Introduction: While the rate of orthopaedic infections has remained constantover the years, the burden on healthcare systems continues to rise with anaging population. Local antibiotic delivery via polymethyl methacrylate bonecement is a common adjunct in treating bone and joint infections.Dalbavancin is a novel lipoglycopeptide antibiotic in the same class asvancomycin that has shown efficacy against Gram-positive organisms when usedsystemically but has not been investigated as a local antibiotic. This studyaims to identify whether dalbavancin is thermally stable at the temperaturesexpected during the polymerization of polymethyl methacrylate cement.Methods: Stock solutions of dalbavancin were prepared and heated using apolymerase chain reaction machine based upon previously defined models ofcuring temperatures in two clinically relevant models: a 10 mmpolymethyl methacrylate bead and a polymethyl methacrylate articulating kneespacer model. Aliquots of heated dalbavancin were then transferred to beincubated at core body temperature  using a standardmicrobroth dilution assay.Results: The average MICS. aureus. There were no significant differences in therelative MICConclusions: Dalbavancin is thermally stable at the curing temperatures ofpolymethyl methacrylate cement and at human core body temperature over28 d. Future in vitro and in vivo studies are warranted to further investigate the roleof dalbavancin as a local antibiotic prior to its clinical use. The incidence of periprosthetic joint infection (PJI) isreported to range between 1 % and 2 % in primary joint replacement and up to10 % in revision cases . Infection after internal fixation of closedfractures is reported to be approximately 1 %–5 % but increases to as highas 30 % in cases of open fractures . These rates inorthopaedic trauma vary significantly when considering the location of the injuryand the degree of soft-tissue injury, with increasing rates of infection withhigher-grade Gustilo–Anderson open-fracture types . Although the overall rate of bone infection appears low, because thereis such a high prevalence of both total joint arthroplasty and fracturesannually, surgical site infections pose a significant problem fororthopaedic surgeons.The benefit of using local antibiotics is the high local concentration thatcan be achieved while maintaining low systemic concentrations, thereby lowering the riskof systemic side effects. Local antibiotic delivery using bone cement wasfirst introduced in 1970 in the context of PJI in total hip arthroplastywith an overall first attempt treatment success rate of 77 % . Polymethyl methacrylate (PMMA) cementremains the most common delivery material for local antibiotic delivery.Since its introduction, antibiotic delivery using bone cement has evolved,resulting in approximately 90 % success in the treatment of PJI and between70 % and 95 % success in the context of infection after fracture fixation orseptic non-unions . Although a large proportion of infections can successfully beeradicated, there remains a significant number of patients impacted byfailure of these treatments, resulting in lower patient quality of life and alarge economic burden on the healthcare system .Staphylococcus aureus (MRSA)infections are failing treatment with traditional agents such as vancomycin,as many MRSA isolates are showing reduced susceptibility to this agent.Considering this, alternative agents to combat treatment-resistant infectionsare necessary. Dalbavancin is a lipoglycopeptide antibiotic that acts byinterrupting cell wall synthesis, leading to bacterial death . In vitro studies have demonstrated that dalbavancin has a higher potencyagainst MRSA and other Gram-positive infections compared with vancomycin. Additionally, dalbavancin is incurrent use in the treatment of bone and joint infections as a systemicagent and has the advantage of being able to be dosed weekly as opposed tothe daily dosing of vancomycin . It is of note that musculoskeletalinfections are frequently biofilm-associated infections which often requirehigher antimicrobial concentrations to eradicate them, measured by the minimum biofilmeradication concentration (MBEC) . Whencomparing the MBEC to the traditional minimum inhibitory concentration (MIC), theMBEC of an antibiotic is often significantly higher; thus, higherconcentrations of antibiotics may be necessary to combat these infections. However, there are no clinically relevantperformance standards for biofilm eradication at present .An increasing number of methicillin-resistant While studies have shown that dalbavancin is a promising agent to treat MRSAinfections that are less susceptible to vancomycin, there are fewavailable data investigating the use of this agent as a local antibiotic inthe context of bone and joint infections. For antibiotics to be consideredfor clinical use locally, it is important to define their efficacy throughin vitro and in vivo studies. An important consideration is that the antibiotic agent used shouldbe thermally stable at the temperatures produced during the exothermic cementpolymerization reaction as well as at body temperature during the durationof expected antibiotic activity. For example, minocycline and meropenem donot retain their antimicrobial activity after heating in a 10 mm PMMA cement-bead model and subsequent incubation at human core body temperature. Additionally, an antibiotic must be stable overlonger periods of time at human core body temperature when utilized inlong-term carriers such as hydrogels or calcium sulfate.This study aims to assess the thermal stability of dalbavancin through twoclinically relevant models of PMMA cement: bone cement as a bead or as partof an articulating knee spacer. Further, by incubating at human core bodytemperature  wereobtained. Stock solutions of dalbavancin were prepared at concentrations