Background: As time evolved, traditional Chinese medicine (TCM) became integrated into the global medical system as complementary treatments. Some essential TCM herbs started to play a limited role in clinical practices because of Western medication development. For example, Fuzi  is a toxic but indispensable TCM herb. Fuzi was mainly used in poor circulation and life-threatening conditions by history records. However, with various Western medication options for treating critical conditions currently, how is Fuzi used clinically and its indications in modern TCM are unclear. This study aimed to evaluate Fuzi and Fuzi-based formulas in modern clinical practices using artificial intelligence and data mining methods.Methods: This nationwide descriptive study with market basket analysis used a cohort selected from the Taiwan National Health Insurance database that contained one million national representatives between 2003 and 2010 used for our analysis. Descriptive statistics were performed to demonstrate the modern clinical indications of Fuzi. Market basket analysis was calculated by the Apriori algorithm to discover the association rules between Fuzi and other TCM herbs.Results: A total of 104,281 patients using 405,837 prescriptions of Fuzi and Fuzi-based formulas were identified. TCM doctors were found to use Fuzi in pulmonary (21.5%), gastrointestinal (17.3%), and rheumatologic (11.0%) diseases, but not commonly in cardiovascular diseases (7.4%). Long-term users of Fuzi and Fuzi-based formulas often had the following comorbidities diagnosed by Western doctors: osteoarthritis (31.0%), peptic ulcers (29.5%), hypertension (19.9%), and COPD (19.7%). Patients also used concurrent medications such as H2-receptor antagonists, nonsteroidal anti-inflammatory drugs, β-blockers, calcium channel blockers, and aspirin. Through market basket analysis, for the first time, we noticed many practical Fuzi-related herbal pairs such as Fuzi–Hsihsin (Asari Radix et Rhizoma)–Dahuang (Rhei Radix et Rhizoma) for neurologic diseases and headache.Conclusion: For the first time, big data analysis was applied to uncover the modern clinical indications of Fuzi in addition to traditional use. We provided necessary evidence on the scientific use of Fuzi in current TCM practices, and the Fuzi-related herbal pairs discovered in this study are helpful to the development of new botanical drugs. Traditional and complementary medicine (T&CM) has played an increasingly significant role in the global medical system. The World Health Organization (WHO) started to facilitate the integration of T&CM into national health systems in member states, produced guidelines for T&CM complying with international standards, stimulated strategic research into T&CM, and advocated the rational use of T&CM through clinical evidence . TraditiFor example, Fuzi  has been widely used in TCM for more than 2000 years . In TCM,Fuzi was also used in Ayurvedic and Kampo medicine to treat several clinical conditions such as neuralgia, polyuria, poor circulation, heart failure (HF), and even impotence . In JapaAlthough the therapeutic effect of Fuzi and Fuzi-based formula are widely recognized among TCM doctors and therapists, the toxicity of Fuzi has always been the main concern for their applications and further promotion . The majIn Taiwan, TCM has been formally adopted into the Taiwan National Health Insurance (NHI) system since 1996 , and theAnalyzing the Taiwan NHI database, previous epidemiologic TCM studies have successfully observed the effectiveness and adverse effects of TCM formulas on a specific single disease . At presThis retrospective cohort study using a longitudinal cohort of Taiwan NHI database comprises a randomly sampled representative database of one million people from all NHI enrollees alive in 2000 . The sinWe searched for prescriptions of Fuzi and Fuzi-based formulas from outpatient medical claims with the specific drug codes in the cohort between January 2003 and December 2010 . There wFirst, the prescription numbers of Fuzi and Fuzi-based formulas and their growth rate were estimated. In Taiwan, only Western medicine doctor can prescribe Western medications. Similarly, only TCM doctors can prescribe TCM drugs. To specify the primary diagnosis documented by the TCM doctors prescribing Fuzi, we grouped the primary ICD-9-CM diagnosis as diagnostic categories for analysis . The diaSecond, the third quartile patients who experienced higher prescription numbers or prescription duration were defined as the long-term users of Fuzi or Fuzi-based formulas. To identify long-term users' underlying comorbidities diagnosed by Western medicine doctors, we analyzed the selected corresponding ICD-9-CM codes in outpatient medical claims before the prescription date of Fuzi or Fuzi-based formulas . The medFinally, the common Western medications were evaluated, including aspirin, clopidogrel, lipid-lowering agents , xanthine oxidase inhibitors, uricosuric agents, colchicine, β-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARBs), H2-receptor antagonists, proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, sulfonylurea, insulin, COPD inhalants, thyroxine, and α-adrenoreceptor antagonists . To idenMarket basket analysis, a data mining technique introduced by Agrawal et al., is frequently used to discover the rules of association between sets of items in large databases . In our The association rules derived from market basket analysis were demonstrated in the following three measures: support, confidence, and lift . 1) The Demographic statistics were demonstrated as means ± standard deviation, median, interquartile, or number (percentages). SAS version 9.4  was used for data collection, and statistical analyses. Market basket analysis was calculated by the Apriori algorithm using Python version 3.7.A total of 104,281 patients using 405,837 prescriptions of Fuzi and Fuzi-based formulas were identified between January 2003 and December 2010. Among the users, 11.7% were older adults (≥65 years old), 9.5% were children or adolescents (≤18 years old). The mean age of the users was 41.2 ± 18.0 years. The users received 1.4 ± 0.7 types of Fuzi prescriptions during the evaluation period, and the average prescription number in each patient was 3.9 ± 7.2 . The average duration of the prescriptions was 304.3 ± 589.0 days . The number of long-term users (number of prescriptions >4) was 28,978 patients, including 12.5% older adults and 8.3% of children or adolescents.The total prescriptions of Fuzi and Fuzi-based formulas increased annually, from 28,578 prescriptions in 2003 to 75,058 prescriptions in 2010 . Among tOf the total number of prescriptions, Fuzi and Fuzi-based formulas were commonly used in clinical conditions including pulmonary (21.5%), gastrointestinal (17.3%), rheumatologic (11.0%), neurologic (10.1%), and gynecologic (8.7%) diseases . Of surpFrom the viewpoint of Western medicine, the most frequent comorbidities of long-term Fuzi or Fuzi-based formulas users were osteoarthritis (31.0%), gastric or peptic ulcers (29.5%), hypertension (19.9%), COPD (19.7%), hyperlipidemia (16.4%), and chronic liver diseases (16.3%) . The useFuzi may be combined with other TCM herbs according to the knowledge and experience of the TCM doctors. We analyzed the co-prescription TCM single herbs with Fuzi. Of total Fuzi prescriptions, the top 10 Fuzi-related herbal pairs were Fuzi–Dahuang (Rhei Radix et Rhizoma) (16.5%), Fuzi–Hsihsin (Asari Radix et Rhizoma) (15.9%), Fuzi–Ganjiang (Zingiberis Rhizoma) (15.5%), Fuzi–Fuling (Poria) (13.8%), Fuzi–Baizhu  (10.3%), Fuzi–Quizhi (Cinnamomi Ramulus) (10.1%), Fuzi–Huangqi  (9.0%), Fuzi–Banxia (Pinelliae Rhizoma) (8.3%), Fuzi–Rouqui (Cinnamomi Cortex) (8.0%), and Fuzi-Gancao (Glycyrrhizae Radix et Rhizoma) (7.1%)  in neurologic diseases . The assFor gastrointestinal diseases, Dahuang, Hsihsin, Fuling, and Banxia were four herbs common in two combinations , and eveTseng and Chang proposed that new correlations of TCM herbs could be established by big data analysis, which could trigger further studies from bench to bedside and bring more innovation into clinical practices . For theContradictory to previous reports tand knowledge, this study showed that the prescriptions of Fuzi were not limited to cardiovascular and rheumatologic diseases, which were emphasized in ancient TCM books. Interestingly, the use of Fuzi in pulmonary, gastrointestinal, and neurologic diseases was more recommended in modern TCM doctors . Our resAfter TCM was integrated into the Western medical system, the combined use of medicine has become an important issue. Understanding the patients’ comorbidities diagnosed by Western doctors also helps TCM doctors to evaluate and prescribe suitable TCM formulas more comprehensively. From this perspective, TCM doctors should be concerned about possible synergic effects and drug–drug interaction while prescribing Fuzi. Our result provided such practical information; for example, long-term Fuzi users frequently suffered from osteoarthritis, peptic ulcers, hypertension, and COPD with the use of NSAIDs, antacids, anti-hypertensive drugs, and COPD inhalants . From anMarket basket analysis was mostly applied to identify concurrent-drug patterns and food consumption. We are first to demonstrate the practicality of market basket analysis in evaluating TCM herbal pairs of more than two drugs. The association rules derived from the market basket analysis lifted the veil of the combination strategies in TCM.We proposed with scientific data that Fuzi–Dahuang–Hsihsin herbal pair was useful in headache, neurological, and gastrointestinal diseases . In a TCWe also founded that Fuzi–Fuling pair was prescribed in many conditions . Fuling The current study discovered some innovative Fuzi-related herbal pairs in specific clinical conditions, which were unknown to most Western researchers. This information, which was extracted from the big database, overcame the knowledge gap in the Western researchers’ minds about using TCM herbs. We not only ignited scientific TCM issues but also proposed issues that need further scientific evidence.For example, Suanzaoren (Ziziphi Spinosae Semen), which was well known to regulate the central nervous system, improve memory function, depression, and sleep , was fouFuzi in combination with Yanhusuo , Chuan-niuxi (Cyathulae Radix), Niuxi (Achyranthis Bidentatae Radix), or Duzhong (Eucommiae Cortex) were frequently prescribed for rheumatologic diseases . Among tThe major strength of this study is that it is the first time to evaluate the modern clinical use of Fuzi and Fuzi-based formulas using a large population-based cohort with AI or data mining techniques such as market basket analysis. However, the study results also had some limitations. First, some of the medical records of patients who took TCM decoction but not commercial TCM granular powders were not documented in the Taiwan NHI database. That was because NHI did not pay for TCM decoction in the current TCM system, and patients must pay for themselves. Therefore, the prevalence of Fuzi use might be underestimated. Second, although the Fuzi commercial products were mostly manufactured according to herbal pharmacopeia, the dosage of each commercial powder prescribed by TCM doctors was not standardized and documented in the Taiwan NHI database. Third, we only evaluated the numbers of prescriptions, the prevalence of comorbidities, and concurrent Western medications. The dose-response relationship could not be precisely evaluated. Finally, we evaluated the TCM pairs only with the support values above 5% in the market basket analysis. There might be some interesting TCM pairs with a low prevalence rate that were not discovered.The current study is the first to demonstrate the usefulness of market basket analysis in evaluating the combination principle of TCM herbs. We provide epidemiologic evidence on the clinical applications of Fuzi and Fuzi-based formulas in the healthcare system dominated by Western medicine. Our study also supports the traditional usage of Fuzi-based formulas and inspires future pharmacological, observational, and clinical studies of Fuzi-related herbal pairs. In sum, the results light up the road to the development of new Fuzi-based botanic drugs.


