The association between migraine and narcolepsy remains controversial. We aim to investigate whether migraine is associated with an increased risk of developing narcolepsy in children.In this longitudinal study, nationwide medical-claims data of pediatric patients (0-17y) with migraine are identified using the National Health Insurance Research Database (NHIRD) between 1997 and 2010 in Taiwan. Two cohorts are selected: migraine cases  and propensity score-matched non-migraine controls . Children with previous history of narcolepsy or headache before the index date are excluded. Cohorts are followed until the end of 2012, their withdrawal from the NHI program, or incidence of narcolepsy (ICD-9-CM: 347). Cox proportional hazards regression models are used to estimate hazard ratios (HRs) and 95% confidence intervals of developing narcolepsy in children with migraine compared to their non-migraine controls.p = 0.006). This finding persisted after controlling for potential confounders like baseline comorbidities and concurrent medication uptake, and in our analyses with migraine subtypes.A total of 13 incident cases with narcolepsy are observed during follow-up, with incidence rates of 0.1915 and 0.0278 per 1,000 person-years in migraine and non-migraine children, respectively. After a mean follow-up period of 4.68 and 5.04 years in the case and control cohort, respectively, the former exhibited a greater risk of developing narcolepsy compared to the latter (adjusted hazard ratio (aHR) = 5.30, 95% confidence interval (CI): 1.61, 17.4; Migraine is an independent risk factor for narcolepsy development in children. Further studies are needed to validate our findings and to explore the exact pathophysiological mechanisms linking migraine and narcolepsy. The association between migraine and narcolepsy has been evaluated in several hospital-based studies and still remains controversial –3. TheseMigraine has been considered a disturbance in the brain of the subcortical aminergic sensory modulatory systems, in addition to hypothalamic, thalamic and brainstem structures ,6. HypotA population-based longitudinal study was designed for this investigation. Our data source was the Taiwan National Health Insurance Research Database (NHIRD), which is a large computerized medical claims-based database released by the National Health Insurance Administration (NHIA) and maintained by the National Health Research Institutes (NHRI) for research purposes.The NHI is a compulsory health insurance program in the country, offering a comprehensive benefits package. It currently has a national coverage of over 99% and is contracted with 97% of the health services providers in Taiwan. Thus, the NHIRD compiles an ample set of medical-claims records from preventive screening to medication history that is valuable for studying the health and service utilization of the entire population. For this study, we specifically used NHIRD registry files for children (aged <18 years) who are enrolled under the NHI program. From 1996 to 2012, a random, national-representative sample of enrolled children less than 18 years old were selected . Outpatient, inpatient and medication records of these selected children were obtained for subsequent analysis. All diagnoses and disease definitions in this study were specified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.All data from the NHIRD has been electronically encrypted for confidentiality reasons. Before its public release, all data with personal identification information, including patient identification number, birth date, gender, physician identification number and physician specialty, are all encrypted so that subjects can never be purposefully traced. The design and protocol of this study has been approved by the Research Ethics Committee at the China Medical University Hospital (CRREC-103-048(CR-2)).For our study (migraine) cohort, we identified children aged less than 18 years from the random, national-representative sample who have newly diagnosed migraine between 1997 and 2010 . We included different types of migraine including migraine with aura (ICD-9-CM: 346.0x), migraine without aura (ICD-9-CM: 346.1x) and unspecified migraine (ICD-9-CM: 346.9x). For ascertainment of cases, any identified subject should have at least two ambulatory care and/or inpatient visits with migraine diagnosis during the study period. We excluded those diagnosed with headache , missing information regarding subject’s sex and birthday, their date of narcolepsy diagnosis , or those who had withdrawn from the NHI program before migraine diagnosis  . A sum oOur primary outcome was the occurrence of narcolepsy (ICD-9-CM: 347), defined as the initial outpatient visit or hospital admission for narcolepsy during the follow-up period. Both cohorts were followed up until December 31 of 2012, their withdrawal from the NHI program, or the incidence of narcolepsy.We considered baseline demographic variables including sex, age and urbanization level. Age was categorized into 3 groups: 0–5, 6–11 and 12–17 years old. For defining urbanization level of each subject’s area of residence, we used townships within which subjects enrolled their insurance as reference; four levels of urbanization (1 highest to 4 lowest) were classified based on a score calculated by incorporating variables indicating population density (number of people per squared kilometer), population ratio of different educational levels, elderly, agricultural workers and the number of physicians per 100,000 people . BaselinIn our descriptive analysis, continuous data was expressed as means with standard deviation (SD) and categorical data were expressed as percentages (%). We compared baseline characteristics between children with and without migraine using standardized mean difference (SMD). SMD of less than 0.2 SD is indicative of negligible effect size in means or proportions of a propensity-score matched sample . IncidenAfter propensity-score matching, we selected 8,923 children with migraine and 35,692 control children without migraine for analysis. A total of 13 subjects were newly diagnosed with narcolepsy during the follow-up period, with incidence rates of 0.1915 and 0.0278 per 1,000 person-years in the migraine and non-migraine cohorts, respectively. Stratified by sex, the incidence rates of narcolepsy in girls and boys with migraine were 0.1382 and 0.2492 per 1,000 person-years, respectively; higher than those in the control cohort  . In addiThis nationwide, population-based cohort study demonstrated that migraine in children less than 18 years of age was associated with a 5.30-fold increased risk of narcolepsy. This association was still present after controlling for the effects of potential confounders such as demographic characteristics, comorbidities and concurrent medication uptake. Furthermore, the elevated risk in migraine children was consistently detected in migraine with aura and migraine without aura subtypes, indicating that the study results were robust.The major strength of the present study was the use of a nationwide population-based database, which enrolled a large sample size and appropriate observation period, thus providing sufficient power to delineate the differences between the two study cohorts. Moreover, a propensity score-matched comparison cohort was used to eliminate possibilities of subject selection bias and the influence of medical care-seeking behavior, thus reinforcing our conclusions that migraine increased the risk of narcolepsy in children. Although not many population-based estimates of narcolepsy in children are available, a European study has indicated an incidence rate of 0.83 out of 100,000 person-years in children between 5 and 19 years of age . Here weThe association between migraine and narcolepsy was inconclusive. In the first hospital-based observational study, migraine showed a 2-fold to 4-fold increase in patients with narcolepsy . In contThe exact pathophysiologic mechanisms linking migraine and narcolepsy are unknown. Loss of orexinergic neurons in the hypothalamus has been considered playing a causative role in narcolepsy with cataplexy. There is evidence that dysfunctional hypothalamic activity contributes to narcolepsy as well as altered pain processing via hypothalamic orexinergic neurons, while hypothalamus has been demonstrated in functional and structural brain imaging for migraine –15. On oNevertheless, our results need to be interpreted with caution as several limitations are associated with the present study. First, the diagnoses of migraine and narcolepsy were entirely identified on the basis of ICD-9-CM codes, and therefore, were dependent on the diagnostic accuracy of the NHIRD database. These data may be less accurate than those diagnosed made in a prospective setting through standardized procedures, which may be an inherent weakness for all database research. The NHIA in Taiwan samples the medical charts routinely and has made every effort to verify the accuracy of the diagnoses in the database from every contracted medical institution . IdeallyThis population-based longitudinal study provides evidence that migraine diagnosis is associated with an increased risk of narcolepsy in children. The higher narcolepsy incidence in the pediatric migraine population may indicate a common pathway of pathophysiology relevant to both disorders. Further research is warranted to describe the exact pathophysiological mechanisms linking migraine and narcolepsy.The association between migraine and narcolepsy in children has not been explored in a large-scale longitudinal study.As almost one-third of migraine patients become symptomatic before reaching the age of 15, there is an increasing level of attention given on the development of narcolepsy early in life.Using a nationwide population-based study approach, our results support the emerging notion that migraine is associated with the risk of developing narcolepsy in children.This derived association suggests a plausible pathophysiological mechanism that needs to be further investigated.