of1024 United States Pharmacopeia (USP) reference standards of dalbavancin. The cement was mixed according to manufacturer instructions andplaced into the respective molds via manual mixing without vacuum . Using a thermocouple, placed in the center of thebead (5 mm depth) or spacer (4 cm from the furthest surface and 1.5 cm fromthe closest surface) where maximum temperatures would be expected,the temperature in each model was measured at 30 s intervals until itreached human core body temperature  machine , followed by static incubation athuman core temperature , which is derived from a clinical isolate parental strain of S. aureus (ATCC0173K), was obtained. S. aureus was streaked on tryptic soy agar and incubatedovernight. One colony was isolated into 5 mL of tryptic soy broth and placedin a shaking incubator for 24 h; this solution was then diluted by a factor of 50 andplaced in a shaking incubator for 1.5 h. Bacteria were washed twice in phosphate-buffered saline (PBS) and resuspended in tryptic soy broth. Spectrophotometer absorbance was used todetermine the optical density at 600 nm (OD600) of 0.490–0.510 A, indicative oflog-phase growth. The bacterial solution was diluted to achieve a concentrationof 10Methicillin sensitive 2.4S. aureus isolates were inhibited.MIC33.1S. aureus.The control group microbroth dilution assays of dalbavancin aqueous solutionsproduced a MIC3.2Microbroth dilution assays for samples exposed to the simulated thermalprofile 10 mm PMMA bead model demonstrated comparable MIC3.3Microbroth dilution assays performed after heating at curing temperatures ofa PMMA articulating knee spacer model demonstrated comparable MIC3.4Microbroth dilution assays performed after incubation at human core bodytemperature over a period of 4 weeks to represent long-term antibioticcarriers such as hydrogels and calcium sulfate demonstrated comparableMIC4As antibiotic resistance continues to be a growing problem in the managementof orthopaedic infections, novel antibiotics that can be utilized locallywill need to be identified. To the authors' knowledge, this is the first study evaluating dalbavancin,a novel antibiotic with great efficacy in orthopaedic infections when usedsystemically, in the context of local delivery via PMMA cement. While thisstudy demonstrates that dalbavancin is thermally stable in the context ofclinically relevant PMMA cement polymerization temperatures, this study isonly one step in establishing dalbavancin as an efficacious local antibioticin PMMA cement for the treatment of orthopaedic infections. Additionally,this study also provides evidence that dalbavancin is thermally stable overa 28 d period at human core body temperature; this demonstrates that it may beappropriate for study in multiple local carriers, including powders andhydrogels, as well as resorbable carriers, such as calcium sulfate, which havea slower antibiotic release.These results lay the foundation for further evaluation of dalbavancin as alocal antibiotic. It has been demonstrated that antibiotic elution is notnecessarily improved with higher antibiotic loading in PMMA cement and thathigher concentrations lead to decreased compressive mechanical properties. Future studies will need to evaluate the elutionkinetics of dalbavancin in PMMA cement and other local antibiotic deliverymaterials to evaluate whether this antibiotic reaches concentrations overthe course of treatment to adequately eradicate bacteria while alsomaintaining adequate compressive mechanical properties of the PMMA cementfor its intended use. Additionally, future studies will be necessary todefine the MIC of dalbavancin against multiple strains of clinicallyrelevant bacteria in orthopaedic infections. Additionally, while dalbavancinhas been shown to be safe when administered intravenously, including noreports of “red man syndrome” seen with vancomycin infusion, potentialsystemic toxicities include nausea, vomiting, diarrhea, pruritus, rash, andhypersensitivity reactions .While an advantage of local antibiotics is decreased systemic toxicitiesfrom lower systemic concentrations, future studies are necessary to identifyany toxicities unique to the local delivery of dalbavancin as well as theappropriate concentrations to mitigate the risk of antibiotic resistancefrom overexposure.A major limitation of this study is the absence of kinetic measurements ofdalbavancin release from PMMA. Limitations of this study are related to theinherent limitations of in vitro study designs. This study does not mimic in vivoconditions, which can vary based on the local tissue environment.Additionally, this study only replicates two of the many clinical models ofPMMA cement application in orthopaedic surgery. Although this study shows thatdalbavancin is thermally stable over time at core body temperature as well as upto a peak temperature of 100 Overall, our study results demonstrate that dalbavancin is thermally stableduring exothermic reactions in two clinically relevant models of PMMA cementuse in orthopaedic surgery as well as at human core body temperature over a28 d period. This study is foundational in establishing which localantibiotic carriers may be used for the local delivery of dalbavancin prior toits clinical use. Further studies are warranted to assess the clinicalefficacy of dalbavancin against multiple strains of relevant Gram-positiveorganisms; the elution kinetics of dalbavancin from PMMA cement and otherlocal delivery materials; the effect of dalbavancin on setting time,mechanical strength, and chemical interaction with PMMA; appropriate dosingof dalbavancin when used for local delivery; effectiveness against biofilm-associated infections; and in vivo models studying the effect of the local tissueenvironment on the efficacy of infection treatment prior to clinical use ofdalbavancin as a local antibiotic.


