The purpose of our study was to determine the interest of hepatic steatosis index (HSI) in the detection of hepatic steatosis in patients with type 2 diabetes in order to establish an appropriate screening program of this disease in our population.cross-sectional study involving 281 type 2 diabetics hospitalized in the Department of Endocrinology in collaboration with the Hepato-gastroenterology Department at the University Hospital Ibn Rochd Casablanca between January 2018 and June 2018. Anthropometric variables studied were, biological, hepatic steatosis index (HSI) and liver ultrasound. The HSI score of> 36 predicted the presence of fatty liver. The HSI score (fatty liver index) was calculated for all patients using the following formula: 8 × (ALT / AST) + BMI + 2 (if type 2 diabetes) + 2 . Statistical analysis was performed with SPSS Version 2, the average waist circumference was 99.51 ± 10.98 cm. 39.1% of patients were hypertensive, 58% were dyslipidemic. Abnormalities in transaminases were found in 6% of patients. Prevalence of NAFLD was 45.2% based on the HSI score > 36. This prevalence is consistent with the findings made by the liver ultrasound (47.7% of cases). Hepatic steatosis was significantly correlated with dyslipidemia (P=0.006), overweight (P=0.00015), obesity (P=0.001) and hypertriglyceridemia (P=0.0003). The sensitivity of HSI was 89.55%, negative predictive value (NPV) was 90.91%, specificity was 95.24%, and positive predictive value (PPV) was 94.49%. AUROC for HSI was at 0.979 .average age of patients was 54.15 ± 13.14 years with a female predominance (76.9% of cases), and a sex ratio of 3.32. Mean duration of diabetes of 10.5 ± 8.03 years with an average glycated hemoglobin of 10.23 ± 1.96%. BMI was 29.53 ± 4.55 kg/mhepatic steatosis is common among our patients; it is correlated with dyslipidemia, obesity and hypertriglyceridemia. Metabolic steatopathy is a global public health problem; it is the leading cause of chronic hepatopathies in Western countries. It encompasses several disorders ranging from simple hepatic steatosis to nonalcoholic fatty liver hepatitis (NASH), fibrosis and liver cirrhosis. Its association with type 2 diabetes is common . Indeed,This is a cross-sectional study involving 281 type 2 diabetics hospitalized in the Department of Endocrinology in collaboration with the hepato-gastroenterology department at the University Hospital Ibn Rochd Casablanca between January 2018 and June 2018. The study included any unknown type 2 diabetic patients followed for chronic hepatopathy, or notion of taking hepatotoxic drugs nor alcohol abuse. The variables were studied: age, sex, duration of diabetes, diabetes treatment, glycemic control, cardiovascular risk factors associated with the laboratory tests and liver ultrasound. The HSI score (Hepatic steatosis index) was calculated in all patients using the following formula: 8×(ALT / AST) + BMI + 2 (if type 2 diabetes) + 2 . HSI score of > 36 predicted the presence of hepatic steatosis. Data collection is based on a detailed operating record. For statistical analysis, SPSS version 19 was used. The sensitivity and the specificity of the HSI score were calculated by contingency table. The area under the receiver operating characteristic curve (AUROC) was also analyzed.2, the average waist circumference was 99.51 ± 10.98 cm. 39.1% of patients were hypertensive, 58% were dyslipidemic . The average age of patients was 54.15 ± 13.14 years with a female predominance (76.9% of cases) and a sex ratio of 3.32. The mean duration of diabetes was 10.5 ± 8.03 years with average glycated hemoglobin of 10.23 ± 1.96%. BMI was 29.53 ± 4.55 kg/mipidemic . Abnormaipidemic . The AURipidemic .Metabolic fatty liver disease is characterized by an abnormal accumulation of fat in hepatocytes. In the literature, its prevalence in type 2 diabetic patients is between 5 and 87% . It is cIn our study, fatty liver disease was common in patients with type 2 diabetes with normal transaminases. Thus, hepatic steatosis should be screened for in type 2 diabetic patients regardless of their level of transaminases. The non-invasive HSI score is a simple, inexpensive screening for fatty liver, offering the possibility of early diagnosis and prevention of complications related to this condition, it should be part of liver monitoring in patients with type 2 diabetes.Metabolic steatopathy is a frequent and often asymptomatic in patients with type 2 diabetes;The HSI score is an easy and inexpensive tool offering mass screening for hepatic steatosis.The study reveals that HSI score may be used to facilitate mass screening for hepatic steatosis.


Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2–3, 269 patients in target range 2–3.5 and 98 patients in target range 2.5–3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers’ TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2–3, 2–3.5 and 2.5–3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers’ INRs were much more stable than non-switchers’.Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase. Vitamin K antagonists (VKAs) are prescribed to treat and prevent thrombosis in venous thromboembolism, atrial fibrillation, heart valve replacement, and some other indications. Their effect is unpredictable and requires frequent monitoring to obtain an anticoagulation intensity ) within the therapeutic range. Treatment is safest and most effective when the time within the therapeutic range (TTR) is high ,2 and thWith the introduction of the direct oral anticoagulants (DOACs), the treatment arsenal expanded. Many patients have switched from a VKA to a DOAC. However, DOACs are contraindicated in mechanical heart valves, renal insufficiency, and in combination with certain interacting drugs. Furthermore, because a poor TTR can be the result of poor medication adherence, physicians may be reluctant to switch such patients to a DOAC. Therefore, interventions to optimise VKA treatment remain relevant.A possible intervention is to switch to a vitamin K antagonist with a longer half-life. Theoretically, a longer-acting drug would be less sensitive to suboptimal medication adherence and produce more stable INRs. In the Netherlands, only short-acting acenocoumarol  and long-acting phenprocoumon  are available. Data on the effect of switching from acenocoumarol to phenprocoumon on TTR are lacking completely; studies with other VKAs ignore natural variation in TTR. We aimed to determine whether switching from acenocoumarol to phenprocoumon increased TTR and decreased INR variability in practice.This is a retrospective cohort study with patients from two first-line thrombosis services in the Netherlands. Of patients who switched to phenprocoumon, we compared TTR and INR variability before and after the switch. We also assessed whether this change differed from that in matched non-switchers, to account for the natural evolution of TTR and INR variability over time. We hypothesised that the switch to phenprocoumon would increase TTR and decrease INR variability.In the Netherlands, VKA management is delegated to dedicated first-line regional “Thrombosis Services” that organise INR checks and adjust the VKA dose. Each thrombosis service uses one preferred VKA. Certe Trombosedienst and Trombosedienst Maastricht UMC+ are two thrombosis services, in the north and south of the Netherlands, respectively, that routinely use acenocoumarol. Thrombosis Service physicians can suggest switching a patient to phenprocoumon; the treating physicians usually follow this suggestion.We extracted INR and VKA dosing records of adult patients who used acenocoumarol or switched from acenocoumarol to phenprocoumon, in target ranges 2–3, 2.5–3.5 or 2–3.5 , indicated for atrial fibrillation (AF), venous thromboembolism (VTE) or mechanical heart valve replacement (MVR). Data were extracted on July 17th, 2018 (Certe Trombosedienst) and June 20th, 2019 (Trombosedienst Maastricht UMC+). We excluded the first 90 days of treatment with vitamin K antagonists because INRs are unstable in the initiation period.All data were anonymised before they were provided to the researchers. The Medical Ethics Review Board of the University of Groningen confirmed that this study required no ethical approval.We selected patients who used acenocoumarol for at least 180 days  before switching to phenprocoumon, and had follow-up INR measurements for at least a further 180 days. The study size was based on the number of patients who switched.Non-switchers were defined as patients who used acenocoumarol during their entire treatment course or up to date of data extraction. For every calendar date on which a switcher switched, we selected patients who used acenocoumarol for the previous 180 days  and next 180 days, with the same target range. At this stage, one non-switcher could be selected to be a control for multiple switch dates, if their follow-up was long enough. We then later randomly selected one instance per patient, to prevent over-representation of long-term non-switchers in the matching strategies.We defined subgroups of special interest, based on the prompt for switching and special clinical considerations. A switch could be prompted by a low acenocoumarol dose requirement, a suboptimal TTR or high variability. We separately analysed patients who used less than 1.5mg acenocoumarol per day, patients who had a TTR <60% and patients with a baseline INR variability above the 75th percentile in their target range. In addition, we provide specific information about patients with a mechanical heart valve (who are confined to VKA), and the elderly .We calculated the proportion of time in the therapeutic range (TTR) as well as the time below and above the range for each patient using linear interpolation according to the Rosendaal method . AdditioWe distinguished three periods: the 180 days before a patient’s switch to phenprocoumon, the 180 days after switch, and a period from 180 to 360 days see . For nonFor the initial analysis, we summarised the TTR and INR variability as median and interquartile range. Differences were tested using a one-sample Wilcoxon rank-sum test. Intra-individual correlations were summarised using the Spearman correlation.We compared the differences in VKA quality parameters between switchers and non-switchers, to isolate the effect of the switch to phenprocoumon. Non-switchers were matched to switchers in a 2:1 ratio using propensity scores based on age, sex, indication for VKA therapy, duration of VKA therapy until  switch, the mean acenocoumarol dose in the six months before  switch, the times below and above range and the log-transformed INR variability. The propensity score was determined by logistic regression, and matching was performed using the MatchIt package  in R verDifferences from baseline were analysed using a mixed linear effects model  to accouValues are reported as mean ± SD or median [interquartile range], as appropriate. A p-value below 5% was considered significant for all analyses; estimates are given as point estimate .Patient selection is outlined in The thrombosis service