Enterobacteriacae carrying blaKPC and blaNDM-1, MRSA and VRE. blaKPC carrying Klebsiella pneumonia and Enterobacter cloacae were the most common Enterobacteriacae drug resistant bacteria found in the sewage locations we sampled. Klebsiella pneumonia, Enterobacter spp., Escherichia coli and Citrobacter spp. were the 4 main CRE isolated from Israeli sewage and also from clinical samples in our clinical microbiology laboratory. Hospitals and Community sewage had similar percentage of positive samplings for blaKPC and blaNDM-1. VRE was found to be more abundant in sewage in Israel than MRSA but there were more locations positive for MRSA and VRE bacteria in Hospital sewage than in the Community. Therefore, our upgrade of the pour plate method for heterotrophic plate count technique using commercial selective agar plates can be a useful tool for routine screening and monitoring of the population for pan-resistant bacteria using sewage.The presence of pan-resistant bacteria worldwide possesses a threat to global health. It is difficult to evaluate the extent of carriage of resistant bacteria in the population. Sewage sampling is a possible way to monitor populations. We evaluated the presence of pan-resistant bacteria in Israeli sewage collected from all over Israel, by modifying the pour plate method for heterotrophic plate count technique using commercial selective agar plates. This method enables convenient and fast sewage sampling and detection. We found that sewage in Israel contains multiple pan-resistant bacteria including carbapenemase resistant  Antibiotic-resistant bacteria are a growing problem worldwide and thus possess a major threat to global health. Extensive use of antimicrobial agents in hospital settings and animal husbandry, has led to the emergence of pan-resistant "superbugs", which creates serious ecological and epidemiological challenges for humans –4.Carbapenem-Resistant Enterobacteriaceae (CRE), that have developed resistance to carbapenems , which are most often the last option for therapy. Klebsiella pneumonia carbapenemase (blaKPC) and New-Delhi Metallo-β-lactamase (blaNDM-1) are among the most important carbapenemases. [Among the most common resistant bacteria are the nemases. –8.Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) represent the biggest therapeutic hurdles among the gram-positive organisms. [Methicillin-resistant ganisms. , 10–13.There is increasing concern about the growing resistance of pathogenic bacteria in the environment. These resistant bacteria are excreted by humans and animals and have been found in different environmental compartments. Most typically, in hospital effluent, municipal sewage, surface, ground and drinking water, as well as sediments and soil. .Klebsiella pneumoniae [blaKPC pathogens in Israel, blaKPC is almost exclusively healthcare acquired with no significant community transmission. Experience with community acquired extended spectrum β-lactamase (ESBL) microorganisms [During 2006 Israeli hospitals faced a clonal outbreak of carbapenem-resistant eumoniae . Since teumoniae –19. As Srganisms  and the rganisms , the sprSince there are no standard methods or commercial selective plates for environmental sewage samples which meet our needs, we developed a method that utilizes clinical selective plates for environmental sewage samples analysis.Here we demonstrate that the detection of pan-resistant bacteria can be done on environmental samples using commercial selective agar plates in a manner that could be used in routine screening of the population. The identity of the microorganism and the drug resistance mechanism can then be identified by classical bacteriological identification, sensitivity tests and Real Time-Polymerase chain reaction (RT-PCR).Using this method we sought to evaluate the presence of CRE, MRSA and VRE bacteria in Israeli sewage from hospitals and community collected from all over Israel, representing the population carriage of pan-resistant bacteria and to establish a convenient and fast method for sewage sampling.Haifa District: Haifa: Includes the cities Haifa, Nesher, Krayot and Tirat-HaCarmel (STF). Tel Aviv District and Central Region: (1) Tel Aviv: Eight different sampling locations in the city of Tel Aviv-Jaffa (All of the sampling sites in Tel Aviv are sampling sites on sewer systems). (2) ShafDan (Wastewater Treatment Plant of Dan Region): An STF that includes the following cities: Tel Aviv-Jaffa, Ramat-Gan, Bnei-Brak, Giv'atayim, Petah-Tikva, Giv'at-Shmuel, Kiryat-Ono, Tel-HaShomer, Ramat Ef'al, Azur, Bat-Yam, Holon, Rishon-Lezion and Rehovot. Jerusalem City: Three different sampling sites in the city of Jerusalem, which cover the entire city. Due to the unique mountain topography of Jerusalem, each sampling site stands on its own. Sorek and Og are STF's. South District: Three different locations were sampled: Rahat and Kuseife and the biggest city in the south of Israel Be'er-Sheva. Be'er-Sheva and Rahat are STF's  Sewer systems that drain sewage from the local municipal surroundings and (2) Sewage treatment facility (STF) that drain all the lines of the communities that are included in that line. The sampling locations were divided into four major areas: North, Center, East and South and were categorized as follows: re STF's  (The IsrAll sewage samples were collected using automatic composite samplers . The finStaphyloccocus aureus and (3) CHROMagarVRE is selective for VRE .Sewage samples were plated according to the pour plate method for heterotrophic plate count technique described in the Standard Methods for the examination of water & waste water  with minBriefly, the overlay agar was prepared by diluting 1:1 one of the chromogenic agars with distilled water. The agar was finely chopped and then gently mixed with slightly cooled down boiled distilled water until melted. 1 ml of sewage was added to 6 ml of the pre-melted and diluted chromogenic agar resulting in an overlay with a final dilution of 1:12. The mixture was gently mixed and then poured into 90 mm plates containing the specific CHROMagar growth media and were incubated at 35°C ± 2 for 48 hours.™  and MALDI-TOF MS  systems. Uncertain bacterial identifications were tested by classical/biochemical methods according to the literature [From each overlayed CHROMagar plate a certain percentage of suspected to be CRE, MRSA or VRE (according to instructions of manufacturer) were isolated, Gram stained using AerosprayWescor, Slide stainer Cytocentrifuge and observed with a light microscope . Identification and susceptibility of CRE and MRSA was performed using the Phoenixterature , 27 and terature , 27.™ DNA Tissue Kit according to the protocol recommended by the manufacturers. Briefly, from bacterial colonies: a 2.0 McFarland-standard bacterial suspension was prepared from isolated colonies in saline, and bacterial NA was extracted from 200 μl (1.2 X108 CFU) of the suspension. Extracted bacterial NA was eluted from the columns in 100 μl elution buffer and stored at -20°C.Automated Nucleic Acid (NA) extractions were carried out from fresh well-isolated colonies by NuclisensEasyMAG  or by EZ1 advanced  using EZ1blaKPC and blaNDM-1 amplicons by TaqMan technology. For sequences of primers and probes see previously published papers [The ABI Prism 7500 sequence detection system  was used for the amplification and detection of the d papers , 29.The clinical samples reviewed in this study were blood cultues, general cultues and rectal swabs for screening received by the Clinical Microbiology Laboratory in The Chaim Sheba Medical Center in Israel during 2013. General cultures include synovial, pericardial, pleural and peritoneal fluids, peritoneal dialysate, brain abscess, lung biopsy/tissue, pericardial fluid/tissue, heart valve, bone, joint, internal organs tissues, biopsies, heart valves, electrodes, catheters and wounds. All cultures suspected to be CRE were tested by Modified Hodge test, MBL E-test and by E-tests for imipenem, meropenem and ertapenem  following CLSI guidelines .8 CFU/ml blaKPCKlebsiella pneumoniae, blaNDM-1Escherichia coli, MRSA or VRE positive bacteria were serially dilluted logarithmically in sewage that was negative for these targets. Diluted bacteria were overlaid (as described above) or classically streaked on selective agar. Plates were incubated for 18–24 hours at 35°C ± 2 and analyzed after 48 hours. We found that the overlay did not cause bacteria death as the LOD was similar (5–10 CFU/ml) between the two methods for the different bacteria.In order to determine the limit of detection (LOD) for the overlay method, 1.5X10Pseudomans spp., Acinetobacter spp. and Enterococcus spp.) grew on each CHROMagarKPC overlayed plate of which an average of 50–100 colonies were big blue or pink, members of the Enterobacteriacae family. Of the colonies isolated, 10–15% were tested. An average of 200 colonies of different types of bacteria  and fungi grew on each CHROMagarMRSA overlayed plate of which an average of 10% were pink colonies that were suspected to be MRSA. Fifty percent of these colonies were tested. An average of 200–300 colonies of different types of bacteria  grew on each CHROMagarVRE overlayed plate of which 10–15% were pink colonies suspected to be VRE. Fifty percent of these colonies were tested  of the locations sampled; Northern Israel, represented by Haifa, had both samplings positive for blaKPC. In the center of Israel which included 8 locations in Tel-Aviv and the ShafDan-STF, 75% of the locations were positive for blaKPC. Jerusalem and the South of the country had 67% locations positive for blaKPC. However, blaNDM-1 was detected only in 2/16 (13%) of the locations sampled; 1 location in Jerusalem and 1 location in the south , MRSA and VRE out of the number of samplings analyzed is indicated.The State of Israel was divided into four main areas for sewage sampling; Haifa district in the north, Central district including Tel-Aviv and the Shafdan-STF, Jerusalem City in the East and the South district. Each district was divided to sub-districts. The boundaries and population size are mentioned for each sampling site. The number and percentage of positive samples for pan-resistant bacteria; CRE (https://www.google.co.il/maps).All geographical coordinates were done using "Google maps"  Israel 2012.** Tel Aviv-Jaffa, Ramat-Gan, Bnei-Brak, Giv'atayim, Petah-Tikva, Giv'at-Shmuel, Kiryat-Ono, Tel-HaShomer, Ramat Ef'al, Azur, Bat-Yam, Holon, Rishon- Lezion and RehovotblaKPC and blaNDM-1 in sewage that contains hospitals and nursing homes  to sewage that does not contain hospital and/or nursing homes (Community). We found no significant differences in the percentage of positive samples for blaKPC and bla-1NDM between Hospital and Community sewage (78% and 63% for blaKPC and 11% and 13% for blaNDM-1) (We compared the percentage of positive sewage samples for laNDM-1) .blaKPC positive isolates (19%) compared to the rest of the country (47–71%) but has the most blaNDM-1 positive samples (13%) compared to the rest of the country (0%)  .blaKPC positive by RT-PCR. All blaKPC positive bacteria were further analyzed and the distribution of these isolates by genera is shown in Citrobacter braakii (3), Citrobacter freundii (4), Enterobacter asburiae (1), Enterobacter cloacae (14), Escherichia coli (7), Klebsiella oxytoca (4) and Klebsiella pneumoniae (19). Only 3 carbapenem-resistant colonies out of the 112 (3%) were positive for blaNDM-1 by RT-PCR. Final bacteria identification revealed that 2 isolates were of Escherichia coli and 1 was Klebsiella pneumoniae  CRE colonies isolated around Israel were eumoniae .blaKPC carrying Klebsiella pneumoniae is also the most common CRE isolated from clinical samples in our clinical microbiology lab. The second, third and fourth most isolated CRE bacteria in our lab are E.coli, Enterobacter spp. and Citrobacter spp., respectively. These bacterial species were also the main species found in the sewage  . When exblaKPC and blaNDM-1, MRSA and VRE.Since there were no commercial methods for environmental sewage sampling using selective plates to meet our needs, we developed a method that combines the selective ability of the clinical selective plates with the environmental sewage sampling. We found that this method has an average LOD of 5–10 CFU/mL and thus can be easily used by laboratories for sewage screening. We have shown that sewage in Israel contains multiple MDR bacteria including CRE carrying blaKPC carrying Klebsiella pneumonia followed by Enterobacter cloacae.   Tables . This isOur study shows many more locations positive for VRE than MRSA in Israeli sewage   but dataWe conclude that (1) our upgrade of the pour plate method for heterotrophic plate count technique using commercial selective agar plates can be a useful tool for routine screening and monitoring of the population for pan-resistant bacteria using sewage and (2) that the content of MDR bacteria in sewage represents the distribution of pan-resistant bacteria in the population and that (3) similar resistant bacteria are present in the Hospitals and in in the Community in Israel.blaOXA-48, blaVIM and blaIMI in sewage systems.More research should be conducted in order to estimate the possible use of environment sampling to predict outbreaks of pan-resistant bacteria in the population and to look for other resistance genes such as


