The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by "the 3Ks", while trying to clarify the numerous aspects that still need to be addressed.

Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat.

BACKGROUND: Severe acute malnutrition (SAM) is a major global health problem affecting some 16.9 million children under five. Little is known about what happens to children 6-24 months post-discharge as this window often falls through the gap between studies on SFPs and those focusing on longer-term effects. METHODS: A protocol was registered on PROSPERO (PROSPERO 2017:CRD42017065650). Embase, Global Health and MEDLINE In-Process and Non-Indexed Citations were systematically searched with terms related to SAM, nutritional intervention and follow-up between June and August 2017. Studies were selected if they included children who experienced an episode of SAM, received a therapeutic feeding intervention, were discharged as cured and presented any outcome from follow-up between 6-24 months later. RESULTS: 3,691 articles were retrieved from the search, 55 full-texts were screened and seven met the inclusion criteria. Loss-to-follow-up, mortality, relapse, morbidity and anthropometry were outcomes reported. Between 0.0% and 45.1% of cohorts were lost-to-follow-up. Of those discharged as nutritionally cured, mortality ranged from 0.06% to 10.4% at an average of 12 months post-discharge. Relapse was inconsistently defined, measured, and reported, ranging from 0% to 6.3%. Two studies reported improved weight-for-height z-scores, whilst three studies that reported height-for-age z-scores found either limited or no improvement. CONCLUSIONS: Overall, there is a scarcity of studies that follow-up children 6-24 months post-discharge from SAM treatment. Limited data that exists suggest that children may exhibit sustained vulnerability even after achieving nutritional cure, including heightened mortality and morbidity risk and persistent stunting. Prospective cohort studies assessing a wider range of outcomes in children post-SAM treatment are a priority, as are intervention studies exploring how to improve post-SAM outcomes and identify high-risk children.

/pdf/follow-up-between-6-and-24-months-after-discharge-from-2i9lh6afd8.pdf

Follow-up between 6 and 24 months after discharge from treatment for severe acute malnutrition in children aged 6-59 months: A systematic review.

Background 

Established in 2000, Millennium Development Goal 4 (MDG4) catalysed extraordinary political, financial, and social commitments to reduce under-5 mortality by two-thirds between 1990 and 2015. At the country level, the pace of progress in improving child survival has varied markedly, highlighting a crucial need to further examine potential drivers of accelerated or slowed decreases in child mortality. The Global Burden of Disease 2015 Study (GBD 2015) provides an analytical framework to comprehensively assess these trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time.

 Methods 

Drawing from analytical approaches developed and refined in previous iterations of the GBD study, we generated updated estimates of child mortality by age group (neonatal, post-neonatal, ages 1–4 years, and under 5) for 195 countries and territories and selected subnational geographies, from 1980–2015. We also estimated numbers and rates of stillbirths for these geographies and years. Gaussian process regression with data source adjustments for sampling and non-sampling bias was applied to synthesise input data for under-5 mortality for each geography. Age-specific mortality estimates were generated through a two-stage age–sex splitting process, and stillbirth estimates were produced with a mixed-effects model, which accounted for variable stillbirth definitions and data source-specific biases. For GBD 2015, we did a series of novel analyses to systematically quantify the drivers of trends in child mortality across geographies. First, we assessed observed and expected levels and annualised rates of decrease for under-5 mortality and stillbirths as they related to the Soci-demographic Index (SDI). Second, we examined the ratio of recorded and expected levels of child mortality, on the basis of SDI, across geographies, as well as differences in recorded and expected annualised rates of change for under-5 mortality. Third, we analysed levels and cause compositions of under-5 mortality, across time and geographies, as they related to rising SDI. Finally, we decomposed the changes in under-5 mortality to changes in SDI at the global level, as well as changes in leading causes of under-5 deaths for countries and territories. We documented each step of the GBD 2015 child mortality estimation process, as well as data sources, in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).

 Findings 

Globally, 5·8 million (95% uncertainty interval [UI] 5·7–6·0) children younger than 5 years died in 2015, representing a 52·0% (95% UI 50·7–53·3) decrease in the number of under-5 deaths since 1990. Neonatal deaths and stillbirths fell at a slower pace since 1990, decreasing by 42·4% (41·3–43·6) to 2·6 million (2·6–2·7) neonatal deaths and 47·0% (35·1–57·0) to 2·1 million (1·8-2·5) stillbirths in 2015. Between 1990 and 2015, global under-5 mortality decreased at an annualised rate of decrease of 3·0% (2·6–3·3), falling short of the 4·4% annualised rate of decrease required to achieve MDG4. During this time, 58 countries met or exceeded the pace of progress required to meet MDG4. Between 2000, the year MDG4 was formally enacted, and 2015, 28 additional countries that did not achieve the 4·4% rate of decrease from 1990 met the MDG4 pace of decrease. However, absolute levels of under-5 mortality remained high in many countries, with 11 countries still recording rates exceeding 100 per 1000 livebirths in 2015. Marked decreases in under-5 deaths due to a number of communicable diseases, including lower respiratory infections, diarrhoeal diseases, measles, and malaria, accounted for much of the progress in lowering overall under-5 mortality in low-income countries. Compared with gains achieved for infectious diseases and nutritional deficiencies, the persisting toll of neonatal conditions and congenital anomalies on child survival became evident, especially in low-income and low-middle-income countries. We found sizeable heterogeneities in comparing observed and expected rates of under-5 mortality, as well as differences in observed and expected rates of change for under-5 mortality. At the global level, we recorded a divergence in observed and expected levels of under-5 mortality starting in 2000, with the observed trend falling much faster than what was expected based on SDI through 2015. Between 2000 and 2015, the world recorded 10·3 million fewer under-5 deaths than expected on the basis of improving SDI alone.