Groningen contributed 28,756 eligible patients from September 25, 1991, onwards, with a total follow-up of 207,963 patient-years. The thrombosis service Maastricht contributed 3,645 patients from January 02, 1997, onwards, with 28,994 patient-years of follow-up.There were relatively more switchers in Maastricht than in Groningen. Although Maastricht contributed only 11% of patients, they contributed 47% of switchers . Four hundred and ninety-one switchers could be matched to 982 controls.Characteristics of switchers are summarised in Switchers achieved a lower TTR and their INRs were more volatile in the period before they switched than unmatched non-switchers.The daily acenocoumarol dose differed between cases and controls as well: switchers from Maastricht, where a low dose requirement is a trigger to consider switching, indeed required a lower dose than unmatched non-switchers. In Groningen, where no such trigger is formally defined, switchers generally use a higher dose than the other patients in the anticoagulation clinic.Men are less likely to be switched across all target ranges, yet they still outnumber women in target range 2.5–3.5, as they are more prone to cardiac indications for anticoagulation.Patients who switched from acenocoumarol to phenprocoumon were given a lower VKA dose in milligrams. For target range 2–3, the phenprocoumon dose was lowered to 91 [78–101]% of the acenocoumarol dose (in mg) in the first 180 days. In the other target ranges, the conversion factors were lower: 86 [75–97]% for target range 2–3.5 and 88 [73–96]% for target range 2.5–3.5.Patients in target ranges 2.0–3.5 and 2.5–3.5 were monitored more often than before their switch; this was not observed in patients in target range 2.0–3.0 . PatientAfter the first 180 days, the phenprocoumon dose was lowered further, to 85 [71–99]% of the baseline acenocoumarol dose in target range 2–3, 78 [67–92]% in target range 2–3.5 and 79 [66–94]% in target range 2.5–3.5.Monitoring intervals were prolonged across all target ranges . For tarThe evolution of VKA quality parameters after switching from acenocoumarol to phenprocoumon is summarised in The TTR achieved after the switch was only weakly related to the TTR before the switch: Spearman ρ was 0.26 (95% CI 0.09 to 0.42) for target range 2.0–3.0, 0.22 (95% CI 0.10 to 0.33) for target range 2.0–3.5 and 0.05 (95% CI -0.15 to 0.24) for target range 2.5–3.5. In target range 2.5–3.5 there was a moderate positive association between the time above the range at baseline and after the switch (ρ 0.43 (95% CI 0.26 to 0.58)), that persisted in the later period (ρ 0.45 (95% CI 0.27 to 0.59)). The same was found for the time below the range (ρ 0.41 (95% CI 0.24 to 0.56) and 0.37 (95% CI 0.19 to 0.53)). In other target ranges, this effect was not observed.Four hundred and ninety-one switchers could be matched with 982 non-switching controls, with a high similarity between the two groups . The coefficients from the propensity score matching and the patient characteristics from matched patients are shown in When comparing switchers with non-switchers, the initial effect of switching is negative: TTR decreases mainly owing to an increase in the time above the range. At the same time, the INR variability increases, though only statistically significantly in target range 2–3.5. In the first six months, switchers are less likely to obtain or maintain a TTR ≥65%: the absolute risk difference was -13 (95% CI -22 to -3) percentage points for target range 2.0–3.0; for target range 2.0–3.5 it was -20 (95% CI -27 to -12); for target range 2.5–3.5 the risk difference was -5 (95% CI -12 to 3). Switchers’ INRs were monitored more often, with 24% (95% CI 18 to 29) less time between INR measurements for target range 2–3; 22% (95% CI 18 to 25) for target range 2–3.5 and 29% (95% CI 23 to 35) for target range 2.5–3.5.Positive effects occur in the second six-month period after switching. TTR mildly increases, with 0.8 (95% CI -4.4 to 6.1), 3.9 (95% CI 0.4 to 7.4) and 6.4 (95% CI 0.8 to 12.1) percentage points in target ranges 2.0–3.0, 2.0–3.5 and 2.5–3.5, respectively. The INR variability strongly decreases across all target ranges. During this period, switchers in target ranges 2–3 and 2–3.5 were slightly more likely to obtain a TTR ≥65%: absolute risk differences were 2 (95% CI -9 to 13) and 6 (95% CI -1 to 13). The effect was more pronounced in target range 2.5–3.5, where patients were 15 (95% CI 6 to 25) percentage points more likely to obtain a TTR ≥65%. Switchers in target ranges 2–3 and 2.5–3.5 were no longer monitored more often than their matched non-switching controls (they had 2% (95% CI -6 to 12) and 2% (95% CI -6 to 12) more time between measurements). Patients in target range 2–3.5 had 14% (95% CI 8 to 22) more time between INR measurements.We compared the effect of a switch in several groups of special interest. Patient characteristics of switchers in these groups, and their matched non-switchers, are summarised in The effect of a switch relative to non-switchers is summarised in The effect of a switch on TTR was consistent in groups with different prompts for switching . In target ranges 2–3 and 2–3.5, patients with a poor TTR and patients with high INR variability who switched were initially relatively over-anticoagulated compared with patients with a low VKA dose before their switch. This difference disappeared after the first 180 days. In target range 2–3.5, the INRs of patients whose switch was prompted by a low VKA dose stabilised quicker than the INRs of patients with a poor TTR.We also evaluated the effect of a switch in patients who require specific clinical consideration: i.e. the elderly and patients with a mechanical heart valve. Initially, the effect of a switch on TTR in these groups is comparable to the effect in the whole population. In the long term, however, the TTR of elderly patients in target ranges 2–3.5 and 2.5–3.5 seems not to improve by switching, nor does the TTR of patients with a mechanical heart valve and target range 2.5–3.5.In this study, we analysed the effect of switching from acenocoumarol to phenprocoumon on the achieved quality of anticoagulation in patients from two Dutch anticoagulation clinics. We found that patients’ time in the therapeutic range and INR variability do not improve in the first six months, compared with non-switching matched controls. In the second six-month period after a switch, however, INR variability decreases and TTR improves.Although the question which vitamin K antagonist to prefer is far from new, we are the first to observe the real-life effect of switching from acenocoumarol to phenprocoumon using matched non-switchers. Previous research only compared groups of patients using different VKA. Already in the 1960s and early 1970s phenprocoumon showed favourable properties compared with warfarin  and acenTwo studies describe the switch from acenocoumarol to warfarin. An Italian group found no increase in the number of prothrombin times in range . The resIn our study, we separated the switching effect from the natural course of anticoagulation therapy and bias by indication with the use of matched non-switching controls. However, matching is sensitive to unmeasured confounders. We have included almost all the limited data available to anticoagulation clinics in the matching, and we believe they included the most relevant confounders. However, we could not control for a switch due to the start of interacting medication (e.g. rifampicin).We could not assess the effect of a switch on the incidence of bleeding and thrombotic events, because we lacked the data. Instead, we measured TTR and INR variability. TTR and INR variability link the joint pharmacological effect of all vitamin K antagonists to bleeding and thrombotic complications –3. AdditThe observational nature of our study only allowed us to analyse patients who actually switched. Strictly speaking, our study cannot be generalised to patients whose physicians do not see an indication to switch. However, our results are similar to those from earlier studies comparing patients on the two drugs without switching ,13. NeveOther strong points of our study are the real-life setting and the analysis in contemporary target ranges; previously, higher intensity anticoagulation therapy was prescribed. Our findings are more robust because they stem from two independent thrombosis services.The eventual increase in TTR and decrease in INR variability after switching to phenprocoumon are intuitive; factor VII levels fluctuate more during the day under acenocoumarol than under phenprocoumon ,21. ThisThe transition period following a switch is characterised by unfavourable effects on VKA control: a decreased TTR and a higher INR variability. Patients are more prone to bleeding, owing to a higher proportion of time above the target range . A possiIn the long run, switching from acenocoumarol to phenprocoumon leads to improved VKA control. In all target ranges, the switch to phenprocoumon significantly decreases INR variability. A lower INR variability reduces the risk of bleeding and thrombosis –29, but A switch to phenprocoumon also significantly improves TTR in target ranges 2–3.5 and 2.5–3.5, relative to non-switching controls. The TTR improvement is most pronounced in target range 2.5–3.5, with a difference of 6.4 (95% CI 0.8 to 12.1) percentage points. The associated clinical benefit cannot be quantified exactly because the relationship between TTR and incidence of events is not linear [The benefit of an improved TTR does not extend to patients with a mechanical heart valve prosthesis, nor to elderly patients in target range 2–3.5 or 2.5–3.5 (the latter even seem to decline). Although the findings in this group are less robust, owing to the smaller sample size and less perfect matching, they are cause for concern. The efficacy and safety of VKA are paramount in these groups because alternative forms of anticoagulation might be contraindicated.Fortunately, elderly patients in target range 2–3 do increase in TTR after the switch. Elderly patients across the target ranges, and patients with mechanical heart valves, obtain a lower INR variability. However, it is questionable whether the decreased INR variability cancels out the neutral or unfavourable effect on TTR, the risks associated with the transition period, and the risk of medication errors with drugs that are less commonly used.Eventually, the switch from acenocoumarol to phenprocoumon improves the time in the therapeutic range and decreases the INR variability. However, this is preceded by a transition period, where TTR is lower and mostly the time above the range is increased. Physicians and their patients should weigh the benefit of a small improvement in VKA control and the risk of the transition period.S1 Table(DOCX)Click here for additional data file.S2 TableSee also (DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 TableEstimate with 95% confidence interval. An asterisk indicates that values were log-transformed in the analyses.(DOCX)Click here for additional data file.


