an automatic system  and diethyl ether  as a solvent. The crude ash content was estimated according to the AOAC 942.05 method. Two grams of each sample were weighed, placed in a furnace, and heated at 550°C for 4 h. The amount of remaining ash was recorded. The crude fiber content was determined from defatted samples [2SO4 and 0.313 M NaOH in a GERHARDT Fibretherm FT12 apparatus . The acid detergent fiber (ADF) was determined with the same equipment by using ADF solution prepared from N-cetyl-trimethyl-ammonium bromide dissolved in 0.5 M H2SO4 (100 g/5 L) and a few drops of antifoaming agent. The chitin content was determined as the difference between ash-free ADF and protein linked to ADF (ADIP) (chitin% = ADF% − ADIP%) according to Finke [The chemical composition of test ingredients, feeds, and faeces was analyzed by standard methods of the AOAC . Crude p samples . The samto Finke  and Maroto Finke . The groThe fatty acid composition of different samples was analyzed by the capillary gas chromatographic method. Lipids were extracted from the samples with a 2 : 1 mixture of chloroform and methanol. The extracts were purified according to the method by Folch et al. . Aliquotμm column (Waters), and AccQ Tag Ultra eluents A, B, and water in the gradient mode, the flow rate being 0.7 mL/min. The chromatograms were evaluated at 260 nm, using amino acid standards. Acid hydrolysis was carried out for amino acid analysis. Twenty-five milligrams of the samples were hydrolyzed by 6 N HCl containing 1% of phenol in a Milestone Ethos One Microwave digestion system. Hydrolysates were completed to 5 mL by 1 M borate buffer (pH 8.51).The amino acid content of samples was analyzed using the UPLC-DAD method  after acid hydrolysis and precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) reagent. The analysis was performed with AccQ UPLC BEH C18 2.1 × 100 mm, 1.7 Yttrium, calcium, and phosphorus contents were analyzed by the ICP method. The digestion of samples was carried out with mixtures of acids, including nitric acid (R.G. 65%) and hydrogen peroxide (R.G. 30%). The extraction was realized by using the microwave digestion technique under high pressure and a Milestone Ethos Plus  microwave apparatus. The concentrations of elements were measured by Thermo Scientific 6500 ICP-OES  equipment.Ydiet is the dietary yttrium level, Yfaeces is the faeces yttrium level, Ddiet is the dietary nutrient level, and Dfaeces is the faeces nutrient level.The apparent digestibility coefficients (ADCs) of dry matter, protein, lipid, fiber, chitin, ash, phosphorus, amino acids, fatty acids, and gross energy for the test ingredients and diets were calculated as follows , 53. (1)Dcontr is the % nutrient (or kJ g−1) of control diet (dry matter basis) and Dingr is the % nutrient (or kJ g−1) of insect ingredient (dry matter basis).The apparent digestibility coefficients of the test ingredient  were calculated according to Bureau et al.  as follot-test. All statistical analyses, including Pearson correlations between dietary nutrient levels in insects and ADC values, were performed by the SPSS 22  software package.All data are presented as means ± SD and subjected to one-way analysis of variance (ANOVA) to determine whether significant differences occurred among treatments. If a significant difference was identified, differences among means were compared with Tukey's post hoc test and two-sample 2S2O3 solution using a 1% starch indicator [The peroxidation and microbiological status of the diets were evaluated during a six-month period of storage. The experimental feeds were stored in the storage room of the fish rearing facility. Samples were collected at appropriate times and stored at −80°C until analysis. The peroxide value (POV) is defined as the reactive oxygen content expressed in terms of milliequivalents (meq) of free iodine per kilogram of fat. It is determined by titrating iodine liberated from potassium iodide with sodium thiosulphate solution. Briefly, 50 g of each feed sample was extracted with petrol ether (30–40°C) and evaporated at 40–45°C. The etheric fat solution (approx. 0.3 g fat) was vacuum evaporated and mixed with 0.5 g of KI (powdered) and 10 mL of an acetic acid and chloroform (3 : 2) solvent mixture. Titration was carried out with 0.1 M Nandicator .Enterobacteriaceae, E. coli, Salmonella, and Clostridium perfringens cell numbers were measured to assess the microbial contamination of feeds. Samples were taken on weeks 1, 4, 8, 16, and 21 of the storage period. An aliquot of each sample (1.0 g) was weighed under sterile conditions into 9 mL peptone salt solution for the determination of mesophilic aerobic microbes and mold or into an enrichment broth in the case of Enterobacteriaceae, E. coli (EE-Mossel broth), Salmonella (Rappaport Vassiliadis (R.V.S.) broth), and Clostridium (DRCM broth). The samples were vortexed intensively for 30 s and allowed to dissolve, and from the salt solution, serial decimal dilutions were prepared and 0.1 mL of each dilution was spread onto dishes containing Dichloran Rose-Bengal Chloramphenicol (DRBC) agar for mold and Plate Count Agar (PCA) for mesophilic aerobic microbes and incubated at 25°C for 2–3 days. The enrichment broths were incubated at 35°C for 24–48 hours. For the identification of Enterobacteriaceae, E. coli, Salmonella, and Clostridium Violet Red Bile (VRB) agar, FluoroBio® VRBL agar, Harlequin™ Salmonella ABC agar, and Tryptose Sulfite Cycloserine (TSC) selective agar were used, respectively. If any of the investigated bacteria were identified from the enrichment broth, the quantitative analysis was carried out from the original sample by using the selective media. All experiments were performed in triplicates.The mesophilic aerobic microbial cell count, the mold, The apparent digestibility coefficients of dry matter (ADCDM), crude protein (ADCPr), crude fat (ADCF) and gross energy (ADCGE), essential amino acids (ADCEAAs), fatty acids (ADCFA), phosphorus (ADCP), crude ash (ADCA), and chitin (ADCCh) of the diets were estimated based on the digestibility trial and sampling of faeces. The results of different test diets and the control diet are shown in p < 0.001) higher than those of MW. The chitin digestibility was relatively high for BSL (96.05%) and significantly differed from other meals. In respect of the digestibility of several micronutrients of the insect meals, the ADC values are summarized in Following the calculated ADC values of the diets, the ADC of the test ingredients could be determined using the equations presented in p > 0.05), the acid detergent fiber (ADF) levels in the MW meal and also in its experimental diet  were significantly higher (p < 0.01) compared to the other tested insect meals and diets, respectively  between the control diet and the experimental diets after four weeks of storage, where the highest value was detected in the control diet (3.98 ± 0.16 meq/kg fat). Moreover, the POV of the BBF diet was significantly lower than those of the BSL and MW diets . The hig2–103, except for the BSL feed, which was outstanding in terms of the number of mesophilic aerobic bacteria, containing 2–3 orders of magnitude of more microorganisms than the other samples. Nevertheless, there was a significant difference between the samples (p < 0.05) except for MW and CONTR. During the 21-week storage period, the total mesophilic aerobic bacterial cell counts did not change much from a microbiological point of view, as only one order of magnitude increase or decrease was observed, but for BBF and BSL, the cell numbers at the end of the storage were statistically significantly higher (p < 0.05) compared to the first week. The cell numbers in the MW and CONTR samples did not change significantly during the storage, although a slight decrease was observed in the MW sample , E. coli, and Clostridium perfringens were not found (<102 CFU/g) in the samples during the storage period.In a more detailed examination, the number of molds and the The digestibility of the feed ingredients and the availability of nutrients are the most important factors in fish nutrition. In the current study, the ADCs of three possible insect protein sources were assessed in a digestibility trial for African catfish juveniles.Dicentrarchus labrax) (91–93%) ([Oncorhynchus mykiss) (87–91%) [Psetta maximus) (81.1%) [Acipenser baerii) [Gryllus bimaculatus) was fed. In terms of ADC of the ingredients, the protein digestibility of the BSL is in line with data presented for hybrid grouper (81–88%) [BSL is one of the most frequently studied insects in fish nutrition. In the current study, the ADCs of dry matter, crude protein, and gross energy in the BSL diet were not significantly different from the reference control feed, while others such as ADCF and ADCP were significantly higher compared to the control . The ADC91–93%)  , and Atl(87–91%) , but it  (81.1%)  and clos baerii) . African baerii)  when cri(81–88%) , higher (81–88%)  and lowe(81–88%) , and Atl(81–88%) .The lipid ADC was higher than the protein digestibility value. Lipids are a preferable energy source to carbohydrates and are almost completely digestible by fish. The high ADCF indicates a strong ability of African catfish to utilize the lipid components of insects. Comparable high ADCFs of the diets and ingredients have been reported for Atlantic salmon, rainbow trout, turbot, and hybrid grouper , 55, 