text:
1Department of Gastroenterology,
2Laboratório de Gastroenterologia Clínica e Experimental (LIM-07) do Departamento de Gastroenterologia e Hepatologia do Hospital das Clínicas HCFMUSP da Faculdade de Medicina da Universidade de São Paulo,
4Div.of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine,
5Viral and Metabolic Liver Unit, Department of Hepatology,
6Department of Hepatology,
Correspondence Address: Dr. Arun J. Sanyal, Professor of Medicine, Physiology and Molecular Pathology, Virginia Commonwealth University School of Medicine, MCV Box 980341, Richmond, VA 23298-0341, USA. E-mail: firstname.lastname@example.org
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Aim: To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents.
Methods: A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed.
Results: A total of 70 lean [body mass index (BMI) < 25 kg/m2] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m2) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions.
Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences.
Non-alcoholic fatty liver disease, phenotype, epidemiology, demographics
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality. Nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD, can progress to cirrhosis and end-stage liver disease more frequently than non-alcoholic fatty liver (NAFL). The principal risk factors for NAFLD include obesity and insulin resistance (IR) and its associated conditions such as type 2 diabetes[3-5].
Numerous reports from Asia and other parts of the developing world have identified NAFLD, including NASH, in lean subjects without biochemically obvious IR[6,7]. NAFLD has also been described in lean subjects in western countries[8-10]. There is however only limited information on the clinical, laboratory, and histological profile of lean versus obese subjects with NAFLD in the West. It is also not known if the histological spectrum of NAFLD and its relationship to IR is similar from one continent to another when subjects of identical body mass index (BMI) are considered. Similarly, when considering afflicted individuals with similar degree of IR, the distribution of histological findings from one continent to another is not known. These are likely to be relevant for either continuing a “one set of risk factors fits all” paradigm globally or informing development of “region-specific” risk stratification approaches.
In this study, we report data from four cohorts of subjects from the USA, Brazil, France and India to address the trans-continental drifts in disease phenotype across the spectrum of BMI and IR. The specific aims were to: (1) define the similarities and differences in disease expression between lean vs. obese subjects with NAFLD in the countries represented in this study; and (2) to compare the disease phenotype within specific weight and IR strata from one country to the next.
The current study is a retrospective cross-sectional analysis of a cohort of subjects with NAFLD at the participating centers. The participating centers were in Virginia, USA (PI: AJS), Brazil (PI: CPO), France (PI: LS) and India (PI: AC). The data sheets were developed at EUA: (2008-2013); France: (1999-2014); Brazil: (2009-2014); India (2008-2014); and analyzed by the investigators. The study involved an anonymized data set from an existing larger data set and was therefore considered exempt from IRB review.
Subjects with biopsy proven NAFLD with a full set of histological and laboratory data were included in this analysis from each site. Exclusion criteria included age < 18 years, absence of full data set including measures of IR, liver injury and function, anthropometric data, lipid profile and liver histology. Subjects with concomitant presence of alternate causes of liver disease, e.g., hepatitis C were also excluded to avoid their confounding effects. Finally, those with drug-induced NAFLD, TPN-associated NAFLD, and bariatric surgery within last 5 years or known infectious, e.g., HIV or known genetic disorders, e.g., abetalipoproteinemia associated with NAFLD, were excluded to keep the analysis focused on “garden-variety” NAFLD.
The liver histology was read by an experienced hepatopathologist at each site with multiple prior publications related to NAFLD. The presence of NAFLD was defined by the presence of hepatic steatosis (> 5%) confirmed by a liver biopsy in all instances; the nonalcoholic nature was established by clinical assessment of alcohol consumption to be less than 2 units daily for women and 3 units daily for men over the last 2 years. Steatohepatitis was defined by the presence of steatosis (> 5%) along with lobular inflammation and cytological ballooning. The severity of individual histological features of NAFLD was scored using the NIDDK NASH CRN criteria.
Lean, overweight and obese states were defined according to the World Health Organization and Modified National Cholesterol Education Program, Adult Treatment Panel III guidelines. For subjects from India, two separate analyses were performed. In the first, the same body mass index cutoffs used in the West were used to define these states to directly relate the clinical-laboratory-histological findings across continents matched for BMI. A second analysis using the thresholds used for the Asian subcontinent was used in order to evaluate those who were lean versus obese using physiologically relevant parameters for the region[14,15].
IR was derived from fasting blood glucose and insulin. The Homeostatic Model of Assessment for IR (HOMA-IR) was calculated from the formula: [22.5 × fasting insulin (mU/mL) × glucose (mmol/L)].
To further visualize the relationship of glucose and insulin, the plasma insulin was plotted as a function of fasting plasma glucose. The resulting plot was divided in to four quadrants based on a fasting glucose threshold of 100 mg/dL and fasting insulin of 12 μU/mL. A fasting glucose below 100 mg/dL represents euglycemia and a fasting insulin level above 12 μU/mL has been associated with IR[17,18].
Subjects with a glucose < 100 mg/dL and a fasting insulin < 12 μU/mL were considered insulin sensitive. Those with a glucose < 100 mg/dL but insulin levels > 12 μU/mL were considered to have IR with relatively intact beta cell function. Those with higher plasma glucose (> 100 mg/dL) and insulin > 12 μU/mL were considered to have severe IR. When the fasting plasma glucose levels were higher than 100 mg/dL and the corresponding insulin levels declined below 12 μU/mL subjects were considered to have advanced IR with beta cell failure. Type 2 diabetes was defined by a fasting blood glucose > 126 mg/dL in patients who had a hemoglobin A1c level of 6.5% or greater, an FPG level of 126 mg/dL or greater.
Data were analyzed using SPSS version 2. Descriptive statistics of subjects from each site was performed. Data for lean versus overweight versus obese subjects were compared for each country individually. Numerical data were compared using analysis of variance for normally distributed data. Quantitative variables with asymmetric distribution were described as median and interquartile range and compared between groups using the Kruskal-Wallis test. Next, subjects within each BMI strata from each country were compared to other countries correcting for multiple comparisons using Tukey’s test. A similar analysis of overweight or obese subjects was also performed. In another analysis, the cohort was stratified by the HOMA scores of < 2, 2-4 and > 4 and a similar analysis performed. Finally, a multivariable regression analysis was performed to evaluate the interactions between BMI, IR and other clinical parameters on liver histology in lean subjects with NAFLD in each region. Significance was set at a P value of 0.05.
A total of 430 subjects with biopsy-proven NAFLD was enrolled (USA:Brasil:France:India 139:125:96:63) [Table 1]. They included 70 lean (BMI < 25 kg/m2) subjects (Fr:Br:In:US 22:16:19:13), 136 overweight (Is this BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 52:28:33:23) and 224 obese subjects (BMI > 29 kg/m2) (n = 22:81:11:103). Subjects in the Indian and French cohorts were younger (mean 38.06 ± 1.6; 49.7 ± 1.2, respectively) compared to those from US and Brazil (mean 53.3 ± 0.92; 55.08 ± 0.2, respectively). In France about 70% of the subjects were male while in Brazil and USA approximately 70% were female. In the Brazilian cohort the prevalence of type 2 diabetes mellitus (T2DM) and hypertension were globally higher than other countries.
Demographics and clinical profiles across-country in subjects with NAFLD
|Age (years)||53.3 ± 0.92||49.7 ± 1.2*||55.08 ± 0.2||38.06 ± 1.6*|
|Triglycerides (mg/dL)||204.9 ± 10.3||112.5 ± 11.4*||218.0 ± 7.9||198.3 ± 12.4|
|Total Cholesterol (mg/dL)||197.8 ± 4.2||206.5 ± 5.5||193.5 ± 4.2||165.8 ± 7.7|
|LDL-XOL (mg/dL)||125.8 ± 4.5||135.6 ± 7.1||115.5 ± 3.2||93.3 ± 6.6|
|HDL-XOL (mg/dL)||44.0 ± 5.4||43.0 ± 5.2||46.0 ± 5.5||40.0 ± 4.7|
In the US cohort, obese subjects were younger than overweight and lean subjects, respectively (51.9 ± 1.0; 53.3 ± 2.1; 61.8 ± 1.9; P = 0.02) [Table 1]. While the proportion of subjects with hypertension or requiring lipid-lowering therapy were similar across the different weight strata, overweight subjects had less type 2 diabetes compared to lean and obese subjects (3.7% vs. 22.2% vs. 28.4%, P = 0.01). In the Brazilian cohort the prevalence of T2DM was high in lean subjects, approaching 66% [Figure 1]. In the French cohort, the proportion of individuals with features of the metabolic syndrome increased progressively from lean to overweight to the obese groups. The Indian cohort had more males in the lean group (P < 0.001 vs. other groups) and had a progressively greater proportion of subjects with T2DM with progressively higher weight strata.
The distribution of insulin and fasting glucose values yielded interesting insights in all regions [Figure 2]. In the US, approximately 20% of lean subjects had a fasting blood glucose < 100 mg/dL and a fasting insulin less than 12 mIU/mL. The remaining subjects had evidence of increasing IR with 4 subjects demonstrating IR with beta cell failure, i.e., low fasting insulin (< 12 mIU/mL) despite a fasting glucose > 100 mg/dL. As expected, obese subjects had a substantially greater number of insulin resistant subjects with and without beta cell dysfunction. Interestingly, 11 (11.45%) obese subjects had both low fasting glucose and insulin levels suggesting that they were relatively insulin sensitive.
Figure 2. Insulin resistance and insulin sensitivity in nonalcoholic fatty liver disease lean subjects vs. overweight vs.obese across regions. A: lean subjects; B: overweight subjects; C: obese subjects
In the Brazilian cohort, 4 (25%) lean subjects had relatively low fasting insulin and glucose levels while the rest showed IR with or without beta cell failure [Figure 2]. As noted in the US cohort, a subset of subjects in the overweight and obese categories also were relatively insulin sensitive (fasting plasma glucose < 100 mg/dL, fasting plasma insulin < 12 µU/mL). In France, the majority of lean subjects were relatively insulin sensitive and IR increased progressively from lean-overweight-obese subjects and most overweight and obese subjects have more advanced IR. Subjects from India had lower fasting insulin levels compared to the other cohorts especially those from the US and Brazil even amongst obese subjects. Lean and obese subjects in the Indian cohort had similar insulin sensitivity.
The steatosis grade was similar across lean, overweight, and obese subjects in the US cohort [Figure 3]. Similarly, the inflammation, ballooning grades and fibrosis stage were similar across the weight strata. The spectrum of liver histology in subjects from Brazil was similar to that seen in the US. Importantly, the severity of steatosis, inflammation and ballooning were similar across the three weight strata in this country.
Figure 3. The histological spectrum of nonalcoholic fatty liver disease in lean vs.overweight vs.obese across regions. A: steatosis grade; B: lobular inflammation grade; C: hepatocellular ballooning; D: fibrosis stage