The aim of this study was to assess time on treatment with abiraterone and enzalutamide, two androgen receptor targeted (ART) drugs, the impact on time on treatment of time interval without drug supply between prescription fillings, and adherence to treatment.By use of data from The National Prostate Cancer Register, The Prescribed Drug Registry and the Patient Registry, time on treatment with the abiraterone and enzalutamide was analyzed in all men with castration resistant prostate cancer (CRPC) in Sweden 2015–2019. Three time intervals between consecutive fillings, i.e. time without drug supply, were assessed. Adherence to the treatment was evaluated by use of the Medication Possession Ratio. Kaplan Meier analysis and multivariable Cox regression model were used to assess factors affecting time on treatment.Between January 2015 and October 2019, 1803 men filled a prescription for abiraterone and 4 534 men filled a prescription for enzalutamide. With a time interval of 30 days or less between two fillings, median time on treatment was 4.9 months (IQR 2.6–11.7) for abiraterone and 8.0 months (IQR 3.6–16.4) for enzalutamide. In sensitivity analyses, allowing for no more than 14 days without drug supply between fillings, median time on treatment was 3.9 months (IQR 2.1–9.0) for abiraterone and 5.9 months (IQR 2.8–12.1) for enzalutamide. Allowing for any time period without drug between fillings, median time on treatment was 5.7 months (IQR 2.7–14.0) for abiraterone and 9.8 months (IQR 4.4–21.0) for enzalutamide. Adherence to treatment was above 90% for both drugs.Time on treatment with abiraterone and enzalutamide was shorter in clinical practice than in randomized controlled trials and varied almost two-fold with time interval without drug. Adherence to treatment was high. The main limitation of our study was the lack of data on use of chemotherapy. S1 Table)  71–82) for abiraterone and 76 years (IQR 71–81) for enzalutamide. Median time from diagnosis to start of treatment was 5.5 years for both abiraterone and enzalutamide. Time from ADT start to abiraterone or enzalutamide start was more than 5 years in almost 40% of men and less than 1 year in less than 10% of men. The majority of men, almost 70%, had CCI ≤ 2.Fig 2). We also assessed shorter and longer time intervals between two fillings. For a shorter time interval, up 14 days without drug supply, median time on treatment was shorter, 3.9 months (IQR 2.1–9.0) for abiraterone and 5.9 months (IQR 2.8–12.1) for enzalutamide. For a longer time interval without drug supply, allowing for any time period without drug before the next filling, median time on treatment became longer, 5.7 months (IQR 2.7–14.0) for abiraterone and 9.8 months (IQR 4.4–21.0) for enzalutamide.Median time on treatment was 4.9 months (IQR 2.6–11.7) for abiraterone and 8.0 months (IQR 3.6–16.4) for enzalutamide, using 30 days or less as time interval between two consecutive fillings without drug supply . By use of a time interval of 30 days, the duration of mean time on treatment covered by drug was 8.5 months for abiraterone and 11.6 months for enzalutamide . These findings remained after adjustments in the multivariable Cox regression analysis .A shorter time on treatment was found in old men, in men who had receive non-curative primary treatment, in men with high comorbidity, and in men with short time on ADT prior to ART S3 Fig).Men who received ART after chemotherapy had a shorter time on treatment than men who received ART before chemotherapy, however only 12% of men were reported to have received chemotherapy . We argue for the use of a 30-day limit for the time interval without drug supply for ART drugs as a reasonable compromise to be applied in observational studies based on data in Prescribed Drug Registries.No consensus exists on what time interval between fillings should be used when assessing time on treatment for ART drugs from drug registries. In previous registry studies there has been a large range in the allowed time interval without drug supply from 45 to 90 days ,16. HoweMean time on treatment was longer than median time on treatment for both abiraterone and enzalutamide, which shows that some men use ART drugs for an extended time, e.g. 10% of men had a time on treatment longer than 23 months for abiraterone and 30 months for enzalutamide. Mean time on treatment is a reliable measure of the average amount of drug used, since it accounts for men with very long or short time on treatment better then median treatment duration –37.In line with previous reports, adherence to the treatment with abiraterone and enzalutamide was above 90% for both the drugs –44, likeIn line with previous findings, time on treatment was shorter in old men, in men who had received primary non-curative treatment, in men with a short time on ADT before start of ART, and in men with high comorbidity .In this register-based study of all Swedish men with mCRPC in 2015–2019, time on treatment was 5 months for abiraterone and 8 months for enzalutamide. The concern that men with mCRPC continue to use ART drugs for too long in clinical practice was not substantiated in our study. Adherence to treatment was high. Men with aggressive prostate cancer had shorter time on treatment.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


ObjectivesHypertension is strongly related to body mass index (BMI). Obesity has been the single main contributor to hypertension. Furthermore, the clinical manifestations are normally associated with BMI in hypertensive patients. This study aimed to evaluate the relationship between clinical features and BMI among hypertensive patients in both males and females.MethodologyA retrospective cross-sectional study was conducted among 296 patients having a self-reported history of hypertension and on anti-hypertensive medication. The study was conducted in the medical outpatient department of a secondary care hospital in Karachi during six months (January 2020 to June 2020). A detailed history was taken from each patient about hypertension-related symptoms, and clinical examination was performed. Blood pressure was measured using a sphygmomanometer with a stethoscope.ResultsOf the 296 patients, 156 (52.2%) were males and 140 (47.3%) were females; 16 (5.4%) of them were underweight, 91 (30.7%) were normal weight, 129 (43.6%) were overweight, and 60 (20.3%) were obese; in addition, 106 (35.8%) reported edema and 71 (24.0%) reported nausea and so on. As far as the association of clinical features and BMI was concerned, our study results showed that only edema (p=0.017) and nausea (p=0.044) were significantly associated with the BMI of the patients. Patients with edema were more likely to be obese than those without edema (29.2% vs. 15.3%), whereas patients with nausea were more likely to be overweight than those without nausea (57.7% vs. 39.1%).ConclusionsOur study showed that among the clinical features, edema and nausea were significantly associated with the BMI of the patients, whereas the relationship with others was insignificantly related to BMI of the patients in both male and female patients. Hypertension (HTN), also known as raised or high blood pressure (HBP), is a condition in which the blood vessels have persistently elevated pressure . If HBP 2 [In addition, obesity and related cardiovascular, metabolic, and renal ailments have swiftly become a main risk to universal health . Global 2 . Numerou2 .As far as studies in Pakistan are concerned, it has been reported that approximately 30% of HTN in patients occurs because of obesity in males up to 45 years; nevertheless, in few patients, it is as high as 60% . One morDuring various previous years, there are more elements that boost the pathophysiology of obesity accompanying HTN as metabolic illnesses and raised BPs are persistent and leading cause of dyslipidemia, target organ injury, and diabetes mellitus, leading to CKD . Our objA retrospective cross-sectional study was conducted of patients having HTN, which was self-reported, and on anti-hypertensive medicines. A total of 296 patients aged 18 years or above were recruited in the study from the medical outpatient department of a secondary care hospital in Karachi using a consecutive sampling technique. The duration of the study was from January 2020 to June 2020.A thorough history was recorded from every patient about HTN-related clinical features, and clinical examination was performed. Patients with a history of diabetes, cardiac events, neurological disorders, cluster headache, gastrointestinal disease, and morbid obesity were excluded from the study. Blood pressure was measured using a sphygmomanometer through stethoscope.Data analysis was performed using Statistical Package for Social Sciences (SPSS) Version 26.0 . The descriptive analysis was expressed as frequency and percentages. After checking for normality, inferential analysis was executed using Spearman’s correlation. A p-value of <0.05 was considered as statistically significant.Of the 296 patients, 156 (52.7%) were males and 140 (47.3%) were females; 16 (5.4%), 91 (30.7%), and 129 (43.6%), 60 (20.3%) of them were underweight, normal weight, overweight, and obese, respectively. Also, 196 (66.2%) of patients gave a positive history of headache, 146 (49.3%) reported vertigo, 106 (35.8%) reported edema, 120 (40.5%) reported chest pain, 140 (47.3%) reported vision problems, 139 (47.0%) reported dyspnea, 9 (3.0%) reported epistaxis, 112 (37.8%) reported increased urinary frequency, 71 (24.0%) reported nausea, 99 (33.4%) reported sleep apnea, 94 (31.8%) reported palpitation, 190 (64.2%) reported fatigue, and 161 (55.4%) reported confusion  and nausea (p=0.044) were substantially linked to BMI of patients; patients with edema were more likely to be obese than those without edema (29.2% vs. 15.3%), whereas patients with nausea were more likely to overweight than those without nausea (57.7% vs. 39.1%). None of the other clinical features were significantly associated with the BMI of the patients  is due to elevated blood pressure that affects the blood-brain barrier that weakens its functioning, resulting in cerebral hyperperfusion and ultimately leading to brain edema . Our stuTassaduqe et al. found an elevated occurrence of HTN with increasing age . HoweverOur study was also consistent with past studies that revealed that HTN was correlated with BMI rather than age. Tesfaye et al. conducted research among Asians and Africans and reported that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively correlated with age, whereas BMI was negatively correlated with age in some patients . In contThe results of our study, in accordance with other same studies, provide beneficial clinical statistics when measuring, handling, and counselling patients with HTN. Furthermore, these interpretations and more studies are needed taking into account more aspects and features to determine the impact of weight reduction on the occurrence or severity of HTN-related manifestations.Our study showed that among the clinical features, only edema and nausea were significantly associated with the BMI of the patients. Patients with edema were more likely to be obese than those without edema, whereas patients with nausea were more expected to have overweight than those without nausea. However, the relationships with other features were insignificantly related to the BMI of the patients in both male and female patients.