To identify which anthropometric measurement would be the best predictor of metabolic syndrome (MetS) in Brazilian adolescents.Cross-sectional study conducted on 222 adolescents (15-17 years) from a city in southern Brazil. Anthropometric, physical activity, blood pressure and biochemical parameters were investigated. MetS criteria were transformed into a continuous variable (MetS score). Linear regression analyses were performed to assess the associations of BMI, hip circumference, neck circumference (NC), triceps skinfold, subscapular skinfold and body fat percentage with MetS score. ROC curves were constructed to determine the cutoff for each anthropometric measurement.2 = 0.31). BMI predicted MetS with high sensitivity (100.0%) and specificity (86.4%).The prevalence of MetS was 7.2%. Each anthropometric measurement was significantly (p < 0.001) associated with MetS score. After adjusting for potential confounding variables , the standardized coefficients of NC and body fat percentage appeared to have the strongest association (beta = 0.69 standard deviation) with MetS score. The regression of BMI provided the best model fit (adjusted ROur results suggest that BMI and NC are effective screening tools for MetS in adolescents. The early diagnosis of MetS combined with targeted lifestyle interventions in adolescence may help reduce the burden of cardiovascular diseases and diabetes in adulthood. The prevalence of overweight and of its comorbidities have increased in adolescents and have reached epidemic proportions in both developed and developing countries . The incOne of the consequences of being obese or overweight is the risk of developing metabolic syndrome (MetS) , a complThe prevalence of MetS is increasing worldwide due to the rise in obesity and poor lifestyle . Excess In the last decade, MetS has been identified in younger populations ,10–12. TIn recent years, several authors have suggested the use of neck circumference (NC) to identify MetS in adult populations –24. OtheSince the diagnosis of MetS is invasive, expensive, and labor intensive on the part of health professionals, noninvasive and low-cost methods are needed, particularly in low-resource settings. The aim of this study was to evaluate BMI, hip circumference, NC, triceps skinfold, subscapular skinfold and BF% as potential alternatives for the diagnosis of MetS in adolescents.This was a cross-sectional study conducted in two phases on 15- to 17-year-old high school students from Joinville, a city of about 500,000 inhabitants, Santa Catarina, Brazil. Details of the recruitment process have been described previously . In the All of the 1,104 students were invited to participate in the second phase. They were contacted by phone and by a personal visit in the residence and were informed about the day and place of data collection. At the end of the study, 222 students participated in the data collection . AssessmThe study was carried out in accordance with the Declaration of Helsinki and the Research Ethics Committee of the University of Joinville Region approved this study .® digital scale  to the nearest 0.1 kg. Height was measured with a Cardiomed® stadiometer  to the nearest 0.1 cm. Waist circumference was measured midway between the lowest rib and the top of the iliac crest during the mid-expiratory phase. Hip circumference was measured with the tape at the widest portion of the buttocks. Neck circumference was measured horizontally above the cricothyroid cartilage with the tape not compressing the skin  to the nearest 0.1 cm.The anthropometric measurements were made in the morning after an overnight fast, with the subjects wearing light clothing and no shoes. The adolescents were weighed on a Filizolathe skin . All cir® skinfold caliper  was used to measure triceps and subscapular skinfold thickness at a pressure of 10 g/mm2 over the contact surface area to the nearest 0.1 mm. Triceps skinfold thickness was measured on the back of the arm and at a point midway between the acromion and olecranon process. With the arm hanging loosely, subscapular skinfold thickness was measured 2 cm below the inferior angle of the right scapula. All anthropometric variables were measured three times and the arithmetic mean of these measurements was used as the final result.A Cescorf2)] following the classification of the World Health Organization for the calculation of BMI according to age and sex .Body mass was evaluated by calculating the BMI . All measurements were performed in a laboratory accredited by the Brazilian Society of Clinical Analysis.Fasting glucose, LDL-c, and HDL-c were analyzed by colorimetric enzymatic methods on the Bayer ADVIA 1650 automated analyzer using the GLUO, D-LDL and D-HDL kits, respectively , version 22.0, was used for statistical analysis. Central tendency and absolute and relative frequencies were estimated as descriptive statistics. Continuous