 Interpretation 

Gains in child survival have been large, widespread, and in many places in the world, faster than what was anticipated based on improving levels of development. Yet some countries, particularly in sub-Saharan Africa, still had high rates of under-5 mortality in 2015. Unless these countries are able to accelerate reductions in child deaths at an extraordinary pace, their achievement of proposed SDG targets is unlikely. Improving the evidence base on drivers that might hasten the pace of progress for child survival, ranging from cost-effective intervention packages to innovative financing mechanisms, is vital to charting the pathways for ultimately ending preventable child deaths by 2030.

 Funding 

Bill & Melinda Gates Foundation.

Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015

BACKGROUND: Polysubstance dependence, stress, and sleep disturbances are inter-related by shared physiological pathways. No study has investigated the relationship between sleep and concurrent use of alcohol and khat. OBJECTIVES: The aim of the study was to assess the effect of the concurrent use of alcohol and khat as well as concurrent alcohol, khat, and tobacco smoking on sleep patterns. METHODS: A sample of community-dwelling adults (n = 339, age = 25.5 ± 5.7 years, body mass index = 22.0 ± 2.2 kg/m2) from Mizan-Aman, Ethiopia, participated in a cross-sectional study. Semi-structured tool for sociodemographics, substance use habit, and the Pittsburgh Sleep Quality Index (PSQI) were used. The difference in sleep patterns among substance use groups, i.e., nonusers, alcohol use only, concurrent alcohol and khat use, and concurrent alcohol, khat and tobacco smoking was assessed. RESULTS: The poorest sleep quality was found among concurrent users of alcohol, khat, and tobacco smoking (PSQI global score = 8.2 ± 2.4), followed by concurrent users of alcohol and khat (PSQI global score = 7.3 ± 2.9) (F (3.335) = 23.64, P CONCLUSION: Concurrent use of alcohol, khat as well as alcohol, khat, and tobacco smoking was associated with poor sleep. Sleep disturbances in this group need management to avoid the prospective development of psychosocial disturbances in polysubstance users.

Poor sleep in concurrent users of alcohol, khat, and tobacco smoking in community-dwelling Ethiopian adults.

The interrelationship between wasting and stunting has been poorly investigated. We assessed the association between two indicators of linear growth, height-for-age Z-score (HAZ) change and occurrence of accelerated linear growth, and selected indicators of wasting and wasting reversal in 5,172 Cambodian children aged less than 24 months at enrolment in the 'MyHealth' study. The specific objectives were to evaluate the relationship between temporal changes in wasting and 1) change in HAZ and 2) episodes of accelerated linear growth. At enrolment, the stunting and wasting prevalence were 22.2 (21.0;23.3) % and 9.1 (8.1;10.1) %, respectively, and reached 41.4 (39.3;43.6) %, and 12.4 (11.5;13.3) % respectively, two years later. Between 14-19% of stunted children were also wasted throughout the whole study period. For each centimetre increase in Mid-Upper Arm Circumference (MUAC) from the previous assessment, the HAZ increased by 0.162 (0.150; 0.174) Z-score. We also observed a delayed positive association between the weight for height Z score (WHZ) unit increase and HAZ change of +0.10 to +0.22 units consistent with a positive relationship between linear growth and an increase in WHZ occurring with a lag of approximately three months. A similar positive correlation was observed for the occurrence of an episode of accelerated linear growth. These results show that interventions to prevent and treat wasting can contribute to stunting reduction and call for integrated wasting and stunting programming.

The relationship between wasting and stunting in Cambodian children: Secondary analysis of longitudinal data of children below 24 months of age followed up until the age of 59 months.