On the other hand, obese subjects in the French cohort had significantly greater steatosis grade compared to both lean and overweight subjects (P < 0.002). There was also a stepwise increase in inflammation grade from lean to overweight to obese subjects which reached significance (lean vs. obese P < 0.01). There was a trend for lower ballooning scores in the lean subjects (P = 0.06). Lean and overweight subjects also had a significantly lower fibrosis stage compared to the obese subjects (P < 0.01 for both).
Lean Indian subjects had similar degrees of steatosis compared to overweight and obese subjects. The lobular inflammation grades were also similar across the three weight groups. However, in contrast to other regions, the ballooning grade was significantly lower in lean and overweight subjects compared to obese subjects (P < 0.01 for both). The fibrosis stage was similar across the three weight categories. Recalibrating BMI threshold for Indians to 22 kg/m2 for the diagnosis of obesity did not alter the results qualitatively.
Lean subjects in the US were also more likely to be hypertensive (55.6%) compared to those from Brazil (33.3%), France (14.3%), and India (15.8%). Only 9.5% of lean US subjects had T2DM compared to 26% of subjects in India and 66% of subjects in Brazil [Table 2]. There were no differences in the lipid profile of lean subjects across the various cohorts. However, subjects in Brazil were more insulin resistant than those in the other groups.
Comparison of lean subjects across study cohorts
|Age (years)||58.3 ± 0.7||57.7 ± 4||46 ± 6||40.5 ± 3|
|Type 2 diabetes (%)||22.2||55.6||9.5||26.3|
|AST (IU/L)||50 (40-78)||35 (20-93)||29 (19-47)||45 (24-60)|
|ALT (IU/L)||49 (30-114)||52 (22-101)||60 (45-79)||56 (31-84)|
|GGT (IU/L)||170 (134-276)||50 (25-286)||75 (50-134)||45 (36-72)|
|Triglycerides (mg/dL)||83(83)||129 (99-221)||52 (22-100)||132 (111-187)|
|HDL cholesterol (mg/dL)||47(47)||51 (38-66)||44 (37-63)||43 (35-49)|
|INR||1 (0.9-1)||1 (1-1)||1.03 (1-1.10)||1.2 (1.17-1.22)|
|Steatosis grade - 0/1/2/3 (%)||0/33/44/23||0/22/55/22||0/55/20/25||10.5/36.8/47.4/5.3|
|Lobular inflammation - 0/1/2/3 (%)||12.5/62.5/12.5/12.5||33/22/33/12||50/40/10/0||26.3/63.2/10.5/0|
|Ballooning - 0/1/2 (%)||44.4/22.2/33.4||11/77/12||35/60/5||53/40/7|
|Fibrosis stage - 0-none/1-perisinusoidal/2-portal-periportal/3-bridging/4-cirrhosis (%)||11.1/33.3/0/33.3/22.2||0/44/44/12/0||21.4/50/14.3/14.3/0||57.9/15.8/15.8/10.5/0|
|Glucose (mg/dL)||95 (87-107)||88 (85-126)||90 (83-95)||84 (80-95)|
|Insulin (mU/mL)||10 (7-12)||11 (6-15)||5 (3-14)||7 (6-10)|
In line with greater IR, lean subjects from Brazil (mean grade 2.8) had a higher steatosis grade (P < 0.0005) compared to subjects from the US (mean grade 1.9), France (mean grade 1.8), and India (mean grade 2.2). Lean subjects from Brazil also had greater lobular inflammation (mean grade 1.5) compared to subjects from the other countries (mean grade range 0.5-0.7) (P < 0.0001). The ballooning grade was similar across the US, Brazilian, and Indian cohorts but was lower in lean subjects from the French cohort (P < 0.0001). Similarly, the mean fibrosis stage was similar across the US, Brazil, and India but higher than that seen in the French group (P < 0.0013).
The prevalence of hypertension and T2DM was higher in the subjects from Brazil. The mean HOMA scores were similar across the four groups. As noted in the lean subjects, a proportion of subjects were still relatively insulin sensitive whereas a proportion was insulin resistant with beta cell failure. Subjects from Brazil had more advanced IR with a majority of subjects with a fasting plasma glucose > 100 mg/dL. Interestingly, the ballooning grade was more severe in overweight subjects from India compared to those from the USA and France (1.7 vs. 1 vs. 0.8, P < 0.0001). Subjects from Brazil had intermediate degrees of ballooning injury (mean grade 1.2). The fibrosis stage in overweight subjects in the Indian cohort was modestly higher than the other cohorts (mean: 1.8 vs. 0.6 vs. 1 vs. 1.2 India vs. US vs. France vs. Brazil) [Table 3].
Comparison of overweight subjects across study cohorts
|Age (years)||54.1 ± 6||55.1 ± 2||51 ± 7||34.1 ± 5|
|Type 2 diabetes (%)||3.7||56.8||19.3||14.3|
|AST (IU/L)||50 (39-84)||30 (22-41)||31 (23-48)||40 (29-56)|
|ALT (IU/L)||60 (46-95)||36 (27-57)||63 (48-80)||45 (38-79)|
|GGT (IU/L)||83 (38-156)||66 (30-160)||50 (27-103)||46 (33-55)|
|Triglycerides (mg/dL)||141 (76-195)||150 (107-241)||66 (40-108)||120 (112-155)|
|HDL cholesterol (mg/dL)||50 (40-61)||48 (38-52)||40 (30-52)||37 (32-45)|
|INR||1 (1-1)||0.98 (0.95-1)||1.08 (1.02-1.13)||1.2 (1.14-1.27)|
|Steatosis grade - 0/1/2/3 (%)||25/30/15/30||5.4/40.5/43.2/10.8||0/50/40/10||15.4/69.2/15.4/0|
|Lobular inflammation - 0/1/2/3 (%)||20.8/58.3/20.8/0||14.3/54.3/25.7/5.7||19.6/64.3/14.3/1.8||23.1/61.5/15.4/0|
|Ballooning - 0/1/2 (%)||45.8/37.5/16.7||60/40/10||12.5/71.5/16||67/33/0|
|Fibrosis stage - 0-none/1-perisinusoidal/2-portal-periportal/3-bridging/4-cirrhosis (%)||0/57.7/19.4/15.4/7.7||36.1/13.9/27.8/17.7/5.6||26.2/35.7/19.0/7.1/11.9||53.8/7.7/30.8/7.7/0|
|Glucose (mg/dL)||91 (83-102)||110 (94-141)||103 (94-113)||78 (72-84)|
|Insulin (mU/mL)||16 (10-19)||16 (12-21.5)||7 (5-16)||7 (6-12)|
In Brazil almost 80% of the obese subjects were hypertensive while 49.5%, 44.4%, and 18.2% of obese subjects in US, France, and India respectively were hypertensive. 100% of the obese subjects in the Indian cohort had T2DM [Table 4]. The lipid profiles were comparable amongst obese subjects from different countries.
Comparison of obese subjects across study cohorts
|Age (years)||52.4 ± 2||55.1 ± 5||50.7||38.4 ±5|
|Type 2 diabetes (%)||28.4||51.9||44.4||100|
|AST (IU/L)||40 (27-63)||35 (20-93)||48 (29-58)||36 (23-62)|
|ALT (IU/L)||53 (34-83)||52 (22-101)||76 (57-99)||33 (29-78)|
|GGT (IU/L)||38 (27-66)||53 (27-87)||55 (36-128)||33 (28-46)|
|Triglycerides (mg/dL)||149 (107-211)||129 (99-221)||141 (107-256)||126 (99-155)|
|HDL cholesterol (mg/dL)||43 (36-50)||51 (38-66)||43 (36-48)||38 (32-42)|
|INR||1 (0.97-1.0)||1 (1.0-1.0)||1.04(0.96-1.06)||1.3 (1.2-1.3)|
|Steatosis grade - 0/1/2/3 (%)||6.5/44.6/33.7/15.2||5.3/20.0/45.3/10.8||0/13/57/30||0/36.4/63.6/0|
|Lobular inflammation - 0/1/2/3 (%)||8.8/76.9/14.3/0||8/46.7/37.3/8||12.5/68.8/18.8/0||0/90/10/0|
|Ballooning - 0/1/2 (%)||38.6/45.5/15.9||46.6/52/1.3||12.5/68.8/18.8||9/63.6/27.4|
|Fibrosis stage - 0-none/1-perisinusoidal/2-portal-periportal/3-bridging/4-cirrhosis (%)||36.6/28.9/8.9/21.1/4.4||22.7/44/10.7/16/6.7||12.5/18.8/31.3/12.5/25.0||45.5/36.4/18.2/0/0|
|Glucose (mg/dL)||101 (86-124)||103 (90-127)||104 (96-143)||93 (81-106)|
|Insulin (mU/mL)||20 (14-37)||17 (11-26)||17 (14-20)||7 (5-20)|
As expected, most subjects had IR. Interestingly, a subset of obese subjects from each country had a fasting plasma glucose < 100 mg/dL as well as a fasting plasma insulin < 12 µU/mL indicating that they were relatively insulin sensitive. The proportion of such individuals was greatest in the cohort from India. The US cohort had somewhat lower steatosis grade whereas subjects from India had more inflammation and ballooning. The fibrosis stages were similar across the groups.
A potential reason for the variability in histology from one country to another could be the variable degree of IR in each weight strata. In order to evaluate this, subjects were stratified into those with mild, moderate and severe IR (HOMA: 0-2, 2.1-4 and > 4 respectively). The severity of individual histological features was then assessed across the four study cohorts.
As expected, the severity of steatosis was largely similar across the four groups with the exception of somewhat lower steatosis in the Indian group in those with moderate IR (P < 0.01 vs. France). On the other hand, the group in Brazil had lower scores for lobular inflammation compared to other groups across multiple IR strata. They also had lower ballooning grades especially in those with moderate or severe IR. This was accompanied by less fibrosis across all strata of IR.
Body weight and IR are two of the best-known risk factors for NAFLD. While it is known that many subjects with NAFLD in Asia are lean and do not have the usual biochemical features of IR, it was not known if a similar profile was also seen in lean subjects in other regions of the world. It is however generally believed that the relationship between body weight and severity of IR on one hand, versus liver histology is generally similar in all parts of the world. The current study challenges this “one size fits all” approach and demonstrates substantial differences and heterogeneity from countries in one continent versus even within similar weight strata.
The prevalence of obesity, T2DM and hypertension are higher in the USA and Brazil than in some European countries like France[20-23]. In Brazil, the prevalence of arterial hypertension found was 21.4% (95%CI: 20.8-22.0) using the self-reported criterion, 22.8% (95%CI: 22.1-23.4) for measured arterial hypertension, and 32.3% (95%CI: 31.7-33.0) for hypertension arterial pressure and / or report of medication use. Furthermore, according IDF Atlas, in Brazil and USA, the prevalence of T2DM in 2019 was 8.5% and 11.1% respectively, while in Europe was 6.3%. USA is the third-highest country with patients with T2DM in the world, and Brazil the fifth. Also, caloric consumption in American countries is higher than in some countries and in Europe. In addition, patients in Brazil and the USA come from large tertiary-level university hospitals, where patients of greater severity are referred to them.
An important observation in this study is the remarkable range of laboratory-histological findings when comparing lean subjects with overweight and obese subjects in the different countries where this study was conducted. In France, a clear stepwise worsening of IR and severity of liver histology was noted with increasing BMI. In contrast, lean subjects in Brazil were more insulin-resistant and like overweight and obese subjects with respect to both the severity of their IR and liver histology. Subjects from the United States and India had an intermediate relationship with Indian subjects tending to demonstrate generally lower insulin levels than those from the other cohorts at all weight strata. These corroborate the concept that the severity of NAFLD is not a simple function of increasing body mass and that these relationships can be variable from one region to another.
The current study further demonstrates that the spectrum of IR and liver histology is variable from one country to another even when the body mass is accounted for. Lean subjects in the Brazilian cohort were more insulin-resistant and had greater steatosis than subjects from other regions. However, the severity of cytological ballooning was similar in the US, Brazil, and India and higher than that seen in the French subjects. These data are in line with the concept that development of liver injury is more than a simple function of IR and that additional factors are likely to play a role. While theoretically possible, we believe it is unlikely that these data purely represent differences in how the histology was read by the local pathologists since all of the pathologists involved are senior and experienced pathologists who have previously published in the field.
Another noteworthy finding in this study is that even in Western countries, a subset of overweight and even obese subjects with NAFLD were relatively insulin sensitive, i.e., with a fasting insulin < 12 µU/mL and [glucose] < 100 mg/dL. The lower blood glucose could not be attributed to the use of anti-diabetic therapy alone although it may have played a role in a few subjects. The only potential exception was the obese Indian cohort where all subjects were known to have diabetes and many also had a fasting plasma glucose < 100 mg/dL. While the presence of insulin sensitive obese individuals is well established, there is a general perception that these so called “fit-fat” subjects do not develop end organ diseases typically associated with IR. The current study further demonstrates that the distribution of liver histology in these subjects includes the full spectrum of NAFLD. The mechanisms underlying the liver disease in these subjects are not well understood. Unfortunately, due to the retrospective nature of this current analysis, the subjects were not genotyped and their PNPLA3 and TM6SF2 and other SNPs associated with the metabolic syndrome were not available. This is now a logical future direction of research in the field.