variables are reported as median and interquartile range. The chi-square test was used to compare the prevalence of categorical variables according to the presence of MetS. The Mann-Whitney Spearman correlation coefficients were calculated to evaluate the association of the anthropometric parameters with MetS score, MetS components and HOMA-IR. Multiple linear regression analysis was applied to analyze the relationship between the anthropometric parameters and MetS score. Since the anthropometric parameters showed skewed distributions, they were log-transformed. Multivariable linear regression models were developed adjusting for age, sex, physical activity and maternal education. The standardized regression coefficients from these models were used to compare the relative effects of the anthropometric measurements on MetS score, regardless of the anthropometric measurement units.We also carried out analyses to determine cutoff values of BMI, hip circumference, NC, triceps and subscapular skinfolds, and BF% to predict MetS. These cutoffs were determined by constructing receiver operating characteristic (ROC) curves for girls and boys separately. The area under the curve (AUC) was used as a measure of the diagnostic power of the test, considering the anthropometric measurements investigated. The greater the AUC, the greater the discriminatory power of the anthropometric measurement. Subsequently, the sensitivity  and specificity  were determined. The outcome, MetS score, was analyzed separately for each anthropometric parameter . Statistical significance was defined as p < 0.05.U test showed no significant difference in maternal education or BMI  between adolescents enrolled in the first and second phases. Excess body weight (overweight and obesity) was observed in 20.3% of the participants and 7.2% had MetS. All analyses were conducted in the second phase of the study (n = 222), corresponding to individuals who returned the consent form of the first phase . The Mann-Whitney The Spearman correlation coefficients of all anthropometric parameters were positively correlated (p < 0.001) with MetS score and HOMA-IR. The correlation coefficients of MetS score (rho = 0.46), triglycerides (rho = 0.21), waist circumference (rho = 0.81) and HOMA-IR (rho = 0.39) with BMI were higher when compared to the other anthropometric parameters . However, SBP (rho = 0.41) and HDL-c (rho = −0.39) showed a higher correlation with NC than with BMI, hip circumference, triceps and subscapular skinfolds, or BF%.2) was higher for the regression analysis that included BMI when compared to any of the other anthropometric measurements  was higher than that reported in other studies involving Brazilian adolescents (2.6%) , IranianFew studies conducted on adolescents ,41 have Although BMI was the stronger predictor and showed higher accuracy in identifying MetS, the use of NC has advantages. For example, NC eliminates the need for a scale, stadiometer and undressing the subject, thus reducing the time necessary for evaluation and permitting to increase the number of subjects to be investigated . Given iThe use of sex- and age-specific criteria to identify adolescents with MetS was a strength of this study . AdditioAnother important strength of this study was the simultaneous association of multiple anthropometric measurements, including BMI, hip circumference, NC, triceps and subscapular skinfolds and BF%, with MetS in the same population of adolescents. This approach is important for clinical practice since it permits better comparison of different anthropometric indicators to diagnose MetS and to identify the best parameter to be used. Finally, this study has some limitations. First, its cross-sectional design does not allow conclusions about causality. Second, the lack of an international consensus classification of MetS in adolescents restricts the comparison of results between studies. Third, the small number of participants with MetS may limit the generalizability of our findings. Lastly, the MetS score derived in this study cannot be compared to other studies since it is sample specific.In conclusion, all anthropometric measurements were associated with MetS score, with BMI showing the strongest relationship. However, in situations in which the measurement of height and weight is not possible, NC might be an interesting surrogate measurement because it can be obtained only with a tape measure at no cost. Health professionals should be made aware of this important tool for predicting MetS, even in apparently healthy adolescents. Since risk factors for MetS progress from childhood into adulthood, early lifestyle interventions are important to reverse the rising trend of noncommunicable diseases in adolescents. This approach may help decrease or prevent the onset of CVD and type 2 diabetes in adulthood, thus reducing the economic burden for the public health system.