Heroin and cocaine are among the most dangerous illicit drugs available and their presence on the market is increasing. These facts have led to the investigation of the quality of heroin and cocaine samples seized in Luxembourg by police and customs but also collected at the national supervised drug consumption facilities.t test.Samples obtained from 2019 to 2020 were analyzed to determine their composition and content using GC–MS, HPLC-UV and LC-Q-ToF. The statistical evaluation of concentration changes depending on the source of collection is based on an ANOVA single factor test and a two-tailed Results showed important differences between seizure and collection sources. For both drugs, customs samples had significantly higher concentrations than police samples and the latter had significantly higher concentrations than samples from drug consumption facilities, whereas for heroin two cutting steps were identified, for cocaine samples only one appears to occur on the local market. Indeed, cocaine samples seized by police consisted of a mixture of low and high concentration samples.The results show that extensive adulteration with pharmacological active and inactive compounds takes place at local levels, which, however, are different for heroin and cocaine. This knowledge on variability of quality of drugs should be considered in the elaboration of drug and harm prevention strategies. In Europe, cocaine and heroin are considered being among the most dangerous psychoactive drugs sold on the illegal market when considering overall harm, that is to say physical, psychological and social effects to users and to others . FurtherCocaine is extracted from coca plant leaves. Extracts are most often cut with adulterants  and diluents  . AdulterHeroin is an opium extract consisting of diacetylated morphine, commonly adulterated with paracetamol and caffeine. In Western Europe, it is predominantly sold in the base form as brown/grey powder . Black tCollection of data on drug quality mainly relies on the analysis of illicit products seized by customs (CUS) and police (POL). The determination of composition and quality of illegal heroin and cocaine is routinely performed by the National Laboratory of Health. Toxicological evidences are used for law enforcement, for criminal justice ruling but also for the drafting of national drug policies, intervention strategies and awareness campaigns. Thus, the national ministry of health is collecting data notably in the framework of its early warning system on controlled drugs and emerging drug use patterns. This enables decision making and actions to be implemented in case of new or unforeseen developments such as the detection of new or unsuspected adulterants or new psychoactive substances with potentially increased risks for health.Several projects have been implemented nationally to increase data collection on the use of heroin and cocaine. These include a collaboration with national drug consumption rooms (DCR) to collect samples from their clients (± 200 per day). In return for providing a small amount of their substance, drug consumers obtain feedback on its quality.In this paper, an investigation on heroin and cocaine quality, according to the source of sample collection is presented. The study includes samples from 2019 to 2020 collected by customs and police or obtained from DCR clients during the same period.The goal was to assess drug quality on the local markets, to investigate quality differences according to various sample collection sources and thus, to provide reliable information for political decision makers and evidence-based drug policies.n) in a seizure was < 10 all of them were analyzed. If n was between 11 and 100 in a seizure, only 10 samples were analyzed. In the great majority of cases n was < 10, no seizures with more than 30 samples have been collected. Drug samples from heroin and cocaine users at DCRs were collected by social health care workers. These collected samples were analyzed using LC-Q-ToF to determine drug composition and content.Seized drug samples were received from customs and police for routine screening. Qualitative analyses were realized using GC–MS technique. X-ray fluorescence analyses and quantification of targeted drugs and adulterants by HPLC-UV were performed on a limited number of samples, representative of the seizure, as suggested by UNODC  and SWGDHeroin (diacetylmorphine), paracetamol (acetaminophen), caffeine, cocaine, phenacetin, levamisole hydrochloride, lidocaine, all at 1 mg/mL were obtained from either Cerilliant , LGC Standards  or Lipomed . HPLC water, acetonitrile and methanol for HPLC-UV analyses were purchased from Biosolve . For LC-Q-ToF analyses, UPLC water with 0.1% formic acid (solvent A), UPLC acetonitrile with 0.1% formic acid and UPLC methanol with 0.1% formic acid were purchased from Fisher Chemical .Acetic anhydride was obtained from VWR . Pyridine was bought from Sigma-Aldrich . Potassium dihydrogen phosphate and ethyl acetate were provided by Chem-Lab .v/v) mixture of A and B (solvent C) was used to dilute samples prior to injection. HPLC eluents for cocaine quantification by HPLC-UV consisted of aqueous buffer adjusted to pH 2.18 using 20 mM potassium dihydrogen phosphate (solvent A) and acetonitrile (solvent C). A 92/8 (v/v) mixture of A and B (solvent D) was used to dissolve and dilute samples prior to injection. LC eluents for LC-Q-ToF analyses were UPLC grade water with 0.1% formic acid (solvent E) and UPLC grade acetonitrile with 0.1% formic acid (solvent F).HPLC eluents for heroin quantification by HPLC-UV consisted of aqueous buffer adjusted to pH 2.18 using 20 mM potassium dihydrogen phosphate (solvent A) and methanol (solvent B). A 9/1 (v/v). A volume of 1 µL was injected into the GC–MS system for analysis using splitless mode.About 10 mg of the sample was acetylated using 50 µL of pyridine plus 50 µL of acetic anhydride for 15 min at 80 °C. The mixture was evaporated to dryness using a gentle stream of nitrogen at 40 °C. The residue was dissolved in ethyl acetate/methanol  equipped with an HP-Ultra2 column (12 m × 0.33 µm) coupled to a 5977B mass selective detector. The front inlet temperature was 260 °C. Chromatographic separation was achieved by varying the oven temperature from 70 to 280 °C at a rate of 20 °C/min. The final temperature was held for 11.5 min. Total run time per sample was 24 min. Helium was used as carrier gas at a flow rate of 1.1 mL/min and the solvent delay was 4 min. Mass selective screening was from Identification was performed using retention time and against MS databases . IdentifAbout 50 to 100 mg of each sample was analyzed on an ARL QUANT’X EDXRF spectrometer  to search for the presence of chlorine, as indicator for the presence of cocaine or heroin in the hydrochloride form.About 10 mg of each sample was weighted exactly and dissolved in 10 mL of methanol using an ultrasonic bath for 5 min. The solution was diluted per 100 in solvent C and 10 µL of this solution was injected into the HPLC-UV system.LC separation was achieved on an Ultimate 3000 system  equipped with a Dionex Acclaim RSLC PolarAdvantage II column (100 mm × 2.1 mm × 2.2 µm). The oven temperature was set up at 50 °C. The separation was obtained using a gradient of B from 12 to 20% in 1.45 min, 28% at 2.69 min, 58% at 4 min with a flow rate of 0.7 mL/min. UV DAD was monitored from 208 to 375 nm, quantification wavelength was 208 nm. A 5-point calibration curve was established by injecting 1, 2.5, 5, 7.5 and 10 µL of a heroin, paracetamol and caffeine mixture containing 10 µg/mL of each compound.r2 ≥ 0.99, signal to noise ratio ≥ 10 and retention time for heroin at 2.81 min ± 0.5 min. Identification and quantification criteria for each compound were: peak match ≥ 950 compared to a reference spectrum, relative standard deviation of peak purity index ≤ 3%, signal