About a third (36.7%) of poly-drug users experienced sexual arousal due to drug effects, which is higher than the rate among other drug users. Poly-drug users had the highest prevalence of HIV (10.5%) and syphilis (3.6%), but heroin-only users had the highest prevalence of HCV (66.0%)  among three groups. Logistic regression shows among poly-drug users, having sex following drug consumption and using drugs ≥1/day were the major risk factors for both HIV (Adjusted odds ratio (AOR) = 2.4, 95% CI [1.8–3.4]; 2.3, [1.6–3.1]) and syphilis infection . Elevated risk of both HIV and syphilis infection have been established among poly-drug users.The number of poly-drug users who mix use heroin and synthetic drugs (SD) is increasing worldwide. The objective of this study is to measure the risk factors for being infected with hepatitis C (HCV), human immunodeficiency virus (HIV) and syphilis among SD-only users, heroin-only users and poly-drug users. A cross-sectional study was conducted in 2015 from a national HIV surveillance site in Southwest China, 447 poly-drug, 526 SD-only and 318 heroin-only users were recruited. Poly-drug users have higher drug-use frequency, higher rates of drug-sharing and unsafe sexual acts than other users ( While the number of drug users has continued to grow over the past five years, but access to health services underpinned by harm reduction principles remained low (about one in six persons with drug use disorders have such access)1. Human immunodeficiency virus (HIV) and hepatitis C (HCV) infection is a major concern among injection drug users (IDU), as injection drug use carries a high risk of blood-borne transmission of infections, it is reported that HIV infection risk per needle sharing acts can reach 2.38%2. Consequently, specific disease burdens in this population are disproportionally high: in 2015, approximately 13.3% of people who inject drugs were living with human immunodeficiency virus (HIV), and 50.8% were living with chronic hepatitis C (HCV) infection1.In 2016, an estimated 250 million people worldwide used non-prescribed drugs and about 29.5 million of those drug users suffered from drug use disorders6. Consumption of these drugs has increased rapidly since 2009, first in North America and Europe and gradually spreading to the rest of the world7. In 2015, problematic use of SDs was reported in 95 countries, with the largest proportion seen in East and South-East Asian countries1. Further, studies in well-known drug trafficking zones in the Asia-Pacific region, including Thailand, Myanmar and Malaysia, have shown an alarming increase in SD consumption, with a particularly notable increase among young people11.The widespread use of synthetic drugs (SDs) has also caused rising concern globally. Synthetic drugs are processed, artificial chemicals that mimic the effects of traditional recreational drugs. They include both amphetamine-type stimulants  and new psychoactive substances 12. Recreational drugs in China consisted primarily of traditional opiates, SD, and toxic medicinal drugs, with the former two types accounting for more than 90% of the drug market. By 2016, 2.5 million drug users were registered with the Chinese authority , which represents a significant increase from the 1.1 million drug users registered in 200813. Among all drug users, there has been an unprecedented increase in the proportion of people using SD: from 20% in 2008 to 61.3% in 2016 14. Due to the substantial stimulatory and euphoric effects of SDs, they are commonly used in nightclubs and among sexually active populations for recreational purposes16. Drug users are more likely to engage in unprotected sex, and with more and more drug-facilitated sexual assaults are occurring under the influence of mind-altering SDs18. It has been estimated that the transmission risk of HIV, a known sexually transmitted infection (STI), per unprotected sexual acts is 0.3%19. So the rising popularity of SDs may fuel HIV and STI epidemics, especially syphilis, which has become increasingly prevalent in China during the past decade.Despite its strong prohibitive drug policies, China, has also conformed the shifting global drug use patterns21. In this study, we defined poly-drug use as simultaneous mixed use of an SD and heroin. In contrast with SD-only users, poly-drug use is associated with more harmful drug effects and high-risk behaviours22. Because drugs have acute and chronic effects on bodily functioning, the combined use of multiple drugs can magnify their pharmacological effects23, for example, the co-use of cocaine and heroin has a synergistic impact on reducing norepinephrine release and reuptake24. So the same dosage of poly-drugs can cause stronger stimulation than either heroin or SD alone, resulting in users having a higher possibility of engaging in high-risk behaviours, such as condomless sex and/or group sex25. Moreover, in China, poly-drug users are more likely to inject drugs and share injection equipment than SD-only users. This behaviour also leads to higher risk of blood-borne viruses.It has been documented that 30–40% of heroin users in China also use SDs, and that proportion is expected to grow rapidly in the coming years26. However, in contrast to these national and international efforts to decreasing the disease burden of blood-borne viruses and sexually transmitted infections (BBVSTIs) disease burden, the rapid increase of SD and poly-drug use in recent years is further fueling these epidemics. In fact, an alarmingly high prevalence of HIV (6.0%) and syphilis (7.8%) infection has already been observed among drug users29, and meta-analysis estimated an HCV prevalence of 67.0% among injection drug users and 60.1% among all drug users in China29. Because the expanding drug-using population can potentially transmit BBVSTIs to the general population, a better understanding of the risk factors associated with HIV, HCV and syphilis infection, and the adverse effects associated with different kinds of drug users, are urgently needed to develop effective harm reduction strategies to slow further BBVSTIs transmission in a rapidly changing drug era30.In order to curb the rapid increase of BBVSTIs transmission nationally, the Chinese government announced in 2009 a 10-year syphilis plan (2010–2020) to control syphilis incidence and more recently introduced a 5-year HIV plan (2017–2022) to reduce HIV infections from the sexual and drug injection transmission routes. The World Health Organization has set an ambitious goal to eliminate HCV by 203031. Yunnan province accounts for 3.3% of the total population in China and due to the ease of access to a wide range of new and often affordable recreational drugs across its border, it had 160,000 registered drug users in 2014 32. According to China’s 2017Annual drug report on drug control, the top five drugs abused in China are methamphetamine, heroin, magu (a mixture of methamphetamine and caffeine)33, ketamine and methadone34. These drugs are all commonly and popularly used in Yunnan province, so the results of this study may be extrapolated to drug users in other parts of China. We consider this area an optimal study setting to assess the changing patterns of drug use and the impacts of those patterns on local HIV, HCV, and syphilis epidemics. This study aims to assess the prevalence of HIV, HCV and syphilis infection and their associated risk factors among poly-drug users, SD-only users and heroin-only users and compare the differences in socio-demographic characteristics, drug use practices and drug-related effects among these three groups.Yunnan province is a large province in Southwest China and borders the ‘Golden Triangle’, which is a major heroin manufacturing site at the borders of Myanmar, Thailand, Laos and VietnamA total of 1, 291 new entrants at the largest detoxification centre in Yunnan Province were enrolled in the study, 447 (34.6%) were poly-drug users, 526 (40.7%) were SD-only users, and 318 (24.6%) were heroin-only users according to their self-reported drug consumption patterns. Education status is similar in three groups, however, gender, age, marriage status, and monthly income demonstrated a graded distribution among three groups, poly-drug users were consistently ranked between SD-only users and heroin-only users. As shown in Table p < 0.01). Poly-drug users reported higher drug use frequency, with 36.2% of them using at least once-daily over the last three months compared with SD-only users (13.0%) and heroin-only users (27.4%). Poly-drug users exhibited the highest rate of drug sharing, the average number of poly-drug users shared drugs was 2.9 ± 1.1 in the last drug use, while SD-only and heroin-only users shared drug among 2 ± 0.8 and 1.7 ± 0.5 people in the last act, respectively. The age of first drug use was similar among the three groups, but heroin-only users had a longer duration of drug use  than the other drug users. Magu (67.4%) was by far the most commonly reported drug of choice in the past three months, followed by heroin (59.3%), methamphetamine (16.1%), ecstasy (9.5%) and ketamine (8.9%).A striking difference related to drug injection was observed among the three groups: while 62.0% (277) of poly-drug users reported ever injecting any drugs, almost all heroin-only users , but only 7.2% (38) of SD-only users reported a history of drug injection (p < 0.01). Corresponding to the sexual arousal rate, the number of users engaging in sexual activities following drug use in the past month was significantly higher among poly-drug users  than SD-only users  and heroin-only users  (p < 0.01). Additionally, sex with a non-regular partner  after recent drug consumption in the past month was highest among poly-drug users engaging in sexual activity following drug use . Of interest, reported rates of engaging in condomless sex did not differ significantly between the three groups. Hallucinations were more likely to be reported by SD-only users . Violent acts, however, were more likely to be committed by heroin-only users  (p < 0.01) . More than half of poly-drug users were confirmed  to be HCV-positive . The highest HCV prevalence was observed among heroin-only users  compared with no more than 5% of SD-only users . Similarly, but on a much smaller scale, confirmed rates of syphilis infection  were highest in the poly-drug users compared to SD-only users  and heroin-only users  (Table As shown in the last section of Table Engaging in sex following drug consumption and using drugs ≥1/day were the main risk factors for HIV infections (adjusted odds ratio (AOR) = 2.4, 1.8–3.4 and AOR = 2.3, 1.6–3.1, respectively) among poly-drug users. Longer duration of drug use  and injecting drugs  were independently associated with confirmed HIV infection among poly-drug users. For the SD-only users, engaging in sex following drug consumption  and having a monthly income higher than 2000 RMB  were both positively correlated with HIV infection. Heroin-only users with elder age , longer drug use duration  and those who inject  had a higher risk of HIV infection Fig. . This moInjecting drugs remained the strongest risk factor associated with HCV infection among poly-drug users . In addition, poly-drug users with monthly income lower than 2000 RMB  and longer duration of drug use  had a higher risk of being HCV infected. Notably, engaging in sex following drug consumption  and duration of drug use  were two factors associated with HCV co-infection among SD-only users. Similarly to poly-drug users, injecting was a high-risk factor contributing to HCV infection among heroin-only users . Other independent variables correlated with HCV-infection among heroin-only users included lower monthly income  and a longer duration of drug use  Fig. . The modConsistent with the above results for HIV infection, engaging in sex following drug consumption and using drugs once or more per day  were the main risk factors associated with syphilis infections among poly-drug users. Among this population, lower education  and drug-sharing rate  were also associated with syphilis infection. For SD-only users, female drug users , with lower education , who engaged in sex following recent drug