In the concrete manufacturing industry, a large amount of waste is generated. Such waste can be utilised in the production of more sustainable products with a low carbon footprint. In this study, concrete sludge, a difficult-to-utilise waste that is obtained from residual concrete by washing a concrete truck, was investigated. During washing, aggregates from the concrete mixture are separated, and the remaining insoluble fine particles combine with water to form concrete sludge. Dried and wet concrete sludge were used in the tests. Samples with different compositions were produced with dried and wet concrete sludge, cement, superplasticiser, and tap water. Seven cement pastes with different compositions were made by partially replacing cement with dried concrete sludge . In compositions with wet concrete sludge, cement was replaced by the same amounts as in the case of dried concrete sludge. The slump, setting time, and their changes with different amounts of concrete sludge were determined for fresh cement pastes. It was found that with different forms of concrete sludge, the technological properties of the mixtures change, and the setting time decreases. The density and compressive and flexural strength results were confirmed by SEM and XRD tests. The research results show that dry concrete sludge causes the deterioration of the mechanical properties of cement stone, while wet concrete sludge improves the mechanical properties of cement stone. However, it was found that replacing 5% cement with dry concrete sludge does not significantly affect the properties of hardened cement stone. In mixes with wet concrete sludge, the recommended amount of replaced cement is 10%, because the technological properties of the mixture are strongly influenced by larger amounts. Ecology, the environment, and sustainability are current topical issues . AccordiConcrete production volumes increase year by year. According to a published study, 915 million cubic metres of ready-mixed concrete was produced by nearly 30,000 concrete plants in 2018. The same study, carried out by the European Ready-Mixed Concrete Organisation, estimated that ready-mixed concrete producers in the organisation’s member countries used 260 million tonnes of cement . The amoCurrently, there is an active search for alternatives to natural materials used in concrete production. By-products that are obtained in other industrial areas during the production process could be used as alternatives to natural materials. Using such materials provides not only benefits to nature but also economic benefits ,17,18. MWaste is also generated in the concrete manufacturing industry, and it is possible to use these by-products in the production of various more sustainable products with a low carbon footprint . DespiteMost of the research into concrete waste has been performed with recycled aggregates and their use in the production of ready-mixed concrete, whereas particles with sizes below 5 mm have been researched less . Some reOther researchers received positive results by using concrete returned to the batch plant as an aggregate . They adOther researchers tried to use concrete sludge in the manufacture of precast concrete blocks. They used dry concrete sludge and washed sand from residual concrete processing systems and hardened the obtained composite cementitious material in a CO2 environment. Tests showed that the wall blocks made from this mix were carbon-neutral and sustainable.There were attempts to use concrete sludge from batching plants as a raw material in cement manufacturing . The tesResearchers also tried to use concrete sludge as a microfiller for mortars . They foResearchers also tried to use concrete sludge instead of cement to stabilise road foundation layers . PositivResearchers  tested iThis paper analyses the effects of wet concrete sludge and dry concrete sludge on the properties of hardened cement paste. The chemical and mineral compositions of the sludge were analysed. The thermal stability of the material and its fraction of volatile components were determined by means of thermogravimetric analysis. The slump flow and the setting time were determined for the cement paste, and the density and compressive and flexural strengths were determined for the hardened cement paste.Cement CEM I 42.5 R that meets the requirements of LST EN 197-1 [The density and dry solids content of wet concrete sludge were determined. This was carried out according to LST EN 1008-2005 .3. The dry solids content of the sludge was 500 kg/m3. The pH of the wet sludge, determined according to LST ISO 4316:1997 [The density of concrete sludge used for the tests was 1220 kg/m316:1997 , was 11.The particle size distribution analysis of dry concrete sludge revealed that particles with an average size of 15.85 µm prevailed in the tested sludge. At 10%, the particles were 3.35 μm; at 50%, they were 10.18 μm; and at 90%, they were 12.88 μm. The size of CEM I 42.5 R particles ranged from 0.1 to 70 μm. The particle diameter was 0.75 μm at 10%, 7.88 μm at 50%, and 39.66 μm at 90%. The mean particle diameter was 14.21 μm. The cement pastes were prepared according to the mix design in After mixing, the fresh pastes were cast in 160 × 40 × 40 mm steel moulds and compacted on a vibrating table for 20 s. After compacting, all specimens were left for 12 h at an ambient temperature of 20 ± 2 °C and then demoulded and placed under water at a temperature of 20 ± 2 °C. All specimens were cured under water for 28 days.The dry method was used to determine the specific surface area and particle size distribution of dry concrete sludge particles using the particle size analyser Cilas 1090 LD in the interval from 0.01 µm to 500 µm using air as a carrier. The particles were dispersed by ultrasound until a 12% distribution of