It is also not known if obese insulin-sensitive subjects respond to insulin sensitizers and improve their liver histology in the same manner as obese insulin resistant subjects. In the PIVENS trial, baseline HOMA scores did not predict histological response to pioglitazone[27,28]. This study however did not evaluate assess the insulin sensitivity status by HOMA alone but by graphical analysis of the relationship of glucose and insulin. It is also recognized that an euglycemic hyperinsulinemic clamp is the gold standard for measurement of insulin sensitivity. In this retrospective analysis, this was not possible. However, it will be valuable to perform these in obese subjects with NAFLD who have a low fasting glucose and insulin level in the future to be certain that they are indeed insulin sensitive. Regardless, more information about the pathophysiological mechanisms underlying disease development and progression in obese or overweight insulin sensitive subjects will help future efforts to tailor specific therapies that are most likely to engage the relevant therapeutic targets in these individuals.
There is a difference in the aggressiveness of NAFLD between American and European countries, mainly Mediterranean countries. One interesting example is the number of liver transplantations in USA secondary NASH compared with Europe countries. In Brazil there has also been an increase in the numbers of liver transplantations secondary to NASH. Several hypotheses can be considered for the greater severity of fibrosis in American countries, including lean NASH: (1) Higher caloric intake in the Americas, diet rich in fructose and trans lipids low consumption of Mediterranean diet, including fiber and omega 3; (2) greater sedentary lifestyle in American countries; (3) presence of genetic factors such as PNPLA3; and (4) dysbiosis, even in Lean NASH patients. Furthermore, in the USA and Brazil, there is also admixture with genes from non-caucasian Hispanic and native American genes. American Hispanics have more severe NASH. The complex genetic background may be another potential explanation. Unfortunately given the sample size of this initial assessment, it is not feasible to address the role of genetics. Similarly, there may be differences in diet and also microbiome functionality that are not captured by current methods that could play a role. NASH is a complex disorder driven by gene environment interactions.
There were also differences in the spectrum of other end organ diseases within lean subjects with NAFLD. These corroborate the concept that the pathogenesis of each of these conditions is complex and there are regional variations in the prevalence rates and severity. All of these data further attest to the trans-continental drifts in phenotype development of this cluster of diseases.
There are several potential explanations for the observed variations in NAFLD phenotype and associated conditions across the four cohorts studied. These include genetic differences in susceptibility, regional variation in diet patterns, differences in the intestinal microbiome, exercise, environmental exposures etc. While a detailed analysis of these is beyond the scope of this manuscript, such studies are now indicated to better understand the variations in phenotype development in different regions.
Perhaps the most relevant implication of the current study is that it provides proof of concept that there are differences in both the histological phenotype and associated clinical features in subjects with NAFLD in different regions of the world and that region-specific data are now needed to provide optimal guidance for clinical care on various regions. Also, it raises the possibility that therapeutic responses in one region may or may not be similar from one region to another. A clearer understanding of variable disease mechanisms underlying the differences in phenotype development should help targeting therapeutics towards the most relevant targets in a given region and phenotype in the future.
The principal limitations of the current study are the relatively modest size of lean subjects with NAFLD in various regions and the potential for ascertainment bias. The small numbers of lean subjects however reflect the fact that they represent a small fraction of all subjects with NAFLD. Also, another limitation is that we report the prevalence of fibrosis stage in patients with NAFLD who had a biopsy at the centers in this study. Since this was done according to standard of care, the selection of patients for a biopsy was variable across centers. Further, the distribution of fibrosis could also be impacted by ascertainment bias due to the nature of the center. It was seen in the Indian cohort probably because increasing age is linked to higher stages if fibrosis and is generally considered to be due to longer exposure to disease state. It is potentially possible that the low fibrosis stage in India reflected the lower age of the population studied. It is noted in the section about variations across centers and as a potential explanation for the differences in fibrosis stage in India vs. other sites. However, most published studies of NAFLD also have the same ascertainment bias associated with tertiary care academic medical centers. These limitations notwithstanding, the current study demonstrates substantial variability in disease phenotype from one region to another.
In summary, the current study provides novel information on the variability in disease phenotype in lean as well as overweight and obese subjects in different parts of the world. It challenges the paradigm that all lean subjects with NAFLD have mild IR and have mild forms of liver disease. Conversely, it also demonstrates that a fraction of obese subjects with the full spectrum of NAFLD may be relatively insulin sensitive. Future studies to define the mechanistic basis for these differences may inform therapeutic choices in subjects in different regions.
Design: Paredes A, Siddiqui M, Boyett S, Sanyal AJ
Performance: Oliveira CP, Paredes A, Siddiqui M, Serfaty L, Chowdhury A, Stefano JT, Vanni DS, Boyett S, Sanyal AJ
Analysis: Oliveira CP, Paredes A, Serfaty L, Chowdhury A, Sanyal AJ
Writing: Oliveira CP, Serfaty L, Chowdhury A, Stefano JT, Vanni DS, Sanyal AJAvailability of data and materials
Not applicable.Financial support and sponsorship
None.Conflicts of interest
All authors declared that there are no conflicts of interest.Ethical approval and consent to participate
This was a retrospective study, approval from the study number 164.116 at the local Ethics Committee.Consent for publication
© The Author(s) 2020.
1. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017;65:1557-65.DOIPubMed PMC
2. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-55.DOIPubMed
3. Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int 2009;29:113-9.DOIPubMed
4. Ercin CN, Dogru T, Genc H, Celebi G, Aslan F, et al. Insulin resistance but not visceral adiposity index is associated with liver fibrosis in nondiabetic subjects with nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2015;13:319-25.DOIPubMed
5. Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 2014;146:46-62.DOIPubMed
6. Feng RN, Du SS, Wang C, Li YC, Liu LY, et al. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol 2014;20:17932-40.DOIPubMed PMC
7. Akyuz U, Yesil A, Yilmaz Y. Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. Scand J Gastroenterol 2015;50:341-6.DOIPubMed
8. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 2012;91:319-27.DOIPubMed
9. Margariti E, Deutsch M, Manolakopoulos S, Papatheodoridis GV. Non-alcoholic fatty liver disease may develop in individuals with normal body mass index. Ann Gastroenterol 2012;25:45-51.PubMed PMC
10. Das K, Chowdhury A. Lean NASH: distinctiveness and clinical implication. Hepatol Int 2013;7 Suppl 2:806-13.DOIPubMed
11. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874-82.DOIPubMed
12. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21.DOIPubMed
13. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486-97.DOIPubMed
14. Misra A. Revisions of cutoffs of body mass index to define overweight and obesity are needed for the Asian-ethnic groups. Int J Obes Relat Metab Disord 2003;27:1294-6.DOIPubMed
15. Misra A, Chowbey P, Makkar BM, Vikram NK, Wasir JS, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India 2009;57:163-70.PubMed
16. Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, et al. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003;26:3320-5.DOIPubMed
17. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005;48:634-42.DOIPubMed
18. Arata M, Nakajima J, Nishimata S, Nagata T, Kawashima H. Nonalcoholic steatohepatitis and insulin resistance in children. World J Diabetes 2014;5:917-23.DOIPubMed PMC
19. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA 2015;314:1021-9.DOIPubMed
20. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018;138:271-81.DOIPubMed
21. Matta J, Carette C, Rives Lange C, Czernichow S. French and worldwide epidemiology of obesity. Presse Med 2018;47:434-8.DOIPubMed
22. Martins-Silva T, Vaz JDS, Mola CL, Assunção MCF, Tovo-Rodrigues L. Prevalence of obesity in rural and urban areas in Brazil: national health survey, 2013. Rev Bras Epidemiol 2019;22:e190049.DOIPubMed
23. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-81.DOIPubMed PMC
24. Malta DC, Gonçalves RPF, Machado Í, Freitas MIF, Azeredo C, et al. Prevalence of arterial hypertension according to different diagnostic criteria, national health survey. Rev Bras Epidemiol 2018;21:e180021.DOIPubMed
25. UN Food and Agricultural Organization FAOstat food balance sheets. Chapter 3: Calculation Of The Energy Content Of Foods - Energy Conversion Factors. Food and Agriculture Organization of the United Nations. Available from: http://www.fao.org/docrep/006/Y5022E/y5022e04.htm. [Last accessed on 24 Sep 2020].
26. Duncan GE. The “fit but fat” concept revisited: population-based estimates using NHANES. Int J Behav Nutr Phys Act 2010;7:47.DOIPubMed PMC
27. Pacana T, Sanyal AJ. Vitamin E and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012;15:641-8.DOIPubMed PMC
28. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85.DOIPubMed PMC
29. Borai A, Livingstone C, Ferns GA. The biochemical assessment of insulin resistance. Ann Clin Biochem 2007;44:324-42.DOIPubMed
30. Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin Gastroenterol Hepatol 2020; doi: 10.1016/j.cgh.2020.05.064.DOIPubMed
31. Vilar L, Oliveira CP, Faintuch J, Mello ES, Nogueira MA, et al. High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects. Nutrition 2008;24:1097-102.DOIPubMed
32. Mazo DF, Malta FM, Stefano JT, Salles APM, Gomes-Gouvea MS, et al. Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population. Ann Hepatol 2019;18:466-71.DOIPubMed
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Oliveira CP, Paredes A, Siddiqui M, Serfaty L, Chowdhury A, Stefano JT, Vanni DS, Boyett S, Sanyal AJ. The transcontinental variability of nonalcoholic fatty liver disease. Hepatoma Res 2020;6:72. http://dx.doi.org/10.20517/2394-5079.2020.73
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The most awaited and anticipated film of the year, Jackpot’s official posters have finally been released. Directed by S Kalayaan and produced by Suriya Sivakumar, the movie features Jyothika and Ravathi in the lead roles. Hyped to be a comedy entertainer, the poster of the movie reveals the roles of Jyothika and Revathi in the film. The two female actresses will be stepping into the shoes of a cop. Suriya, the producer of the film and Jyothika’s better half, took to his twitter account to unveil the posters of the film. He wrote, ‘Presenting the first look of #JACKPOT get ready for an action packed fun ride! It’s a Jackpot for us to have both #Revathi & #Jyotika on board’.
Presenting the first look of #JACKPOT get ready for an action packed fun ride! It’s a Jackpot for us to have both #Revathi & #Jyotika on board 👍🏼@DirKalyan @iYogiBabu @Composer_Vishal @anandakumardop @editorvijay @2D_ENTPVTLTD@rajsekarpandian @SF2_official@SonyMusicSouth pic.twitter.com/cpb4NXC8F0
— Suriya Sivakumar (@Suriya_offl) April 30, 2019
Yogi Babu, Anandraj, Rajendran, Jagan and Mansoor Ali Khan will also be seen in the movie in key roles. Reportedly, the film is slated to hit the cinemas in 2019. However, its official release date has not been announced yet.