consumption , and used drugs more than once daily  were more likely to be infected with syphilis. For heroin-only users, lower education  and engaging in sex after drug consumption  were positively correlated with syphilis infection Fig. . The modIn this study, poly-drug users demonstrated the highest prevalence of HIV and syphilis infections, while heroin-only users demonstrated the highest prevalence of HCV infection among the three groups. Engaging in sex following drug consumption and using drugs once or more per day appear to be the major risk factors for both HIV and syphilis infection among poly-drug users. Drug injection remains the main risk factor contributing to HCV infections among heroin-only users and poly-drug users. Notably, unsafe sexual behaviour is the major factor contributing to increased risk of HIV, HCV and syphilis infection among all SD users. Elevated risks of both HIV and syphilis infection have been established among poly-drug users. Harm reduction interventions should target the growing population of poly-drug users for effective control of BBVSTIs epidemics.35. Another reason may be that the stimulant effects of synthetic drugs can mask the signs of heroin overdose (e.g. respiratory depression), leading users to mistakenly feel that they can take more to maximize satisfaction36. Furthermore, our study shows that poly-drug users are more likely to share drugs than other sole drug users. This is perhaps because some drug users especially young people initiate poly-drug use in social situation for instance at parties where multiple drugs are used due to peer pressure35, so they may share drugs together among their circle of friends. This may lead to higher risk among poly-drug users of using contaminated syringes, engaging in unprotected sex and increasing the drug use frequency than the heroin-only and SD-only users. Notably, the comparison of demographic characteristics showed that SD-only users are the youngest and have the shortest history of exposure to drug consumption among all the drug users considered in the study. This may be partly explained by the fact that SDs have only become widely available in China in recent years37. Previous studies in other countries have reported that SD users are likely to become poly-drug users39, so further studies could be conducted to confirm whether drug use duration is linearly related to the possibility that SD-only users will become poly-drug users.Our findings indicate that poly-drug use may result in high-risk behaviours and is becoming the leading cause of BBVSTI transmission. First, poly-drug users have the highest drug-use frequency among the three groups of drug users. This may be due to using of multiple drugs is to reduce unwanted side-effects or withdrawal symptoms, so poly-drug users may have to use drugs more frequently40. Our results suggest that unsafe sexual behaviours may contribute more to HIV infection than injecting behaviours among poly-drug users, which could indicate that unprotected sexual acts have become the dominant transmission route in this population. Furthermore, poly-drug users have higher likelihood of injecting SDs than SD-only users, in a process called ‘slamsex’, which means injecting rather than snorting or orally taking SDs in order to get a more intense high from synthetic drugs41. This behaviour may lead to a more intense high and thus to more serious behavioural consequences. In addition, needle sharing for ‘slamsex’ can also spread BBVSTIs41. Effective interventions should be implemented for poly-drug users who face this dual risk.Compared with heroin-only and SD-only users, poly-drug users were more likely to experience sexual arousal following drug consumption. Correspondingly, poly-drug users reported a higher incidence of subsequent sexual behaviours and sex with casual partners. However, the prevalence of condomless sex in such contexts was not significantly different among the three groups and all exhibited rates higher than 60%. This situation raises a severe concern with regard to transmitting BBVSTIs as using drugs to enhance sex becomes more prevalent among drug users; in addition, it has been found that drug use can result in the lowering of inhibitions among those who would normally use condoms,leading to unprotected sex44. However, with the increasing number of SD classes on the market, the potential combinations of different drugs may lead to more side effects and even lethal outcomes among poly-drug users. Violent acts are also a major concern associated with heroin-only users, as uncontrolled violent behaviours are often related to sexual violence46, which is a risk factor associated with sex crimes and STI transmission48. This drug influence was also observed among poly-drug users.In the present study, hallucinations and uncontrolled body movements were more commonly reported as adverse reactions after drug consumption by SD-only users than by their counterparts. This is also the main symptom observed among poly-drug users, a result that is consistent with the documented side effects of SDs, which can cause either short-term delirium or long-term psychotic reactions49. Globally, it is common to help drug users by using psychological approaches including motivational interviewing, meditation, family support and light physical activities such as yoga50. It is necessary to implement national intervention programs targeting SD users in China. For example, China has developed a national methadone maintenance treatment program for people with opioid dependence.Given the rapid increase in synthetic drug and poly-drug use and its serious consequences, interventions to mitigate harm are imperative. First, current synthetic drug users should be encouraged to cease SD use. However, quitting synthetic drug use is difficult as withdrawal has been shown to cause psychological rather than physical symptoms51. However, in light of the ever-increasing number of drug users and the amounts of drugs seized by police in recent years, the Chinese government should also consider a new experimental trial using more compassionate and humanitarian methods of SD harm reduction. As an example, Portugal decriminalised the acquisition, possession, and use of small quantities (up to a 10-day supply) of all psychoactive drugs for personal use in 200152. The general view is that the strategy has caused a reduction in the rates of drug use, drug-related deaths and blood-borne viruses among existing users53. In 2009, the government of Mexico also enacted a law to decriminalise the possession of small amounts of drugs, which has had positive effects on the control of drug use54. Although such drug-policy reform remains controversial, its results merit conducting a pilot study that would combine the decriminalisation policy with intervention to scale up BBVSTIs testing, treatment and prevention programs for SD users as an alternative to harsh penalties in China. This might ameliorate the negative effects of increased drug use on BBVSTIs.Second, drug policies should be altered to protect and treat drug users. Currently, in line with similar policies aimed at controlling heroin use, China has announced strict policies to reduce use of synthetic drugs. Chinese drug law states that those who smuggle, sell, transport, or manufacture methamphetamine or other narcotics in an amount greater than fifty grams can be sentenced to fifteen years in prison, life imprisonment, or death55. This study indicates that intravenous drug injection is still the primary route of HCV transmission57 for both poly-drug users and heroin-only users. Also, our research shows that drug users with lower income are more likely to be HCV-positive. This is an alarming signal, suggesting that low-income users cannot afford clean needles. Furthermore, the rate of drug sharing was observed to be higher among poly-drug users, and longer drug use duration was shown to be one risk factor associated with HCV infection58. It is reasonable to estimate that there will be an increasing trend of HCV infection among poly-drug users, highlighting the urgent need for clean syringes. Our study further suggests that an elevated HCV risk is attributable to sexual transmission in the context of drug use among SD-only users59. This is a plausible conjecture, as a recent meta-analysis showed that sexual transmission of HCV is highly probable in HIV-positive men who have sex with men60. Reducing high-risk sexual behaviours under drug influence may also benefit the prevention of HCV infection.Finally, promoting needle and syringe programs among drug users should be considered to reduce transmission of blood-borne diseases, as this approach has proven to be an effective intervention in other countriesThere are several limitations in this study. First, we cannot assess the specific poly-drug use of each user; for example, we could not determine whether a drug user used heroin first then used SDs or SDs first and then heroin. The order may have an impact on the prevalence of BBVSTIs. Second, practices related to recreational drug use, which is illegal in China, relied exclusively on self-reports, which can lead to recall and social desirability biases. Third, detailed reasons for consuming SDs and heroin were not collected, limiting our ability to provide further contextual information to illuminate the main findings. Despite these limitations, our study is the first in China to reveal that (a) poly-drug users have elevated risks of both HIV and syphilis infection and (b) a potential outbreak of BBVSTIs is highly likely among younger drug users who have only recently initiated SD use if the status quo continues.Our findings underscore the necessity of implementing effective harm reduction interventions and BBVSTI testing, treatment and prevention to support the chronic, complex and ever-changing needs of poly-drug users and address the potential shift to younger, more recently initiated SD-only users. Against the background of already harsh drug regulation and drug user crackdown policies for synthetic drugs and heroin in China, it has become more important to expand practical and effective harm-reduction programs for current poly-drug and SD users in order to curb the rise in BBVSTIs resulting from risky sexual behaviours and the chronic drug injection.61, so the population of detoxification centers can represent the general population of drug users in China.A cross-sectional survey, as a part of the routine sentinel drug user surveillance carried out in the largest detoxification centre in Yuxi, which is also one of the Chinese national HIV sentential surveillance sites that routinely collect data from designated priority populations. China has adopted a compulsory ‘detoxification’ policy, which means that drug users arrested by the police or reported by the community are compelled to enter a detoxification center for treatment. China has 700 detoxification centers, and these centers are housing more than 350,000 drug usersData was collected on the first day of admission to the detoxification centre between mid-January and mid-December of 2015. Eligibility criteria included the following: 1) use of recreational drugs in the previous week; 2) being 18 years of age or older; 3) residing in Yuxi in the previous three months; and 4) provision of written informed consent. In this study, SD includes methamphetamine, ecstasy, ketamine, and magu. We distinguished ‘poly-drug users’ (those who used both heroin and any SD concurrently in the previous three months) from heroin-only users (never used SD before) and SD-only users (never used heroin before). We excluded drug users who used heroin and SD concurrently earlier than the previous three months to avoid bias. The participants were classified into the aforementioned three categories. Participants completed a paper survey via self-interviewing, with 15 minutes average completion time. This was followed by serological tests for HIV, HCV and syphilis confirmation and a urine test. The results of urine detection of drug residuals were used to corroborate self-reported drug consumption in the previous week.The study reports findings from the secondary data analysis  of these local routinely collected bio-behavioural surveillance data, which was approved by the Monash University Human Research Ethics Committee (CF16/942 - 2016000495). The collected data were analyzed only for the purposes of this study. No further informed consent about this study was required.62; HCV-positivity was confirmed by the detection of HCV antibodies through repeated, independent ELISA testing63; and syphilis-positivity was established by Rapid Plasma Reagin (RPR) Circle Card Test screening and Treponema Pallidum Particle Agglutination Assay (TPPA) validation. Laboratory