to noise ratio ≥ 10.Calibration acceptance criteria for each compound were: Preparation of cocaine samples was the same as for heroin except that the final dilution occurred in solvent D.LC separation was achieved on the same HPLC/UV system using the same column as for heroin. The oven temperature was set up at 50 °C. The separation was obtained using a gradient of C from 8 to 10% in 1.2 min, 23% at 1.5 min, 32% at 1.9 min, 50% at 3.9 min with a flow rate of 0.7 mL/min. UV DAD was monitored from 206 to 375 nm, quantification wavelength was 235 nm. A 5-point calibration curve was established by injecting 1, 2.5, 5, 7.5 and 10 µL of a mixture containing 10 µg/mL cocaine and adulterants such as levamisole, phenacetin, ketamine and others when considered necessary.Calibration acceptance criteria and identification plus quantification criteria were identical to heroin samples’ analyses. For cocaine, retention time was 2.58 min ± 0.5 min.v/v)). Samples were analyzed on a G6550A ifunnel Q-ToF LC–MS system  equipped with a 1290 Infinity HPLC system. The separation was performed onto an Acquity UPLC BEH C18 column  by using a gradient of solvents E and F. The LC and Q-ToF operating conditions have been described in detail in Dahm et al. [About 10 to 25 mg of each DCR sample was weighted exactly and dissolved in 1 mL of methanol using an ultrasonic bath for 5 min. The solution was diluted per 10,000 in a solvent mixture E/F 9/1, /1, v/v).α = 0.05) and a two-tailed t test (p < 0.05). All concentrations presented in this article are expressed in percentage weight/weight.The evaluation of concentration changes depending on the source of collection  is based on two statistical approaches: an ANOVA single factor test  were not included in this study.A total of 659 heroin and 1078 cocaine samples have been analyzed. A summary of sample origins, CUS, POL or DCR, is given in Table After identification of heroin by GC–MS, a FRX analysis was carried out to check for the presence of chlorine and other elements. Only the heroin base was detected. Nearly all heroin samples (99.5%) contained paracetamol  and caffeine (stimulant). No other cutting agents were detected in any samples analyzed . The addition of caffeine may be helpful for heroin to vaporize at lower temperature thus giving a faster rush when smoked and to counterbalance the sedative effects of heroin. Paracetamol may be added because of its analgesic properties and its bitter taste which can disguise poor quality heroin.The overall heroin concentrations varied from 0.1 to 55.6%. Mean, median and minimum heroin concentrations were highest in CUS samples, followed by POL and DCR samples. In DCR samples 2.7% were of very low quality (heroin < 1%) and 20.7% were of low quality (heroin 1–5%). In the POL seizures 10.3% of the samples had a heroin concentration < 5% and in the CUS seizures no sample contained less than 5% heroin. The heroin, paracetamol and caffeine concentrations are presented in Fig. α = 0.05) and by a two-tailed t test (p < 0.05 between pairs).On average, heroin concentrations in CUS samples were 168% and 235% higher than in POL and DCR samples, respectively. The significant difference was confirmed by an ANOVA single factor test  to POL (78.8%) and decreased from POL to DCR (64.7%) Fig. . These fOnly heroin samples seized by CUS showed similar concentrations than the ones reported for the European market by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) for 2018 [As for heroin, a GC–MS analysis was performed to identify psychoactive or pharmacologically active drugs, adulterants and diluents. A FRX analysis showed that only cocaine chlorhydrate was available on the local market.Main adulterants identified were levamisole , phenacetin  and caffeine . Minor adulterants (< 2% samples) detected were lidocaine, ketamine, hydroxyzine. As only few CUS and DCR samples contained adulterants above the lower limit of quantification no statistical interpretation on adulterants was carried out.There is much speculation about the rational of adding prohibited and withdrawn pharmacologically active substances to cocaine and no undisputed explanation has emerged so far. Possibly, lidocaine is added because some of its effects resemble those of cocaine  and caffeine may be added, because it is a stimulant, thus enhancing the cocaine effects . DiluentCocaine samples are more heterogeneous than heroin samples. The concentration range varied from 3.4 to 100% cocaine chlorhydrate. Only one sample from POL and one sample from DCR were found to be of low quality (< 5%). A summary of the content of cocaine and its major adulterants is presented in Fig. α = 0.05) and a two-tailed t test (p < 0.05). Thus, on average, cocaine concentrations in CUS samples were 143% and 171% higher than in POL and DCR, respectively.Samples originating from CUS were in the concentration range 40.5 to 96.8% with a mean concentration of 72.6%. Samples originating from POL and DCR had mean cocaine concentrations of 50.2% and 42.1%, respectively. As for heroin samples, a significant decrease in cocaine content was found from CUS > POL > DCR, confirmed by an ANOVA single factor test  using high-quality cocaine and socially marginalized groups  consuming more cut, low-quality cocaine. To our knowledge, this has not been reported before and deserves further investigation at the European level.Unlike the heroin market where two cutting levels were observed, the cocaine market seems to be operating on a single cutting step: uncut samples found at CUS and POL or samples cut by a factor of ± 2, found at the POL and DCR. This is in concordance with two major consumer groups: ‘Analysis of adulterants detected is difficult, because many are near or below LOD/LLOQ values. Thus, a significant qualitative difference could only be detected for caffeine. It was present in 6.5% of CUS and 6.3% in POL samples but 83.1% of the DCR samples. Overall, a cutting of CUS samples using caffeine and/or carbohydrates is the most plausible explanation for the significant decrease in cocaine concentrations in DCR samples.When comparing cocaine samples from CUS, POL and DCR to EMCDDA values , as expeToxicological analysis of heroin and cocaine samples seized by customs and police or collected from end-users at drug consumption rooms was carried out in 2019 and 2020.No NPS , fentanyl or fentanyl derivatives were detected in any of the samples. For both heroin and cocaine, however, a significant decrease in concentration was observed from CUS to POL and from POL to DCR. Heroin concentrations decreased from 22.6% for CUS to 13.4% for POL and 9.6% for DCR samples. An adulteration with paracetamol and caffeine probably takes place in a first step followed by cutting with caffeine and/or non-pharmacological compounds.Cocaine concentration also decreased from 72.6% for CUS to 50.2% for POL and 42.1% for DCR samples. The digressive gradient in quality may be explained by addition of sugars and/or caffeine as they are cheap, legal and readily available. Unlike heroin, POL cocaine samples revealed two different quality batches, one with high levels of cocaine, similar to the CUS samples, and one with low-quality cocaine, similar to the one found in DCR samples.Our results show that cutting of heroin and cocaine occurs at different levels on their way to end users; presumably by a two steps’ process for heroin and in a single step for cocaine. Knowledge and surveillance of the cutting processes, adulteration practices and variability of quality and purity of street drugs should be considered in the elaboration of drug and harm prevention and law enforcement strategies. Also, more international research is needed to further assess quality and adulteration gradients along the distribution chain in controlled substances available on illicit markets in order to enrich evidenced-based drug policies.