domain: entertainment


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Thomas Ryan RHA (right) with the late Terry Wogan and Joe Leddin, former Mayor of Limerick in 2007
Mayor of Limerick city and county pays tribute to the late Thomas Ryan, RHA
By I Love Limerick Correspondent Ann Mc Donald
The Mayor of Limerick city and county has paid tribute to the late artist, Thomas Ryan RHA who has died on Thursday, 16 September.
Thomas Ryan was born in St Joseph’s Street, Limerick in 1929 and grew up in Davis Street in the city. He was educated in the former Limerick School of Art and what is now the National College of Art and Design in Dublin.
From his medallic work designing the old Irish pound coin and millennium fifty pence piece to his stunning art pieces working across a variety of media including oil paints, watercolours, chalks, charcoal and pencil, he painted some of the country’s most prominent figures such as Éamon de Valera and Seán Keating. His works, ‘Flight of the Earls,’ and ‘GPO1916,’ are two of the country’s most important historical artworks.
Mayor Butler described the late Dr Ryan as an ‘extraordinary talent and one of Ireland’s most significant artists’ who had a long association with the Mid-West and was extremely proud of where he came from.
Mayor @DanielButlerFG has paid tribute to the late Thomas Ryan, RHA
Dr Ryan received the Freedom of the city of Limerick in 2007. Ar dheis Dé go raibh a h'anam dílishttps://t.co/sRSy8Y53yJ
— Limerick Council (@LimerickCouncil) September 16, 2021
“As a young boy he played in the People’s Park and in the heart of Georgian Limerick and despite his success and talent, he was a man with a lifelong attachment to this city,” Mayor Butler said.
Although Ashbourne and Co Meath became his home, he was always a proud Limerickman and was very touched when he received the Honorary Freedom of Limerick city along with broadcaster Terry Wogan in 2007.
He reached the highest level in his career but never forgot his roots and celebrated his 90th birthday in his home city.
“We were honoured that one of his last exhibitions of 40 of his paintings from his long working life spanning over 70 years went on display at the People’s Museum of Limerick in 2019, just across from the park where he spent so much time as a young boy. I would like to extend my condolences to Dr Ryan’s wife Mary, children, Pearse, John, Ann, Myles, Eavan, Aengus, 16 grandchildren, extended family and his many friends,” Mayor Butler said.
Ar dheis Dé go raibh a h’anam dílis.
For Thomas Ryan’s art go HERE
For more stories on community go HERE

domain: news


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Welcome to the free printable Mickey Mouse coloring pages below. Mickey Mouse is one of the Disney characters that almost every kid loves, so these Mickey Mouse coloring sheets are sure to get kids excited as they color their favorite character.
Mickey Mouse is the logo of the Walt Disney Animation Studios of the Walt Disney Company. An anthropomorphic mouse usually wears red shorts, big yellow shoes, and white gloves; Mickey is one of the most recognizable fictional characters in the world.
Immediately collect the famous cartoon characters that the children love so they can freely experiment with colors for the characters. The colorful cartoon world is waiting for you. Have fun and get creative now!

domain: artistic


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Watersmeet is the first novel in the Watersmeet series by Ellen Jensen Abbott. It is tagged Young Adult, but unlike some of today’s YA books this one can be read by younger YA readers. It’s about a girl who lives in a land with mythical creatures–including centaurs. You know how I am about horses, centaurs, unicorns, pegasi–you get the idea. On Amazon and Goodreads, this book gets a lot of rating abuse. I think those low stars are from YA readers who are expecting something edgier/more violent/sexier. Watersmeet is not like that.
Abisina is a human girl, heavily discriminated against because of her coloring and her absent father. Luckily, her mother’s healer skills are valued and Abisina is tolerated. An event turns the girl’s life upside down when she is forced, under penalty of death, to leave her village and find Watersmeet, where her father lives. She finds cruelty and discrimination as well as loyalty and love.
The world Abisina travels through is rich with history and races of creatures. The reader learns along with the girl as she encounters new things. Something I enjoyed was when Abisina is forced to realize the depth of her own prejudice–something many of us never fully understand. Discovering your own prejudices and overcoming them is an excellent theme for a YA book, and you don’t need violence and sex to accomplish it!