56.Ictalurus punctatus) compared to our results obtained for African catfish. However, investigated insects are still more digestible than several plants such as maize in the case of striped catfish  [The ADCs of amino acids in the diet were comparable to those reported for Atlantic salmon , rainbowthalmus)  and sunfthalmus) . Regardithalmus) , 61 demoArgyrosomus regius), a limited capacity to utilize MW was found, with a 10% dietary inclusion already resulting in significant impairment of fish digestive capacity and growth performance [Sparus aurata), 79–87% was determined by Piccolo et al. [All ADC values determined for the MW diet were the lowest among the tested diets in this study and differed significantly from the control diet in respect of all investigated macro- and micronutrients . Based oformance . There aformance  reportedo et al. . These vo et al.  for raino et al. .Pseudoplatystoma reticulatum) [The ADC data calculated for the BBF diet were not significantly different from the control diet in respect of dry matter, crude protein, crude ash, and gross energy. At the same time, a significant increase was found for ADCF and ADCP. Generally, ADCs of BBF meal were significantly lower than those of BSL, but higher than those of MW. Compared with other feed ingredients, the ADCPr data indicates that BBF meal is better digested than plant feedstuffs. Such ADC data were reported for several catfish species like striped surubim (culatum)  or stripculatum)  except fβ-(1/4) linkages. Chitin is known to interfere with protein use [The digestibility of nutrients may depend on other components also present in insects. One such compound is chitin, a nondigestible fiber, that is, a polymer of N-acetyl-glucosamine with tein use . Based otein use  found 4.tein use  and 13.7tein use . In thisp > 0.05) from each other, suggesting that the chitin level was not the primary factor influencing the markedly lower ADCs obtained for the MW meal.The role of chitin in feed digestion may be influenced by several factors, considering that chitin has an immunostimulatory effect to the intestine , 70 and Imbrasia belina) meal; however, the results showed no discernible trend with increased mopane worm inclusion [The digestibility of chitin was determined in the current study, together with other nutrients. The ADCs for chitin  show thanclusion .p < 0.01). The ADF content of MW meal was much higher (27.7% d. m.) than the 7–11% and 7.2% reported by Marono et al. [Whole insects contain variable but significant amounts of fiber as measured by ADF, although the components that make up the ADF fraction have not yet been fully characterized . Finke  reportedo et al.  and Picco et al. , respectp < 0.05) to the ADF content in an in vitro digestibility study of T. molitor and H. illucens insect meals [in vitro digestibility of organic matter  and lower in vitro digestibility of crude protein  in experiments using crude enzyme extracts from digestive tracts of meat-type ducks [Clarias gariepinus) juveniles [Many studies have shown that as ADF increases, digestibility and nutrient availability decreases . Crude pct meals . Pearsonpe ducks . Similaruveniles .Another factor that may impair insect protein digestibility is the release of insects' proteases and phenoloxidases during the grinding of whole insects . PhenoloEnterobacteriaceae (4.2–7.8 logCFU/g), bacterial endospores or spore-forming bacteria (0.5–5.8 logCFU/g), lactic acid bacteria (LAB) (5.2–9.1 logCFU/g), psychrotrophic aerobes (4.5–7.2 logCFU/g), and yeasts and molds (3.4–7.2 logCFU/g) [E. coli to a lesser extent, which is similar to our results. The observed differences between the microbial characteristics of the investigated samples might be explained by the distinct insect types, geographic locations, and different rearing and postharvest processes. During storage, a fraction of the initially present microbial species will become dominant [The intestinal tract of insects harbors high numbers of microorganisms, which play an important role in the insects' life activity, mainly in the digestion of feed , 81. TheogCFU/g) . HoweverogCFU/g) , 81. De ogCFU/g)  reportedogCFU/g) –85. AfteogCFU/g) . In a twogCFU/g)  found hidominant . Vandewedominant  have fouThe insect microbiota is complex and contains a great variety of different microorganisms due to the abovementioned effects. These and the postharvest processes of feed production could play an important role in the distinct results obtained for feeds . HoweverThe oxidation of fat in the experimental diets was low during the storage period compared to rancid oils , despiteThe apparent digestibility coefficients determined for the BSL meal in African catfish hybrid juveniles agreed with those reported earlier for other fish species. Based on our digestibility experiments, the BBF meal also seems to be well digestible for African catfish, similarly to BSL. However, significantly lower digestibility coefficients were obtained for the MW meal in the current study. An interaction effect between the digestibility of various insect meal ingredients and between the ADF levels was indicated by correlation analyses. Overall, our data suggest that replacing fish meal with up to 30% BSL or BBF meal in the African catfish diet would not cause difficulties in the digestibility and utilization of nutrients. On the other hand, the tested MW meal proved less suitable for African catfish, partly due to its high ADF content and possibly also due to certain enzymes that may occur among its ingredients. From the feed safety aspects, the BSL containing diet showed a potential for increasing numbers of mesophilic aerobic bacteria during storage that would require further microbiological characterization of this type of diet, regarding its origin, production, and postharvest processes.


To estimate the association between Social Determinants of Health  and caries indicators in Chile's Metropolitan Region preschool children.A multilevel cross-sectional study of Social Determinants of Health (SDH) and caries in children aged 1 to 6 years in Chile's Metropolitan Region was conducted in 2014–2015, with three levels: district, school and child. Caries were assessed by the dmft-index and the prevalence of untreated caries. The structural determinants analyzed were Community Human Development Index (CHDI), urban/rural location, school type, caregiver's education and family income. Poisson multilevel regression models were fit.The sample size was 2,275 children from 40 schools in 13 districts. While the highest CHDI district had an untreated caries prevalence of 17.1% (12.3–22.7%), in the most disadvantaged district it was 53.9% (95% CI 46.0–61.6%). As family income increased, the probability of untreated caries prevalence decreased (PR = 0.9 95% CI 0.8–1.0). Rural districts had an average dmft-index of 7.3 (95% CI 7.2–7.4), while in urban districts, it was 4.4 (95% CI 4.3–4.5). Higher probabilities of untreated caries prevalence (PR = 3.0 95% CI 2.3–3.9) were observed in rural children. Greater probabilities of untreated caries prevalence (PR = 1.3 95% CI 1.1–1.6) and prevalence of caries experience (PR = 1.3 95% CI 1.1–1.5) were observed in children whose caregivers had a secondary educational level.A strong association was observed between the social determinants of health, specifically the structural ones, and the caries indicators studied in children of the Metropolitan Region of Chile. There were notable differences in caries between districts according to social advantage. Rurality and caregiver's education were the most consistent predictors.The online version contains supplementary material available at 10.1186/s12903-023-02778-6. Dental caries is an ongoing and critical public health problem worldwide, with prevalence up to 90% in children and adolescents in South America , 2. The The Commission on Social Determinants of Health of the World Health Organization (CSDH-WHO) has emphasized the relevance of studying structural and intermediate social determinants of health to understand the causes of the unequal distribution in population's health status and implement public policies considering them .Several studies have shown a strong association between both structural and intermediate social determinants with oral health in children , 5–11. DMost recent systematic reviews report that there is evidence of sufficient quality to establish an association between a lower level of parental education and an increase in early childhood caries in preschoolers –13. HoweDespite the fact that Social Determinants of Health (SDH) studies in Latin-American children are more limited, some reports have suggested that oral health differences are strongly associated with family socioeconomic level, caregivers’ educational level, family income and access to fluoridated water –18. HoweChile is one of the most economically developed countries in the Latin America ; howeverTo date, the relationship between Chilean children’s oral health status and SDH is unknown. Our study aimed to estimate the association between Social Determinants of Health  and caries in preschool children in Chile’s Metropolitan Region, the most densely populated area of the country.This manuscript reports our study using STROBE  guidelines  and the A multilevel cross-sectional study was conducted in 2014–2015 with three levels: district (administrative unit in