Khat (Catha edulis Forsk) is a psychostimulant herb widely cultivated and used in Ethiopia. The link between khat use and body composition is little known. The aim was to determine the association between body composition and khat use. We recruited 415 individuals 18–78 years of age from Jimma Town. Sociodemographic and lifestyle data were collected using structured questionnaires. Fat mass (FM, kg) and fat-free mass (FFM, kg) were estimated from whole-body bio impedance. Weight (kg), FM and FFM were indexed to height (m) as BMI (kg/m2), fat mass index (FMI) (kg/m) and fat-free mass index (FFMI) (kg/m), respectively. Independent predictors of BMI, FMI and FFMI were identified using regression analysis. Participants’ mean ± SD of age was 37 ± 13 years and 205 (53.2 %) were males. Mean ± SD of BMI, FMI and FFMI were 21.0 kg/m2 ± 4.1, 6.8 kg/m ± 5.2 and 27.9 kg/m ± 3.8, respectively. Multivariable model showed that, compared with non-chewers, khat chewers had a lower BMI (B = −1.56, 95 % CI −0.78, −2.33) and FMI (B = 2.19, 95 % CI −1.32, −3.06). FMI was lower in cigarette smokers than non-smokers by −1.36 kg/m (95 % CI −0.23, −2.49). Concurrently, khat and cigarette users increased FMI by 2.78 (95 % CI 0.11, 5.44). FFMI decreased with age (B = −0.02, 95 % CI −0.05, −0.002). FMI and BMI were lower in khat users than non-users, but there was no difference in lean mass. The consequence of this body composition change should be investigated.

/pdf/association-between-body-composition-and-khat-chewing-in-2ljk9jm0pj.pdf

Association between body composition and khat chewing in Ethiopian adults.

After recovery, children with severe acute malnutrition (SAM) remain vulnerable to sub-optimal growth and malnutrition relapse. Although there is an increased interest in understanding these problems, data are scarce, and contextual factors can cause variability. We prospectively followed a cohort of Ethiopian children (215 post-SAM cases and 215 non-wasted controls), monthly for one year. The post-SAM cases were: age 6–59 months at admission into the community management of acute malnutrition (CMAM) program and being successfully discharged from CMAM (MUAC>11.0cm, weight gain of 20%, absence of oedema and clinically stable for two consecutive weeks). The controls were apparently healthy children from same village who had no history of an episode of AM and were matched 1:1 to a post-SAM child by age and sex. The primary outcomes were: cumulative incidence of acute malnutrition; growth trajectory; cumulative incidence of reported common morbidities, and cumulative proportion and incidence of deaths. The burden of common morbidities was higher among post-SAM than controls; post-SAM children had more frequent illness episodes (Incidence Rate Ratio of any illness 1.39, 95% CI: 1.14, 1.71; p<0.001). The prevalence of SAM was consistently higher among post-SAM cases than the control group, having a 14 times higher risk of developing SAM (Incidence Rate Ratio: 14.1; 95% CI: 3.5, 122.5; p<0.001). The divergence in weight and growth trajectory remained the same during the study period. Our results advocate for the design of post-discharge interventions that aim to prevent the reoccurrence of acute malnutrition, reduce morbidity and promote catch-up growth. Research is needed to define the appropriate package of post-discharge interventions.

Nutrition status and morbidity of Ethiopian children after recovery from severe acute malnutrition: Prospective matched cohort study

To compare levels of immunity in children recovering from severe acute malnutrition (cases) against those of community controls (controls). At baseline children recovering from severe acute malnutrition had lower, mid upper arm circumference (122 mm for cases and 135 mm for controls; p < 0.001), weight-for-height Z-score (− 1.0 for cases and − 0.5 for controls; p < 0.001), weight-for-age Z-score (− 2.8 for cases and − 1.1 for controls; p < 0.001) and height/length-for-age Z-score (− 3.6 for cases and − 1.4 for controls; p < 0.001), than controls. Age and gender matched community controls. At baseline, prevalence of a positive tuberculin skin test, assessed by cutaneous delayed-type hypersensitivity reaction skin test, was very low in both cases (3/93 = 3.2%) and controls (2/94 = 2.1%) and did not significantly increase at 6 months follow up (6/86 = 7.0% in cases and 3/84 = 3.4% in controls). The incidences of common childhood morbidities, namely fever, diarrhoea and cough, were 1.7–1.8 times higher among cases than controls. In conclusion, these results show that tuberculin skin test does not enable any conclusive statements regarding the immune status of patients following treatment for severe acute malnutrition. The increased incidence of infection in cases compared to controls suggests persistence of lower resistance to infection even after anthropometric recovery is achieved.

/pdf/use-of-tuberculin-skin-test-for-assessment-of-immune-3fyw3f7cqt.pdf

Use of tuberculin skin test for assessment of immune recovery among previously malnourished children in Ethiopia.

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Association between body composition and khat chewing in Ethiopian adults.

Nutrition status and morbidity of Ethiopian children after recovery from severe acute malnutrition: Prospective matched cohort study

Use of tuberculin skin test for assessment of immune recovery among previously malnourished children in Ethiopia.