results (performed as part of routine surveillance at community sites) and additional serological tests were then linked through a unique study ID for each participant by local CDC data experts. Those with laboratory-confirmed HIV, HCV or syphilis infections were then notified and referred to treatment whenever possible, following standard clinical referral pathways.The survey consisted of four sections: socio-demographic characteristics, patterns of recreational drug use, specific reactions following recreational drug use, and subsequent sexual behavioural patterns after drug consumption. The questionnaire was pilot-tested before the formal roll-out. Serological detection of HIV, HCV and syphilis followed standard national diagnostic guidelines in China: HIV-positivity was confirmed by Enzyme-linked immunosorbent assay (ELISA) screening and Western Blot (WB) validationp-value of less than 0.05 was considered significant in the final logistic regression models.For this paper, the analysis was performed on a selected sub-group of surveillance participants according to their drug use. All data were managed and analysed using the statistical software SAS 9.4 . Descriptive and inferential statistical analyses were performed. Medians and interquartile ranges (IQRs) were calculated to summarise numerical variables, whereas frequencies and percentages were presented to describe categorical variables. A chi-square test was built to assess key factors differentiating SD-only users, heroin-only users and poly-drug users. Three multivariable logistic regressions were used to identify factors associated with increased prevalence rates of BBVSTIs within each group. The final model was adjusted for demographic characteristics confounding, which are the variables with a p-value < 0.2 in the univariate analysis were included in the multivariate analyses. Collinearity was checked by evaluating the impact factors of all the indicator variables in multivariate analyses. A Dataset 1


Multiple micronutrients (MMN) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines. Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity. Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth. The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed.We undertook a double-blind randomised controlled trial of small-quantity lipid-based nutrient supplements (SQ-LNS) fortified with 23 micronutrients in children aged 6 months (mo) to 5 years (y) presenting with an illness at a rural primary healthcare centre in The Gambia. Primary outcomes were repeat clinic presentations and growth over 24 wk. Participants were randomly assigned to receive 1 of 3 interventions: (1) supplementation with micronutrient-fortified SQ-LNS for 12 wk (MMN-12), (2) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6), or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0) to be consumed in daily portions. Treatment masking used 16 letters per 6-wk block in the randomisation process. Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled.p = 0.037; equivalent to 2–5 mm depending on age). No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups . In post hoc analysis, clinic visits significantly increased by 43% over the first 3 wk of fortified versus unfortified SQ-LNS , with respiratory presentations increasing by 52% with fortified SQ-LNS . The number of severe adverse events during supplementation were similar between groups . No participant withdrew due to adverse effects. Study limitations included the lack of supervision of daily supplementation.Between December 2009 and June 2011, 1,101 children  were enrolled, and 1,085 were assessed . MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment  are prescribed widely in low- and middle-income settings.There are currently no established evidence-based international clinical guidelines for the use of MMN in ill children.Community-wide trials of MMN within a lipid-base supplement have shown improvement in linear growth in some settings, although the effect on morbidity is underresearched.Our study was designed to investigate the effect of lipid-based MMN in ill children in relation to the frequency of subsequent primary health clinic visits and growth.We performed a prospective, double-blind randomised controlled trial of small-quantity lipid-based MMN in ill children presenting to a rural primary healthcare clinic in West Africa.We enrolled 1,100 children aged 6 months (mo) to 5 years (y).Children were supplemented either with the lipid-base alone or a micronutrient-enriched lipid-based supplement for 6 wk or 12 wk.The trial showed no effect of small-quantity lipid-based MMN supplementation compared to unfortified supplement on subsequent all-cause morbidity as assessed by clinic visits over 6 mo, but post hoc analysis revealed a significant 43% increase in clinic presentations over the first 3 wk of supplementation.Despite a significant increase in children’s reported appetite, there was only a small benefit on linear growth.Randomised trials have so far failed to demonstrate consistent beneficial effects of MMN supplementation (lipid-based or not) on growth and morbidity, and there is some evidence of potentially harmful effects, likely related to iron in the supplements.Blanket prescribing of MMN in primary health clinics in similar settings is not supported by current evidence. It has been estimated that vitamin and mineral deficiencies affect more than 2,000,000,000 people worldwide. Together with other manifestations of malnutrition , such deficiencies contribute to over 3 million child deaths worldwide; approximately 45% of the total. In recognition of the fact that children in deprived populations tend to suffer from a combination of nutrient deficiencies, recent intervention programs have favoured the use of multiple micronutrients (MMN). MMN are also widely, and often indiscriminately, prescribed in primary healthcare clinics, despite the absence of a supporting evidence base. MMN are available as liquids, dispersible tablets, micro-encapsulated powders, or embedded in lipid-based nutrient supplements (LNS). Lipid-based MMN supplements may lower the risk of overdosing, address macro- as well as micronutrient deficiencies, and can enhance the absorption of fat-soluble vitamins. Despite Because of the tight interplay between nutrition and infection , we reasEthics approval was granted by the joint Gambian Government/Medical Research Council (MRC) Unit The Gambia Ethics Committee  and the London School of Hygiene and Tropical Medicine Ethics Committee (5629) . CommuniWe undertook a double-blind randomised placebo-controlled trial of a SQ-LNS in children presenting to a primary healthcare clinic in Kiang West an isolated, rural district of The Gambia. The trial was conducted to good clinical practice (GCP) standards.Kiang West has a population of around 15,000. Rural subsistence farming is the main livelihood, which is heavily influenced by the unimodal annual rainy season. The under-5 mortality rate is lower than the national average .  The popuThe Keneba Electronic Medical Records System (KEMReS) was developed as an enabling technology to capture clinical data.  KEMReS iAll Kiang West children aged 6 to 60 months (mo) presenting with an acute illness to the Keneba primary healthcare centre were eligible for inclusion in the study. Children enrolled in another research study, or those with known haemoglobinopathies or severe malnutrition were excluded. Children with severe malnutrition as defined by the World Health Organization (WHO)  were treA doctor assessed all presenting children and completed an eligibility form. A trial team member then provided information about the study to the caregiver of the child, and oral and written consent were taken before enrolment.All children enrolled in the trial were followed-up daily for 1 week (wk) and then fortnightly until the end of the 12-wk supplementation period to gather caregiver-reported morbidity and compliance data. Anthropometry measurements were taken at recruitment and 6 wk, 12 wk 24 wk, and 24 mo after enrolment. Re-presentation with any illness to one of the 3 clinics in Kiang West was monitored over 6 mo after enrolment.Participants were randomised into 3 groups: (1) supplementation with micronutrient-fortified SQ-LNS for 12 wk (MMN-12); (2) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6); or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0). Balance with respect to date of recruitment was achieved using block randomisation (blocks of 12). Participants were allocated their randomisation code according to sequence of presentation.The third, eighth, thirteenth, and subsequently every fifth child within each supplement group were assigned to a subgroup for micronutrient status measurements at the end of the 12-wk supplementation period  vitamin D (25(OH)D) and selenium).Supplement jars were identical apart from their label, using 16 letters per 6-wk supplementation period to minimise bias. The code was only known to the MMN producer  and an independent person. Investigators, study team members, statistician, and participants were masked to the composition of the supplementation until after the results of the analysis according to the preagreed statistical analysis plan were available.The intervention was a SQ-LNS developed in collaboration with Valid International, Nairobi, Kenya. The SQ-LNS contained 23 micronutrients . Two difTo mimic a possible programme setting, a 14-day supply of supplement was given to the caregiver of the enrolled children every 2 wk. The supplement was supplied in jars containing 60 g of LNS. Supplementation of the child was not observed by a study team member. Trial members were trained in delivering clear instructions on how to supplement the children. Caregivers were asked to administer SQ-LNS on a daily basis by mixing 4 levelled teaspoons of supplement  with the child’s food. Self-reported noncompliance was defined as any participant consuming less than 70% intended. Advice was given when to present to the primary healthcare facility for an illness and to continue with the supplementation unless advised otherwise by a member of the medical team.After the initial daily visits for morbidity data collection during the first wk of supplementation, a team of trained trial fieldworkers (FWs) visited each child fortnightly during the 12-wk supplementation period, recording morbidity using data collection procedures previously trialled in the study population. FWs also counted used supplementation jars and replenished the supplement held by the caregiver to provide the next 14-day dose. At each visit to the child’s family, the caregiver was interviewed to obtain information on child’s appetite, presence or absence of diarrhoea, vomiting, cough, rapid breathing, and perceived fever in the preceding 72 h. Diarrhoea was defined as 3 or more loose stools per day.Anthropometric measures were undertaken by trained trial staff and clinic team members using standardised methods. Two sets of anthropometric data were taken and entered into the database. If they were the same or within the accepted error range, the first data set was used. If the data differed, measurement had to be repeated. Quality control checks were set within the electronic patient record system and performed according to standardised operating procedure . Trial sChildren self-referred to the clinic were assessed each time by 1 of 3 medical officers using a standardised proforma within KEMReS.  Based onVenous blood was collected at the end of the supplementation period at 12 wk in the subset selected for micronutrient status analysis. Haemoglobin concentration was measured using an automated haematology analyser . Plasma was separated and stored at −70°C. Samples were then transported to MRC Human Nutrition Research (HNR), Cambridge, United Kingdom on dry ice and analysed for plasma zinc and selenium using inductively coupled plasma-mass spectrometry. Plasma retinol levels were analysed by high-performance liquid chromatography and plasma 25(OH)D by a chemiluminescent assay. Plasma C-reactive protein (CRP) was measured using a commercial colorimetric immunoassay, and alpha(1)-acid glycoprotein (AGP) was measured by an immunoturbidimetric specific reaction (Sentinel Diagnostics). Zinc, selenium, retinol, and 25(OH)D levels were adjusted for CRP and AGP in the analysis.Our primary outcomes were morbidity measured as presentations to a clinic in Kiang West within 6 mo and growth at 6 mo after enrolment.Secondary outcomes included the following: (1) caregiver-reported morbidity collected daily for the first wk and then fortnightly during the 12-wk supplementation period; (2) repeat presentation to clinic ; (3) micronutrient status for zinc, retinol, selenium, and 25(OH)D and haemoglobin levels at the end of supplementation; (4) caregiver-reported appetite during supplementation; and (5) growth at 2 y after enrolment.Any self-referred clinic visit was recorded as a potential adverse event, and a summary of events was sent at agreed intervals to the trial and data safety monitors. Any clinic presentations with severe illness or any deaths were registered as severe adverse events, and the data safety monitor was informed within 24 h, followed by a detailed description and assessment of each case. Any visits to clinics outside Kiang West were recorded as part of the 2 wk FW visit.There were no published data on the effect of nutritional intervention on repeat clinic visits in this age group on which to base a power calculation. Prior to the introduction of KEMReS, limited data was available on clinic presentations at MRC Keneba in patients over 3 y old and from those residents outside the ‘core villages’ in Kiang West.  