However postoperative pain remains problematic. No strategy to reduce phrenic nerve irritation, including heating or humidifying the insufflating gas, alternatives to CO100 women undergoing laparoscopic surgery were randomly allocated, having either 40ml of 0.25% levobupivacaine or 40ml 0.9% sodium chloride solution administered into the peritoneal cavity following surgery. The patients and the main researcher were blinded. All women received standardised anaesthetic and laparoscopic technique, and postoperative pain control including nursing position and nature of analgesia. Postoperative pain was assessed 3 hours, 8 hours, day 1 and day 4/5 postoperatively.100 patients were recruited undergoing surgery for benign causes aged 19-73(mean 40.3±13). There was no difference between the groups for age(p=0.64) or length of operation(p=0.56). There were no adverse events related to use of intraperitoneal instillation. There was a significant reduction in shoulder-tip pain scores in the levobupivacaine group at 3 hours(p=0.04). Furthermore, there was a significant reduction in wound-pain scores in the levobupivacaine group at 8hrs(p=0.04) and at day 4(p=0.04). No difference was found in pelvic pain between the two groups. No significant difference was found in the use of post-operative analgesia.Intraperitoneal instillation of 40ml of levobupivacaine has some benefit in reducing postoperative pain and need for analgesia in the initial hours following gynaecological surgery. However, further well-designed randomised control trials are required to decide the optimum route and concentration of administering local anaesthetic. Laparoscopic surgery has transformed modern gynaecological surgery. Its many advantages include shorter hospital stay, reduced blood loss, smaller incisions, and overall reduced morbidity for the patient . However2. Shoulder tip pain arises due to phrenic nerve irritation, again as a result of CO2 trapped under the diaphragm  narcotics are effective medications but increase morbidity and delay discharge . Non-nar2 to peritoneal fluid might lead to acidic irritation of the peritoneum, however, NO2 did not reduce pain in a randomised controlled trial . The trial was registered on the European Union Clinical Trials Register (EudraCT No. 2009011207-23). The women had an American Society of Anesthesiologists (ASA) anaesthesia risk classification status 1-2 and were scheduled to have laparoscopic surgery under the same gynaecological surgeon. Exclusion criteria were women with a BMI>35 due to increased surgical risks and complexity, those who weighed less than 50kg due to risk of local anaesthetic toxicity, those with an ASA >2, or those with a known previous adverse reaction or any contraindication to levobupivacaine.The patients were informed about the numerical pain rating scale (NRS) with 0 being no pain and 10 being the worst possible pain. This allowed answers to be conveyed over the telephone following discharge. A score would be requested for pain for the abdominal wound sites, pelvis, and shoulder tip.The patients were randomly assigned into two groups by computer randomisation. Group 1 (n =50) would receive 40 ml of intraperitoneal 0.25% levobupivacaine, and Group 2 (n = 50) would receive 40ml of intraperitoneal sodium chloride 0.9%. Due to the lack of conformity in the literature, the dose of levobupivacaine was decided due to the clinical experience of the team and the maximum non-toxic dose of the minimum weight patient included in the study. The study was double blinded; the patients, surgical and anaesthetic teams were blinded to the medication used. The packets containing either 0.9% saline or 0.25% levobupivacaine solutions were prepared within pharmacy by computer randomisation code, blinded, and opened by the anaesthetists after induction of anaesthesia.2 +N2O and Sevoflurane. Standard ventilator settings were: PCV-VG mode, Vt of 500mls, frequency 12/min, inspiratory to expiratory ratio of 50% and maximum inspiratory pressures were limited to 30cm H2O. The aim was to achieve mild hypocapnia at 4.5-4.8% end expiratory CO2 and haemoglobin saturation with O2 of 96-98%. Prior to the insertion of umbilical port every patient received 10 mg of Morphine intravenously (iv). All patients underwent their planned gynaecological surgery in a Lloyd Davis position with the table in a 20 degree Trendelenburg tilt.After intravenous cannulation, all patients received intravenous antiemetic prophylaxis consisting of Atropine 400-600ug, Metoclopramide 10mg, Ondansetron 8mg and Dexamethasone 6.6mg followed by 100ug of Fentanyl. Following pre- oxygenation, general anaesthesia was induced with 2-3 mg/kg of Propofol and 0.5mg/kg of Atracurium. All patients were mechanically ventilated with 50% mixture of OLaparoscopic technique was standardised as far as practicable. The same lead surgeon performed a closed umbilical laparoscopic entry with a Verres needle, initial 20mmHg pressures to facilitate a 10mm umbilical and two 5mm lateral port insertion followed by operating pressure of 12mmHg.2 values and the total requirement of anaesthesia was recorded at 5-minute intervals. Following completion of the surgery Group I was instilled with 40ml of 0.25% levobupivacaine and Group II 40ml of normal saline via the lateral port and directed under vision towards the pelvis. The CO2 was then expelled from the abdomen through the umbilical trochar and the tilt was corrected. The incision sites were closed with a 2/o caprosyn suture.During surgery, heart rate, non-invasive arterial blood pressure, oxygen saturations, end-tidal COOnce the patient was taken into the postoperative recovery area this was defined as hour 0, with the first pain score being taken 3 hours following this time. Pain scores were assessed via questionnaire at 3 hours, 8 hours, 24 hours, and 96-120 hours post- operatively. Routine safety monitoring took place in the recovery area, including blood pressure, pulse and pulse oximetry, urine output, vaginal loss, and the patients were all nursed in the same position. Monitoring continued postoperatively at standard intervals until discharge. Standard postoperative pain control had been agreed, with a record of all postoperative analgesia administered whilst in the hospital and taken after discharge until the final pain score at day 4/5. The patients were asked to give a pain score for the pelvis, shoulder tip and wound site at 3, 8, 24 hours and day 4/5 following the surgery.Using the data from a previous study by Sharma et al.  a power Descriptive data is presented as mean ± SD for continuous data and n (%) for categorical data. T-tests were used to compare continuous data, Mann Whitney for ordinal data (e.g. pain scores) and Chi- square tests for categorical data. For the primary outcome measure (NRS), Mann Whitney tests were used to compare pain scores between groups at each time point. For the primary endpoint (8 hours), ANCOVA was used to compare pain scores between groups, whilst adjusting for baseline scores. In addition, potentially confounding variables were included (age and operative time).100 patients were included in the study; 50 received 40mls intraperitoneal 0.9% saline and 50 received 40mls 0.25% intraperitoneal levobupivacaine. Patients were aged 19-73 (mean 40.3 ± 13). There was no significant difference between the groups for either age (MW p=0.64) or operative time (MW p=0.56) . All patThere was a significant difference in the wound pain scores, with the 0.25% levobupivacaine group having lower pain scores at 8hrs (MW: p=0.04) and at day 4 (MW: p=0.04), compared to 0.9% sodium chloride group , althougThere was a significant difference in shoulder tip pain scores, with the 0.25% levobupivacaine group having lower pain scores compared to the 0.9% saline group at 3 hours (MW p=0.04), although significance was lost at 8hrs (MW p=0.06) and not regained.No significant difference was found for pelvic pain at any timepoint. An ANCOVA test was used to compare reported pain at 8 hours when adjusted for the pain score at 3 hours thereby adjusting for baseline pain. No significant difference between the groups was seen for pelvic (MW p=0.20), shoulder tip (MW p=0.19) or wound pain (MW p=0.18). Similarly, no difference between groups was seen when adjusted for age or length of operation.The requirement for post-operative analgesia was also assessed . There wA subgroup analysis was performed on patients who had undergone laparoscopy for treatment of endometriosis (n=50), 25 in the 0.9% saline group and 25 in the 0.25% levobupivacaine group, all of whom had stage 3 or 4 disease. There was a significant reduction in wound pain at 3 hours (MW p=0.015), 8 hours (MW p=0.016) and 4 days (MW p=0.013) as well as shoulder pain at 3 hours (MW p=0.04) and 4 days (MW p=0.04) in the 0.25% levobupivacaine group.2 . This is likely due to the residual pelvic pain which was not altered by the intervention. However, the need for analgesia is a complex interaction of experienced pain, patient expectations, and nursing protocols. We undertook several other measures to reduce the post-operative need for analgesia including the use of intra-operative fentanyl and careful expulsion of residual COa et al.  demonstra et al.  reportedAndrews et al.  comparedAn RCT on women undergoing laparoscopy for gynaecology procedures by Butala et al.  instilleThere was no difference between the groups for adverse events (p>0.1). There were 3 adverse events in total. One in the 0.25% levobupivacaine group, where the patient reported pain secondary to pre-existing irritable bowel syndrome. One patient experienced itching at the cannulation site following administration of IV morphine, and one patient aspirated under anaesthesia  requiring a prolonged hospital admission. There were no significant surgical intra-operative complications.A recent Cochrane review has assessed the use of wound infiltration of local anaesthetic in post-operative pain following laparoscopic cholecystectomy. They conclude that whilst serious adverse events are rare, the quality of evidence for reduction of pain is low and the clinical importance is small . FurtherIn conclusion, intraperitoneal instillation of 40ml of 0.25% levobupivacaine has some benefit in reducing postoperative pain in the initial few hours following gynaecological surgery. It is a safe and easy to perform technique with, no additional need for equipment, time or training, and may have some reduction in need for analgesia.


Objective: This study was to explore the role and necessity of muscle mass [fat-free mass index (FFMI) and appendicular skeletal muscle index (ASMI) measured by bioelectrical impedance analysis (BIA)] in nutritional status evaluation of patients with locally advanced  nasopharyngeal carcinoma (NPC).Methods: One hundred and thirty locally advanced NPC patients were recruited. Their nutritional status was assessed by albumin (ALB), body mass index (BMI), Nutritional Risk Screening 2002 (NRS 2002), Patient generated-Subjective Global Assessment (PG-SGA), and muscle mass. Consistency test and McNemar test were used to evaluate the consistency of muscle mass with ALB, BMI, NRS 2002, and PG-SGA, and correlation analysis was performed on muscle mass and PG-SGA or BMI.Results: 61/130 (46.9%) of the patients had nutritional risks according to NRS 2002, 68/130 (53.1%) of the patients had malnutrition according to PG-SGA assessment. FFMI and ASMI could determine the loss of muscle mass that cannot be detected by albumin (30.2 and 65.6%), BMI (28.0 and 35.3%), NRS 2002 (26.1 and 25.0%), and PG-SGA (18.6 and 55.6%). McNemar test showed that the malnutrition results assessed by FFMI and BMI were inconsistent (P <0.001), but further Pearson correlation analysis showed that BMI was positively correlated with FFMI .Conclusion: The commonly used nutritional assessment scale/parameters cannot identify the muscle mass loss in patients with locally advanced NPC. Analysis of human body composition is important for nutritional assessment in patients with locally advanced NPC. Nasopharyngeal carcinoma (NPC) is a type of malignant tumor originated from nasopharynx and is one of the most common head and neck malignant tumors in China . Due to Expert Consensus on nutrition therapy for head and neck cancer in Mainland and Taiwan China, and the United Kingdom recommended either Nutritional Risk Screening 2002 (NRS 2002) as a nutritional