To curb future antibiotic resistance it is important to monitor and investigate current prescription patterns of antibiotics.To examine trends in antibiotic prescription to children aged 0–6 years old and the association with socioeconomic status of municipalities in the Capital region of Denmark between 2009 and 2018.This is a register-based study combining data on antibiotic treatments from 2009 to 2018, inhabitant-data and socioeconomic municipality scores. Subjects were children aged 0–6 years, residing in the Capital Region of Denmark. The study quantifies the use of antibiotics as number of antibiotic treatments/1000 inhabitants/year (TIY), inhabitants defined as children aged 0–6. Socioeconomic status of the municipalities is evaluated by a score from 3 to 12.The average TIY of the municipalities decreased from 741.2 [95%CI 689.3–793.2] in 2009 to 348.9 [329.4–368.4] in 2018. The difference between the highest and lowest prescribing municipalities was reduced from 648.3 TIY in 2009–212.5 TIY in 2018. The average increase in TIY per unit increase in socioeconomic municipality score changed from 20.05 [7.69–31.06] in 2009 to −4.58 [-16.02–5.60] in 2018, representing a decreasing association between socioeconomic municipality score and use of antibiotic in the respective municipalities.The trend in antibiotic prescription to children aged 0–6 years old decreased substantially in all the investigated municipalities in the 10-year study period. Local differences in prescription rates declined towards a more uniform prescription pattern across municipalities and association with socioeconomic status of the municipalities was reduced. KEY MESSAGESAntibiotic prescriptions for children have been reduced by 46.3% from 2009 to 2018Local variation in antibiotic prescriptions between municipalities are becoming more uniformAn association between prescription rates and socioeconomic status was found by 2009 but declined towards disappearing by 2018Antimicrobial resistance (AMR) is one of the biggest threats to global health, and both national and international agencies have published action plans to curb the rising resistance ,2. The cA group that has been in focus for receiving unnecessary antibiotics is children of the pre-school age. As far back as 1975, it has been described that a major part of prescribed antibiotics for young children is based on indications such as upper respiratory tract infections, where antibiotics have been proven to have either limited or no effect . This agAnother aspect of antibiotic prescription patterns is that there is a considerable geographical variation both between  and withIn Denmark, the primary healthcare sector prescribes 90% of all antibiotics for human use ,19. The This study examines the trend in antibiotic prescription to children aged 0–6 years old between municipalities in the Capital Region of Denmark from 2009 to 2018 and to investigate the association between reduction of antibiotic prescriptions and socioeconomic composition of municipalities.This is a register-based study combining data on antibiotic treatments from the past ten years, inhabitant-data from Statistics Denmark and socioeconomic municipality scores by the Capital Region of Denmark. The study population comprised children aged 0–6 years, living in the Capital Region of Denmark in each calendar year of the study. The Capital Region is one of five regions in Denmark, with 1,795,868 inhabitants in 2018. The region is divided in 29 municipalities, with the largest being Copenhagen with 622,698 inhabitants and the smallest Dragoer with 14,279 inhabitants  in 2009, which decreased to 348.9 [329.4–368.4] TIY in 2018. The socioeconomic municipality score remained stable in the 10-year period, with only one municipality changing score with more than one point. Characteristics of demographics and antibiotic treatments for the 28 municipalities are shown in A general trend across municipalities of decreasing TIY during the 10-year period was observed . The munSupplementary Material S2.The municipality of Ishoej had the highest prescription rate throughout the 10-year period. In 2009 a total of 1 202.4 TIY were prescribed, in 2018 the highest rate declined to 467.9 TIY. The municipality using least antibiotics in 2009 was Alleroed with 554.1 TIY, in 2018 the lowest number of treatments was recorded in the municipality of Egedal with 255.4 TIY. Local variation is visualised in In 2009, the differences between the municipalities with the highest and lowest TIY were considerable, with a gap of 648.3 TIY between Ishoej and Alleroed. This gap decreased with two thirds during to 10-year period, to 212.5 TIY between Ishoej and Egedal.The analysis of the association between socioeconomic municipality score and use of antibiotics in the 10-year period, showed a trend of significant association at the beginning of the period that disappeared towards the end of the period . The anaThis study demonstrated that during the 10-year timespan from 2009 to 2018, there has been a considerable reduction in use of antibiotics among children aged 0–6 years. All municipalities in the Capital Region of Denmark reduced the number of antibiotic treatments by 40–60% for this age group. The difference between the highest and lowest prescription rate declined with two thirds during the 10-year period, indicating a more uniform prescription pattern between the municipalities. We found a declining association between socioeconomic municipality scores and antibiotic treatments from 2009 towards 2018, indicating a reduced association of socioeconomic status with antibiotic treatment patterns.This study contains strengths and limitations that need to be addressed. A strength of our study is the availability of high-quality data from Statistics Denmark and Danish National Prescription Database ,26. The This study focussed on redeemed prescriptions within the primary care sector; hence we have no knowledge of actual compliance. However, compliance may differ among different social classes and should be studied further.Data included in this study was based on information about antibiotic treatments on an aggregated level, therefore, we were not able to distinguish between children receiving few or several prescriptions. In addition, it was not possible to control for potential confounders on an individual level, such as gender, siblings and birth weight, which have been shown to affect the risk of infections ,27.Health profile of the Capital Region and municipalities, which is published every 2nd to 4th year [The socioeconomic municipality score was based on the report 4th year . The soc4th year ,23.The socioeconomic score was based on three parameters; income, education and employment status. In the reports from 2008 and 2017 ,23, the Various variables that may be confounder candidates for the association between socioeconomic status and infection rates, and thereby the use of antibiotics, may rather be viewed as aspects of or caused by the socioeconomic status, e.g. birth weight . If we cOur study’s observed decrease in antibiotic treatments is in line with data from national report on antibiotic use (DANMAP) .Many studies have investigated the association between variations in antibiotic use and socioeconomic factors but the findings disagree. A between-country variation on the impact of socioeconomic status of parents on antibiotic prescription patterns for children has been found . StudiesSaust et al. (2018) measured quality of antibiotic prescribing in general practice, and found overuse of antibiotics for respiratory tract infections . This fiAntibiotika eller ej’ (Antibiotics or not), addressing both medical professionals and the general population - especially parents [Different efforts have been set out to limit the use of antibiotics and thereby curb the rising AMR in Denmark. In 2007, a new 7-valent conjugated pneumococcal vaccine was introduced in the Danish Childhood Vaccination programme . In 2012 parents . We beliAccording to the National action plan on antibiotics  the goalOur study investigated the correlation between a decrease in antibiotic consumption and socioeconomic status, which to our knowledge has not been done before. Knowledge of prescription patterns and driving factors of these is important to target efforts to reduce the overuse of antibiotics. The mechanisms behind the notable change in prescription patterns found in our study are yet to be understood and further research is needed to fully understand what has led to this significant reduction in use of antibiotics. The drivers of the association between socioeconomic status and use of antibiotics are not determined and would benefit of more elaborative research. Furthermore, the trend towards a more uniform prescription pattern shows a need for a more generalised effort contrary to 10 years ago, where a focus towards the socioeconomic deprived municipalities would have been advantageous.Our study shows that the seemingly increase in antibiotic prescription to children aged 0–6 years old has turned and additionally been subject to a substantial reduction in the 10-year timespan. The local differences in prescription rates have declined towards a more uniform prescription pattern across municipalities. The association between socioeconomic status of the municipality and the prescription of antibiotics declined towards disappearing by 2018.Click here for additional data file.