We origiAll participants, who received at least 1 dose of SQ-LNS were included in the analysis using STATA (version 12) based on a predefined analysis plan agreed with the trial monitor . Childrehttp://www.controlled-trials.com/).The trial was registered as ISRCTN 73571031 before the start of recruitment . They also approved the statistical analysis plan  prior toBetween 12 December 2009 and 3 June 2011, 2,743 children presenting to the primary care clinic were assessed for eligibility, of whom 1,642 children were either not eligible, the research clinician was unable to perform trial assessment, or the caregiver did not give consent. The remaining 1,101 children entered the trial . SixteenThe 3 groups were similar at baseline for a range of indicators including distance to the health facility and crowding . DiseaseOverall mean compliance when including those lost to follow-up or withdrawn was 85% (87% excluding those lost to follow-up) and was similar across intervention arms . We did Overall, there were 2,514 return clinic visits within 24 wk of recruitment. Of those, 2,224 visits (89%) were included in subsequent analysis according to the statistical analysis plan . Median p = 0.016; risk difference = 8/100). Respiratory infections were increased by 52%, although the effect was only borderline significant . There was no significant increase in severe presentation seen within the first 3 wk . Severe adverse events overall were also not different between intervention groups  . MMN supn groups .Stunting was prevalent in 25.4%  of our study population at baseline. Similarly to usual trends among infants and young children in this population, HAZ declined across all intervention arms over the 6-mo follow-up . Howeverp = 0.037). There was no difference between the MMN-6 and MMN12 groups . The proportion of anaemic children (Hb < 11.0 g/dL) was lower in the MMN groups .p = 0.011) change in plasma 25(OH)D levels with MMN supplementation relative to unfortified SQ-LNS. The effect was dose-dependent with a significant difference between MMN-6 and MMN-12 (p = 0.027). Overall, 30% (59/195) of the children tested were zinc deficient (plasma zinc <647μg/l), 22% (42/194) had mild vitamin A deficiency (plasma retinol <0.70 μmol/l), and 14% (27/195) had plasma selenium levels below the recommended level for maximal activity of glutathione peroxidase and selenoprotein P (plasma selenium concentration >1.2 μmol). MMN supplementation did detectably not improve the status of plasma zinc, selenium, and retinol among study participants  showed that symptom scores and symptom resolution over the first wk of supplementation was not different across intervention groups , Fig 2. p = 0.018) (p = 0.010). The effect was even more pronounced during the first 6 wk after enrolment .Appetite was recorded daily for the first week after recruitment and fortnightly thereafter until the end of active intervention at 12 wk. Supplemented participants were 8% more likely to show an improved appetite within the first week  . MMN supTo our knowledge, this is the first randomised controlled trial to investigate the effects of micronutrient-fortified versus unfortified SQ-LNS in children presenting to a primary healthcare facility. We studied a well-described population with a high rate of stunting, little migration, and low loss to follow-up. Reported compliance was probably the best that can be achieved when supplementation is not directly observed  and exceThere was no reduction in repeat clinic attendances and very minimal benefit to growth despite an enhancement of appetite with added MMN. The suggestion, upon secondary analysis, that morbidity was elevated by micronutrients is potentially concerning.lactobacilli and bifidobacteria, and this increases inflammation in the gut. [Point of care provision of SQ-LNS-MMN compared to unfortified SQ-LNS did not reduce return clinic presentations within a 6-mo period despite the high compliance. Neither was there an effect on the duration of the clinical symptoms associated with the initial presentation. However, appetite improved appreciably with MMN. In the primary analysis, there was a nonsignificant trend to increased morbidity over the entire 6-mo follow-up. The incidence of severe illness during follow-up did not differ between the groups, although this was based on few events. However, post hoc analysis revealed a 43% increase in total return visits to clinic (95% CI 7%–92%) within the first 3 wk of intervention in the 2 SQ-LNS-MMN groups. There are several grounds to suspect that the 12 mg per day iron in the MMN could be responsible for this effect.  Iron liethe gut.  These fiThere is an extensive, though heterogeneous, evidence base on the effects of single micronutrient interventions  on morbidity outcomes, but the effect of MMN supplementation on child mortality and morbidity is underresearched.  MorbiditReceiving SQ-LNS with MMN had a very small benefit on growth. It reduced the typical decline in linear growth seen in this population by 0.084 z-score compared to unfortified SQ-LNS—equivalent to 2–5 mm depending on the age of the children with debatable clinical relevance. Twelve-week supplementation did not show significant advantage over a 6-wk supplementation period. The duration of supplementation was shorter than other SQ-LNS studies  Shorter www.ilins.org). [p < 0.001). A prior study in Ghana compared an earlier version of SQ-LNS (Nutributter) to crushable multiple-micronutrient tablets and encapsulated multiple-micronutrient powders (Sprinkles ©). [p = 0.006; MMN: −0.91, p = 0.009). [p = 0.022) compared with providing IFA to mothers and MMN to children. [When we initiated our study, there was considerable optimism that lipid-based micronutrient supplements would have a significant impact on community-based nutritional intervention, and several trials coordinated by the International Lipid-Based Nutrient Supplements (iLiNS) consortium were in progress (ns.org).  Some of ns.org).  In all gns.org).  The prevkles ©).  The base 0.009).  Similarlhildren.  None of Short-term supplementation with RUTF for 2 wk to nonmalnourished and moderately malnourished children in Nigeria during recovery from malaria, diarrhoea, or LRTI did not reduce the incidence of malnutrition over a 24-wk period compared to no supplement , whereasIn common with most other MMN trials in low-income settings, we achieved a small but significant improvement in haemoglobin levels (+0.44 g/dl), but after 12 wk intervention, 33% of the children remained anemic (46% in the unfortified group). Some of the remaining anaemia might have been related to nonnutritional factors. It has also been suggested that for populations with African ancestry, lower thresholds for the diagnosis of anaemia may be more appropriate  but not in vitamin A, zinc, or selenium status. Reasons for the lack in difference for vitamin A, zinc, and selenium may be related to a suboptimal amount contained in the supplement, poor absorption, homeostatic control mechanisms, and/or adequate levels in the study population  .n = 1,101 versus n = 1,500). With the number of study participants enrolled, we would only detect a difference of 18%  in the main outcome of clinic representations with 80% and 5% significance levels. Given that the secondary outcomes of reported morbidity and severe adverse events did not differ between intervention groups, the authors cannot rule out that the small difference in clinic re-presentations (when adjusted and using combined groups) may be a chance finding.We acknowledge several limitations when considering our results. Supplementation was not directly observed, and although recorded compliance was similar between groups and sharing was not reported, this cannot be guaranteed. The main outcome measure of morbidity, i.e., clinic re-presentation, is significantly influenced by distance from the home village to the health centre and families’ access to transport.  However,Our trial had many strengths. It was appropriately randomised and blinded, and loss to follow-up and missing data were minimal compared to other trials. In particular, the targeting of children presenting to a rural clinic had the potential to self-select a subpopulation at greatest need and to enhance recovery from the presenting condition. If it had proved effective, such a strategy would be more cost-effective and much easier to implement in terms of supply and distribution than population-wide mass administration.We conclude that prescribing micronutrients via SQ-LNS to acutely ill nonmalnourished and mild-to-moderately malnourished children presenting at a primary care clinic in rural Gambia had only a minimal effect on growth compared to unfortified SQ-LNS. Micronutrient supplementation also did not reduce morbidity, and evidence for an early increase in repeat visits indicates that caution is warranted when prescribing MMN in a primary care setting, particularly if they include iron. It is highly likely that a combination of recurrent infection, persistent gastrointestinal enteropathy, and chronic inflammation are major factors in limiting the response to nutritional intervention.S1 CONSORT Checklist(DOC)Click here for additional data file.S1 Text(DOC)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S4 Text(DOCX)Click here for additional data file.S5 Text(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Seventy-five (68%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the complete response rate after myeloablative therapy was 59%. The estimated 5-year overall survival, disease-free survival and progression-free survival rates were 44%, 54% and 39%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible.Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified ( Therefore, for defining a treatment standard, we must preferentially rely on prospective phase II studies. Owing to the dismal prognosis of patients with PTCL treated with conventional chemotherapy, to date, four other prospective studies specifically dedicated to PTCL investigated the role of upfront autologous stem cell transplantation (autoSCT).15Peripheral T-cell lymphomas (PTCL) comprise a group of rare and heterogeneous hematologic malignancies, characterized by an aggressive disease course chronology in order.et al.13 published the combined results of two prospective phase II studies investigating the role of intensified sequential chemotherapy followed by upfront autoSCT in patients with PTCL with estimated 12-year overall survival (OS), disease-free survival (DFS) and event-free survival (EFS) rates of 34%, 55% and 30%, respectively. These results have to be interpreted with caution, as 19 of the total 62 patients (31%) had ALK-positive ALCL, a subentity with a much better prognosis than all other PTCL entities. The analysis of the remaining 43 patients with PTCL yields an OS of 21% and an EFS estimate of 18%.In July 2006, Corradini et al.15 in 2007, 19 of 26 patients received autoSCT, with 3-year OS and progression-free survival (PFS) rates of 85% and 59%, retrospectively.In the small study published by Rodriguez 14A Spanish group reported a 4-year OS rate of 39% in 41 patients with PTCL in 2008. In this study only 41% of the 41 patients eventually received autoSCT.These three studies have a relatively small sample size if the good prognosis patients are excluded from analysis and therefore, the possibility of substantial bias needs to be considered.11 For this prospective study, 83 patients were enrolled, excluding ALK-positive ALCL as well as PCTL. At the time of publication, the estimated 3-year OS, PFS and DFS rates were 48%, 36% and 53%, respectively.In January 2009, a paper by our group presented data on patients with PTCL who were treated with upfront myeloablative radiochemotherapy and autoSCT following