text: This study compares the accuracy of a two-dimensional accelerometer worn on the ankle (a step activity monitor) with that of an electronic, digital pedometer worn on the belt line. Twenty-nine human subjects were evaluated while they briskly walked 400 M, slowly walked 10 M, and ascended and descended a flight of stairs. The step activity monitor had less error in all activities; its mean absolute error was 0.54%, whereas that of the pedometer was 2.82%. The difference was more pronounced in obese subjects (body mass index greater than 30), with an overall mean absolute error of 0.48% for the step activity monitor and 6.12% for the pedometer (nearly 13 times that of the step activity monitor). For subjects with a body mass index less than 30, the step activity monitor had an overall error of 0.56% and the pedometer had an overall error of 1.56% (less than 3 times that of the step activity monitor). The absolute error of the pedometer was positively correlated with body mass index (r = 0.792, p < 0.0001) and weight (r = 0.753, p < 0.0001), whereas the error of the step activity monitor was not significantly correlated with either. Neither device was significantly biased by age, gender, or the presence of a lower-extremity joint prosthesis. The accuracy and additional capabilities, including a real-time memory record of activity, of the step activity monitor make it well suited for objectively quantifying ambulatory activity, especially for obese subjects.

domain: medical


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It looks like nothing was found at this location. Maybe try a search?
We have had a really wonderful stay at Anantmaya, Manali. Beautiful property with not just a view but with some great views. It has that personal touch service that can not be beaten. Food – Superb. Comfort – It has lots of that. Highly recommended. Thanks so much for a very enjoyable holiday!
It is an awesome place to stay, very good location away from the crowds. Great views, newly constructed resort. Staff is really very helpful and prompt. Food is one of the best I ever had. Give it a try, you will not regret it
One of the best places we have stayed at so far. Amazing resort, amazing hospitality and amazing location
Devika Chatterjee Ahluwalia
One of the best stays in Manali….Was there for 4 nights
Awesome resort & Services. one of my best stays
The Use of Low Dose Naltrexone in the Management of Chronic Pain
Chronic pain is a serious medical condition affecting 1 in 5 people worldwide and up to 40% of the US population. 1,2 Currently available medical therapies for treatment of chronic pain may be unsatisfactory, risky, and expensive to employ. 3,4 Until very recently, physicians utilized opioid therapy widely in the management of chronic non-cancer pain. Because of their highly addictive qualities and side effects such as sedation, dizziness, nausea, etc, opioids have become stigmatized. 5
Low dose naltrexone (LDN) is a novel pain therapy which may fulfill the “4 L’s” that many patients and clinicians look for: low risk, low side effect profile, low dose, and low cost. (Image: iStock)
The opioid crisis has caused and is still causing serious public health issues in our country; in 2017, 29% of people were abusing opioids, 47,000 people died from opioid overdose, and nearly 2 million people were diagnosed with a substance abuse disorder. 6 Many of the over-the-counter (OTC) and non-opioid prescription medications are unsuitable alternatives for treatment of chronic pain as they have many unwanted side effects including GI bleeding, kidney and liver damage, dizziness, and nausea. 3,7 Additionally, both OTC medications/supplements and “alternative” treatments such as cannabidiol (CBD) can be costly to patients, resulting in thousands of dollars a year in out of pocket expenses. 4,8 This financial burden can result in patients receiving little and sometimes no care at all for their chronic pain issues.
There is an emerging interest on the part of patients to seek out nontraditional treatment options for managing their chronic pain. Low dose naltrexone (LDN) is a novel therapy which may fulfill the “4 L’s” that many patients look for when using nontraditional therapies: low risk, low side effect profile, low dose, and low cost . Naltrexone is a mu receptor antagonist medication originally designed and approved for the treatment of opioid addiction at a dose of 50 mg to 100 mg per day. More recently it has been suggested that low dose naltrexone may be utilized for the treatment of chronic pain, in an off-label fashion at a much lower dose: 0.5 mg to 4.5 mg/day. 9 Although the exact mechanism is unknown, it is believed that in this lower dose, naltrexone acts as a glial/immune cell modulator, which decreases pain by helping reduce inflammation. 9,10
In this retrospective case, the authors discuss the outcomes of patients taking once-daily LDN for the treatment of chronic pain.
Real-world evidence is presented from 16 patients who took prescribed LDN for 1 to 6 months and who were considered LDN-responders (LDN-R) or LDN-partial responders (LDN-PR) (see Table I). Ten patients were female (ages 28 to 83); 6 were male (ages 51 to 89) and, excluding two younger outliers of 28 and 34 years, the average age was about 70 years.
Most patients reported constant pain that was negatively impacting activities of daily living (ADLs) and quality of life, including inability to pursue activities such as house chores, walking, or sitting for an extended period of time. Pain intensity was reported to increase throughout the day.
All the patients’ chief complaints were reported as affecting the cervical and/or lumbar spine, hip and/or sacroiliac regions, or a combination of these locations. Radiation of pain to the arms/shoulders/jaw was common for patients reporting cervical spine pain, and pain radiating into the legs or diffusely into the lower back area was common for hip, lumbar spine, and SI patients. Specific ICD-10 codes for patients in this study included those coding for scoliosis, radiculopathy, intervertebral disc degeneration, myalgia, spondylolysis, cervicalgia, stenosis, neuropathy, arthritis, spinal enthesopathy, multiple sclerosis, and osteoarthritis. Past medical and family histories were otherwise not found to be pertinent to the study results.
Since patients in this study were receiving care at an interventional pain management practice, many had previously undergone interventional pain procedures including steroid injections, trigger point injections, and platelet-rich plasma (PRP) injections, as well as nerve blocks and radiofrequency ablation in the affected area(s).
During the observation period, many patients were taking and/or continued to take various other pain medications such as gabapentin, cyclobenzaprine, naproxen, tramadol, ibuprofen, Tylenol, etc., which were either providing insufficient relief or causing undesirable side effects. As a result of these relative treatment failures, patients were offered treatment with LDN.
Management and Outcome
During the six-month observation period a total of 35 patients received prescriptions for low dose naltrexone. Of the 35 patients receiving LDN prescriptions, 16 continued to use LDN because of improvements in pain and/or function. Patients receiving 50% or better relief in their chronic pain were considered LDN responders (LDN-R). Patients who did not meet 50% pain relief, but who chose to continue LDN because of perceived improvement in quality of life as a result of taking LDN, were considered partial responders (LDN-PR).
Out of 35 patients who received LDN prescriptions, 10 were considered LDN-R, while 6 were considered LDN-PR. The responder rate (total number of LDN prescriptions ÷ number of LDN responders + partial responders) was 46%. Nineteen of the 35 patients discontinued the use of LDN and were determined to be non-responders (LDN-NR) either due to receiving no improvement or experiencing undesirable side effects such as jitteriness or insomnia. Figure 1 shows the distribution of patients in each category.
All patients in the observation period were provided with a printed information and instruction form regarding the use of LDN in the treatment of chronic pain. In addition to written instructions, patients were counseled to only use LDN if it was causing “zero to minimal” side effects, and to discontinue the medication if any unpleasant side effects occurred. A “low and slow” approach to titration of LDN dose was used, and patients were verbally counseled that, vis-à-vis LDN therapy, “more is not necessarily better.” Initial prescriptions were sent electronically to a compounding pharmacy of the patient’s choice. Naltrexone is not a scheduled substance and a medical provider does not require a DEA number to prescribe it.
Patients were provided with an initial quantity of 90 to 120 tablets of naltrexone 1.5 mg. Patients who were finding no relief with low dose opioids (MME <20 mg per day) were advised to discontinue opioids for at least 1 to 2 weeks prior to initiating LDN. Patients who were taking minimal dose tramadol (<100 mg/day) were advised that they did not need to discontinue tramadol prior to institution of LDN therapy, because of tramadol’s low affinity (6,000 times less than morphine) for the mu receptor, and only partial inhibition by naloxone. 11 All patients, including patients taking tramadol, were advised that a withdrawal syndrome could develop if LDN and opioids were taken simultaneously, due to naltrexone’s mechanism of action. 9,12
Some patients who were noting initial improvements in pain at the 0.75 mg to 1.5 mg starting dose asked to accelerate the titration schedule. The clinician on a case-by-case basis approved this, however, patients were reminded that lower doses of LDN could be just as effective as or more effective than higher doses. No patient in the observation period was taking more than 4.5 mg/day.
Follow-up data was collected either during routine follow up or via telephone. Patients deemed to be LDN-NR were not involved in further questioning. Of the LDN-R and LDN-PR, 25% began taking 0.75 mg of LDN once daily on day one, 69% took 1.5 mg on day one, and 6% took 4.5 mg on day one. Eighty-eight percent of these patients increased their dose over a period between 1 week and 1 month to arrive at a stable dose of 4.5 mg daily, and 13% settled on a dose of 3 mg daily. All dosing was once daily. Side effects noted by these patients during the observation period included insomnia (6%), tiredness (6%), hot flashes (6%), and possible increase in migraine headache (6%), however, 75% of patients reported no side effects whatsoever. As a result of patient self-reports of side effects, we now recommend that patients dose LDN once-daily in the morning.
Patients were asked during routine follow-up visit to rate their perceived degree of pain relief from LDN using a modified PGIC questionnaire. 13 Figure 2 shows a summary of patients’ responses to the question, “Compared to before you started LDN, how much better do you feel after taking LDN?” This question was asked by a medical assistant at follow-up visit, or by the research assistant via telephone if patient was not scheduled for a follow-up visit during the observation period. Figure 3 shows perceived improvement over baseline.
A patient was categorized as an LDN responder (LDN–R) if they reported 50% relief or better. Patients in the LDN–R group reported average pain relief of approximately 77%. Figure 3 summarizes the degree of pain relief in LDN–R patients. In some cases, patients who fell into the LDN–PR category still felt very strongly and positively about the impact of LDN on their quality of life, and opted to continue taking LDN.
As an example, one LDN-PR patient reported only 20% relief in pain relief but went on to state that the amount of relief being provided by LDN was helping her in terms of everyday functioning to a significant enough degree that she chose to continue therapy with LDN. Other examples of functional improvements noted by LDN–R and LDN–PR patients are noted in Table II.
There is little clinical reporting available on the safety, efficacy, and “how-to-use” of many currently available alternative therapies. This results in many patients resorting to the use of OTC, “herbal,” and “natural” supplements without professional medical guidance, and oftentimes without any clinical benefit whatsoever. While physical harm may not occur frequently as a result of this practice, subtle financial harm may occur, since many “alternative” therapies are expensive; often costing patients hundreds of dollars per month.
There is a general lack of knowledge regarding the use of low dose naltrexone in the management of chronic pain.
Two significant factors contributing to the utility and efficacy of both prescription generic medications and OTC medications are out-of-pocket costs and potency. Although prescriptions for LDN are not typically covered by commercial and federal drug plans, the average monthly cost of $16 to $20 was found to be affordable (see Figure 4) by most of the patients in the presented study, as well as previously published studies. 14 Currently, LDN therapy requires formulation by a compounding pharmacist, who is subject to federal and state regulations and is able to perform intermittent potency and sterility studies on the medications being prepared for patients.
The potential mechanism of action of LDN has been discussed in the literature (see also, “Naltrexone as an Alternative Treatment for Chronic Fatigue Syndrome,” next page); an in-depth review of the MOA of LDN is beyond the scope of this case series presentation. 9,10 One theory is that LDN acts as a “glial/immune cell modulator,” and in this regard may explain why the medication seemed to have particular benefit for patients suffering with a more “neuropathic” component to their pain. Additionally, it was interesting to note that some patients who were receiving less than 50% relief chose to remain on LDN as it was improving activity tolerance and generalized “energy levels.” The perception of benefit in the patients receiving less than 50% overall relief is consistent with postsurgical pain models, where improvements of 33% are generally considered clinically significant. Our impression is that patients expect far less than 100% relief in order to consider treatment with LDN “successful.” 15,16 When counseling patients we felt it important to set realistic expectations at the outset of therapy; specifically stating that LDN is not a panacea, and that it fails in more instances than it works. In this cohort, however, we found that for LDN–R patients the degree of relief was very high.
This was a non-randomized, retrospective, non-blinded case series in a limited cohort of patients suffering with a variety of pain conditions. The generalized nature of our study can be viewed as a both a “pro” and a “con.” If future research aims to “demystify LDN,” then the applicability of LDN in multiple medical conditions may be suggested by the heterogeneity of the cohort in the presented study. The limited duration of the observation period may be considered a negative. Not all LDN–R patients had been taking LDN for 6 months. Therefore, some of these patients may have experienced a placebo effect. If the observation period was longer, then the placebo effect would likely be less of a factor.
Additionally, the types of pathology/pain treated with LDN in this study was quite varied. However, the liberal application of LDN prescriptions across many different pathological pain states was intentional and should not necessarily be viewed as a negative. In other words, there are very few contraindications to trying LDN in patients suffering from almost any kind of pain, as long as the patient is not taking any form of opioid, and does not have any other known contraindication for the use of LDN (allergy, pneumonia, liver failure, or moderate to severe kidney failure) prior to institution of LDN. A larger sample size and more specific ICD-10 selection criteria would help to clarify indications for and efficacy of this form of therapy.
To better study how LDN works, and for which specific conditions it is best-suited, the cohort needs to be more precise, and larger prospective, double-blind, placebo-controlled studies should be performed. Since LDN is being prescribed off-label and is generic, sponsorship for a large, randomized, double-blind, placebo-controlled study is unlikely. Therefore, further knowledge regarding LDN MOA, dosing, and efficacy may need to come from additional clinical reports documenting “real world evidence” as opposed to a definitive clinical trial.
LDN is a low risk, low cost, and simple to use medication that may be a viable non-opioid treatment option for the management of chronic pain. Despite these positive clinical attributes, professional and public awareness regarding the use of LDN is lacking, and widespread adoption of LDN for the treatment of chronic pain has not occurred. Especially in the setting of a healthcare system where increasingly the financial burden for care is being placed on the shoulders of patients, safe and low-cost alternatives for treatment of pain are needed. Additionally, in the setting of recent documentaries highlighting the lack of consistency in foreign-made generic medication preparations, sources for reliable and consistent prescription medications are needed. Compounding pharmacies that are able to accurately manufacture compounded prescription drugs with consistent potencies will be an ally for both patients and clinicians. Finally, despite the fact that LDN does not provide clinically meaningful reduction in pain for a large percentage of patients who try it, we found that patients in the LDN–R category tended to report a high degree of pain relief, spontaneously described by some patients as being “miraculous.” •