the material in the media was reached. The measurement span was 60 s. A standard operating system (Fraunhöfer) was used.The XRD analysis was conducted with an X-ray diffractometer . The following XRD parameters were used: CuKα radiation, Ni filter, detector step of 0.02°, intensity measuring span of 0.5 s, anode voltage Ua = 40 kV, and current I = 40 mA. The accuracy of XRD measurements was 2θ = 0.01°.X-ray fluorescence spectroscopy was performed with a spectrometer (Bruker X-ray S8 Tiger WD). A Rh target X-ray tube was used with an anode voltage of up to 60 kV and a current (I) of up to 130 mA. The specimens were measured in a helium atmosphere. The SPECTRA Plus QUANT EXPRESS method was used for the measurements. The microstructures of the materials were observed with a scanning electron microscopy (SEM) device  GmbH, Freising, Germany).The compositions of hardened cement pastes are presented in The main properties of concrete were determined according to the following standards: LST EN 12350-5:2019 for the slump flow , LST EN The following materials were identified in the XRD spectra of dry concrete sludge: 36% calcite, 16% portlandite, 14% dolomite, 11% quartz, 7.6% kuzelite, and 3.8% ettringite. The microstructure of concrete sludge was observed using the Helios NanoLab 650 SEM instrument. The obtained physical property results of dry concrete sludge are presented in Thermogravimetric analysis was carried out for dry concrete sludge. The analysis results revealed an intensive endothermic effect and mass loss of about 13% at a temperature between 100 °C and 200 °C. These results can be attributed to the loss of hydrated water in cement minerals and the decomposition of ettringite and monocarboaluminate. The decomposition of ettringite, with about 9% weight loss, shows an endothermic effect in the temperature range of 100–140 °C. Such results confirm the XRD data in which the presence of ettringite and kuzelite is identified . HoweverThe slump flow tests of cement paste are presented in The initial setting time of the specimens with both dry and wet concrete sludge decreased with a higher sludge content in the specimens. It was observed that the change in the initial setting time was very similar irrespective of the form of concrete sludge added to the mixtures. This can be explained by the presence of a significant amount of calcite in the sludge, as calcite is known to decrease the setting time . A decreTo determine the difference in the chemical compositions of samples without concrete sludge and with dried and wet concrete sludge, XRD analysis was performed. Specimens with no additive, with 10% dry concrete sludge, and with 10% wet concrete sludge were tested. The tests showed that all the samples consist of portlandite, calcite, dolomite, ettringite, and CSH. Only the amounts of these compounds in the samples differ. The results are shown in The amount of portlandite in all of the samples, despite different cement contents, is almost the same, but with a tendency to increase in compositions with sludge, and it is around 41–45%. This may mean that portlandite from sludge can additionally contribute to the portlandite amount in a sample. However, bearing in mind that the amount of portlandite, according to the results of X-ray analysis calculations for dry sludge , is 16%,3S and C2S were detected; in the first sample, without concrete sludge, there was 15.4%; in the second sample, with dried concrete sludge, there was 9.5%; and in the third sample, with wet concrete sludge, there was 5.6%. This decrease in C2S and C3S is obvious, because the amount of cement was decreased in the samples with sludge. However, in the sample with wet concrete sludge, unreacted C2S and C3S is almost 1.7 times lower than in the sample with dry concrete sludge. This result shows that the hydration of cement minerals in the presence of wet sludge takes place much more actively. The amounts of ettringite are also different. The amounts of ettringite for the same time CSH-type mineral amounts in the samples with concrete sludge are different: 2.7% in the sample with dried concrete sludge, 5.9% in the sample with wet concrete sludge, and 3.2% in the control sample. This may mean that wet concrete sludge promotes CSH-type mineral crystallisation. It seems that wet conditions in the wet sludge promote more active cement mineral hydration, which may be due to a specific layer of water covering sludge particles. In the control sample, no quartz is obtained. In the samples with sludge, some amount of quartz is identified. Dolomite is obtained in all three samples, but in the samples with sludge, the dolomite amount is about 3 times higher than in the control sample.In different samples, similar amounts of calcite were found: 20.3% with dried concrete sludge, 18.1% with wet concrete sludge, and 23.0% in the control sample. These results show that in the sample with wet concrete sludge, more calcium ions participate in the hydration products’ crystallisation process. Different amounts of non-reacted C3 in comparison to the control specimen, whereas the density of the specimens in which 30% of cement was replaced with wet concrete sludge increased by 88 kg/m3. This could have happened due to the wet concrete sludge’s density; because the sludge is denser (1220 kg/m3) than the used water, a lower slump flow also creates denser microstructures of specimens. Additionally, it can be noticed that the amount of ettringite is lower in specimens with wet sludge than in specimens with dry concrete sludge.Density tests on the specimens with dry and wet cement sludge  showed tAs with the density results, the strength results revealed different trends in the moulded specimens containing dry and wet concrete sludge. These trends are visible in There was a slight drop in