Chile), school (preschools and kindergarten) and child  in each district. Thirteen districts were randomly selected within CHDI quintiles. Then, forty schools were selected within each district, through simple random sampling using a random number generator app. All selected districts participated, but the private pre-schools of the highest CHDI district declined the invitation; thus, that district had only public pre-schools participating. Estimation of the necessary number of children and pre-schools to include considered the expected Intraclass Correlation Coefficients (ICCs) and Variance Inflation Factors (VIFs) based on national studies. All eligible children of each school were invited to participate, and refusal (by parents) was less than 1%.Dental examinations were carried out between March 2014 and April 2015 in accordance with WHO guidelines . Two cliAll children were examined to create three dental indicators of caries: (1) Untreated caries prevalence (UCP) corresponding to decayed teeth at the time of the examination, not including white spot. (2) Prevalence of caries experience  equal to 0 if dmft = 0, or equal to 1 if dmft ≥ 1; dmft corresponding to the sum of decayed, missing or filled deciduous teeth, by child and (3) Caries damage count (dmft ≥ 1) corresponding to a truncated positive count variable of dmft, excluding dmft equal to zero. The truncated analysis was done because the variables that explain having one more tooth with caries may be different from those that explain the possibility of ceasing to be healthy, although the unit of change mathematically in both cases is one.Five socioeconomic indicators were included as SSDH: 1) Community Human Development Index (CHDI), (2) urban/rural location of the district, (3) school type, (4) caregiver’s education, and (5) family income , secondary (8 to 12 years), and post-secondary (more than 12 years). Family income at the examination was considered as an ordinal variable of six categories, with the lowest category at the Chilean monthly minimum salary CLP $225,000 (approximately USD $300), and each category increasing in increments of CLP $500,000 (approximately USD $700).Ten explanatory variables were included as ISDH: (1) educational programs of oral health (available or not), (2) school topical fluoride program (available or not), (3) healthy snacks kiosk (yes/no), (4) biological sex (boy/girl), (5) child age, (6) type of health insurance (public or private), (7) tooth brushing frequency (times a week), (8) gingivitis prevalence , (9) ever having a dental visit (yes/no), (10) current use of a feeding bottle (yes/no), and (11) dietary intake. Dietary intake considered the consumption of sugar-sweetened beverages, candy, sugar-sweetened cookies or cakes, honey or jam .p < 0.01), which found fixed effects to be preferable to random effects. For each model, we used random intercepts for school level and fixed effects for district level  and caries damage count dmft ≥ 1). Then, we fitted a multilevel regression model to incorporate cluster‐specific fixed effects at the district level and random effects for the school level, according to the data structure , 27. We . Then, wAs suggested by Monsalves et al.  we incluThis study was approved by the Research Ethics Committee of the Faculty of Medicine, University of Chile, Chile. A letter of invitation was sent to each school selected in the 13 districts included in our study. Subsequently, a letter of informed consent was sent to all parents or caregivers of eligible children in the schools that agreed to participate. Finally, parents provided the signed informed consent for examination, and children provided verbal assent.A total of 2,275 children between ages 1 and 6 years in 13 districts in the Metropolitan Region were examined. Table Overall, the mean dmft-index was 1.9 (95% CI 1.8–2.0) and untreated caries prevalence was 36.0% (95% CI 34.0–37.9). Differences were observed as age increased. The highest difference was observed between two-year-old mean dmft-index of 0.8 (95% CI 0.6–1.1), and three-year-old mean dmft-index of 1.6 (95% CI 1.3–1.8). Rural districts were the most affected, with an average dmft-index of 7.3 (95% CI 7.2–7.4), while in urban communities it was 4.4 (95% CI 4.3–4.5) in the adjusted model.There were important differences in caries indicators between districts, especially in UCP Table . The mosTable Community human development index (CHDI), school type, family income and health insurance type showed a social gradient, but these differences were not conclusive for all caries indicators Table . There wAdditionally, Fig. PR = Prevalence Ratio. Some districts do not have estimates in the final model because the effect at this level was explained by the co-variables of the final model.Our study aimed to estimate the association between social determinants of health , and untreated caries prevalence and experience  in preschool children in Chile’s Metropolitan Region. Our results support the association between structural social determinants of health and the caries indicators studied in Chilean children. The social disparities, measured through the structural social determinants of health explained in large part the unequal distribution of caries among preschool children in Chile.Globally, analyses of structural social determinants related to oral health in children are scarce, even though UCP in deciduous teeth peaks at almost 40% at age 5 . To dateOur study has some limitations. This study does not represent the entire reality of Chilean children, since there are many regions of Chile that have higher rates of poverty, rurality, and vulnerability than the Metropolitan Region. In addition, the limitations associated with the different schooling coverage throughout the study group should be considered. In Chile there is low school coverage in the group under four years old (between 42% in 2014 and 49% in 2021). However, this increases to more than 90% in six-year-olds . BecauseThere are also limitations related to the caries indicators analyzed. Not cavitated caries or white spot were not considered, including them could increase the differences between the children. In addition, it is important to be careful when analyzing the differences between indicators. For example, one can define ‘caries-free children’ as those that have no UCP  or no prevalence of caries experience  at the moment of the examination. However, only those with no prevalence of caries experience  may be defined as “really caries-free”. This is because untreated caries prevalence obscures the history of fillings done before the measurement. Untreated caries prevalence may be determined by access to oral-health services rather than the disease itself, and in the specific case of Chile, 25.7% of the total number of people waiting for health care are waiting for oral-health services . Thus, iAs expected, caries indicators studied were associated with social determinants. But poor oral health status was explained strongly and consistently by structural determinants more than by intermediate determinants. Similar studies concluded that the former are better at explaining the health differences between individuals than the latter , 5–18. DWe observed higher caries damage count (dmft ≥ 1) in preschoolers whose parents have lower educational levels, in accordance with previous international studies –9, 12–14Districts with lower CHDI influenced the possibility of having poorer caries indicators. This association was less robust in our study than in other reports by other Latin-American authors –37. HoweIn relation to the intermediate social determinants of health analyzed, our findings support that age is an important variable in the possibility of having UCP (3.7 IC95% 2.2–6.3), dmft-prevalence (3.7 IC95% 2.2–6.4) and caries damage count (1.8 IC95% 1.2–2.6) from 2 years, increasing risk for each year. The greatest increase in risk of no longer being a caries-free child  was noted when a child is two years of age, settling down by the child’s 3rd birthday. This does not mean that age is more relevant than social stratification, since age-related progression in poorer oral health comes along with social disadvantage accumulation, described by some authors as embodiment . From a The use of feeding bottle and toothbrushing frequency were not consistently associated with the caries indicators of our study, in accordance with findings reported by other authors , 48. WheThe caries differences among Chilean children were explained mainly through structural determinants. Rurality and parental education were the structural determinants most strongly associated with caries indicators, and district-level factors explained much of the variation in caries indicator disparities between districts.These findings emphasize that the distribution of caries in a population can be a sensitive predictor of country-level disparities. Therefore, in addition to current policies for children's health, new strategies should focus on children from rural areas, addressing contextual structural determinants, and on children from urban areas addressing proximal determinants .Additional file 1. 1. Equations for multilevel mixed effects Poisson regression models used in the study. 2. Variance partition coefficient and 95% confidence intervals of random effects between- district and between- schools within district.