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Wife strangles husband to death, remanded till 27
Walapane Police have arrested a wife who strangled her husband, while he was sleeping reportedly after the husband had not allowed her to go to an alms giving at a relative’s house.
The suspect a mother of two children was ordered to be remanded till April 27 after being produced in the Walapane Court. The 38-year-old suspect Sunethra Damayanthi is a resident of Palugedara, Rambuke. Her husband 44 year old K.H.M. Dharmadasa was found dead mysteriously in his bed on March 31. The wife had told the police that she and her husband slept in the same bed that night with their 7-year-old and 12-year-old children.
She had said that when she woke up the next morning, made tea and called her husband, he did not wake up, so she called the neighbours and took him to the hospital. He had been pronounced dead on admittance.
Later forensic experts at the Nuwara Eliya General Hospital after a post-mortem had reported that this was a case of strangulation.


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1912 eti training center —–2076 youngstown warren road 15-dec-2012 12-jan-2013 16-feb-2013 16-mar-2013 niles trumbull 1937 quality health care training center, llc
Competency to become a certified nurse aide in your state. The NNAAP was developed by the National Council of State Boards of Nursing, Inc., (NCSBN) All candidates applying to take the NNAAP Exam in North Carolina MUST complete an Application for Registration by
Training, but you will have to take both the written and clinical nurse aide exams to become registered. C. I’m registered in another state as a CNA. Can I work while I am waiting to receive my exemption paperwork and take the test?
Certified Nursing Assistant Training Provider: Rochester City School District – Workforce Preparation Address: Family Learning Center Career Centers Address: Canandaigua Career & Resource Center 5253 and 5263Parkside Dr. Canandaigua, NY 14424
A certified nurse aide can become a qualified medication aide. North Carolina Yes SB 622 (2005) adult day care facilities and assisted living centers. The sponsoring facility must provide 24 hour of clinical training.
Homes, home health settings, and rehabilitation centers. Duties vary, but may . include taking vital signs, the student is eligible to take state testing to become a Certified Nursing Assistant. This course is offered traditional (121 for NC). (Chester campus courses
License Program Name Program Location City, State, Zip Program Phone Number 1068 5 Star Training Center, Inc. 39 Nw 166 St. Suite 4 North Miami Beach, FL 33169 ML: 305-947-8141 ˜ 1233 A. Philip Randolph Health Science 1157 Golfair Boulevard Jacksonville, FL 32209 ML: 904-924-3011 167˜HM: 3
Undated), and in a 2002 North Carolina study, it was 95 percent (PHI and NCDHHS, March 2004). 1.2 Federal and State CNA Training Requirements the Centers for Medicare and Medicaid Services Certified Nursing Assistant Information Bulletin.
NC, OH, OK, OR, PA, RI, SC, TN, TX, UT, VA, WA, WI SIC Description New 505101 Metals Service Centers & Offices – Wholesale New SICs for CNA 0106.xls 1 of 3. Additional and New SICs for CNA Available in AL, AR, AZ, CA (no WC), CO,
Medical centers and their subsidiaries are growing and adding Mount Eagle has two programs to train clinical nursing assistants (CNA-I) who work in hospitals and Shallua said each training program must be approved by the North Carolina Community College System. For some fields
Contact Directory Certified Nursing Assistant Training Programs Updated October, 2012 Colleges and Universities Allegany College Special Health Initiatives
NORTH CAROLINA CARE-LINE 1-800-662-7030 This is a number that you can call to find out about community resources all over North Carolina. www.co.guilford.nc.us Page 1 Employment Assistance and Job Training Comments/Appointments Employment
Homemaker Home Health Aide Training Program Facilities Listing 1 of 9 License # Name Street Address City, State, Zipcode County 2008-0335 Atlantic Cape Community College 5100 Black Horse Pike Mays Landing NJ 08330-
Facilities in North Carolina. The Department shall include CNA, certified nurse aide, nursing assistant. • Nurse aides must hold a current listing on the NC Nurse Aide I Registry. offices and dialysis centers) Adult/Family Care Home 6739 6%
.php/prmID/143; American Red Cross: Become a First Aid CPR/AED Instructor (2009). Cabarrus County Chapter, Concord, ; NC. Psychiatric Centers employ Mental Health Workers. Certified Nursing Assistant
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Summer, July, occasional rainbows
The weather has been awfully nice around here. Not the ridiculous 95-degree weather, not the equally ridiculous wave of 50-degree drench that followed it -- but strong sunlight and rainclouds, silhouetted against each other in layers. The full Spiral celestial archipelago, for those of you who remember Michael Scott Rohan.
Sorry, slightly euphoric.
HL got cranked firmly along this month, so you can go home and reassure the cats that June was just a temporary aberration. Number of puzzles implemented... I think the correct count is five, although things are getting complicated and it felt like more work than that.
The situation I dealt with (just to give you the idea) is "getting outside the starship". This is a minor complex of puzzles in its own right, with two different external areas, three access points, two magic items, different possibilities at different stages of the game -- you get the idea. As I said a couple of months back, I am implementing everything twice and the specter of untested plot combinations looms over me like, like a specter. Spectrally. It's somewhat exhausting.
But now you can get outside the starship, in all possible ways and by all possible means. Unless I decide to implement that sixth red-herring option. That'll be extra work.
Otherwise -- taking breaks from the airlocks -- I made some progress on the iOS board game that I've also been putting off. And I pushed the Seltani project a ways forward, although I managed to keep my hands off it for the latter half of the month. (I do well juggling two big projects at once. Three, not so well.)
What remains on the puzzle list is... hm. Surprisingly few major items. Several ways to mess around with lead weights. Some hijinks outside the starship which I will not detail. A lot of irritating map-navigation cases. (You acquire shortcuts as the game goes on, which complicates the automatic "go to X" code.)
I won't claim I'm getting near the end of mechanical implementation, because there's an inevitable shedload of minor game reactions and interactions too minor to be called puzzles. (Unless I'm in a mood for academic discourse. But that's not this post.) But I can hope to have those major items done in August. That would be good news.
So, short update for the month, but encouraging, I hope.
Reminder: Sept 14-15 is IF meetup weekend here in Boston.
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Hadean Lands full-page, full-color map poster! This map will be part of the game docs, but this poster will be larger and prettier. (Plus the game for Mac/PC/etc, and iPhone, and the postcard.) (Belated note: the poster will be added to all rewards $50 and larger.)
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Your name will appear in Hadean Lands, in some form, as an ancient alchemist or sage or spell-rubric. ("The Sulphuric Dragon of Andricus Plotinus", that kind of thing.) (Plus the game for Mac/PC/etc, and iPhone, and the postcard.)
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A mystical alchemical calligraphical formula of ancient (made-up) lore, hand-written on (freshly-made) ancient paper. With incomprehensible mystical symbols! (Plus special credit as Hero of the Coagulation, and the game for Mac/PC/etc, and iPhone, and the postcard.)
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The traditional Kickstarter "I'll fly out to visit you and bake you cookies!" offer. (Continental US only please.) We can hang out and talk about IF, or play the game together, or go out for Peruvian -- whatever's agreeable. Plus all of the above.
- (36 days)