risk screening tool or Patients Generated-Subjective Global Assessment (PG-SGA) as a nutritional assessment tool , 6. Body2 (<70 years)/<22 kg/m2 (70 or older)] as one of the two alternative criteria to diagnose malnutrition  suggested reduced fat-free mass index (FFMI) combined with %weight loss [alternatively, BMI < 20 kg/m2 <0 years/<utrition . Patientutrition –11. Presutrition .This study was to investigate the consistency of FFMI and ASMI  with the commonly used nutritional assessment scale/parameters , and to explore the effect of body composition analysis on nutritional assessment in patients with locally advanced NPC.This study recruited 130 patients with locally advanced NPC diagnosed from June 2018 to October 2019. Informed consent was signed by all of the recruited patients. The inclusion criteria were: (1) age 18–90 years old, (2) with newly diagnosed NPCs according to the diagnostic criteria, (3) the patients had no more than 10 times of radiotherapy and no more than three times of chemotherapy, (4) no serious ascites and edema, and (5) no surgery before 8 a.m. the next day and the hospital stay was more than 24 h.The InBodyS10 analyzer, a multifrequency BIA  was used to estimate the human body composition. InBody uses an eight-point quadrupole electrode system method to evaluate the impedance of small alternating current applied to the body at three specific frequencies  and six specific frequencies . The BIA measurements were conducted by trained personnel in accordance with the standardized procedures.The enrolled patients were firstly diagnosed with nasopharyngeal carcinoma and had no more than 10 times of radiotherapy and no more than three times of chemotherapy. BIA was measured when patients were firstly enrolled. Patients had an overnight fast, emptied the bladder by urinating, took off the clothes, and kept a standing posture during the measurement, during which the ambient temperature remained at 25°C.2 for men or <15 kg/m2 for women was defined as low FFMI (+) according to the cut-off values for FFMI by ESPEN (2 for men or <5.7 kg/m2 for women was defined as low FFMI (+) according to the cut-off values for ASMI by Asian-based reference (FFMI = fat free mass/(height × height). FFMI of <17 kg/meference .2 indicates malnutrition (BMI +). Albumin was measured by fasting blood, Albumin <30 g/L was considered low Albumin (Albumin +). Nutritional risk was screened by NRS 2002, and a NRS 2002 score ≥3 was a suggestive of nutritional risk (NRS 2002 +)  . PG-SGA  2002 +) .P < 0.05 was considered statistically significant.SPSS version 17.0  was used for statistical analysis. NRS 2002, PG-SGA, BMI, albumin, ASMI and FFMI were subjected to normal distribution test. Normally distributed variables  were expressed as mean ± standard deviation (SD); NRS 2002 was classified as 3, 4, and 5 scores. PG-SGA was classified as 0–3 scores, 4–8 scores, and ≥9 scores. Use McNemar test and consistency test analysis to perform consistency on NRS 2002, PG-SGA, BMI, or albumin with FFMI or ASMI. Pearson correlation analysis was used between FFMI or ASMI and BMI. A value of One hundred and thirty locally advanced NPC patients were recruited into the study, 67.7% of whom were men, the mean age is 49 ± 11.3 years old. The tumor, node and metastasis (TNM) stages were ranging from III to IVa periods. The characteristics of patients and tumor are shown in 2. Of them, 30.8% had low FFMI, including 27 males and 13 females. The mean ASMI was 7.24 ± 0.54 kg/m2. Of them, 35.4% had low ASMI, including 39 males and 7 females. Only 3.8% of the patients had a BMI lower than 18.5 kg/m2 , and the mean BMI was 22.5 ± 2.3 kg/m2. Only 0.8% of the patients had an albumin lower than 30 g/L, and the mean albumin was 40.0 ± 3.3 g/L  of the patients had nutritional risk when assessed with NRS 2002 (NRS 2002 ≥3 scores). The patients with a score of 3 were 43 cases (33.1%), a score of 4 were 15 cases (11.5%), and a score of equal or more than 5 were three cases (2.3%). An assessment with PG-SGA showed 53.1% of the patients had suspected malnutrition (PG-SGA ≥4 scores). The patients with a score of 0–3 were 61 cases (46.9%), a score of 4–8 were 37 cases (28.5%), and a score of equal or more than 9 were 32 cases (24.6%) .The mean age of our patients was 49 ± 11.3 years old. We analyzed the FFMI, BMI and albumin of the patients by age stratification and found that FFMI was lower in patients with lower BMI. We found FFMI a growing polarization of trends with age. FFMI is lower in patients with age <40 years or older than 60 years . We also2)  .P = 0.001) but the consistency was poor (Kappa = 0.165). The rate of low FFMI was 30.8%, significantly higher than that of low BMI (3.8%), and the difference was statistically significant (P < 0.001). Inconsistency was noted between FFMI and albumin, FFMI and NRS 2002, FFMI and PG-SGA in the assessment of malnutrition . The rate of low FFMI was 30.8%, significantly higher than that of low albumin (0.8%), and the difference was statistically significant (P < 0.001)  .2 have low FFMI. Among patients with albumin equal or more than 30 g/L, the rate of low FFMI was as high as 30.2%  but the consistency was poor (Kappa = 0.092). The rate of low FFMI was 35.4%, significantly higher than that of low BMI (3.8%), and the difference was statistically significant (P < 0.001). Inconsistency was noted between ASMI and PG-SGA in the assessment of malnutrition (P = 0.961)  . Among tas 65.6% .P = 0.001; and rs = 0.67, P < 0.001, separately  had hypoproteinemia, showed the importance of albumin is questioned in malnutrition evaluation among locally advanced NPC patients.FFMI is one of the indexes of muscle mass commonly used in recent years. It has been recognized that the reduction in fat-free mass (FFM) is linked to the poor prognosis of cancer patients –25. Reduectively . Althougectively . Moreoveectively . ESPEN aectively . In this2 combined with poor general status could be assessed as malnutrition. This standard will still be used by many people in China to assess malnutrition. However, we found 28.0% of the patients with normal BMI had low FFMI in our study. We analyzed the FFMI and BMI of the patients by age stratification and found that FFMI was lower in patients with lower BMI. Surprisingly, we found FFMI a growing polarization of trends with age. FFMI is lower in patients with age <40 or older than 60.Our study also showed that 26.1% of the patients screened as having no nutritional risk by NRS 2002 had low FFMI. This means that if we only use NRS2002, we may neglect a number of patients who had low muscle mass. ESPEN guidelines in 2008 recommend that BMI lower than 18.5 kg/m2).Meanwhile, we analyzed the ASMI of the patients by age stratification and found that ASMI was lower in older patients. In addition, every time there is weight loss there is an added increase in the risk of further loss of muscle mass. Further studies showed that FFMI was lowest on average among those who had lost more than 10% of their body weight in the last 6 months , China. The patients/participants provided their written informed consent to participate in this study.ML led the study design and approved the final version of the manuscript. XP, HL, GF, MW, JX, XX, ZR, JW, and ML collected and analyzed the data. XP, HL, and ML drafted the manuscript. All authors have read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Tyrosine kinase inhibitors (TKIs) have improved progression-free survival in patients with advanced thyroid cancer. So far, few studies have investigated the efficacy of TKIs in a second-line setting. The purpose of our study was to explore the salvage therapy efficacy in patients with advanced thyroid cancer. Methods: We retrospectively evaluated 63 patients with progressive advanced thyroid carcinoma treated with TKIs divided into a Study group (23 patients) treated with salvage therapy, and a Control group (40 patients) treated with only one TKI. Results: Similar clinical benefits  and progression free survival between the first and the second line TKI were observed in the Study group . Median overall survival (OS) was 67.7 months in the Study group and 22.6 months in the Control group . After stratifying the whole population by age (<65 and ≥65 years), OS was significantly different (p < 0.001) with the best survival curve in younger patients, treated with salvage therapy and the worst in older subjects, treated with only one TKI. Conclusions: Salvage therapy showed a significant improvement of OS in patients with advanced thyroid cancer who experienced disease progression during prior TKI therapies. Approximately 5–10% of patients with differentiated thyroid cancer (DTC) develop metastatic disease over time and among them two-thirds have iodine refractory disease . In meduIn our retrospective study, we try to evaluate the efficacy of salvage therapy in patients with advanced thyroid cancer, including DTC, poorly differentiated thyroid cancer (PDTC) and MTC, who experienced disease progression after first-line TKI treatment.The primary objective of this study was to evaluate the efficacy of TKI, when used as first- or second-line, in terms of best overall response (BOR) and progression free survival (PFS). The secondary objective was to compare the overall survival (OS) among patients treated with only one TKI and patients treated with salvage therapy after failure of the first TKI treatment.We retrospectively evaluated 63 patients with progressive advanced thyroid carcinoma who received first-line treatment with TKI from November 2004 to September 2017 at our institution. The extended follow-up continued to January 2020. The patient data collected included age, sex, histological findings, site of distant metastases, information about treatment with TKIs , information about any salvage treatments received, tumor response, and follow-up time or date of death. The patients were divided into two groups: the Study group included patients treated with sequential TKIs after first TKI failure  and the Control group was composed of patients treated with only one TKI.Patients were submitted at baseline and every 8–12 weeks to radiological evaluation by total body computed tomography (CT) or magnetic resonance imaging (MRI). The response to therapy was evaluated according to RECIST criteria v.1.1 . PFS wast-test or the Mann–Whitney test were performed for normal or non-normal variables, respectively. Qualitative variables were presented as absolute frequencies and percentages and to evaluate significant differences in data frequency we analyzed 2 × 2 contingency tables by the Fisher exact test. Tables with size larger than 2 × 2 were examined by the Chi-squared test or by numerical approximation of the Fisher exact test, when all expected frequencies were greater than 5 or not, respectively. The progression free survival and the overall survival were evaluated by Kaplan–Meier curves and to evaluate differences between two or more survival curves log-rank test was performed. Stepwise Cox regression was used to examine factors contributing to overall survival and the hazard ratio (HR) with their 95% confidence interval (CI) are estimated. A p-value <0.05 was considered statistically significant. Statistical analysis was performed using the software StatView for Windows version 5.0.1  and the SPSS Statistics version 22.0.Quantitative variables were presented as the mean ±SD, and with median when normality cannot be statistically established. The Anderson–Darling test was used to assess normality of variables’ distribution. The independent n = 63) had a mean age of 56.4 ± 17 years and 52.4% of them were males. Mean age at the time of TKI treatment was 63.5 ± 15.2 years and the time-lapse between the diagnosis of thyroid cancer or the appearance of distant metastases and the start of therapy with TKI was 7 ± 6.81 years and 3.6 ± 3.3 years, respectively. Fifty-seven percent of the entire cohort had three or more metastatic sites. Bone metastases were present in 29/63 patients (46%), lung metastases in 43/63 (68.2%) and the target lesion sum at baseline was 84.83 ± 55.2 mm.Clinical and pathological features of study population are reported in Patients were divided into two groups: the Study group consisted of 23 patients treated with sequential TKIs after first TKI’s failure  and the Control group was composed by 40 patients treated with only one TKI . Among cn = 23) and those treated with only one TKI  were not statistically different except for age, in details the patients of Study group were younger both at the time of cancer diagnosis  and at the time of starting TKI   .p = 0.22). Specifically, in the Study group, sorafenib was the most frequent TKI used (43.5% of subjects), followed by vandetanib (26.1%), motesanib (13%), sunitinib (8.7%) and lenvatinib (8.7%). Similarly, in the Control group the majority of patients were treated with sorafenib (52.5%), followed by vandetanib (25%), lenvatinib (17.5%) and motesanib (5%), while no patients were treated with sunitinib.TKIs used as first line therapy did not differ between the Study group and the Control group  patients and for drug-related adverse events in 4/23 (17.4%) cases. The second line therapy included lenvatinib in 8/23 (34.8%) patients, sorafenib in 5/23 (21.7%), sunitinib in 6/23 (26%), cabozantinib in 2/23 (8.7%), pazopanib and vandetanib one patient each (4.3%).n = 5). Best overall response with the second TKI was PR in 4/17(23.6%), SD in 10/17 (58.8%) and PD in 3/17 (17.6%) patients ) was PR in 5/22 (22.7%), SD in 14/22 (63.7%), and PD in 3/22 (13.6%) patients. For the second TKI the BOR was analyzed only in patients who stopped the first TKI for disease progression , excluding from the statistical analysis patients who experienced toxicity that led to discontinuation of first TKI (patients .p > 0.99). These results were obtained after a median of 6.5 ± 6.4 months (range 1.6–24.8 months) with the first TKI and after a median of 3.78 ± 10.0 months (range 1.26–40.40 months) with the second TKI. In a subgroup of patients who experienced a clinical benefit (with a first-line TKI in 21/22 patients (95.4%) and with a second-line TKI in 15/17 patients (88.2%)), we evaluated the median percentage reduction of the sum of target lesions. It was 18.6% (range −58.9%–+14.5%) and 16.7% (range −44.8%–+10.8%) with the first and the second TKI, respectively without significant difference (p = 0.8). The median PFS was 17.1 months  with first-line TKI, not significantly different (Log rank test p = 0.5) from that observed with salvage therapy  in the Study group  of patients during treatment with the first TKI and in 14/17 (82.3%) of patients according to second TKI  without a significant difference between the first and second TKI (dy group .p = 0.003). The median OS in the Study group  was 67.7 months , which was longer than that observed in the Control group  . Specifically, the 3- and 5-year survival rates were 78% (CI: 62%–97%) and 60% (95% CI: 42%–84%) in the Study group and 31% (19%–52%) and 20% (CI: 9%–41%) in the Control group.As shown in p < 0.001). Of note, the best survival curve was obtained in younger patients (<65 years) treated with salvage therapy while the worst in older subjects (>65 years) treated with only one TKI . Kaplan–Meier curve analysis showed an OS significantly different between the four groups ( one TKI .p = 0.04)) while a trend toward significance was observed in younger patients ). Moreover, salvage therapy was more effective in younger patients when compared with older subjects .Salvage therapy was able to significantly improve OS in older patients , presence of bone metastases, sum of the target lesions diameters, age at cancer diagnosis and at the beginning of the first TKI, number of TKI line of treatment (1 TKI vs. >1 TKI) and histology (DTC or PDTC vs. MTC).p = 0.003), a greater sum of the target lesions diameters , older age at the beginning of the first TKI  and treatment with only one TKI , negatively affected OS.We found that more than two sites of distant metastasis . Our results are consistent with those reported by Dadu et al., who evaluated salvage therapy in 60 patients with DTC after discontinuation of first-line sorafenib [Survival data of patients with advanced thyroid cancer treated with TKI are limited. In phase III trials no OS benefit was found in patients treated with TKI compared to placebo ,6,7,8. Morafenib , but unlp = 0.0008). It is known that age represents an important prognostic factor for thyroid cancer mortality, that increases with each decade of life beyond age 40, showing a marked increase of mortality in patients aged >60 years [Through a stepwise Cox regression, we found that more than two sites of distant metastases (HR 2.82), a greater sum of the target lesions diameters (HR 1.01), older age at the beginning of the first TKI (HR 1.07) and treatment with only one TKI (HR 3.23), negatively affected OS. The clinical impact of age and salvage therapy on the survival was also confirmed by Kaplan–Meier analysis. Accordingly, to the age at the time of the first TKI, salvage therapy was able to improve OS in both younger and older patients, although in patients <65 years only a trend toward significance was observed. Moreover, salvage therapy was more effective in younger patients  when compared with older subjects  expression was detected in thyroid cancer, with low level in DTC and more diffuse expression in PDTC and anaplastic cancer (ATC), in which the positive rate reaches up to 70–90% ,31. CombIn conclusion our study shows that salvage therapy in patients with advanced thyroid carcinoma is effective and, if available, should always be offered to patients who develop disease progression under TKI treatment or who cannot continue therapy due to drug-related adverse events.


Children with Type 1 diabetes (T1DM) commonly present in diabetic ketoacidosis (DKA) at initial diagnosis. This is likely due to several factors, one of which includes the propensity for T1DM to be misdiagnosed. The prevalence of misdiagnosis has been reported in non-Asian children with T1DM but not in Asian cohorts.To report the rate of misdiagnosis and its associated risk factors in Malaysian children and adolescents with T1DM.A retrospective analysis of children with T1DM below 18 years of age over a 10 year period was conducted.± 3.9 years. 38.7% of cases were misdiagnosed, of which respiratory illnesses were the most common (37.0%) misdiagnosis. The rate of misdiagnosis remained the same over the 10 year period. Among the variables examined, younger age at presentation, DKA at presentation, healthcare professional (HCP) contact and admission to the intensive care unit were significantly different between the misdiagnosed and correctly diagnosed groups (p <0.05).The cohort included 119 children  with a mean age 8.1 SD Misdiagnosis of T1DM occurs more frequently in Malaysian children <5 years of age. Misdiagnosed cases are at a higher risk of presenting in DKA with increased risk of ICU admission and more likely to have had prior HCP contact. Awareness of T1DM amongst healthcare professionals is crucial for early identification, prevention of DKA and reducing rates of misdiagnosis Type 1 diabetes (T1DM) is a common autoimmune condition of childhood with a peak age of onset at 10–14 years of age . The IntTimely diagnosis of T1DM is essential to initiate prompt treatment and avoid the progression to diabetic ketoacidosis (DKA), which occurs in 30%–70% of children . The incThere is a positive correlation between misdiagnosis of T1DM and DKA , 8. Thisst 2010 and December 31st 2019. A diagnosis of T1DM was made according to the ISPAD guidelines for the year in which the diagnosis was made, as was diabetic ketoacidosis (DKA)  system and the referral letters from the referring physicians. Details on age, sex, ethnicity, symptoms, and contact with a health care professional prior to the initial diagnosis were obtained. Additional details on anthropometry and biochemistry were also extracted. UMMC has an EMR system with a proforma for in-patient admission clerking, into which details on the presenting history are entered on admission. All new diagnoses of paediatric T1DM at UMMC are admitted as inpatients irrespective of whether they present in DKA or not and all are reviewed by the Paediatric Endocrinology team.A retrospective review was conducted on all newly diagnosed cases of paediatric T1DM who presented to University Malaya Medical Centre (UMMC) between January 1is (DKA) –14. MisdStatistical analysis was done using SAS@ 9.4 software . The demographic data, clinical and laboratory features, were analyzed using descriptive statistics. Data are expressed as the median with interquartile range (IQR) or means for continuous variables and frequencies/percentages for categorical variables. Comparisons were made between the misdiagnosed and correctly diagnosed groups for demographic and clinical variables using T-test (two continuous group comparison); and chi-square/Fisher-exact test . A p-value of less than 0.05 was accepted as being statistically significant.This study was approved by the University Malaya Medical Centre (UMMC) institutional ethics board MREC Ref: 2019325-7251.st 2010 and December 31st 2019 at UMMC. Out of these, 62% (n=138) were T1DM, 35% (n=77) T2DM and 4% (n=8) other diabetes. Of the 138 T1DM cases during the study period, 19 were excluded, as misdiagnosis could not be confirmed based on information entered into the EMR system. Seventy-three cases (53.8%) were correctly diagnosed as T1DM, whereas 46 (38.7%) were misdiagnosed.A total number of 223 cases of childhood diabetes were newly diagnosed between January 1The mean age at diagnosis was 8.1 years (± 3.9). The majority, 47.1% (n=56), were aged 5-10 years and 53.8% (n=64) were female. Malay ethnicity representation was 35.6% (n=42), Chinese 32.8% (n=39) and Indian 21.0% (n=25). The majority 63.0% (n=70) of the referrals came from within the UMMC coverage area of 450 sq. kilometres with a 25 km radius within the Klang valley region in the states of Selangor and W.P. Kuala Lumpur. In terms of anthropometric measures, 67.8% (n=61) had normal weight, 19% (n=17) were underweight and 13.3% (n=12) were overweight at presentation. The mean HbA1c at presentation was 12.3% (± 2.5%) and 71.3% (n=82) had presented in DKA. Of those who had presented in DKA, 56% (n=42) were severe DKA. In terms of HCP contact prior to the initial diagnosis of T1DM, 76.3% (n=90) were seen by one healthcare professional prior to referral to UMMC. Referrals from other hospitals accounted for 68.8% (n=77) of the cases to UMMC. Paediatric ICU admission was needed in 20% (n=47) of the T1DM cases.misdiagnosis in this cohort was 38.7% (n=46). The most commonly reported symptoms were polyuria (45.7%), polydipsia (43.5%), weight loss (32.6%) and vomiting (32.6%). Symptoms such as skin infection, headache, polyphagia were reported in less than 5% of cases. The most common erroneous diagnoses made in children presenting with T1DM, were respiratory (36.9%), gastrointestinal (34.8%) and infectious (10.9%) illnesses. The rate of DKA in the misdiagnosed group was 87% (n=40). The rate of Regarding referral source, the total number of visits to primary care made just prior to final diagnosis of T1DM was (n=40). Of these, 52.5% (n=21) were misdiagnosed. The total number of visits made to either secondary or tertiary care institutions was (n=83), and of these 32.5% (n=27) were misdiagnosed.The rate of misdiagnosis over the 10 year period varied between 20-64% with the highest rate being reported in 2019. Between 2012–2017, the rate of misdiagnosis of T1DM remained the same between 26%–40%. In 2018–2019, of those that were misdiagnosed (n=14), 65% (n=9) were diagnosed by primary care and 36% (n=5) by hospitalists. The increase in misdiagnosed cases between these two time periods was not contributed to by an overrepresentation of younger children (<5 years), as 29% were misdiagnosed during 2018–2019 and 33% during 2010–2017. During 2018–2019, the majority of cases were in the age group >5 years; 71% (n=10).non-DKA presentation. The odds ratio for DKA at initial diagnosis in the misdiagnosed group was 5.3 . No significant difference was found in terms of severity of DKA between the two groups. In the misdiagnosed group, 89.3% of cases were seen by ≥ 2 HCP prior to the initial diagnosis of T1DM (p 0.0001) at our centre. A significantly higher percentage of the misdiagnosed cases were referred from primary care doctors . Admission to the paediatric intensive care unit was more frequent in the misdiagnosed group  but no difference in terms of mean length of hospital stay was found. Comparisons of variables between the misdiagnosed and correctly diagnosed children are shown in No significant differences were found in terms of the mean age, gender or ethnicity between the 2 groups, as shown in Our study shows that Malaysian children with T1DM have a misdiagnosis rate of 38.7%. Children are commonly diagnosed with alternative diagnoses, such as respiratory or gastrointestinal illnesses and despite the presence of osmotic symptoms, one-third of children are misdiagnosed. Younger children, < 5 years old, are more frequently misdiagnosed. As a result of the misdiagnosis, there is a higher risk of presenting in DKA and requiring ICU admission. Misdiagnosed cases are frequently referred from primary care services and more likely to have had ≥2 prior HCP contacts. To our knowledge, this is the first study to report on the prevalence of misdiagnosis in T1DM in Malaysian children.