Hepatopancreaticoduodenectomy (HPD) is one of the most complex procedures, and it is very rarely reported. Laparoscopic HPD (LHPD) is even rarer. To date, there are only 3 reports of LHPD for locally advanced gallbladder cancer (GBC) or extrahepatic cholangiocarcinoma (ECC). This is the first report of LHPD for synchronous GBC and ECC.A 75-year-old female patient complained of jaundice for 2 weeks without fever or abdominal pain. She was diagnosed with synchronous GBC and ECC. After a comprehensive preparation, she underwent a laparoscopic pancreaticoduodenectomy and resection of hepatic segments of IVb and V, and her digestive tract reconstruction followed Child’s methods. She was discharged on the 12th day postoperatively without pancreatic leakage, biliary leakage, or liver failure.LHPD is safe and feasible for selected cases of GBCs or ECCs. Hepatopancreaticoduodenectomy (HPD) is one of the most complicated operations which includes hepatectomy and pancreaticoduodenectomy. This operation was first reported in 1974 by Kasumi for locally advanced gallbladder cancer (GBC) , 3 for tA 75-year-old female patient complained of jaundice without fever or abdominal pain for 2 weeks and was diagnosed with ECC with GBC by enhanced CT and MRI. She denied any history of cardiovascular or pulmonary system problems. Her physical examination was negative except for jaundice of her skin and sclera. Her routine laboratory tests were as follows: hemoglobin 108 g/L, total bilirubin 222.8 μmol/L, direct bilirubin 158 μmol/L, plasma albumin 35.2 g/L, ALT 297 U/L, AST 192 U/L, ALP 403 U/L, and γGGT 394 U/L. Her tumor markers were normal, except for a mildly elevated Ca19-9 of 34.06 U/ml. Her hemostatic function was normal. An enhanced CT and MRI revealed that there was irregular thickening of the common bile duct wall and the gallbladder . Her recovery was smooth without pancreatic leakage, biliary leakage, or liver failure. She was discharged on the 12th day postoperatively. The pathology revealed synchronous adenosquamous carcinoma of the gallbladder and common bile duct. This pathological result was finally given after a comprehensive discussion. The diagnosis of adenosquamous carcinoma was based on immunohistochemistry which showed both squamous cell carcinoma and adenocarcinoma. The diagnosis of dual original carcinoma instead of GBC with seeding metastasis to a common biliary duct was based on the fact of extensive lesion of the lower biliary duct without a clear boundary.The indications for hepatopancreatoduonectomy (HPD) are locally advanced gallbladder cancer (GBC) and locally advanced extrahepatic cholangiocarcinoma (ECC) . HPD is As laparoscopic techniques have progressed, more and more complicated operations are completed by laparoscopy , 14 withAccording to the published cases and our experience, LHPD is safe and feasible by specially skilled surgeons. LHPD should be an option for selected patients with GBC or ECC.


Thalidomide is applied in therapy for refractory Crohn's disease (CD) in adults, but systematic and rigorous clinical evidence is scant. The aim was to provide theoretical references for the efficacy of thalidomide in the therapy for refractory CD in adults. A double-center, double-blind, placebo-controlled, randomized clinical trial of refractory CD in adults in two inflammatory bowel disease centers in China. In the double-blind trial, patients were randomly assigned to 100 mg of thalidomide or placebo daily for 8 weeks. The primary outcome was considered as the clinical remission rate calculated based on the Crohn's disease activity index at the eighth week following thalidomide or placebo treatment. In open label, non-response to placebo was additionally treated with 8 weeks of thalidomide; all responders were continuously treated with thalidomide until the 48th week.P < 0.001). After a 48-week follow-up, the continuous treatment rate of thalidomide was 46.3% (19/41). Adverse events during the whole process were reported in 58.5% of patients, mainly involving drowsiness, rash, and peripheral neuropathy that were mild and tolerable.Twenty-five patients were randomly assigned to each group. At the eighth week, the clinical remission rate in the thalidomide group was significantly higher than that in the placebo group (68.0% [17/25] vs 16.0% [4/25]; relative risk, 4.2; 95% confidence interval, 1.8–10.9, Thalidomide can be used in the induction and maintenance therapy of refractory CD in adults. And it could be one of the treatment options for refractory CD. Crohn's disease (CD) is an incurable chronic non-specific inflammatory bowel disease associated with environmental, genetic, infectious, and immune factors. The incidence and prevalence of CD have increased sharply throughout the world, especially in Asia . CurrentIn the 1950s, thalidomide was once used as a sedative and antiemetic drug in the treatment of morning sickness but was later removed from the market because of teratogenic adverse reactions. In 1965, an Israeli dermatologist successfully cured skin lesions of leprosy patients using thalidomide, suggesting its potential anti-inflammatory effect , 10, herThis was a double-center, double-blinded, placebo-controlled, random clinical trial and the allocation ratio was 1:1. Patients paying consecutive visits for refractory and active CD at the Sixth Affiliated Hospital, Sun Yat-sen University  and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine  from August 2016 to January 2020 were recruited. All recruited patients needed to meet all the inclusion criteria and none of the exclusion criteria.Inclusion criteria: (i) diagnosis of CD according to the guidelines proposed by the European Crohn’s and Colitis Organization in 2015; (ii) aged 18–50 years; (iii) have refractory CD; (iv) colonoscopy-revealed terminal ileum or colorectal lesion; (v) active stage of CD; (vi) informed consent for clinical trial of thalidomide therapy. Refractory CD was defined as treatment failure and/or intolerance to steroids, immunosuppressants, or biological agents. CD in the active stage was defined as a minimum Crohn's disease activity index (CDAI) of 150 points. Treatment failure was defined as meeting any one of the following criteria: (i) CD still in the active stage after a 4-week (or longer) oral administration of ≥0.75 mg/kg/d prednisone or the dose of prednisone could not be reduced to 10 mg/d after a 3-month treatment although CD was relieved; (ii) active CD maintained after a 4-month (or longer) oral administration of thiopurine drugs (azathioprine ≥2 mg/kg/d or 6-mercaptopurine ≥1 mg/kg/d) combined with or without steroids or non-response to the maintenance therapy; (iii) active CD maintained after a 3-month (or longer) intramuscular or subcutaneous injection of methotrexate ≥25 mg/week combined with or without steroids or non-response to the maintenance therapy; (iv) active CD maintained after induction therapy with infliximab for 14 weeks or non-response to the maintenance therapy; (v) active CD maintained after a 12-week induction therapy with adalimumab six times or non-response to the maintenance therapy.Exclusion criteria: (i) patients showed symptoms of digestive tract obstruction; (ii) women were pregnant or lactating or planning for pregnancy during the study; (iii) patients with central nervous system diseases; (iv) patients showed cardiopulmonary, liver, or kidney insufficiency; (v) patients showed malignant tumors; (vi) patients showed active tuberculosis, active viral hepatitis, Epstein-Barr virus infection, severe immunodeficiency, organ transplantation history, or severe infection; (vii) the last infliximab treatment was performed within the previous 8 weeks; (viii) the last adalimumab treatment was performed within the previous 4 weeks; (ix) patients took steroids for >20 mg/d; (x) patients participated in other clinical trials.The patients enrolled were then randomly assigned into thalidomide group and placebo group for 8 weeks. Based on the results of previous retrospective studies, patients were recommended to take 100 mg/d thalidomide (or placebo). After an 8-week treatment of thalidomide or placebo, those in the thalidomide group who did achieve clinical response were continuously treated with 100 mg/d thalidomide for maintenance therapy until the 48th week in open label. The patients in the placebo group who did not achieve clinical remission were switching to thalidomide treatment (100 mg/d) for an additional 48 weeks in open label. The patients were followed up at the 12th, 24th, 36th, and 48th weeks  and the therapeutic efficacy and adverse events were recorded. To minimize the sedative effect of thalidomide, thalidomide was