domain: hobby


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Royal Canin Prescription Dog Food We have a huge selection of formulas to provide your dog with a healthy veterinary diet to combat issues including obesity, urinary S/O and much more. Tinned food was all. (predominantly dry)
Purina currently ranks on top 2 as the biggest manufacturer of pet foods worldwide. Alpo prides itself on offering quality and affordable dog food that's produced.
Charlotte Capers never thought to collect her papers. Her colleagues in the Archives have now done it for her, making their choices from a large number that go back for several decades. Here they are.
Don’t want to have to move Fido’s food every time your Coredy cleans? Use the strip to create a perimeter around the Alpo.
by none other than Max the dog: “My human constantly complains.
Oct 2, 2019.
Purina Alpo is one of the oldest dog food companies, founded in 1936 in Allentown, Pennsylvania. The brand is based on the principle that.
Apr 28, 2019.
Alpo Prime Cuts Dog Food – an impartial review, star rating and recall history prepared by the editors of The Dog Food Advisor.
Independent expert review and rating of Alpo dog food with recall information and cost-saving advice.
Alpo dry dog food – an independent review, star rating and recall history by the editors of The Dog Food Advisor.
Buy ALPO Prime Cuts Savory Beef Flavor Dry Dog Food, 16-lb bag at Chewy. com.
With high-quality protein and 23 vitamins and minerals — including calcium.
2 days ago.
Rated with 1 star. Amber of Mikado, MI Verified Reviewer. Original review: Dec. 14, 2019. Got a bag of Purina ALPO Prime Cuts® Dry Dog Food.
Feb 1, 2018.
Summary. You'd be hard pressed to find a cheaper dog food, both in terms of cost and ingredients. Use of controversial food dyes and mystery.
I never would’ve thought of that!’”—Dave Barry 9. “My dog is worried about the economy because Alpo is up to $3.00 a can. That’s almost $21.00 in dog money.”—Joe Weinstein 10. “Don’t accept your dog’s.
Harris Teeter has a new 3-Day Sale through Sunday and a new set of e-Vic deals including some great buys on Pictsweet Roasting Vegetables (FREE!), canned beans, Smithfield whole Boston Butt, Lean.
Top jobs that pay over $100,000 – The consumer company that’s probably behind your cat or dog’s favorite food is also dishing up high marks for its compensation packages. But this position at Nestle Purina PetCare does require a.

domain: food


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To support the flow of CSR funds towards controlling and eradicating the pandemic, the Ministry of Corporate Affairs (MCA) has released two notifications on 24th August 2020.
The amendments are as follows:
(i) Those companies which in their normal course of business, are engaged in research and development activities of new vaccine, drugs and medical devices, can now incur CSR expenditure to undertake research and development activities of new vaccine, drugs and medical devices related to COVID-19 for financial years 2020-21, 2021-22 and 2022-23. The activities need to be in collaboration with specified institutes and organisations. Also, such companies would need to disclose the relevant details in their CSR Annual Report and Board Report.
(ii) The existing list of CSR activities (as per Schedule VII of Companies Act 2013) has been broadened to include contributions made to Department of Pharmaceuticals and Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH). The relevant clause (ix) of Schedule VII now reads as:
(ix) (a) Contribution to incubators or research and development projects in the field of science, technology, engineering and medicine, funded by the Central Government or State Government or Public Sector Undertaking or any agency of the Central Government or State Government; and
(b) Contributions to public-funded Universities; Indian Institute of Technology (IITs); National Laboratories and autonomous bodies established under Department of Atomic Energy (DAE); Department of Biotechnology (DBT); Department of Science and Technology (DST); Department of Pharmaceuticals; Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH); Ministry of Electronics and Information Technology and other bodies, namely Defense Research and Development Organisation (DRDO); Indian Council of Agricultural Research (ICAR); Indian Council of Medical Research (ICMR) and Council of Scientific and Industrial Research (CSIR), engaged in conducting research in science, technology, engineering and medicine aimed at promoting Sustainable Development Goals (SDGs).
Click on the below links for CSR Rules amendment and Schedule VII amendments:


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Passenger numbers at BAA's five UK airports declined 2% year-on-year to 9.52 million in August, while total aircraft movements fell 0.5% to 73,500.
Among its London airports, Heathhrow saw a 1.9% decrease in passenger numbers to 6.46 million, while at Stansted footfall was down 5.2% to 1.88 million.
Both the London gateways saw a fall in aircraft movements, with Heathrow and Stansted posting a 0.3% and 4.4% decline respectively.
Among its other UK airports, Southampton posted a 6.4% decline in passenger numbers, while Glasgow and Aberdeen witnessed increases of 3.1% and 9.2% respectively.
Glasgow and Aberdeen saw an increase in aircraft movements of 2.4% and 5.1% respectively, while Southampton posted a decline of 6.3%.
Total cargo at BAA's five airports increased 2.6% to 142,000t, with Heathrow contributing the lion's share at 121,000t. Glasgow saw the highest proportional increase - up fourfold to 730t.

domain: economics


ATI Outdoors TactLite Stock Fits Most Maverick 88 Mossberg 500/535/590/835 Remington 870 American Tactical MB3 and Winchester 1200/1300 12 GA Pump-Shotguns 12 Gauge Adjustable Side Folding Shotgun Stock with Scorpion Recoil System Black Finish B.
The Advanced Technology Int. Strike force Side-Folding Shotgun Stock fits Maverick 88 12ga & 20ga (proud fit)in Mossberg 500/535/590/835 12ga & 20ga (proud fit)in Remington 870 12ga & 20ga (proud fit)in American Tactical MB3in and Winchester 1200/1300 Pump-Shotguns 12ga & 20ga (proud fit). It is a Six-Position Adjustable Side-Folding TactLite Shotgun Stock w/X2 Recoil Reducing Grip & Butt-Pad. The removable/adjustable cheek rest system has an elongated design to fit all users. It also includes a short cheek rest with 1/2in of adjustment. Adapters for all supporting models are included along with all mounting hardware for easy installation. It is constructed with DuPont(R) Extreme Reinforced Polymer and is scratchproof and weatherproof. Made in USA.
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Sammamish Valley Celebration of Farms and the Arts
Friday to Sunday, July 13, 14, and 15, 2018
July in the Sammamish Valley brings our sixth annual celebration of Summer!
Celebrate the season by exploring the beautiful Sammamish Valley. Visit farms and businesses to enjoy food and farm demonstrations; take a class; chat with a farmer; enjoy farm inspired art. You’ll find a variety of activities that celebrate summer: learn about local farms; sample freshly pressed apple cider; taste farm-fresh food and local wine; dig in some soil and take a walk in a peaceful farm field.
Each location will have its own schedule of events during the Valley celebration. All ages are welcome and some activities are free. Click on the links below for more information and individual schedules on what’s happening throughout the weekend at each farm and business.
Please follow the links for details.
Participants and activities are subject to change. Follow us on Facebook for current information @sammamishvalley.