“true” misdiagnosis is difficult to make. Finally, the survey was conducted on participants from North America, where T1DM in children is more prevalent and hence greater public awareness of the disease as compared to Malaysia (The high rates of misdiagnoses (38.7%) were sustained with no reduction in rates during the study period. This is higher than the misdiagnosis rate of 16% reported by Munoz et al.  in AmeriMalaysia , 15, 16.Respiratory, gastrointestinal conditions, infective and renal conditions were the commonest misdiagnoses given to T1DM children in this study. Other studies have similarly reported that infective conditions are common misdiagnoses in children with T1DM and this may be attributed to the fact that HCPs have greater exposure to common childhood illnesses rather than T1DM . A lack This study showed that there was a significantly higher rate of misdiagnosis in children < 5 years of age, as compared to those children aged > 10 years. These findings are similar to the study by Munoz et al.  also repThe rate of DKA in the misdiagnosed group was higher 48.8%) as compared to the correctly diagnosed group. DKA was also 5.3 times more likely to occur in cases that were misdiagnosed. Though no significant differences in the severity of DKA were found we did show a significantly higher frequency of PICU admission from the misdiagnosed group. Munoz et al.  has also.8% as co4T’s campaign in the UK has also contributed to reducing paediatric DKA rates  institutional ethics board MREC Ref: 2019325-7251. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.NS, MN, AL, and MM contributed to data collection. MM and AA initiated and designed the audit project. EC and MM did statistical analysis. MM analyzed and wrote the paper. AA and MJ corrected and edited the manuscript. All authors contributed to the article and approved the submitted version.Funding assistance for article processing charges came from Institute for Research, Development and Innovation (IRDI), International Medical University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Intravenous unfractionated heparin (UFH) remains one of the most commonly used anticoagulants in the hospital setting. The optimal protocol for initiation and maintenance of UFH has been difficult to determine. Over the past two decades, weight-based nomogram protocols have gained favor. Herein, we present a retrospective study of 377 patients at a single tertiary academic center treated with low intensity (LI) and standard intensity (SI) UFH protocols for therapeutic anticoagulation. UFH levels are measured by anti-Xa assay activity with therapeutic levels of 0.30 to 0.70 IU/mL for SI and 0.25 to 0.35 IU/mL for LI. Patients treated on the LI protocol were more likely to have had a previous history of bleeding and lower baseline hemoglobin. Incidence of new or worsening thrombus while on UFH was comparable between both protocols (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899). Patients on LI protocol had higher incidence of bleeding while on UFH . Our study thus suggests that the LI protocol may have comparable efficacy to the SI protocol in treating venous thromboembolism (VTE) and that target anti-Xa levels of 0.25 to 0.35 IU/mL may be more optimal in high-risk patients. Since the discovery of heparin by Howell in 1916 and its initial use on human subjects in 1935, it has been one of the most commonly utilized inpatient medications in modern medicine . HoweverDetermining the optimal protocol for UFH bolus and subsequent infusion has been controversial. In 1989, the American College of Chest Physicians (ACCP) Clinic Practice Guideline on VTE treatment recommended an initial bolus of 5,000-units followed by 1000-units/hour . More reIn patients deemed high-risk for hemorrhage, a low intensity (LI) rather than standard intensity (SI) protocol is often employed. However, to date, there has been little study of differences in adverse events, namely hemorrhage, and efficacy between LI and SI protocols. Furthermore, identifying the effect of patient-specific factors  on outcomes has the potential to assist in determining the most appropriate protocol.A total of 377 adult patients receiving therapeutic UFH from July 2011 to July 2017 at a single tertiary academic center were retrospectively studied. Patients receiving UFH on a separate acute coronary syndrome protocol and those receiving concomitant thrombolytic agents were excluded. Only those patients treated on LI or SI UFH protocols were included in analysis. Indications for LI or SI UFH use was VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)), atrial fibrillation, acute coronary syndrome, arterial thrombus, cerebral ischemic event, portal vein thrombosis, and for cardiac valves.At our institution, UFH is administered by SI (therapeutic target anti-Xa activity level 0.30 to 0.70 IU/mL) and LI (therapeutic target anti-Xa activity level 0.25 to 0.35 IU/mL) protocols. The anti-Xa activity assay is used preferentially over activated partial thromboplastin time (aPTT) as a method of determining in vivo heparin activity -19. BothIntravenous infusion of UFH is ordered using an Electronic Medical Record (EMR) order set involving all steps for the monitoring of heparin concentrations measured in units/mL using an anti -Xa assay. The decision on whether to use LI or SI protocols is based on the ordering physician’s discretion and their personal assessment of the patient’s bleeding and thrombotic risk and treatment indication.Chart review was done manually using the EMR and data was recorded in REDCap to standardize data collection and decrease researcher variability. REDCap is a secure web application for building and managing online databases. The primary outcomes measured were incidence of new or worsening thrombus and/or bleeding while receiving intravenous UFH. Bleeding was categorized into major and minor, based on the International Society on Thrombosis and Haemostasis (ISTH) definitions . SecondaOf the 377 patients studied, 42.0% (158) and 58.0% (219) were on LI and SI protocols, respectively. The majority of patients (76.1%) received an initial bolus of 60 units/kg (LI) or 80 units/kg (SI) with a higher prevalence of bolus in the SI group (84.0% versus 65.2%.) Median time to therapeutic levels was 5.5 hours in the LI group and 3.3 hours in the SI group (Table Patients were predominately Caucasian (74.0%) with median age of 63 (range of 19-93) years-old. Gender and body mass index (BMI) were similar in both groups. The main indications for therapeutic UFH were VTE (46.9%) and atrial fibrillation (18.6%). The indication for UFH was comparable between both groups with the exception of a higher percentage of those on SI protocol being treated for VTE (53.4% versus 38.0%) Table .Many patients were on home anti-platelet (35.0%) and anticoagulant 33.2%) therapy prior to admission. The percentage of patients on aspirin, anti-platelet, and injectable anticoagulants was similar in both groups. A higher percentage of patients on LI protocol were on oral anticoagulants (36.1% versus 24.2%). LI protocol patients were more likely to have had a history of previous bleeding (24.1% versus 12.8%). HAS-BLED scores  were comparable with a median score of 2 and range of 0-6 in LI and 0-7 in SI groups, respectively. Documented history of peptic ulcer disease within three months of heparin initiation was comparable in both groups  was the same in both groups with a slightly greater range in the SI group. Initial median and range PTT was similar in both groups. Patients with active malignancy were comparable in both groups (24.1% versus 21.0%). A significantly higher percentage of patients on LI protocol had a recent surgery (34.8% versus 11.9%). There was a higher percentage of active smokers in the SI group (20.5% versus 11.4%) (Table The incidence of new or worsening thrombosis was comparable between both protocols (3.2% versus 3.7%). Incidence of bleeding was 44% higher in the LI group (11.4% versus 7.3%). On average, the last anti-Xa level prior to bleeding was therapeutic per both intensity protocols (0.30 versus 0.60). The LI group had 58% higher transfusion rates within one month (29.7% versus 16.4%) (Table New bleeding events were more likely to occur than recurrent bleeding. The incidence of major bleeding was more likely in LI compared with SI (5.0% versus 2.7%). The most frequent site of bleeding was gastrointestinal for both protocols Table .The odds of experiencing new or worsening thrombus while on UFH was comparable (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899) in both groups. In multivariate analysis, the odds of bleeding while on LI was 1.21 times (95% CI 0.51-2.89) more likely than SI (p=0.667). Mortality at three-months from initiation of UFH was also comparable  , a tertiary academic center, intravenous UFH is administered by SI and LI protocols with target anti-Xa activity levels of 0.30 to 0.70 IU/mL and 0.25 to 0.35 IU/mL, respectively. These protocols include a suggested bolus, standard initial infusion rates, and titration parameters until a therapeutic range is reached as noted in Table Given limited available data on the efficacy and risks of the implemented protocol at our institution and others, investigators designed a review of 377 patients treated with intravenous UFH. The primary endpoints studied were new or worsening thrombosis and bleeding. The incidence of new or worsening thrombus was low and similar in both groups and not statistically significant . The incidence of bleeding was higher in the LI group (11.4% versus 7.3%) with those on LI being 1.21 times more likely to experience bleed than the SI group, although not statistically significant (p=0.667). The LI group was more likely to have had a previous history of bleed and had lower average baseline hemoglobin/hematocrit (9.8 g/dL/29.6% versus 11.6 g/dL/35.0%). The LI group was more likely to require transfusion within one month (29.7% versus 16.4%). The increased incidence of bleeding and transfusion requirements in the LI group was likely due to the higher-risk population selected for a low intensity protocol.Given that the decision to use a protocol was based solely on clinician judgement, there was a desire to see if an existing scoring system could be utilized to better serve clinicians in deciding the most appropriate protocol. The existing HAS-BLED scoring system was thus used. The HAS-BLED system was developed to assess the one-year risk of major bleeding events in patients on anticoagulation for atrial fibrillation . InteresWe acknowledge multiple limitations in this project, including its retrospective nature without randomization. However, many baseline patient characteristics  were comparable between both groups. The LI population was higher risk for bleeding based on previous history and comorbidities and thus explains the physician’s choice of LI protocol and the higher noted incidence of bleeding while on UFH. This higher risk of bleeding in patients receiving the LI protocol also likely explains the increased incidence of bleeding when compared to the SI protocol.In conclusion, a LI protocol may have comparable efficacy to a SI protocol based on the similar incidence of new or worsening thrombus. This is of notable importance in patients at high risk for bleeding. In the future, a prospective randomized trial of both protocols matched for comorbidities, risk factors, and indications is needed to further elaborate on the findings of this study with the ultimate goal of developing a risk stratification scoring system and weight-based dosing nomogram for use by clinicians.