recommended to be taken before sleep. In addition, immunosuppressive agents were prohibited during the whole process of the clinical trial. Patients taking glucocorticoids before recruitment were asked to make a gradual reduction in glucocorticoids with a weekly decline of 5 mg until drug discontinuation and the additional use of glucocorticoids was prohibited.Withdrawal criteria: (i) loss to follow-up or request for withdrawal by patients themselves; (ii) unintended pregnancy; (iii) intolerable adverse events; (iv) unsuitable for participating in the current clinical trial as determined by the investigators.The patients were visited at the end of the 0, 4th, and 8th weeks during the double-blind phase and 12th, 24th, 36th, and 48th weeks  during the open-label phase for examining clinical symptoms and signs , laboratory test results , body mass index (BMI), CDAI scores, and inflammatory bowel disease questionnaire (IBDQ) scores. In detail, endoscopy was performed at baseline and 12th and 48th weeks  for recording the simple endoscopic score for Crohn’s disease (SES-CD).The primary outcome was considered as the clinical remission rate calculated based on the CDAI score at the eighth week following thalidomide (100 mg/d) or placebo treatment. Clinical remission was defined as CDAI falling to <150 points.Secondary outcomes included CDAI scores, the response rate, CRP, and ESR at the 4th and 8th weeks, SES-CD scores, the presence of healed mucosa at the 12th week , and the incidence of adverse events.Disease response was defined as a minimal decline in CDAI of 100 points or CDAI <150 points. SES-CD scores calculated by colonoscopy of 0–2 indicated healed mucosa.Any adverse event at each visit was comprehensively assessed, including medical history, vital signs, physical examination, laboratory tests, etc. Because peripheral neuropathy was an adverse event associated with thalidomide use, a complete examination was performed using a standard assessment sheet, particularly for signs and symptoms associated with peripheral neuritis. Moreover, electromyography was performed at Week 8 for peripheral neuropath. In particular, sensory and motor conduction of the median nerve, ulnar nerve, peroneal nerve, and sural nerve were assessed by electromyography. Thalidomide was discontinued if refractory CD patients had both clinical symptoms and electromyographic changes at the same time; otherwise, they were independently monitored by neurologists. Severe adverse events were defined as events during the study that required hospitalization or extended hospital stay, caused disability or impaired ability to work, were life-threatening, death, or congenital malformations.Human chorionic gonadotropin blood test was performed before recruitment and at every visit for all females of childbearing age. Thalidomide should be discontinued immediately once pregnancy is determined and the induction of labor should be assessed by an obstetrician or a gynecologist.According to previous studies on thalidomide treatment for CD, we assumed that the clinical remission rate at the eight week was 60% in the thalidomide group and 20% in the placebo group. Then, a total of 46 refractory CD patients were needed in the present study based on the criteria of α = 0.05, β = 0.2 by using Fisher's precision probability test. Following a withdrawal rate of 10%, a total of 50 patients were recruited.A randomization list with blocks of two was computer-generated by an independent team of researchers. Thalidomide and placebo were independently produced by a pharmaceutical factory  and sequentially labeled with the same appearance and dose (25 mg/tablet), which could not be distinguished from the drug container. All investigators and patients were blinded for the research and outcomes during the first 8 weeks.All recruited patients were informed about the risk of teratogenicity, and contraception was required among female and male patients of reproductive potential until 6 months after the trial had ended. All patients signed a written informed consent before the trial.This clinical trial was approved by the Ethics Committee of the Sixth Affiliated Hospital, Sun Yat-sen University (E2016023) and registered in the National Institutes of Health (NCT02998827).t-test, or otherwise unpaired two-samples Wilcoxon test or Wilcoxon matched-pairs signed rank test was performed. Enumeration data were expressed as absolute value and percentage. Paired enumeration data were compared using the Fisher's exact test or Yates' chi-square test; otherwise, the McNemar exact test was performed. The correlation between baseline characteristics and clinical remission was assessed by introducing the multivariate Logistic regression model. Two-tailed P < 0.05 was considered as statistically significant.SPSS 26.0 was used for statistical analyses. An intention-to-treat analysis was performed for every subject. Measurement data were expressed as mean ± standard deviation and normally distributed paired data were compared using the paired n = 25) and the placebo group (n = 25). In the thalidomide group, 22 (88%) patients completed the 8-week intervention (1 withdrew because of adverse events and 2 were lost to follow-up due to insufficient compliance). In the placebo group, five patients dropped out of the trial because of disease aggravation. The allocation of patients is depicted in P > 0.05, A total of 50 refractory active CD patients were randomly assigned to the thalidomide group (P < 0.001). The mean CDAI score, clinical response rate, and decline of CRP were significantly higher in the thalidomide group at the eighth week compared with those in the placebo group (P < 0.05). Although the above indexes were superior in the thalidomide group at the fourth week to those in the placebo group, no significant differences were obtained (P < 0.05)  .P = 0.005), while the incidence of serious adverse events showed no significant difference between the two groups (P = 0.992)  .Sixteen CD patients in the placebo group who did not achieve clinical remission at the eighth week were additionally treated with thalidomide for another 8 weeks in the open-label trial and eight (50.0%) achieved clinical remission in the end.P = 0.038). Finally, 80.5% (33/41) of patients medicated with thalidomide in the long-term follow-up achieved clinical remission, with a mean duration of 5.9 ± 4.7 weeks. The continuous treatment rate of thalidomide of patients in the thalidomide group and the placebo-switching-to-thalidomide group at the 48th week was 48.0% (12/25) and 43.8% (7/16), respectively; mucosal healing was maintained in 8.0% of patients (2/25) in the thalidomide group and 6.3% (1/16) in the placebo-switching-to-thalidomide group. There were 6, 10, and 6 CD patients who dropped out due to loss to follow-up, disease aggravation, and adverse events, respectively.Response CD patients in the thalidomide group and those in the placebo-switching-to-thalidomide group were followed until the 48th week. The overall clinical remission rate of patients  at the 12th week was 60.9% (25/41). A total of seven patients achieved mucosal healing . The SES-CD score after a 12-week treatment of thalidomide significantly decreased compared with that at baseline  of CD patients in the thalidomide group developed adverse events and 62.5% (10/16) in the placebo-switching-to-thalidomide group developed adverse events. A total of six patients discontinued medication due to adverse events, including four with peripheral neuropathy, one with rash, and one with dizziness. Drowsiness (11 cases) was the most common adverse event, followed by rash (9 cases), peripheral nerve symptoms (7 cases), and constipation (5 cases), and others included swelling of lower limbs, dizziness, and menstrual disturbance. Among the seven patients with peripheral nerve symptoms, four showed positive electromyography results and were partially or completely alleviated after withdrawal.Biological agents have improved the clinical outcomes of CD patients losing response to steroids and immunosuppressants. However, some may not respond to biological agents or lose response. In addition, it remains a challenge to treat refractory CD patients developing secondary loss of response . In ChinP < 0.001). At 12 weeks, the overall clinical remission rate was 60.9% (25/41). A total of seven refractory CD patients achieved mucosal healing. Concerning the comparable clinical remission rate with current biological agents, thalidomide can be an option for refractory CD patients. Consistently with previous findings, the use of infliximab in refractory CD patients did not influence the time to achieve clinical remission .