domain: agronomy


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text:
For decades, residents in certain communities have been divided by their chosen favorite of the local cuisine. In Naples, the debate over the best pizzeria has occurred for at last 150 years. Residents and visitors to France differ on whether crepes should be savory or sweet, in addition to debating where the best place to get them can be found. With the foods that spark controversy and favoritism in mind, the members and editors of travel website VirtualTourist.com (www.virtualtourist.com) chose the best options in our Travel Guides and Things to Do for Top 10 Iconic Foods and the Best Spots to Find Them.
Pastrami Sandwich - New York City, New York
Exterior of Katz's Deli, Photo by Will Steacy Courtesy of NYCgo
Neighborhoods grow and change, but some things do stay the same. A fixture in New York's Lower East Side neighborhood since 1888, Katz's Delicatessen is a holdover from a time that has long disappeared from the old neighborhood. Less than a block from the Tenement Museum, which celebrates the immigrants who inhabited the neighborhood in the early 20th century, Katz's has served its world famous pastrami for over 125 years. The deli's superiority is so renowned that it even has online ordering, shipping all over the US and to any Air Force/Military addresses, a tradition that was established during World War II. As luxury hotels and trendy nightclubs pop up around it, the quality and tradition of Katz's insures it will be a fixture in the neighborhood for the next 125 years.
Pad Thai - Bangkok, Thailand
Photo Courtesy of the Tourism Authority of Thailand
One of Thailand's more accessible and less spicy dishes, pad thai is many individual's first foray into Thai cuisine. Comprised of stir-fried rice noodles, egg, bean sprouts, and peanuts, the dish is traditionally served with lime wedges and can be found all over Bangkok's street food scene. The most famous spot for Pad Thai in Bangkok is Thip Samai, an unassuming storefront across from Wat Thepthidaram in the city's Banglamphu district. The restaurant serves Original Pad Thai for approximately 70 Thai Baht (THB) ($2.13 USD or 1.57 EUR), as well as a version called "Superb Pad Thai," which is Thai noodles served in an egg omelet.
Pizza - Naples, Italy
While pizza has been reinterpreted all over the world, the original slice can be traced back to the working class neighborhoods of Naples, Italy. Traditionally, it was served Marinara or Margherita, with the primary difference between the two styles being that Margherita features mozzarella cheese and basil on top. It was named after Queen Margherita of Savoy, who was served this style by a young chef when visiting Naples in the late 19th century. While there is no shortage of pizzerias, two of the most famous shops are L'Antica Pizzeria da Michele and Pizzeria Di Matteo, the latter located near the Duomo and known for being where President Bill Clinton sampled Naples' famous export during the 1994 G7 conference.
Frites - Brussels, Belgium
Maison Antoine, Place Jourdan Photo courtesy of Visit Belgium
Belgium is well known for many food specialties, including waffles, mussels, and chocolate, but one of their greatest areas of expertise is in frites, or fried potatoes called by some as French Fries. Belgian frites are distinct for two reasons - they are usually made with Bintje potatoes, and they are fried not once, but twice! Vying for top spot in Brussels are Frit Flagey in Place Flagey, Friterie Tabora near the Grand Place, and Maison Friterie Antoine in Place Jourdan. Once you select your chosen vendor, your next decision is how to dress your frites. While the traditional Flemish topping is mayonnaise, Maison Antoine provides over twenty different sauces, including curry, mustard, traditional ketchup, poivre and even cocktail sauce!
Best Coffee and Beignets - New Orleans, Louisiana
Café du Monde photographed by Pat Garin, Photo Courtesy of the New Orleans Convention & Visitors Bureau
A people watching institution in its own right, Café du Monde is a mandatory stop for any coffee connoisseur visiting the Big Easy. Conveniently located on Jackson Square, the patio at Café du Monde is a great spot to enjoy the European ambiance and pace of New Orleans or listen to the city's famous street musicians and performers. While Café du Monde is known around the world, many people do not know that coffee first came to North America by way of New Orleans. After being successfully cultivated by the French in Martinique, they brought it to their new colonies along the Mississippi River. The beignets, a square piece of dough, fried and covered with powdered sugar, are a perfect complement to the chicory coffee. If you cant make it to the flagship on Decatur Street, there are a total of eight Café du Monde coffee stands within the New Orleans metropolitan area.
Steak - Argentina
Steak and beef have played a large role in the culture of Argentina, from the asado cuisine to the image of gauchos on the estancia. Widely considered to have the best beef, Argentina's steaks are a cut above the rest because the cattle are raised on grass in the pampas, not grains in feedlots. A few recommended parillas, or grill restaurants, are El Boliche de Alberto in Bariloche, Don Julio in Buenos Aires, and La Cabrera in the Palermo Viejo district of Buenos Aires. VirtualTourist members recommend the Bife de Lomo at La Cabrera, which comes with a variety of side dishes and promises to be the most affordable 12 ounce steak of your life!
Sushi - Tokyo, Japan
Similar to the steak situation in Argentina, delicious and fresh sushi is available all over Japan, but it is perhaps most associated with the sleek culture of Tokyo. Although there was some concern about the safety of dining on fish after Japan's tsunami and radiation scare, the incident has not affected the popularity or consumption of sushi within Japan. While sushi can be had at any hour of the day in Tokyo, one experience unique to the city is a visit to the Tsukiji Fish Market. Although visitors are presently not allowed to watch the tuna auctions, visitors are still allowed in the Outer Market area, where a sushi breakfast can be had at a much lower price than the standard rate. Visitors should keep in mind most Outer Market restaurants and shops close early in the afternoon. Also, there are plans for the fish market to move to a new location as part of Tokyo's gearing up for the Olympics, but these plans have been delayed for another year, so visit this historic location while you still can! For those who prefer coffee in the morning and sushi for dinner, check out Sushi Saito, which has three Michelin stars and only seven seats, located in the Akasaka district.
Gelato - Florence, Italy
Perhaps the most hotly debated item on our list, gelato is a treat that no traveler visiting Italy can avoid or resist. The well-documented difference between gelato and ice cream is the amount of air whipped into the batch - only 20% for gelato compared to 60% air for ice cream. This difference makes gelato denser and having a richer flavor. Although gelaterias do have some traditional ice cream flavors, they also carry certain flavors more popular for gelato, like nocciola (hazelnuts), stracciatella, and zabaione. VirtualTourist members strongly suggest Bar Vivoli, Perche No, and Grom in Florence. For those not traveling soon, Grom also has locations in Paris, New York, Tokyo, Malibu, and Osaka.
Crepes - Brittany, France
Although crepes can now be found all over, they originated in Brittany, in the northwest region of France. One unique aspect of this iconic food is it can be eaten either savory or sweet. While some people eat the savory galettes for lunch or dinner with cheese, ham, eggs, or vegetables, the more widespread interpretation is as a sweet treat, filled or topped with Nutella spread, whipped cream, or custard. Three widely recommended spots are Crêperie Tout le Monde in Douarnenez, Corps de Garde in Saint Malo, and Breizh Café in Cancale.
Chili crab - Singapore
Although chili crab can be widely found throughout Singapore and Malaysia, it is considered Singapore's signature seafood dish. Crabs are served in a bright red sweet and savory tomato and chili based sauce, often with pullman toast, crusty bread, or steamed buns to sop up the sauce. Members strongly suggest the Jumbo Seafood Restaurant in Singapore's East Coast Seafood Center, although the restaurant has five locations throughout Singapore and a new outpost in Shanghai, China.
Whether you are hungry for spicy, savory, or sweet, these selections are sure to top the competition. For more recommendations from real travelers with refined palettes, check out VirtualTourists Travel Guides, Things to Do, and forums online!


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Writers: Becky Cloonan and Michael Conrad / Artist: Jorge Corona and Sarah Stern / DC Comics
Batgirls is here, and it features Batgirl, Batgirl, and Batgirl. Or better known to their fans as Barbara Gordon, Cassandra Cain, and Stephanie Brown. This series, which had a backdoor introduction in Batman: Fear State, follows the trio as they move across Gotham to an area called “The Hill,” where they plan to hunker down and search for the new villain Seer, who’s basically a dark version of Oracle.
Batgirls #1 was a lot of fun. It had a lot of weight to carry in its setup, but it does a good job of establishing the dynamics of the book and setting up the world. It may feature three Batgirls, but they couldn’t be more different from each other. Stephanie Brown is a little carefree, Cassandra Cain is a little dark and mysterious, and Barbera Gordan is a little too responsible. Together, they balance each other out.
I also like that Barbera is taking a leadership role. It’s the most logical thing for her to do as she’s the oldest and most experienced Batgirl of them all, but it’s still fun to see it fully realized.
I really like the art in this book. It’s stylized in a way where it fits the lighthearted tone of Cloonan and Conrad’s story while leaving room for some gritty action when it’s needed. It’s got a style that really sets it apart from other Bat-centric books, which is a necessity when there are so many of them on the shelves.
My absolute favorite thing about this book so far is its colors. You don’t typically associate an abundance of color with a book set in Gotham, but Sarah Stern is on a mission to change that. While it’s set in a broody atmosphere, Stern does a wonderful job making greens, blues, pinks, and yellows pop in a beautiful and sharp way. You’ll leave this book wanting to book a trip to the city, only to come back to your senses and realize you’ll probably be mugged before you even leave the plane.
Batgirls #1 is a fun entry into a lighter side of Gotham with some of the city’s most balanced heroes both in fighting and personality. If you like lots of action with some laughter mixed in, or if you’re just a huge Batgirl stan, this is a book you’re gonna want to check out.
9 Bat Beatdowns out of 10


text:
Yet the Dolphins didn't get the win in either situation. And for their star receiver, that's a serious problem.
The Patriots jumped on the Dolphins early, getting out to a 21-0 lead in the first half. The Dolphins, though, knocked Jimmy Garoppolo out of the game and then mounted a comeback. Ryan Tannehill threw two second-half touchdowns, Kenyan Drake ran in another and the 'Fins had a chance to win the game on a 29-yard Hail Mary. But the bid fell short.
With a home game against Cleveland slated for next week, an 0-3 start is a possibility for the Dolphins if they don't stop being an "almost team" soon.

domain: game


text:
Synonyms Spoons is a fun, fast-paced card game for small groups. This version provides practice identifying synonyms for commonly used words.
The object of the game is to be the first player to collect four cards with synonyms. Player draw, pass, keep, or discard while attempting to get four synonyms in their hands.
If you don't know how to play spoons, here is a good explanation of the traditional game: How to Play Spoons
This game follows the same rules.
✓ 64 playing cards