Antibiotic stewardship (AS) is at the core of patient safety and prevention of antimicrobial resistance. Healthcare providers prescribe antibiotics for COVID-19 despite low rates of bacterial co-infection. Our regional hospital had antibiotic utilization (AU) rates higher than other health systems even prior to the emergence of SARS-Cov2. We analyzed the effect AS on AU during the pandemic.Total Antibiotic Utilization Rates Before and During COVID-19 Pandemicnd quarter 2019 to 1st quarter 2021. The AS team released yearly antibiogram and individual prescriber’s AU rates and performed weekly, and as needed, review of antibiotic ordering and feedback. To assist in appropriate prescribing decisions, remote educational sessions or mini-lectures and local antibiotic guidelines were developed during the pandemic period. AU rates were monitored quarterly to determine the effects of the AS interventions to prescribing practices.Total and specific AU rates were benchmarked using BD MedMined’s medication analytics system from 2nd quarter 2020, peak of AU during the pandemic. Total, vancomycin, piperacillin-tazobactam and quinolone utilization rates decreased by 19%, 41%, 38%, and 52%, respectively, at 1st quarter 2021 compared to 4th quarter 2019. Steeper decreases were noted with implementation of educational activities. Ceftriaxone use remained high and was 50% greater than comparator hospitals at 1st quarter 2021.Total and specific AU rates were higher  in our index hospital compared to other non-teaching hospitals nationally prior to the pandemic. Total antibiotic utilization increased by only 5.5% in the 2Although problematic during the COVID-19 pandemic, AS can have significant impact on provider prescribing practices and decrease total and specific antibiotic utilization rates. The use of ceftriaxone, an antibiotic commonly used for empiric bacterial coverage for community acquired pneumonia, presents as a continuing challenge.All Authors: No reported disclosures


Lessons from 3 global health programs indicate that human-centered design (HCD) holds great potential for developing more tailored, impactful, and sustainable products and services to improve health and well-being. However, to take advantage of the full benefits of HCD, global health practitioners need to intentionally design and implement programs differently from typical health programs that do not incorporate design. Reflections from 3 global health programs using human-centered design (HCD) offer 3 categories of lessons for those considering similar approaches:Planning while considering the needs of both traditional global health and HCD approachesEngaging key stakeholders to build understanding, alignment, and buy-in from the outsetApplying approaches differently from the way both designers and global health actors are accustomed to working to promote long-term program sustainability and learningIf implemented appropriately, integrating HCD into global health programming can produce a virtuous cycle between co-creation, stakeholder buy-in, and quality of outputs. The more that programs engage stakeholders in an inclusive, participatory process, the greater their continued willingness and motivation. This in turn allows for more iteration and higher quality, better-tailored outputs that are more likely to be sustainably used and scaled.To engender this virtuous cycle, programs that incorporate an HCD approach will need to be scoped differently than traditional global health programs .Because stakeholders may perceive a higher risk of failure with a new approach, proponents of HCD are faced with a substantial burden of evidence to persuade actors to consider its benefits. However, traditional global health actors should consider alternative approaches to measuring HCD’s contributions, including perceived end user value. Human-centered design (HCD) is increasingly being used as a complementary approach to traditional global health methods due to its ability to bring new ideas to entrenched problems, integrate multiple stakeholder perspectives, and bring in a strong human lens among other advantages. To reap these benefits, public health and design practitioners in global health programs can learn from the early experiences of integrating HCD to advance these efforts.This article distills lessons gathered from 3 programs leveraging HCD to advance global health programming: (1) the “V” program which used an HCD approach to reframe the once-a-day HIV prevention pill from a potentially stigmatizing medicine into empowering self-care; (2) the Adolescents 360 program which integrated HCD to create a service for adolescent girls to access contraception in Ethiopia and to scale this offering nationwide; and (3) Reimagining TA which used HCD to help shift perceptions around traditional technical assistance models to one of co-creation, defining a new approach for non-financial support for health systems strengthening.To inform global health programs that are considering employing an HCD approach, lessons learned are distilled into 3 categories: (1) planning: considerations for problem definition and project scoping to allow for flexibility and selection of appropriate methods; (2) engaging: reflections on the means to productively engage different stakeholder groups to build alignment, understanding, and buy-in; (3) applying: adoption of new ways of working during implementation to best take advantage of the benefits of HCD while promoting long-term program sustainability and learning.These lessons represent an important step on the pathway to demonstrate the contributions of HCD to improving the effectiveness of health programs at a time when the global health community needs the most robust set of tools possible to meet the demands of our current pandemic context and beyond. Reflecting on these experiences, this article can benefit both traditional global health funders and implementers seeking to introduce HCD into their work and/or improve the effectiveness of existing projects, as well as designers seeking to use their HCD skills to advance global health. These reflections aim to help both groups successfully integrate their different approaches to reap the benefits of HCD in the context of global health programs.The reflections in this article aim to help both global health practitioners and designers successfully integrate their different approaches to reap the benefits of HCD in the context of global health programs.The 3 programs discussed in this article all integrated HCD into traditional global health programming, but they vary in important ways that can illuminate learnings for a broad range of global health programs .In 2015, the U.S. Agency for International Development (USAID) engaged a consortium of partners led by CONRAD, and including IDEO and Matchboxology, to identify a new approach to offering oral pre-exposure prophylaxis (PrEP) to adolescent girls and young women (AGYW). While access to oral PrEP is scaling up across sub-Saharan Africa, low rates of initiation and retention continue to limit the progress toward ambitious, global goals for AGYW.V” was co-created with AGYW through prototyping and testing, resulting in a radically reframed PrEP experience from a potentially stigmatizing medicine into empowering self-care. V is introduced through brand ambassadors and initiated using a starter kit that mimics a makeup bag, including a small pill case that silences pill rattling and can be shown off or disguised as a lip balm case.Formative research in South Africa included user journey mapping and highlighted a negative, overmedicalized experience of PrEP. Based on this research, “In 2019, USAID engaged the Engage Design consortium—led by McKinsey Design, Matchboxology, and research partner PATH—to partner with USAID/Zimbabwe’s leading HIV prevention service delivery partners to adapt V for program implementation. Due to COVID-19, implementation was paused but has recently resumed, with results expected in late 2021.Adolescents 360 (A360) is a 4-year initiative (2016–2020) to increase adolescent girls’ access to and demand for modern contraception in Nigeria, Ethiopia, and Tanzania. A360 is implemented by Population Services International (PSI) and in partnership with IDEO.org, the Center on the Developing Adolescent at the University of California, Berkeley, and the Society for Family Health Nigeria, and cofunded by the Bill & Melinda Gates Foundation and the Children’s Investment Fund Foundation. A360 used HCD alongside other disciplines of social marketing, developmental neuroscience, and anthropology to develop innovative country-specific interventions through an iterative process of researching, testing, prototyping, and piloting ideas with girls and other stakeholders. The first 2 years were dedicated to program design and optimization, while the second 2 years were focused on implementation and scale-up.The HCD approach applied led to the development of Smart Start, an intervention that uses financial planning as an entry point to engage young married couples in planning their futures and reaching financial stability, positioning contraception as a tool to achieve their self-defined goals. Smart Start supports girls aged 15–19 years and their partners to understand the resources they will need for the families they desire.As of September 2020, Smart Start has reached 76,480 girls in Ethiopia, with 35,887 (79% of eligible girls who are not pregnant and not using contraception) of those voluntarily adopting a form of modern contraception. It is currently being implemented in 1,070 sites across the country and the Ministry of Health (MOH) is embedding it in the national health extension worker program. PSI has also introduced and adapted Smart Start for adolescent girls in Mozambique.–Nigeria and the Democratic Republic of Congo (DRC). To achieve these goals, the project team adopted an integrated approach that combined HCD, co-creation, and systems thinking. The HCD aspects of the process involved activities to understand the human experience of TA, including attitudes, motivations, and behaviors, as well as social determinants, including social norms and group identity. In each country, the project used HCD and co-creation processes that included workshops, design sprints, and stakeholder interviews. The system's thinking included mapping the journey of TA planning and delivery that recognized interactions among international, several national government departments, and subnational actors as opposed to a single project addressing a technical intervention.Reimagining Technical Assistance (Reimagining TA) was a 2-year project (2018–2020) funded by the Bill & Melinda Gates Foundation and implemented by the Child Health Task Force Secretariat through John Snow Research & Training Institute (JSI R&T) and Sonder Collective. TA has been criticized for failing to align with country priorities or coordinate with governments and other stakeholders, often focusing on short-term wins, and lacking systematic approaches to solve public health challenges.The project co-creation teams identified 9 critical shifts and 20 design principles of good TA for global and local stakeholders, which serve as a platform for alignment, inspiration, and action toward a re-imagined TA.Reflections on these projects hold lessons for global health practitioners and designers seeking to advance global health programming through HCD. Learnings can be broadly distilled into 3 categories: (1) planning: considerations for problem definition and project scoping to satisfy integration of HCD methods; (2) engaging: reflections on the means to productively engage different stakeholder groups to build alignment, trust, and buy-in; and (3) applying: adoption of new ways of working during implementation to best exploit the benefits of HCD while promoting long-term program sustainability and learning .Across the 3 programs, early project planning phases were critical to realize the benefits of HCD methods. Traditional global health practitioners needed to adapt their approaches to consider the flexibility, iterative nature, and sometimes elongated time frames that HCD requires to produce robust results. Similarly, designers needed to invest time during the planning phase to understand how design could best add value.Traditional global health practitioners needed to adapt their approaches to consider the