Aims: Data about the prognostic interplay between mitral regurgitation MR and left ventricular (LV) function in the outcome of patients admitted with acute heart failure (AHF) are scarce. We evaluated the prognostic impact of MR severity and LV function on mortality and on recurrent heart failure hospitalization (re-HFH) in patients admitted with AHF. Methods and Results: In total, 6843 patients admitted with AHF were evaluated: 2521 patients with LV ejection fraction (LVEF) ≤ 40% (reduced LVEF), 1238 of them (51%) having ≥moderate MR; and 4322 with LVEF > 40% (preserved LVEF), 1175 of them (27%) having ≥moderate MR. One-year mortality and re-HFH rates were higher in patients with ≥moderate MR unrelated to the baseline LV function . After multivariable analysis, only reduced LVEF, and not the severity of MR, predicted mortality risk ; p < 0.001 for both. There was an increased risk for re-HFH in each group ; p < 0.001 for all. Conclusions: In patients admitted with AHF, the LV function is the main prognostic determinant for mortality after 1 year. Significant (≥moderate) MR is associated with an increased risk of recurrent hospitalization. Mitral regurgitation (MR) is a common finding in patients with heart failure  and manyIn contrast to the extensive literature about the prognostic impact of MR in patients with chronic heart failure ,9, data The aim of the current study was to evaluate the prognostic impact and the interaction of LVEF and MR severity on one-year mortality and recurrent heart failure hospitalization (re-HFH) in a large group of patients admitted with a diagnosis of AHF to a tertiary center. This study included all patients admitted with a diagnosis of AHF at the Sheba Medical Center between 2008 and 2016. All patients underwent a full echocardiographic evaluation during the first 2 days of admission at their index hospitalization. All echocardiographic examinations were performed by specialized echocardiography technologists and further analyzed and reported by a specialized echocardiographist.The left ventricle (LV) and atrial dimensions were measured according to the ASE guidelines for chamber quantification . LVEF wa2, a narrow vena contracta, mitral A wave dominant flow, and a faint, continuous wave Doppler signal were classified as mild mitral regurgitation, while patients with PISA radius > 1 cm2, vena contracta width ≥ 0.7 cm, mitral E wave dominant flow, pulmonic venous flow reversal, and a dense triangular, continuous wave Doppler signal or a central jet occupying > 50% of the LA area or eccentric jets adhering to the left atrial wall and reaching the posterior LA wall were classified as severe mitral regurgitation. Patients with intermediate findings were classified as moderate mitral regurgitation. Clinical data regarding rehospitalization rates were obtained through a chart review. Mortality data were obtained from the Israeli Interior Ministry records. The study was approved by the respective human research review board of Sheba Medical Center. Patients were not involved in the planning and designing of this study. The grading of MR severity  was performed using a combination of semiquantitative and quantitative assessment, as described by the American Society of Echocardiography guidelines and the European Association of Echocardiography ,16. Spect-test and one-way ANOVA. Categorical data were compared with the use of the chi-squared test or Fisher’s exact test as appropriate. Baseline characteristics, laboratory results, pharmacological treatment, and echocardiography data were compared between patients according to the degree of MR (up to mild or ≥moderate) and then further subdivided according to the LVEF categories during the indexed event. Kaplan–Meier curves were used to calculate the probability of all-cause mortality and recurrent heart failure hospitalization at 1 year for the abovementioned divisions. Multivariable Cox proportional-hazard regression modeling was used to evaluate hazard ratios for the events. Adjustments were made according to clinically important covariates that include demographic status ) and comorbidities , anemia (hemoglobin below 13 gr/dL at men and 12 gr/dL in women), diabetes mellitus, and COPD). A further subgroup-sensitive analysis  for above and below median left ventricular end-diastolic diameter was conducted. We used three different models: unadjusted, adjusted , and adjusted model that excluded BSA.Continuous data are presented as mean ± SD and compared using Student’s p < 0.05. Results of the Cox regression analyses are reported as unadjusted or adjusted hazard ratio (HR) and 95% confidence interval (CI). The statistical analyses were performed with IBM SPSS version 25.0  and RStudio 4.0 . Statistical significance was accepted for a 2-sided The total cohort population comprised 6843 patients , the mean age was 76.25 ± 12.6 years, the mean LVEDD was 5.05 (±0.84) (ranging from 4.04 to 9.1 cm), and the mean LVEF was 46.9 ± 11.9% (ranging from 8% to 70%). A total of 2413 patients (35.2%) presented with ≥moderate MR. Compared with 4430 patients (64.8%) admitted with ≤mild MR, patients with ≥moderate MR were older, more of the female gender, had lower BMI and BSA, with larger LV end-diastolic dimensions (LVEDD) and lower mean LVEF . In addiAs patients with LVEF ≥ 50% and patients with LVEF 41–49% behaved similarly , patientSubsequently, each LVEF group was further divided according to MR severity at admission (mild MR or ≥moderate MR), resulting in four subgroups. The subgroup analysis is presented in The preserved LVEF group comprised 4322 patients; among these patients, 3147 (73%) had ≤mild MR, and 1175 (27%) had ≥moderate MR. Preserved LVEF patients with ≥moderate MR were older and more frequently female. Lower rates of diabetes mellitus, hypertension, COPD, and previous MI were noted in these patients.Preserved LVEF patients with ≥moderate MR were less frequently treated with beta-blockers and ACE/ARB. As the rate of atrial fibrillation/flutter was higher in this group, they were more frequently prescribed oral anticoagulants. 2 vs. 23.6 cm2; p < 0.001) and larger LVEDD . More than 80% of patients with preserved LVEF and ≥moderate MR had SPAP above 40 mmHg compared with 55% of the patients with preserved LVEF and ≤mild MR (p < 0.001). Preserved LVEF patients with ≥moderate MR had significantly larger left atrial areas  had ≥moderate MR, compared with 1283 (51%) who had ≤-mild MR. The reduced-LVEF patients with ≥moderate MR were older, female, with lower BMI, and had a lower LVEF, compared with the reduced-LVEF patients with ≤mild MR. The reduced-LVEF patients with ≥moderate MR had lower rates of diabetes, hyperlipidemia, and IHD with prior MI. A significantly higher prevalence of hypertension, chronic renal failure, and atrial flutter/fibrillation was noted in these patients . 2 vs. 25 cm2, p < 0.001) and larger left ventricular end-diastolic dimensions  (p < 0.001). More than 80% of patients with reduced LVEFs and ≥moderate MR had an SPAP above 40 mmHg, compared with 56% in the reduced-LVEF patients with ≤mild MR group (p < 0.001). The reduced-LVEF patients with ≥moderate MR had significantly larger left atrial areas (28 cmp = 0.028), unrelated to the baseline LV function . After further subgroup analysis, this finding remained true regardless of LVEDD , unrelated to the baseline LV function  underwent mitral valve replacement during the first year of follow-up comprising 49 patients in the preserved LVEF group, of which 42 (85%) had ≥moderate MR at the index admission. Twenty-two patients in the reduced-LVEF group underwent MVR during the follow-up period, and 17 (77%) of them had ≥moderate MR at the index admission.The main findings of our observational study are: (1) mortality and morbidity were still very high in this large contemporary cohort of patients admitted with AHF, despite advances in medical management; (2) when comparing patients according to their degree of MR severity during admission, patients with significant (≥moderate) MR had higher mortality rates regardless of LV size; (3) the major independent predictor of mortality was the LVEF; the lower the LVEF, the higher the mortality rate; and (4) significant MR was an independent predictor of rehospitalization.The interaction between MR and LVEF is complicated since they are intrinsically inter-related. The LVEF is a marker of ventricular remodeling, which is the cause of functional MR owing to LV enlargement and papillary muscle displacement, but functional MR can artificially increase the LVEF through its volume overload ,18,19,20Our study, which evaluated almost 7000 contemporary patients admitted with AHF, reinforces the notion that MR severity is associated with all-cause mortality and extends the current understanding by demonstrating in a large group of patients that mortality is mainly mediated by the baseline LV function ,23,24,25In a similar but much smaller study, Kajimoto et al.  evaluatePecini et al.  retrospeMowakeaa et al.  previousThe recently published ARIC HF  communitPagnesi et al.  recentlyFinally, in the current study, patients with enlarged left ventricles and reduced LV functions had a higher risk of rehospitalization irrespective of MR severity, which probably indicates a more long-standing disease with left ventricular remodeling, while the increased risk of rehospitalization found in patients with smaller left ventricles and ≥moderate MR irrespective of their LV function may be explained by a disproportionate MR severity in relation to the LV size, as proposed by Grayburn .p < 0.001, The main limitation of this study is its retrospective and observational nature using a single tertiary medical center. Second, the quantitative analysis of MR severity was available in only 1105 patients, but it correlated well with the multiparametric analysis , the impact of minor inter-individual variation in the assessment of LV function should not affect the results in a large patient population. Fourth, MR is dynamic in that its severity varies based on loading conditions; however, the main idea behind this study is to assess if MR severity at admission, regardless of the clinical conditions under which it was evaluated, can predict mortality in the long-term follow-up. Fifth, only 0.9% of the patient population underwent mitral valve replacement during the follow-up period, a number that should not affect our findings. We cannot exclude that some patients underwent surgery in a different hospital during this period, but this is very unlikely considering that our medical center is the major surgical referral center in the area. Finally, the reported diagnosis of heart failure was based on the clinical judgment of a treating physician in a real-world tertiary care center. In patients admitted with AHF and undergoing echocardiographic evaluation during hospitalization, the LVEF is the main prognostic determinant for mortality after 1 year. Significant (≥moderate) MR is associated with an increased risk of recurrent hospitalization.