four to six cycles of conventional chemotherapy.et al.12 published the results of a large trial of the Nordic Lymphoma Group (NLG-T-01). In this study, 160 patients with PTCL, also excluding ALK-positive ALCL, were treated with conventional chemotherapy followed by consolidation with high-dose chemotherapy and autoSCT. The 5-year estimates of OS and PFS were 51% and 44%, respectively.In July 2012, d'Amore This study was first published in 2009 when 83 patients had been included. Additional 28 patients were treated thereafter according to the study protocol. Here we present the analysis of the in total 111 patients with a median follow-up of almost 5 years. Our study is still the largest German study and the second largest worldwide with a long follow-up.11 Thus, until July 2010, additional 28 patients were treated exactly as stipulated by the study protocol. The outcome of these patients is reported together with a follow-up report on the original cohort of the 83 patients reported previously.After this study was reported in 2009 we decided to treat all consecutive patients according to the study protocol.Altogether between January 2001 and July 2010, 111 patients with newly diagnosed PTCL were treated. Inclusion criteria were as follows: histologically confirmed PTCL, histology reviewed by the Reference Center for Lymph Node Pathology in Wuerzburg, Germany, age 18–65 years, ECOG performance status <4, no severe comorbidity, no pregnancy or lactation, and written informed consent. The study protocol did not allow to include patients with primary cutaneous lymphomas and ALCL.The median age was 49 years (range 23–66 years). The vast majority of the patients presented with advanced disease: 83 patients (75%) had stage III–IV disease. The age-adjusted international prognostic index was low/intermediate low in 44 patients (40%) and intermediate high/high in 64 patients (58%). Patient characteristics are listed in 11 In brief, patients received four cycles of CHOP chemotherapy. If no complete remission (CR) was achieved, two more cycles were allowed. Patients in CR and patients achieving at least a partial remission (PR) after six cycles proceeded to mobilization chemotherapy.The treatment plan has been described before.6 CD34+ cells was required for the patient to be eligible for high-dose therapy.For mobilization of hematopoietic stem cells, the DexaBEAM protocol  was used in 71 of the 84 patients. For 13 patients the ESHAP protocol  was administered. A minimum harvest of 5 × 10n=21) received high-dose therapy according to the BEAM protocol . On day 0 autologous stem cells were transfused.Myeloablative radiochemotherapy consisted of fractionated TBI 2 × 2 Gy/d on days –6 to –4 for a total dose of 12 Gy, followed by high-dose cyclophosphamide (60 mg/kg body weight) on days –3 and –2 in 54 patients. As published studies suggest that TBI is not mandatory to give optimal results in T NHL patients, the more recent patients  responded to the initial CHOP therapy. Sixty-nine of them (62%) achieved a CR, 22 patients (20%) a PR. Twenty patients (18%) failed to achieve a remission and thus were treated off study. The course of treatment of the 111 patients is summarized in n=5), fatal toxicity (n=2) and withdrawal of consent (n=2). Thus, two-thirds (68%) of the intention-to-treat population completed the entire study protocol.Of the 91 responders to initial chemotherapy, 84 patients started stem cell mobilizing therapy. Seven patients were not mobilized because of early relapse or withdrawal of consent. Despite successful mobilization of a sufficient number of stem cells using either method, only 75 of the 84 patients undergoing mobilization therapy proceeded to high-dose therapy and autoSCT. The reasons for not undergoing autoSCT were disease progression after initial response (n=54) received myeloablative radiochemotherapy with 12 Gy total body irradiation followed by 120 mg/kg cyclophosphamide, the remaining 21 patients received high-dose chemotherapy according to the BEAM protocol. Before high-dose therapy and autoSCT, 63 of these 75 patients (84%) were in CR and 12 patients (16%) in PR; after the autoSCT procedure two more patients, that is, 65 patients (87%), achieved a CR.The majority of patients .At a median follow-up time of 59 months (range 1 to 107 months), 58 patients (52%) were still alive, and 43 of them (39%) were in continuous remission. In addition, 15 of them (14%) were alive with disease. Treatment-related morbidity according to the WHO criteria in this study was comparable with other high-dose studies and did not significantly differ from the earlier reported initial evaluation. Overall four patients died from treatment-related infectious complications, resulting in a TRM rate of 3.6%.P<0,02).In contrast to the results of the International T-cell Lymphoma Project, univariate analysis regarding the impact of histologic subtype on OS did not reveal a significant correlation as was the case regarding age, stage, B symptoms and elevated lactate dehydrogenase. This might be caused by the fact that the proportion of patients with limited disease and without the mentioned risk factors was relatively small. In contrast, univariate but not multivariate analyses revealed that there was a significant correlation between age-adjusted international prognostic index low/low intermediate vs high/high-intermediate and longer OS ; P<0,02.7 Also owing to their low incidence and their considerable heterogeneity, a standard therapy has not yet been defined.19 With regard to intensive chemotherapy followed by upfront autoSCT, five phase II studies have been reported. , Mercadal et al. (n=41) and Corradini et al. (n=43) are hampered by relatively small sample size, our own study first published in 2009 had a relatively short follow-up of 33 months.15 The trial recently reported by d'Amore et al.12comprised a relatively large number of patients (n=160), whereas the prospective phase II trial published by Corradini et al. had the longest follow-up of 76 months.13 Taken together, we believe that all studies added substantial evidence that intensive chemotherapy followed by autoSCT is a valid strategy of first-line therapy in patients with PTCL. However, we still felt it difficult to define upfront autoSCT as standard therapy in PTCL and therefore decided to extend the observation time and treat more patients according to the protocol of our previous study. Here we present the final analysis of 111 patients treated, with a median follow-up of 59 months.PTCL represent an aggressive disease with a mostly dismal prognosis after conventional chemotherapy.6Several aspects of our study are important when comparing the results with the other trials investigating the role auf autoSCT for evaluation of treatment standards. All five PTCL trials are prospective phase II trials  avoiding20 Central revision also was an inclusion criterion in the studies by d'Amore, Mercadal and Rodriguez.Before inclusion in our study, reference pathology was mandatory as it is known that the accurate diagnosis of PTCL can be challenging with a relatively low likelihood of a concordant final diagnosis at a referring institution.4 Therefore, entities with the best prognosis after conventional chemotherapy (ALK-positive ALCL and PCTL) usually have not been included in trials investigating the role of autoSCT as part of first-line therapy except that published by Corradini et al. . However, with exception of ALK-positive ALCL in the Corradini trial and ALK-negative ALCL in the d'Amore trial, subgroup analysis in the other studies including our own (data not shown) did not reveal significant outcome differences according to the most frequent subentities. This discrepancy might be explained by the low number of patients in the relevant subgroups compared with the International T-cell Lymphoma Project or the ‘equalizing' effect of autoSCT.The International T-cell Lymphoma Project has shown differences in survival according to histology, with 5-year OS ranges from 90% for PCTL to 7% for hepatosplenic PTCL.et al. used the CHOEP-14 regimen in patients age <60 years.12 Corradini et al., Mercadal et al. and Rodriguez et al. used different induction chemotherapies.15 The debate about the best induction therapy will continue, as neither the more aggressive drug combinations nor the CHOP protocol, with or without etoposide, were able to prevent early progression in 16–41% of the PTCL patients. The retrospective analysis published by Schmitz et al. on 343 patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) showed an improvement of the 3-year event-free survival when etoposide had been added to the CHOP protocol, but preferentially in the ALK-positive ALCL group and in patients younger than 60 years and with normal lactate dehydrogenase levels, that is, in a more favorable subgroup.21 Similar results for younger patients have been reported by Ellin et al.3 Likewise, the role of monoclonal antibodies like alemtuzumab remains unclear, as any additional effect on response is hampered by considerable toxicity, especially life-threatening opportunistic infections.22 Taken together, although CHOP may not be the ideal protocol for inducing remission in PTCL, a truly better regimen has not yet been defined.Conventional chemotherapy consisted of four to six cycles of the CHOP regimen in all patients in our trial, whereas d'Amore There is also a lack of standards regarding the optimal mobilization therapy and/or high-dose protocol before transplantation. Although all reported mobilization therapies proved effective in yielding a sufficient stem cell harvest, their value for increasing CR rates is questionable. The same holds true for the different high-dose chemotherapy and/or radiochemotherapy protocols, which only moderately contributed to the augmentation of CR rates, but obviously are of utmost importance for achieving long-term remissions .This update of the trial published in 2009, reporting more patients with a longer follow-up, confirms the early study results. The survival curves did not much deteriorate over time and the survival plateaus indicate that long-term survival can be achieved after high-dose therapy/ autoSCT in a substantial fraction of patients able to proceed to it. Only few deaths occurred beyond 50 months post transplant . An inteHowever, it is difficult to identify at diagnosis those patients who will have the greatest benefit from upfront autoSCT. In an univariate analysis, IPI defines risk groups in Corradini, d̀Amore, and Mercadal̀s trials, as well as in our patient group. Nevertheless, different risk groups according to IPI should not alter the therapeutic strategy, as even IPI low patients have a disappointing treatment outcome.27 Corradini et al.28 conducted a prospective trial using reduced-intensity conditioning. Owing to the high response rate and low transplantation-related mortality of this trial, alloSCT was considered a promising approach in PTCL for younger patients. In the meantime, a prospective, randomized, European multicenter trial has been performed  to determine the role of upfront alloSCT in PTCL. Unfortunately, this study was stopped prematurely after an interim analysis had shown that the primary end point, that is, improvement of EFS by alloSCT, could not be met with the patient numbers planned to be enrolled.29 Thus, at present, there is no evidence that alloSCT is superior to CHO(E)P chemotherapy plus upfront autoSCT in first-line therapy of most PTCL. However, for extremely aggressive subtypes, such as hepatosplenic lymphoma or adult T-cell leukemia/lymphoma (ATLL), upfront alloSCT might be an option, as graft-versus-leukemia activity can result in long-term survival in a significant proportion of patients.32Is allogeneic stem cell transplantation  able to improve results?34 Romidepsin, belinostat and pralatrexate yield remarkable responses in relapsed patients.39 Once the phase III trials with these drugs are finished, we will know whether these or other new drugs will improve response rates, allowing more patients to achieve the possibility of undergoing autoSCT.40The major challenge for the future is to increase response rates and bring more patients to transplantation. Many new drugs are being investigated. Brentuximab vedotin and crizotinib appear to be promising agents in subentities of PTCL.5 However, PFS remains disappointing ranging from 30 to 50%. Nevertheless, this treatment strategy likely improves the outcome for PTCL patients compared with conventional chemotherapy.In conclusion, based on available data, upfront autoSCT should be recommended as a rational choice for patients with the nodal subtypes PTCL-NOS, AITL, ALK-negative ALCL, as well as high-risk ALK-positive ALCL eligible for high-dose chemotherapy.