The trends coincided in all the subgroups  except for the subgroup of those educated over 15 years, whose percentage of energy intake from fat declined from 37.4% to 36.6% . The estimated percentage of energy intake from carbohydrates declined from 74.0% to 55.0%. The ranges of the estimated percentage of energy intake from fat, within population subgroups stratified by education level, area and Gross national product (GNP) level, were narrowed. Conclusions: Quick improvements in society and the economy effectively curbed undernutrition, but easily triggered overnutrition. Disparities persistently existed between different subpopulations, while the gaps would narrow if comprehensive efforts were made. Education might be a promising way to prevent overnutrition during prosperous progress. The low-social profile populations require specific interventions so as to avoid further disease burdens.Background: China’s diet transition might offer guidance to undeveloped countries on the way to prosperity. This report describes the trends and disparities in energy and macronutrient composition among Chinese adults, and between subpopulations. Methods: Data for the current study were obtained from the 1982, 1992, 2002, and 2010–2012 China National Nutrition Survey (CNNS) rounds, which were nationally representative cross-sectional surveys. We applied 24-h dietary recall and food weighing to assess dietary intake. Results: There were 204,877 participants aged 20 years or older included in the current analysis. From 1982 to 2012, the estimated energy intake declined from 2614.7 kcal to 2063.9 kcal. The trend in the estimated percentage of energy intake from fat showed a spike. It increased from 16.3% to 33.1% (1992 vs. 1982 difference, 7.6%; 95% CI 7.4% to 7.7%; 2002 vs. 1992 difference, 7.7%; 95% CI 7.6% to 7.9%; 2012 vs. 2002 difference, 1.6%; 95% CI 1.4% to 1.7%;  China has been one of the fastest-growing countries over the past three decades. It implemented major social and economic reforms in 1979, and achieved tremendous economic and agricultural productivity improvement . MalnutrData for the current study were obtained from the 1982, 1992, 2002 and 2010–2012 CNNS rounds, which were nationally representative cross-sectional surveys conducted by the Chinese Center for Disease Control and Prevention in order to assess the health and nutrition of the Chinese population . The desEducation level was defined as years the participant had received education. Area was defined as urban or rural because China is a two-class society with rural–urban distinctions in many aspects. The urban sector has gained more benefits from social and economic reforms than the rural sector has. Life style and dietary pattern were distinguishing between the two sectors. Gross national product (GNP) level was classified by provincial level according to the GNP quartiles across provinces. In 1982, the first to fourth classes were classified as ≥284, ,  and <194, respectively, in USD; in 1992, the first to fourth classes were classified as USD ≥482, ,  and <268; in 2002, the first to fourth classes were classified as USD ≥1569, ,  and <743; and in 2012, the first to fourth classes were classified as USD ≥8510, ,  and <4670.The series of national surveys was approved by the ethics committee of the National Institute for Nutrition and Health at the Chinese Center for Disease Control and Prevention.The field work of each round was launched in autumn, considering the comparability between survey rounds. Dietary information was collected for 5 days in 1982 by trained investigators who weighed all available foods in the participants’ homes at the beginning of the first day, recorded (and weighed if necessary) all new foods brought into the homes during the 5 days and weighed all leftovers at the end of the survey to calculate the total amount of food consumed by participants during those 5 days. In the 1992, 2002 and 2010–2012 surveys, diet was assessed via 3 consecutive days (including two weekdays and one weekend) of 24-h dietary recall, in addition to weighing household cooking oil and condiments. For each dietary recall day, investigators went to participants’ homes and helped to record food intake during the past 24 h. Investigators also weighed the household cooking oil and condiments at the beginning and end of each 24 h dietary survey. Nutrient intakes were calculated with the China Food Composition tables (FCTs) ,7,8, whip < 0.05 was considered to indicate statistical significance. Statistical analyses were conducted using SAS statistical software .The post-stratification population sampling weights were applied to the estimated nationally representative population levels for intakes of energy and macronutrients. In order to compare dietary intake across years, the weights were derived from the sampling probability of the 2010 Chinese population aged 20 years or older (based on census data) and applied to estimate the representative dietary intake in each survey round. Means and 95% confidence intervals (CIs) of energy, and the percentages of macronutrients contributing to energy, were determined by adjustment for the sample weights. General linear regression models were used to determine the dietary trends across the survey rounds and the dietary differences between and within years. Regarding the difference between years, the year of each survey was treated as an ordinal variable and as the dependent variable. Regarding the difference within years, the subgroup of the two ends within each group  was treated as an ordinal variable and as the dependent variable. Energy and macronutrient composition were treated as continuous variables and as the independent variable respectively in each model. A two-sided There were 204,877 participants aged 20 years or older included in the current analysis. In the survey rounds of 1982, 1992, 2002 and 2010–2012, dietary intake data were available for 39,084, 58,316, 52,426 and 55,051 participants, respectively. The age structure of the participants was assorted across the survey rounds in accordance with the structure of actual change among the Chinese population. The sex ratios were balanced in the samples. Participants in each round had higher education level than the former round. Urban participants gradually accounted for greater percentages of the samples in the survey rounds, due to urbanization progress in China .p < 0.01 for trend). These were the trends in the population subgroups . The trends coincided in the subgroups  except for the subgroup of those educated for over 15 years. In the most recent two survey rounds, the estimated percentage of energy intake from fat among the well-educated population declined from 37.4% to 36.6%   .p < 0.01 for trend). The trends in the subgroups were the same  .The estimated percentages of energy intake from fat within population subgroups, stratified by education level, were 10.6% (95% CI 10.1–11.1%) in 1992, 9.5% (95% CI 8.8–10.1%) in 2002 and 6.3% (95% CI 5.8–6.7%) in 2010–2012. Those stratified by area were 6.8% (95% CI 6.7–7.0%) in 1982, 10.8% (95% CI 10.6–10.9%) in 1992, 8.9% (95% CI 8.7–9.1%) in 2002 and 7.4% (95% CI 7.2–7.6%) in 2010–2012. Those stratified by GNP level were 2.0% (95% CI 1.8–2.3%) in 1982, 7.3% (95% CI 7.1–7.6%) in 1992, 2.9% (95% CI 2.6–3.1%) in 2002 and 3.7% (95% CI 3.5–4.0%) in 2010–2012. The ranges of the estimated percentage of energy intake from carbohydrates within population subgroups stratified by education level were 13.1% (95% CI 12.6–13.6%) in 1992, 12.4% (95% CI 11.8–13.0%) in 2002 and 9.5% (95% CI 9.0–10.0%) in 2010–2012. Those stratified by area were 8.2% (95% CI 8.0–8.3%) in 1982, 12.9% (95% CI 12.7–13.0%) in 1992, 10.8% (95% CI 10.7–11.0%) in 2002 and 9.6% (95% CI 9.4–9.8%) in 2010–2012. Those stratified by GNP level were 2.9% (95% CI 2.6–3.2%) in 1982, 9.2% (95% CI 9.0–9.5%) in 1992, 4.8% (95% CI 4.5–5.1%) in 2002 and 5.8% (95% CI 5.5–6.1%) in 2010–2012 . The treChina has made substantial progress in improving nutrition. Diet quality improved remarkably from 1982 to 2012 in China. The trends of energy intake constantly decreased in the survey rounds due to the fast pace of modernization and urbanization. The percentage of fat’s contribution to energy spiked, that of carbohydrates fell all the way, and that of protein stabilized within a small range. The macronutrient composition went from poor, to ideal, and then to far from ideal again. Though the composition was not satisfying at the beginning round of CNNS, in 1982, which featured excessive carbohydrates and a lack of fat, it became more ideal in the 1992 survey round. The macronutrient composition was within the national recommendations among most subpopulations around that period . We consThe great achievements following the social and economic shifts after 1979 had a tremendous impact on the diet of the Chinese population . It tookThe disparities persistently existed in different subpopulations across China, but the gaps narrowed in recent years. The Chinese government has put huge effort into poverty reduction, transportation system construction and raising the agricultural yield, which all potentially increased the equity of access to various foods by people with different background. Especially in the most recent survey round, the percentages of fats’ and carbohydrates’ contributions to energy were getting closer between the two ends of the subpopulations as regards area, education level and economic background. It was obvious that the subpopulations with better social profiles  were leading the diet trends, and the rest followed in the next decade or two. Nevertheless, the macronutrient compositions of those with better social profiles had been moving toward the overnutrition pattern since around 2002, which was probably a major cause of nutrition-related NCDs prevailing in China ,10,21. IOne promising trend was discovered in the well-educated subpopulation. In the survey round of 2012, the macronutrient composition distinctively retuned to the recommended ranges among these people. “Eat well” was linked to “live well” in Chinese culture, but people always confused “eat well” with “eat whatever one wants”. Actually, “eat well” means “eat properly” in the modern nutritional theory, and it leads to “live well”. It is clear that some risks of nutrition-related NCDs can be modified though education improvement . Well-edThis study has several limitations. First, 3-day 24-h dietary recalls were used to obtain food consumption information, and so the accuracy of dietary intake was mostly dependent on the participants’ recall and estimation. Second, for the individual income information variabilities in different survey rounds, the classification of GNP level was applied. It was based on each province’s GNP in the survey year, which might not classify each participant meticulously. Third, a recent study mentioned that the quality or food sources of macronutrients might lead to different health outcomes [Quick improvements in society and the economy effectively curbed undernutrition, but easily triggered larger-scaled overnutrition soon after in China. Disparities have persistently existed in different subpopulations, while these gaps would narrow if major efforts were made. Populations with low social profiles might lag behind the trend of diet transition, but would be more vulnerable to the side-effects of the trend. Education might be a promising way of preventing overnutrition during the prosperous progress of developing countries. Low social profile populations require specific interventions so as to avoid the further burdens of diet-related non-communicable diseases, in order to maintain social stability.