Tri-guna : sattva (signifies a tendency to ‘goodness’), rajas (tendency towards ‘activity’), and tamas (tendency towards “inertia”). This cross-sectional study aimed to understand the differences in the expression of gunas in patients suffering from major psychiatric disorders  and age-gender-education-matched healthy controls . Patients were diagnosed by a psychiatrist using DSM 5 criteria and suffered from the following disorders: depression (n = 30), schizophrenia , obsessive–compulsive disorder , anxiety (n = 16), and bipolar affective disorder . Tri-gunas were assessed using a validated tool  and symptoms were assessed using standard scales as per the diagnosis. Multi-variate analysis of variance (MANOVA) was used to assess the differences in guna scores between HCs and patients, and between patients with different diagnoses. A two-tailed Pearson correlation was performed between the gunas and psychometric scales. Results revealed that HCs had significantly higher sattva traits as compared to patients (except those with OCD). Each psychiatric diagnosis also showed a specific guna configuration: (1) Anxiety disorders and OCD: High sattva-rajas, low tamas; (2) Depression: High sattva-tamas, low rajas; (3) Psychotic disorders (SCZ/BPAD): High tamo-rajas, low sattva. Significant positive correlations were observed between rajas traits and anxiety/OC/positive psychotic symptoms, negative psychotic symptoms and tamas traits, and sattva traits and OC symptoms. This finding has clinical implications, both to develop ways of predicting outcomes of psychiatric disorders, as well as to develop psycho-therapeutic and lifestyle interventions targeting the gunas.Yoga philosophy includes the theory of  Although theoretical attempts have been made to bridge the gap between Eastern and Western philosophies , very feVedas, Upanishads, Patanjali’s Yoga Sutra (P.Y.S.), and Bhagavad Gita (B.G.). Hindu philosophy has six different schools of philosophy, called Darshanas. The two major darshanas are Samkhya and Yoga, which explain the psychological attributes or personality of an individual. This is a dualistic philosophy that postulates two interdependent, simultaneously existing realities: the purusha (consciousness) and prakriti , forming the basis for the existence of prakriti. Prakriti, on the other hand, includes everything that follows the law of change over time, whether it is physical or psychological . In the word triguna, “tri” stands for three, while guna stands for “subtle traits of nature.” The trigunas are named as follows: (1) Sattva, (2) Rajas, and (3) Tamas . Rajas guna is the “active quality.” Tamas guna, on the contrary, is a tendency towards inertia, sleep, emotional bluntness, withdrawal from duties, and inflexibility and rigidity of ideas. It is the “quality of inertia” . Such mind is characterized by high levels of cognitive flexibility with a meta-cognitive awareness about the inter-play of the above mentioned three gunas without attraction or aversion towards them  anxiety  in comparison to age, sex, and education-matched healthy controls (n = 113); (2) To observe the variability in guna patterns across different psychiatric diagnoses; (3) To understand the relationship between psychiatric symptoms  and guna traits in patients. We hypothesized that: (1) patients with psychiatric disorders would have higher rajas and tamas traits and lesser sattva traits than healthy subjects; (2) patients with psychotic disorders would have higher rajas and tamas traits than patients with non-psychotic disorders; (3) symptoms of anxiety and positive psychotic symptoms would correlate positively with rajas traits, whereas symptoms of depression and negative psychotic symptoms would correlate with tamas traits.Thus, the present study was planned with following objectives: (1) understanding 2.2.1.One-hundred and thirteen adults  with major psychiatric disorders  were recruited from in-patient and out-patient services of a tertiary mental health care hospital in Bengaluru, India. Likewise, 113 age-, sex -, and education-matched healthy controls  were recruited from students and staff of nearby educational institutions and universities. They were screened using general health questionnaire (GHQ-12), and a clinical interview with a psychiatrist based on Mini International Neuropsychiatric Interview (MINI) Screen 7.0.2 for DSM-5. 2.2.A cross-sectional study design was followed. The inclusion criteria were: (1) subjects aged 18-70 years who could read and write in English, Kannada, or Hindi; (2) Minimum educational qualification of 7th standard; (3) diagnosis of one of the following psychiatric disorders as per DSM-5 with mild to moderate severity of symptoms (only for patient population): anxiety , depression, obsessive compulsive disorder (OCD), bipolar affective disorder (BPAD), or schizophrenia (SCZ); and (4) healthy controls (HCs) with a general health questionnaire (GHQ-12) score ≤ 3. Exclusion criteria were those with: (1) other co-morbid neuropsychiatric disorders; (2) complete remission of clinical symptoms; (3) organic conditions, (4) protracted physical illness, (5) psychotic illness with severe symptoms, (6) cognitive decline , or (7) intellectual disability.Written informed consent was obtained from the participants and their caregivers. The study was approved by the National Institute of Mental Health and Neurosciences (NIMHANS) Institutional Ethics Committee (No. NIMHANS/EC(BEH.SC.DIV.)/11th Meeting/2018). The work described has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.2.3.2.3.1.Sociodemographic proforma: This included the demographic details of the patients with psychiatric history, comorbid physical illnesses, and their mental status examination findings, and standard psychometric tools as described below.2.3.1.1.The 17-item tool is the most widely used scale for controlled clinical trials in depression, with good reliability, validity, and internal consistency . Cut-off2.3.1.2.The HAM-A is a 14-item, clinician-administered, semi-structured interview designed to assess anxiety symptoms not specific to any disorder. It has demonstrated excellent validity and reliability . The opt2.3.1.3.This widely used 10-item scale rates the severity of obsessions and compulsions. Inter-rater reliability for the OCD severity score has been estimated at 0.95 . Total Y2.3.1.4.The BPRS covers 24 items across all psychosis symptom domains. The scale is sensitive to change and has good reliability and validity . A BPRS 2.3.1.5.To assess positive symptoms in psychotic disorders, it consists of 34 items divided into four positive symptom subscales: hallucinations, delusions, bizarre behavior, and positive formal thought disorder . Clinica2.3.1.6.SANS measures negative symptoms and consists of 22 items divided into five subscales. A global score for each subscale intended to summarize all symptoms was also included . Clinica2.3.2.Socio-demographic Proforma: This included the demographic details with history and clinical examination findings to rule out co-morbidities as per the selection criteria.2.3.2.1.The GHQ-12 is a self-reported screening tool with good reliability. It measures the current mental health status of an individual on a 4-point Likert scale, with a total score of 36 .2.3.3.2.3.3.1.Guna scores  were assessed in all subjects (n = 226) using the VPI. VPI was devised by David Wolf to assess the validity of the Vedic concept of the three gunas or modes of nature, as a psychological categorization system , rajas (R), and tamas (T) for each individual were obtained in percentage in such a way that their total (S + R + T) is 100%.n system . The orin system . While s2.4.guna scores between HCs and patients, and between the patients with different psychiatric diagnoses . Examination of data revealed that all the assumptions for applying MANOVA were met. Two-tailed Pearson’s correlation was applied to correlate the scores of psychometric scales with guna scores of all groups of patients.A psychiatrist applied the standard psychometric scales based on the diagnosis of the patient, whereas the VPI was filled by the participant using an online version of the scale. Help was sought, and responses were corroborated by caregiver while filling up VPI for patients with psychosis (who had BPRS score of 41 or above). Psychometric scales were applied first, followed by VPI. Both assessments were performed in the same session for all participants. We used R version 4.1.2 for analyzing the data. The R’s ggplot2 package was used to plot the distribution of data. Since there were more than two dependent variables, multivariate analysis of variance (MANOVA) was applied for analysis. Post-hoc analysis was performed using Scheffe’s test after age and gender correction using a generalized linear model to assess the differences in 3.3.1.The recruited patients had mild to moderate severity of psychiatric illnesses. guna scores for the healthy controls and patients with psychiatric disorders are listed in The average 3.2.3.2.1.sattva than patients with all other psychiatric disorders  = 