flexibility, iterative nature, and sometimes elongated time frames that HCD requires to produce robust results.Because HCD is a creative problem-solving approach, projects must have a clear, baseline problem definition that is developed and refined through research with end users and other stakeholders. However, experiences of these programs also suggest that continuing to iterate on the problem definition throughout the project can advance better outputs.For example, in A360 Ethiopia, the program initially sought to achieve 121,000 new users of contraception, aged 15–19 years over 4 years. However, after the insights gathering phase, the team uncovered 3 different segments in this age bracket that would require different solutions: unmarried girls in school, young married adolescents, and young adolescent mothers. This fueled a conversation about redefining the scope of the project, the user segment, and the appropriate targets, which ultimately laid the foundation for designing a highly tailored program for one of these segments.V’s formative research in South Africa suggested that V would be most impactful if it was positioned as a consumer brand. Consequently, the materials were designed with a look and feel that was intentionally distinct from traditional public health communication materials. However, when translating the product for use in Zimbabwe, users wanted V to be linked to current oral PrEP offerings through public health programs to avoid confusion. For future replication, the team recommended that a rapid, low-resource validation within an existing program be conducted first. This would allow the designers leading the HCD process to facilitate the initial phase of problem definition based on an understanding of the specific country and program context.In Reimagining TA, the timeline, project approach, and funding had been allocated to the implementing partners with the assumption of a single, broad problem definition. However, though all actors agreed that the TA delivery was broken and needed to be reconceived, during the initial in-country workshops the design team discovered that "the problem" with TA was more complex and nuanced than previously understood. For example, while there was consensus that the current timeframes for TA projects were not appropriate, funders preferred shorter-term TA projects and near-term results, while governments wanted several years of TA to strengthen the underlying capacity of the health system to deliver long-term and sustainable results. These multiple and partly diverging problem definitions between global, national, and local stakeholders were at odds with the ability to undertake a fast HCD process. A more collaborative problem definition phase could have helped establish a clear, shared intent for the work and identify solutions more suited to the needs of stakeholders at all levels.The HCD process is rooted in deep inquiry and open exploration to surface new insights and develop innovative products or processes together with the users of those solutions. As a result, the prototype or proposed solution will rarely be the one to scale. This process of iteration and adaptation can often take more time and can be in tension with the more linear structure of traditional global health programs. Recognizing this tension and building in more time and resources for a rigorous, iterative HCD process can enable global health programs to reap the benefits of HCD.Building in more time and resources for a rigorous, iterative HCD process can enable global health programs to reap the benefits of HCD.From the beginning, A360 Ethiopia had a generous timeline and expectation for program adaptation, which allowed the initiative to be successful at scale. In the solution design phase, there were 3 rounds of rapid prototyping before a 6-month pilot. Through these iterations, the team quickly validated the value proposition of financial planning for young couples, experimented with how to best communicate the relationship between financial and family planning, and ultimately, refined the delivery model for this intervention for married adolescents in rural Ethiopia. In the second year, even after the Smart Start financial planning curriculum was launched, a second short design sprint helped condense the curriculum from 60 pages and 1 hour to 12 pages and 15 minutes, making it much easier for health extension workers to integrate these messages into their work.Similarly, in Reimagining TA, the team found that conducting a design process within a complex system requires time. While the donor originally allocated funding for an 8-month timeline, the project ultimately took 24 months for several reasons. First, the project encountered logistical constraints. Co-creation workshops required direct engagement with country-level stakeholders, particularly government officials, who had limited availability, and that was exacerbated by personnel turnover in key roles post-elections. Second, in the case of the DRC, the first round of prototyping surfaced problems at the community level that resulted from poorly designed TA, including lack of consideration of the burden of out-of-pocket health costs on the families, lack of dialogue with community leaders, and duplication of activities in the field. The team decided that a second round of prototyping was needed to identify the root, systems-level problems. Third, once the timeline began to get delayed, amendments to the pre-defined project plan and budget took additional time.To address these challenges, the project concept should be codesigned by the funder, the content and process experts, and the collaborating government entities. With all key stakeholders at the table, expectations would be clarified, roles and responsibilities agreed upon, accountability mechanisms established, and funding allocated based on a realistic timeline and level of effort. Ultimately, a timeline that allows for co-creation of the vision, iteration, and exploration throughout the process is crucial to consider for successfully integrating HCD into health programs.A timeline that allows for co-creation of the vision, iteration, and exploration throughout the process is crucial to consider for successfully integrating HCD into health programs.Commitment to Ethics in Youth-Powered Program Design. Initial IRB feedback stated that A360 did not have an adequate sample size and had to change the wording of questions and limit their methods to a specific set of 9 approaches. The requirement to submit the design research plan 6 to 9 months in advance of project launch also limited the design team’s ability to adapt their methods as needed throughout the process. The IRB process did help pre-articulate the lines of inquiry that would truly advance programming while eliminating those that are potentially extractive and not relevant to programming. A360’s experience demonstrates how adhering to ethical standards in design can be achieved while maintaining the uniquely iterative nature of design research. For example, future HCD practitioners can learn from A360’s approach of including in the final IRB application a range of approaches, such as “inquiry questions may include” “we will speak to a maximum of X people.” By pursuing discovery-driven approaches that also promote documenting methods and results, HCD practitioners can advance the diffusion of potentially catalytic approaches such as design, while ensuring common ethical standards across the global health and design communities.For A360 Ethiopia, navigating the institutional review board (IRB) process surfaced tensions between HCD’s discovery-driven and public health’s pre-articulated research approach. For public health practitioners, IRB approval is required when deemed necessary to protect the human subjects of research. HCD practitioners are accustomed to open and fluid lines of inquiry with users to discover new and unexpected insights and often utilize market research approaches that are exempt from IRB requirements. A360 Ethiopia pursued IRB approval in line with the principles of its Part of the value of embedding HCD in global health programming is the opportunity to use it in combination with traditional public health methods and other complementary methodologies. Each of the program experiences highlighted the importance of identifying the specific areas where HCD can add value and where other approaches can be useful (and where these have limitations). Further detail on the value of design as a complementary methodology is detailed in a separate article in this supplement.The experience of V demonstrates how HCD can be used to build on existing knowledge and derive new solutions. V’s formative findings reinforced well-documented opportunities  and challenges .In Reimagining TA, the team found that with a project as complex as reimagining a system of service delivery at global scale, other approaches such as systems thinking and behavioral science would have been useful in addition to HCD. The project’s HCD approach centered around mapping the human experience of TA, the user needs of different actors involved, and journeys through different TA programs. This helped to understand people, their interactions, and the complexity of those interactions. However, a systems-thinking approach could have helped better identify linkages and power dynamics in these systems that could be targeted for change. In addition, reimagining a system involves changing the behavior of the people in that system. The HCD approach in this project did not apply a behavioral science approach to analyze behavior to propose a behavior change strategy.While implementing these projects, both traditional global health actors and designers found that they needed to adapt their traditional ways of working to successfully collaborate on integrating HCD into global health programming. Teams found an initial start-up phase useful to build alignment, understanding, and trust among the different groups involved. They also found that establishing ownership with MOHs, implementing partners, and other key stakeholders early in the process was particularly important for sustainability, as was identifying partners with strong existing capacity in adaptive management.Embedding HCD in a global health program requires a shift in the way both global health practitioners and designers are accustomed to working. The 3 projects thus noted that a start-up alignment phase would be helpful to clearly delineate roles and responsibilities of each partner in the HCD process and familiarize traditional global health actors with the baseline components of the HCD approach.A start-up alignment phase would be helpful to clearly delineate roles and responsibilities of each partner in the HCD process and familiarize traditional global health actors with the baseline components of the HCD approach.In Reimagining TA, no such start-up phase was built in for Sonder and JSI to align on process and approach. The design team had to orient the JSI team to the HCD methodology and approach while simultaneously kicking off activities in-country, as the JSI team had not worked with HCD before. Equally, the design team needed time to understand the country’s context and effective ways of working with the national governments. The lack of time to align on how to integrate a consultant-led design process into the global health program exposed a lack of mutual understanding in terms of ways of working. This created confusion, mutual questioning of the project approach, and a lack of clarity around roles and responsibilities. Had there been an initial codesign and planning phase for the 2 organizations to deeply engage with the planned approach and methodology, reflect on the country context and its impact on the process, build mutual understanding and trust, map out roles and responsibilities carefully, and align the timeline accordingly, the project would have been delivered in a more targeted, streamlined, and effective manner.Conversely, V invested time and resources to transition formative research conducted in South Africa to testing, adapting, and integrating the approach into HIV programming in Zimbabwe. The prototypes of the V starter kits and distribution plans developed in South Africa were not automatically transferable to a new context given the procurement realities of supplying large, U.S. government-funded