Evidence has shown that people living with nonpsychotic mental disorders experience difficulties in maintaining their daily living, consequently impacting on psychological well-being. However, the role of daily life experience remains unclear. This systematic review and meta-analysis aims to determine the association between daily life experience and psychological well-being in people living with nonpsychotic mental disorders, and evaluate daily life experience as a moderator of psychological well-being in this population.Literature search will be performed using a combination of title/abstract words and subject headings on 7 electronic databases according to predefined inclusion and exclusion criteria. Data will be extracted by 4 independent reviewers . Disagreement will be resolved by discussion with senior reviewers. Observational studies involving subjects with unipolar depression, bipolar disorder, anxiety disorder, acute stress disorder, as post-traumatic stress disorder as distinct groups with quantitative measurement of daily life experience and psychological well-being will be included.I2 index. This review is registered in PROSPERO.Effect sizes will be pooled by random effects model. The quality of the studies will be assessed using Newcastle–Ottawa scale. Heterogeneity between studies will be quantified using While symptoms and existing treatments of nonpsychotic mental disorders could be long term and dependent upon medical regimens, sustaining daily life experience will be a potentially important and concrete pathway that empowers patients to recover from the disorders, maintain or enhance psychological well-being, and be reintegrated into society. Findings of this review will inform prospective interventional trials of enhancing daily life experience in prevention of recurrence and enhancing psychological well-being in people living with nonpsychotic mental disorders. Of these, bipolar disorders and unipolar depressive disorders account for 295 and 1500 per 100,000 population worldwide, respectively. Notably, the burden of these affective disorders ranked first for bipolar  and second for unipolar depressive disorders  in Western Pacific Region. The burden of depressive disorders ranked top in Southeast Asia, with 410 per 100,000) are living with this disease. These collectively led to 24.3 millions of YLD  in male and 41.0 millions  in female globally, representing the top cause of YLD of all human diseases. Nevertheless, this analysis of YLD did not take into account of quality of life, and psychological well-being of individuals other than loss of health. In general, psychological well-being refers to a state of life satisfaction, life engagement, and positive self-recognition.Nonpsychotic mental disorders are associated with significant morbidity and burden of the society. These encompass unipolar depression, bipolar disorder, anxiety disorder, acute stress disorder, and post-traumatic stress disorder (PTSD).–7 A community-based survey revealed that people living with nonpsychotic mental disorders were more likely to report stress  and poorly perceived mental health status (OR = 25.6. 95% CI 14.7–45.0). More clarity is nonetheless needed in conceptualizing and assessing everyday life processes in affective disorders and PTSD. Daily stressors could be either caused or worsened by traumatic experiences or affective symptoms. In addition, previous studies assessed and aggregated a wide variety of daily stressors including activities or behaviors , social partners , relationships , thoughts and feelings , generic conditions , or even objects . Some of these “daily stressors” are indeed ordinary daily life experiences, stress-impacted daily life experiences, or obstacles to sustaining them. In-depth investigation on mental health could be limited without teasing apart variations in the impacts of different everyday life processes that contextualize adaptation.,10Evidence has shown that people living with nonpsychotic mental disorders are prone to daily life stress, consequently impacting on psychological well-being.However, the role of daily life experience remains unclear. This systematic review and meta-analysis aims to determine the association between daily life experience and psychological well-being in people living with affective disorder, and evaluate daily life experience as a moderator of psychological well-being in people living with affective disorder.22.1 This protocol is registered in PROSPERO, an international prospective register of systematic reviews at the National Institute for Health Research and the Center for Reviews and Dissemination (CRD) at the University of York. This review protocol is reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) 2015 checklist.We will conduct literature search on electronic databases including PubMed, (MEDLINE), PsycINFO, Cumulative index to nursing and allied health literature (CINAHL), Scopus, Web of Science, and Excerpta medica DataBase (EMBASE). Relevant articles will be identified using Medical Subject Heading (MeSH) or title/abstract keywords from inception to August 2018 without language restriction. The search terms comprise keywords related to: (1) affective disorders, (2) acute stress and post-traumatic stress disorders, (3) anxiety disorders, (4) psychological well-being, and (5) daily life experience. Details of the search strategies have been summarized in Table 2.2Observational studies with quantitative measurement of daily life experience and psychological well-being in people living with nonpsychotic mental disorders will be included. Study participants with bipolar disorders, dysthymia, major depressive disorders, manic-depression, anxiety disorder, acute and post-traumatic stress disorders should be identified as distinct groups. The diagnosis of nonpsychotic mental disorders should have been confirmed by the following well-established diagnostic criteria: Diagnostic and statistical manual of mental disorders (DSM) 4th edition or International Statistical Classification of Diseases (ICD) and related health problems version 9 or 10. Studies on participants with self-reported mental disorders or without defined participants will be excluded. Qualitative inquiries, interventional studies, and nonoriginal articles are not eligible. The details of the inclusion and exclusion criteria for this systematic review are summarized in Table 2.3 The SIP comprises 7 modules, which evaluates psychological impact, physical impact, sleep, eating, home management, work, and recreation. Psychological well-being can be measured by World Health Organization Well-being Index and Ryff's scale that quantify the aspects of psychiatric symptoms, self-esteem, and life-satisfaction. Studies using other validated instruments that allow objective quantification of the exposure and outcome will also be included in final qualitative synthesis and meta-analysis.Exposures and outcomes are daily life experience and psychological well-being, respectively. Daily life experience can be quantified by validated instruments or their subscales such as hedonic well-being assessment and sickness impact profile (SIP) questionnaire.2.4 This assesses subject selection, comparability, and quality of assessment of daily life experience and psychological well-being. Two independent reviewers will rate the studies according to this scale. Inter-rater reliability will be compared using intraclass correlations coefficient (ICC).Quality of the studies will be appraised by the nine-star system of Newcastle–Ottawa scale for nonrandomized observational studies.2.5Studies will be grouped according to distinct mental disorders of the participants.z transformation will be applied on effect sizes measured as correlation coefficients, weighting by sample size. The weighted average Fisher's z will be back transformed to a mean correlation coefficient. Inter-study heterogeneity will be determined using Cochran's Q statistics and quantified by I2 statistics as small, medium, and high degree based on I2 index of < 25%, >50%, and >75%, respectively. For I2 more than 50% and P < .10 by Cochran's chi-square test, a random effect model will be used to estimate effect sizes in 95% confidence interval. For I2 less than 50%, a fixed effect model will be employed. The presence of heterogeneity will be further investigated by subgroup analyses and meta-regression as appropriate. Sensitivity analyses will be performed according to the quality of studies. Publication bias will be evaluated by Begg's funnel plot and Egger's test, and corrected by Duval–Tweedie trim-and-fill method. All analyses will be performed using Open Meta-Analyst software, an open access and freely available software developed by the US National Centre for Research Resources and Agency for Healthcare Research and Quality.Summary of effect sizes will be presented as odds ratios (OR), standardized mean difference (SMD) in 95% confidence interval as appropriate. Fisher's 3While stress is unavoidable, sustaining daily life experience may be possible. This will be the first systematic review to demonstrate the association between daily life experience and positive psychological well-being in people living with nonpsychotic mental disorders. Findings of this review will inform prospective interventional trials of enhancing daily life experience in prevention of recurrence and promoting psychological well-being in this population.