35.07; p < 0.01), except for OCD  = 35.07; p = 0.09).HCs had significantly higher levels of 3.2.2.sattva  = 35.07; p < 0.05) and higher levels of tamas than patients with other psychiatric illnesses  = 37.87; p < 0.01) as well as HCs  = 37.87; p < 0.01). Patients with SCZ also had significantly higher levels of rajas than patients with depression  = 11.64; p < 0.01) and HCs  = 11.64; p ≤ 0.01). Tamas scores did not significantly differ between patients with BPAD, SCZ, and depression, but all of them had higher tamas scores than patients with OCD  = 37.87; p < 0.01), and HCs  = 37.87; p < 0.01), respectively.It was observed that patients with psychotic disorders (SCZ and BPAD) had significantly lower levels of 3.2.3.rajas scores  = 3.62; p ≤ 0.01) and lower tamas scores  = 5.05; p ≤ 0.01) than HCs. Patients with OCD had significantly higher levels of rajas than HCs  = 11.64; p ≤ 0.01) and patients with depression  = 11.64; p = 0.03), respectively. Patients with depression had higher tamas scores than healthy controls  = 37.87; p < 0.01) and patients with OCD  = 37.87; p < 0.01). guna scores between healthy controls (HCs) and patients with different categories of psychiatric disorders. The distribution of scores of the three gunas  across common psychiatric disorders and healthy controls are displayed in Patients with anxiety had higher 3.3.Rajas scores and anxiety symptoms ; rajas and obsessive–compulsive symptoms ; rajas and positive psychotic symptoms ; (2) Sattva scores and obsessive–compulsive symptoms ; and (3) Tamas scores and negative psychotic symptoms . A significant negative correlation was noted between obsessive–compulsive symptoms and tamas scores , and anxiety symptoms and sattva scores   and sattva and rajas in patients  and HCs . Interestingly, a positive correlation between rajas and tamas was observed in HCs  but not in patients . We also observed a negative correlation of Young Mania Rating Scale (YMRS) with sattva scores  and positive correlation of the same with tamas scores  but sample size of patients with manic symptoms was very low (n = 7). gunas and various psychiatric clinical rating scales.Two-tailed Pearson’s correlation revealed significant positive correlations between the following scales: (1)  = 0.02) . Further4.sattva guna scores compared to patients suffering from psychiatric disorders with mild to moderate illness. We also observed a different pattern of guna distribution in different categories of psychiatric disorders  Depression: High sattva-tamas, low rajas; (3) Psychotic disorders (Schizophrenia/BPAD): High tamo-rajas, low sattva. In addition, significant positive correlations were observed between (1) rajas traits and anxiety/OC/positive psychotic symptoms, (2) sattva traits and OC symptoms, and (3) negative psychotic symptoms and tamas traits. All the above findings are in line with our hypothesis. The only result that is not as per the hypothesis is no significant correlation between depressive symptoms and tamas traits. This understanding of psychiatric disorders as per the guna perspective is relevant to Indian culture and traditions. For example, traditional yogic texts that emphasize Samkhya school of philosophy  specifically categorize mind and its modifications based on guna configurations . Interestingly, yogic texts also provide specific techniques of yoga and lifestyle management strategies such as diet, physical activity, recreation and sleeping patterns to target guna modifications in a particular direction (B.G. 6.17). For example, the approach to manage a patient with depression from Indian traditional perspective would be to first understand the guna configuration. Based on the current findings the guna configuration in depression reveals high sattva and tamas scores, and low rajas scores. Thus, the techniques of yoga and lifestyle advices would focus on reducing tamas and enhancing rajas traits. This would include practices such as dynamic sun salutations (Aditya Hridaya Stotra), exposure to sun light, regular walks two times a day, right nostril (sun-channel) breathing (H.Y.P. 2.50), chanting of the mantra with sound “AAA” (Mandukya Upanishad verse 9) or Gayatri mantra, avoiding daytime sleep, meditation on Manipura chakra (solar energy centre at the navel region) or “fire” principle , or imageries focusing on “Sun” and its energy (Aditya Hridaya Stotra), diet that enhances digestive fire and activates the mind . Such patients may also be advised to undergo yogic-psychotherapy for transcendence from sattva trait to Gunatita trait, especially if sattva scores are high (B.G. 14.22). In this way, specific lifestyle changes can be advised in different psychiatric conditions.In this cross-sectional trans-diagnostic study comparing patients suffering from common psychiatric disorders with age-gender-education matched healthy subjects, we observed that healthy controls had significantly higher isorders : (1) Anxrajas and tamas scores and poorer quality of life than healthy subjects , the description of tamas indicates traits that are not generally seen in patients with anxiety. In fact, a general clinical observation is that people with anxiety disorders have more tendencies toward rajas traits than tamas traits; second, the clinical population involved in our study belonged to the category of mild anxiety (HAM-A mean ± SD: 15.34 ± 6.08). It is quite possible that patients with chronic and severe anxiety may develop tamas tendencies over a period of time, which may manifest in the form of lack of productivity and mental dullness. Thus, the underlying tamas guna, which may be evident in more severe cases, may not have manifested in the current population. It would be interesting to assess the guna profiles across different severity levels within psychiatric diagnoses in future studies.A previous study compared 30 healthy subjects with 30 patients suffering from anxiety disorders and found that patients with anxiety disorder had higher subjects . It was rajas scores in depressed subjects (n = 20) than in healthy individuals . Even then, the subjects in this subgroup showed the lowest scores on rajas (28.9 ± 4.93) as compared to the other two gunas; sattva (38.4 ± 6.03) and tamas (32.7 ± 5.76). Although this is not consistent with earlier research findings, it is in accordance with the description of rajas in ancient yogic texts. The rajas traits of ambitiousness and attachment to action do not reflect the symptoms of depression where the subject feels hopeless, dejected, and less inclined toward activity. At face value, it appears that a depressed subject should show a higher tamas trait, but we observed that their scores were higher on sattva trait than tamas. Sometimes high levels of sattva may make an individual emotionally sensitive and rigid in perfectionism and fairness. Any failure to live up to it may push him/her into depression. A larger sample size may be required in future studies to obtain conclusive findings. It would also be interesting to understand the guna profiles of subjects with moderate and severe levels of depression in future studies.Another preliminary investigation reported higher  n = 20; . In the guna scores of 15 patients with different psychotic disorders were compared with 30 healthy subjects on their guna scores  traits. In the current study, negative correlations were observed between sattva and tamas, and sattva and rajas in patients and HCs, respectively (gunas exist as inherent components of every psyche and serve as the binding forces that bind the consciousness (purusha) to the body (B.G. 14.5), when one trait manifests, the other two are suppressed (B.G. 14.10). Interestingly, a positive correlation between rajas and tamas was observed in HCs, but not in patients  for prognostic modifications of 5.(Guna) scores could differentiate healthy subjects from those with psychiatric disorders. Guna traits also varied between different psychiatric disorders. This may help provide a basis for developing psychotherapeutic and lifestyle modification programs based on the patient’s guna profile. It may also help develop ways of predicting outcomes of psychiatric disorders.Yoga-philosophy based mental traits The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Nimhans Human Behavioral Sciences Ethics Committee. The patients/participants provided their written informed consent to participate in this study.HB and BG conceptualized the idea. NE and HB designed the study and drafted the manuscript. NJ, HB, PM, and VK helped in data collection. BH analyzed the data. NR, RA, SV, BG, and MK reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.HB is supported by DBT/Wellcome Trust India Alliance Early Career Fellowship, Grant/Award Number: IA/CPHE/21/1/505978. SV is supported by DBT/Wellcome Trust India Alliance Intermediate Career Fellowship. Authors also acknowledge the support from Central Council for Research in Yoga & Naturopathy (CCRYN) grant from the Ministry of AYUSH, Government of India (Grant No: 002/208/2016/00925/CCRYN/CRC/NIMHANS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.