programs. Ultimately, implementing V in Zimbabwe required procurement through an existing U.S. government supply chain mechanism focused on pharmaceutical product procurements, which required a competitive contracting process. The start-up planning phase in Zimbabwe was essential to transition from prototyping to program implementation. In addition, because of the investment of time and effort in procuring through an existing U.S. government supply chain mechanism, V is now much more accessible for other country teams who might want to procure it.In traditional global health programming, partnerships are already regarded as important, particularly partnerships with MOHs, to build buy-in and promote sustainability. However, when adding in a less familiar HCD approach, generating early buy-in was even more important.The key to A360 Ethiopia’s sustainability was its early and flexible partnership with the MOH. Because A360’s objectives closely aligned with the National Adolescent and Youth Health Strategy targets for reducing teen pregnancy, the MOH participated early in A360’s proposal development. While the MOH was skeptical of the longer timeline and programmatic delays that an intensive co-creation approach would entail, inviting young designers to present the insights and opportunities that emerged from design research ultimately helped convince the MOH of the approach. It was a powerful signal, coming directly from their constituents, about what change was needed and whose voices needed to be heard to address teen pregnancy. Design afforded the rare and insightful opportunity for the MOH to hear directly from constituents that they may not have had otherwise.For Reimagining TA, a lack of strong government buy-in affected the quality and speed of the co-creation process. Given the limited timeline for securing government buy-in, the government accepted the initiative without full awareness of and commitment to the level of engagement needed for a true co-creation process. As the project was one among many donor-funded projects competing for stakeholder time and attention, it lost out against other priorities that were included earlier in the country’s operational plans. As previously noted, including the country governments in co-creating the project concept could have helped to achieve greater buy-in.The HCD process is based on the rapid development of prototypes and iteration, which means that the output of a project is never truly “finished.” The experiences of these projects suggest that partners with strong adaptive management skills  are those best suited to continue to test, learn, and improve the solution to bring it to scale.The experiences of these projects suggest that partners with strong adaptive management skills are best suited to continue to test, learn, and improve the solution to bring it to scale.For the Reimagining TA project, the Technical Assistance Hub (TA Hub), an initiative of the Bill & Melinda Gates Foundation Nigeria country office and implemented by DAI Nigeria, was able to adopt, adapt, and use the project outputs. The TA Hub is an independent nonprofit organization that coordinates the delivery of comprehensive technical assistance and institutional strengthening support to state governments in Nigeria. DAI staff participated in the Reimagining TA process as co-creation team members and were later able to apply the reimagined TA approach. Now, all partners applying to provide TA to state governments in Nigeria with funding from the TA Hub are required to demonstrate how they will apply the critical shifts and principles of good TA. Identifying a partner with the capacity to adapt and iterate on the project outputs was critical to the project’s implementation.For A360 Ethiopia, a key factor for success was PSI Ethiopia building an institutional culture of adaptive management, which allowed the Smart Start solution to scale beyond the initial design phase. After the initial work was completed, the PSI Ethiopia team created an internal “Learning and Insights Team,” which continued to practice design and adaptive management, including routine data monitoring, conducting focus groups, and taking action to adjust key program components as needed when scaling to a new region or training a new tier of health workers. This has allowed them to quickly identify and adjust program components when scaling to a new region or training a new tier of health workers.When putting HCD into practice in the context of global health programming, both designers and traditional global health stakeholders found they needed to adapt their typical approaches to implement an integrated program. First, to develop outputs tailored to the needs of the end user, teams found it critical to engage in a true co-creation process with end users and other stakeholders throughout the project, with each participant adding equal value; this represented a shift for more traditional global health actors. Second, though some HCD projects end with insight generation, in this work, teams found it necessary to push toward implementation of the product or service to promote uptake of the final outputs. To ensure the program can continue once the core work has concluded, teams found that building HCD capacity among the consortium of partners allowed them to continue to iterate and adapt the solutions based on the needs of the target population. Finally, when designing monitoring and evaluation (M&E) frameworks for these programs, either traditional global health actors or designers needed to adapt their approach to identify a set of indicators well-suited to the integrated approach.Traditional global health programs and HCD projects vary in the degree to which they include and embed input from end users and other key stakeholders. In traditional global health programming, consulting end users and including other key stakeholders at key decision points is not a new concept. However, experiences from these projects suggest that it is necessary to engage in a true co-creation process, involving the end users and stakeholders at each stage of the work, rather than a more prescriptive, donor-recipient relationship.Experiences from these projects suggest that it is necessary to engage in a true co-creation process, involving the end users and stakeholders at each stage of the work, rather than a more prescriptive, donor-recipient relationship.A key component of A360 Ethiopia was co-creation of solutions with young Ethiopian designers. During prototyping young people played a significant role in identifying the most resonant ideas, resolving conflicting feedback in testing, and improving ideas to be more contextually appropriate. For example, when discussing the cost of having a baby, a young designer proposed expressing it in the number of goats, rather than the local currency, which was a more relatable concept for the pastoralist community. A second benefit to co-creation was that having young designers as a core part of solution development gave Smart Start credibility among the MOH stakeholders who saw these young people as their constituents. Engaging youth as team members in this way requires dedicated financial resources, human resources, and time, which may often be at odds with short-term efficiency; yet it was central to the success of the project’s outputs and long-term sustainability.In the case of the Reimagining TA project, the degree of co-creation varied by project stage and country context. The project launch represented a more prescriptive approach; countries were preselected by the funder, and country stakeholders were only involved after funding was approved. Country governments were not involved in developing the problem definition in the proposal to determine if the related process and approach would be meaningful and needed in their country. As a result, throughout the project, it was difficult to achieve stakeholders’ buy-in and commitment, despite intentionally adopting a more collaborative co-creation approach in later project phases. In Nigeria, inconsistent stakeholder engagement in the workshops resulted in fragmented insights and low commitment to the process and the solutions. Conversely, in the DRC, the co-creation team was consistent and engaged throughout the whole process, which resulted in better adoption and implementation of the solutions. By the end of the project, the DRC team was ready and willing to take independent ownership of the next steps. Involving stakeholders not as participants but as co-creators requires global health funders and other traditional stakeholders to engage in a more inclusive process from project conceptualization to implementation.Some HCD projects can run the risk of seeing the insights as an end, rather than a means to an end. When design projects are scoped with insights as an output, traditional global health actors, country governments, or other stakeholders must take the extra step to translate these insights into action to achieve outcomes. Programs that continued beyond insight generation to prototyping and actual implementation achieved greater success in the adoption of project recommendations.Programs that continued beyond insight generation to prototyping and actual implementation achieved greater success in the adoption of project recommendations.In A360 Ethiopia, the insights-gathering phase yielded findings similar to those found in the adolescent and youth sexual and reproductive health sector previously, such as “contraception is at odds with a girl’s identity and what is expected of her” or “proving fertility and having children is culturally revered.” The HCD process was more valuable in translating these insights and learnings into tangible programming opportunities. For example, from these insights, the team built rough prototypes of a baby cost calculator, a newlywed counseling session, a young wives club, junior health extension workers, and many more. Following insights generation with rapid solution prototyping helped to deepen learnings gleaned from the HCD process and make more actionable progress toward behavior change.Conversely in Reimagining TA, the project ended with insights and concept generation, including 20 principles of good TA. The team originally planned for 4 workshops to move stakeholders through a design process. However, this proved unrealistic due to the complexity of the “problem” to be solved, the inconsistency of stakeholder attendance at the workshops, and the time frame allocated. Given the constraints, the team determined that the workshops could be better leveraged to develop a set of design principles to guide and govern TA planning and delivery. Implementation of the design principles in each country would have required additional funding and time but would have been more effective in achieving the intended impact of the program.To address these challenges, first, the project itself should have been co-created with an emphasis on the iterative nature of the HCD process. The full project design, timeline, and funding allocation should have only been developed after defining the design challenge or questions. After understanding the complex nature of the design challenge, all actors in the process, including the funder, should have agreed to a flexible timeline and funding needed to co-create the vision, test solutions, implement, and evaluate.The HCD process and related outputs are highly tailored to the needs of a target population that will shift over time. These projects illustrate how engaging partners throughout the project, and particularly during the insight-generation phase, builds capacity and buy-in to HCD methodology. Including additional budget and time to support the active development of these skills will better enable countries to respond to changing needs of the target population once the “project” has ended.In V, Engage Design, the HCD consortium, partnered with PSI and Pangaea Zimbabwe AIDS Trust to scale V in Zimbabwe. This partnership focused specifically on building HCD capacity and the expertise needed to implement and adapt V independently after the Engage Design support ends. Engage Design sought to empower and inspire local ownership through capacity-building workshops and opportunities for program implementers to work alongside the design team at every stage of the project. PSI and Pangaea Zimbabwe AIDS Trust staff began as observers, then with coaching, gradually became cofacilitators and lead facilitators, working alongside Engage Design project staff. This collaborative approach and tapered support plan were also designed to improve the V product during implementation, demonstrating how HCD capacity building also benefits the quality of global health program outputs.For Reimagining TA, given timeline and budget constraints, there was no time to build the HCD skills of in-country co-creation team members. Therefore, the solutions identified have not been implemented systematically.Both design and traditional global health approaches are valuable when defining suitable M&E frameworks. These projects experienced success with both a more traditional global health approach for measuring longer-term outcomes and with a more design-led approach for iterative process measures. However, both cases required one group to adapt their traditional methods.In A360 Ethiopia, taking a design-led approach to monitoring and evaluating the Smart Start program promoted greater adaptive management that was conducive to continually optimizing the program for scale-up across Ethiopia. Those familiar with traditional global health approaches might be tempted to try to rigorously monitor early prototyping phases and make decisions based on predefined indicators. However, in A360 Ethiopia, the team found it important to regard prototyping phases as formative research, while keeping the suite of indicators broad. For example, instead of only tracking how many girls were reached and how many girls adopted a contraception method in prototyping rounds, it was equally important to gather feedback on how girls were hearing about the program, how their partners felt about the program, and how long it was taking for providers to deliver a counseling session. Tracking this more expansive set of indicators led the team to make important refinements to optimize impact during scale-up . The ability to flexibly apply a mix of qualitative and quantitative methods to gather data early on was instrumental in helping the team to constantly learn and iterate on the program model.For V, an independent impact evaluation failed to launch due to challenges in identifying a sufficiently rigorous methodology at a feasible cost. The evaluation of V in Zimbabwe was therefore designed to leverage existing, routine program monitoring systems. The learning objectives for V included first assessing acceptability and relevance with target end users and second, evaluating the feasibility of integrating V into existing oral PrEP service delivery. Impact will be assessed using PEPFAR’s standard performance indicators for oral PrEP. In addition, a learning agenda was developed, with questions designed to benefit both Zimbabwe and global communities . This blended approach of leveraging existing M&E systems alongside questions that can advance learnings related to HCD can support key decision makers in determining whether—and how—to scale programs like V.The 3 program experiences analyzed in this article offer lessons for planning, engaging, and applying individually. Additionally, several of these lessons are interrelated and illuminate insights for the project approach overall. Reflections from these projects suggest a virtuous cycle between the insights in each category. For example, the more that stakeholders, particularly country governments and end consumers, are engaged in an inclusive, participatory process, the greater their continued willingness and motivation to engage. Deeper engagement allows for more iteration and leads to higher quality, better-tailored outputs that are more likely to be sustainably used and scaled. Intentionally building HCD capacity among stakeholders over the course of the project strengthens this virtuous cycle by allowing the iterative process to continue once the “project” has ended. A360, V, and Reimagining TA in DRC were able to foster this cycle from the beginning and the solutions have continued to scale. Conversely, Reimagining TA in Nigeria was less able to undertake a participatory process from the start, which made securing country buy-in difficult and ultimately hindered implementation of project recommendations.Intentionally building HCD capacity among stakeholders over the course of the project strengthens this virtuous cycle by allowing the iterative process to continue once the “project” has ended.The ability to engender this virtuous cycle depends on another insight previously discussed: the importance of scoping projects appropriately to allow for co-creation, iteration, and HCD capacity building. Programs that seek to incorporate an HCD approach need to be scoped differently than traditional global health programs. The project conceptualization and scoping process itself needs to be more collaborative, and the budget and timeline need to be more flexible and sometimes be longer than traditional programs to allow for greater iteration. However, longer timelines are not always necessary; a nimbler HCD approach can be achieved by building in more built-in stage gates or pivot points for rapid prototyping and iteration at different stages of the process. A more inclusive scoping process may lead to a problem definition and output that is different from donor expectations and perceived as less directly focused on a funder’s mandate.Yet, these projects exemplify that ultimately it helps to reduce rework and wasted resources and promote more sustained impact through investing in stakeholder buy-in and iteration upfront. In this way, HCD practices represent more inclusive and participatory approaches that should inspire us to take further steps toward decolonizing program development in global health; however, more can be done to further define where HCD is additive to those aspirations and where it is further exacerbating historical power imbalances .Of course, expanding the integration of HCD into more global health programs will require convincing funders and other decision makers that these programs are valuable. When considering a new approach, traditional global health stakeholders may perceive a higher risk of failure, especially when weighed against methods that are better understood and supported by well-documented evidence. Thus, there is a substantial burden of evidence required to persuade actors that this approach is not only beneficial but also that the risk of not having local ownership limits long-term benefits if it means projects will require ongoing grant funding.The gold standard in global health programs is demonstrating cost-effectiveness; however, there is little publicly available information on the cost of these programs. Further, it is difficult to clearly break down costs for specific activities and phases, as budgets are allocated at a high level and multiple workstreams often take place in parallel. However, this type of estimation was attempted in a mid-term evaluation of A360, which found it cost between US$2 million—US$3.5 million to design the project approach.Alternative approaches to measuring HCD’s contributions should also be considered. The results of the projects examined in this article demonstrate the value that both program implementers and program beneficiaries received. However, rigorous process evaluations to assess HCD’s contribution throughout programming implementation is an area that merits further investigation and investment, given their acceptance in global health implementation science programming. At the same time, the concept of value to the end user is increasingly being heralded to improve health services, and HCD brings a unique perspective on how best to define those value-based indicators. For example, end users may not only value clinical outcomes but also value improvements in quality and experience of care as well as the quality of life and well-being.The global community continues to seek solutions to achieve the ambitious SDGs for health. The experiences of V, A360 in Ethiopia, and Reimagining TA strongly suggest that integrating HCD into planning, engaging, and applying in global health programming could help traditional global health actors achieve better outcomes. HCD’s iterative and inclusive approach can produce more targeted and effective interventions while building local ownership and promoting more sustained impact. However, not every challenge is well suited for HCD, and programs need to be scoped and implemented thoughtfully to reap the benefits of an HCD approach and promote sustainability. A participatory, collaborative, and iterative co-creation approach from the project outset is important, as well as scoping the project in a way that supports an iterative approach throughout implementation. Further work is needed to better quantify the costs and benefits of integrating HCD methods to provide more evidence-based justification for the appropriate use of HCD. In the meantime, alternative approaches to characterizing the benefits of integrating an HCD approach should also be considered. As the global health field grapples with how to close the growing SDG gap, especially with the disruptions from COVID-19, HCD can be a powerful tool to generate progress toward these goals and more sustained impact.


JAC-Antimicrobial Resistance, we present a PRO/CON debate that discusses the clinical utility of procalcitonin in children with CAP.Although the overwhelming majority of community-acquired pneumonia (CAP) in children is caused by viral infections, treatment of CAP is among the most common indications for antibiotic use in children. This is largely driven by the imprecision of clinical diagnostic tools to differentiate viral from bacterial pneumonia and highlights the need for improved approaches to optimizing management of CAP in children. In this issue of  As the bacterial infection is controlled with adequate antibiotic therapy, procalcitonin is expected to decrease by 50% every 1–2 days. Cytokines more typically produced in the setting of a viral infection, such as IFNγ, downregulate CALC-1 expression, contributing to preferential rises in procalcitonin in response to bacterial infections. While these characteristics make procalcitonin an appealing biomarker to diagnose bacterial infections, as well as to assess response to antibiotic therapy, it is imperfect. For example, non-bacterial infections, including malaria, as well as non-infectious conditions, such as malignancies, surgery, bowel ischaemia and burns, can also lead to elevations in elevations in procalcitonin.Procalcitonin is primarily produced by C cells in the thyroid gland as a precursor of the hormone calcitonin under normal physiological conditions. However, in the presence of a bacterial infection, proinflammatory cytokines, including TNF-α, IL-1β and IL-6, upregulate gene expression of the ,Indeed, the performance characteristics of procalcitonin for diagnosis of bacterial pneumonia in adults are marginal, with no identified threshold that distinguishes viral from bacterial aetiologies with sufficient accuracy to withhold antibiotic initiation.,,,Over two dozen randomized controlled trials (RCTs) have considered this question in adults, examining the impact of procalcitonin-guided algorithms for antibiotic use in adults with acute lower respiratory tract infection (LRTI) in emergency department (ED ), primary care and ICU settings. Most of these studies demonstrated reductions in antibiotic initiation as well as antibiotic duration, though notably, a trial conducted in 14 EDs in the USA with high adherence to the Joint Commission core measures for management of CAP demonstrated that a procalcitonin-based guideline for antibiotic use had no impact on total antibiotic exposure or rate of antibiotic use.JAC-Antimicrobial Resistance, Florin and Williams argue in favour of procalcitonin use, with their ‘pro’ position resting on the value of procalcitonin in excluding bacterial pneumonia at very low values (i.e. <0.1 ng/mL), which could substantially reduce antibiotic use in children where viral infections predominate.In this issue of This work was supported by the Agency for Healthcare Research and Quality [K12-HS026393 to K.C.]. The funder did not participate in this work.None to declare.K.C. and J.S.G. conceived of the content included in this manuscript. K.C. drafted the initial manuscript and J.S.G. critically reviewed the manuscript.