compressive strength when 10% of cement was replaced with dry concrete sludge. In comparison to the control specimen, the compressive strength was reduced by 3.6 MPa. In the specimens in which 30% of cement was replaced with dry concrete sludge, the compressive strength was reduced by 19.5 MPa. On the contrary, in the specimens in which wet concrete sludge replaced different amounts of cement, the compressive strength increased. When 60% of wet concrete sludge (or 30% of dry matter) was added, the compressive strength increased by 19.7 MPa compared to the control specimen.The same trend was observed for the flexural strength from the test results illustrated in Both the compressive strength and the flexural strength of the specimens containing dry concrete sludge decreased significantly, presumably due to the dilution effect  and moreIn this research, the possibility of partial cement replacement by wet and dry concrete sludge was studied. The slump flow, setting time, created structure, and physical–mechanical properties of cement stone have been analysed. The following conclusions were made after conducting the research.The flowability of the cement paste increased in proportion to the amount of cement replaced with dry concrete sludge. When 30% of cement was replaced with dry concrete sludge, the flow rate increased by 56.7%. In cement paste with wet concrete sludge, on the contrary, the flowability of the cement paste decreased. When 30% of cement was replaced by wet concrete sludge, the flowability of concrete was reduced by 45.3%.The results of the setting time in the pastes with dry and wet concrete sludge showed that both dry and wet concrete sludge shortened the setting time. The greater the amount of concrete sludge added, the shorter the setting time. Compared to the control specimens, the setting time of the specimens modified with dry concrete sludge was shortened by 56 min, and in the specimens with wet concrete sludge, the setting time was shortened by 46 min.2S and C3S amounts were 1.7 times lower than in the sample where cement was replaced with dry concrete sludge, but the amounts of CSH-type compounds were 2 times higher. This result shows that wet concrete sludge promotes the hydration of cement and CSH-type mineral crystallisation.XRD analysis shows that portlandite from sludge increased the portlandite amount in specimens and participated in hydration processes. In the sample where cement was replaced with wet concrete sludge, unreacted CThe replacement of cement by dry concrete sludge decreased the density by 4.1% when 30% of cement was replaced in comparison to the control specimen, but the replacement of 30% cement by wet concrete sludge, due to the higher sludge density, increased the specimen density by 4%. In comparison to the control specimen, increasing the replacement of cement by dry concrete sludge decreased the compressive strength of the specimen by up to 32.7%, whereas increasing the replacement of cement by wet concrete sludge increased the compressive strength of the specimen by up to 1.32 times. The strength of the specimens with wet concrete sludge increased due to the denser structure and the promoted hydration of cement. The results of the flexural strength indicate the same trend as was observed for the compressive strength.It was found that a small amount of cement, up to 5%, can be replaced with dry concrete sludge, whereas the optimal amount of cement replaced by wet sludge is 10%.


Castleman’s disease (CD) is a rare disease that has clinical and pathological similarities to lymphoma and is characterized by a high frequency of associated immunological dysfunction. ImmunoglobulinG4-related disease (IgG4-RD) is a collection of systemic disorders that affect numerous organs and are also referred to as IgG4-associated sclerosing diseases. CD and IgG4-RD are difficult to separate because they may manifest similar commin clinical features.This case describes a 53-year-old female who, during routine medical check-up, exhibited a progressive increase in serum globulin levels and a simultaneous worsening of anemia symptoms, raising concern for a clonal plasma cell disease such as myeloma. However, bone marrow punctures did not reveal any abnormal plasma cells. Also, serum and urine immunofixation electrophoresis demonstrated no abnormal monoclonal protein bands. In addition, several laboratory findings excluded chronic liver disease, chronic infections caused by bacteria or viruses. Later, we found elevated serum IgG4 levels , and identified multiple enlarged lymph nodes throughout the patient’s body. Axillary lymph node aspiration revealed no abnormal lymphocytes, ruling out the possibility of lymphoma. Pathological morphology of the axillary lymph revealed a large number of plasma cells in the lymphatic follicles. In addition, there was a reduction in lymphatic follicle size and apoptosis of the germinal centres. Immunohistochemistry revealed IgG4+/IgG + in > 40% of cells, and more than 100 IgG4 + cells per high powered field (HPF) of specimen. As of now, finding strongly suggested IgG4-RD. This patient was treated with glucocorticoids and various immunosuppressive drugs, such as prednisone, cyclosporine, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine and hydroxychloroquine. Unfortunately, the patient did not recover. Ultimately, idiopathic multicentric Castleman disease (iMCD) was diagnosed in relation to the patient’s clinical presentation and laboratory tests, and after combination chemotherapy , durable remission was achieved without serious adverse effects. During the follow-up period of one year and ten months, the patient remained stable.The diagnosis of Castleman must be distinguished from other disorders such as IgG4-RD, malignant lymphoma, reactive hyperplasia of various lymph nodes , plasmacytoma, advanced HIV and rheumatic diseases. Besides observing systemic symptoms, laboratory tests such as immunoglobulin levels, complement levels, interleukin levels, and C-reactive protein levels should also be performed in order to determine a diagnosis. Benjamin Castleman described a clinically rare benign lymphoproliferative condition in 1954, called Castleman disease (CD), characterized as either unicentric Castleman disease (UCD) or multicentric Castleman disease (MCD), depending on the extent of lymph node involvement . There aThe plasma cell type is characteristic of most cases of MCD, which are frequently accompanied by systemic inflammation, fever, anemia, diffuse lymphadenopathy, cytopenia, and even life-threatening multi-organ dysfunction . The majIn 2012, an international multidisciplinary study group approved the term ‘IgG4-RD’ that describes a fibro-inflammatory disorder with elevated serum IgG4 levels and plasma cells with IgG4 + staining in inflammatory lesions , 10. DifIn October 2013, an asymptomatic 46-year-old female was found to have elevated total protein (TP:99.3 g/L) and globulin (GLB:63.6 g/L) during laboratorial investigation. At the same hospital outpatient clinic, immunoglobulin levels  were also elevated. However, peripheral blood immunophenotyping by flowcytometry (CD38 + CD56-CD45dim:0%), the levels of anti-nuclear antibody and immunofixation electrophoresis were all within normal limits. The patient refused admission to hospital, and over the next two years, regular follow-up examinations revealed a gradual increase in TP and GLB levels, but still no symptoms . The patient currently suffers from severe hyperglobulinemia persisted with high levels of serum IgG . Fluorodeoxyglucose positron emission tomography (FDG-PET) indicated diffuse increased 18 F-FDG metabolism in bone throughout the body, splenomegaly with increased 18 F-FDG metabolism, multiple lymph nodes of variable size in the bilateral neck, submandibular, mediastinal, axillary, bilateral hilar, peritoneal, retroperitoneal, bilateral parietal iliac vessels and inguinal areas with increased 18 F-FDG metabolism  between November 2020 and October 2021. Following the completion of the full treatment regimen in October 2021, the patient’s serum levels of GLB, IL-6, and CRP decreased significantly and Hb returned to normal  clinical signs of diffuse or characteristic enlargement, tumors, nodules, or hypertrophy of an organ or multiple organs, (ii) serum IgG4 + > 135 mg/dl, or (iii) high levels of IgG4 + plasma cells . The presence of two or more of the above factors may lead to the diagnosis of IgG4-RD .Both share the common feature of dense lymphoplasmacytic infiltrates and a high proportion of IgG4-bearing plasma cells with a high serum IgG4 level. IgG4-RD shares similarities with Castleman disease, however, there are also differences: (i) Systemic symptoms: IgG4-RD commonly accumulates in multiple glandular organs such as the parotid, lacrimal and salivary glands and the pancreas, and it can occur alone or in association with IgG4-related disease in other organs –18. iMCDThis patient has recurrent fever and rash with generalized symptoms such as malaise, chest tightness, anxiety, insomnia and lethargy, no other glandular involvement, no sensitivity to glucocorticoids or immunosuppressive drugs, and markedly elevated serum IL-6, CRP, IgA, IgM, IgG . Despite the fact that the pathology supported the diagnosis of IgG4-RD, the IgG4+/IgG + plasma cell ratio had just exceeded the 40% threshold. Interestingly, the ratio of IgG4+/IgG + plasma cell decreased dramatically when tested again at another hospital, and as a result, the 40% cut-off point cannot be used with certainty as a gold standard for differentiating iMCD from IgG4-RD, but rather only as a proposal . IgG4-RDWhen selecting treatment for iMCD patients, the severity of the disease must be taken into consideration. However, regardless of disease severity, first-line treatment should primarily focus on anti-IL-6 directed therapy , 20. For


Immunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disorder characterized by tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. We report the case of an 84-year-old male who presented with a history of dyspnea on exertion and cough. The lymph nodes were palpated in the axilla. Urinalysis revealed mild proteinuria and increased levels of NAG and β2-microglobulin. Blood tests showed hyperglobulinemia with a marked elevation of serum IgG4 levels. Chest computed tomography showed bilateral ground-glass and reticular opacities in the lower and peripheral portions of the lungs. Ga-67 scintigraphy showed kidney uptake. The patient was diagnosed with IgG4-related kidney disease based on the renal pathology indicative of typical tubulointerstitial nephritis with extensive IgG4-positive plasma cell infiltration. The patient was treated with prednisolone and showed a prompt response in his clinical condition. The patient achieved normalization of serum IgG4 levels 6 months after the initiation of treatment. Although IgG4-related disease is thought to be potentially associated with organ fibrosis, there are few reports on combination of interstitial pneumonia and IgG4-related kidney disease. Our case report presents a possible pattern of IgG4-related disease. Respiratory organ lesions have also been recognized; however, their rate is low and they are often only detected during close examination. Clinical symptoms vary depending on the organs affected by IgG4-related disease; however, they are usually mild. Thus, IgG4-related disease should be diagnosed based on a combination of clinical, serological, and radiological findings, and pathological features. There have only been a few reports on the coexistence of interstitial pneumonia and IgG4-related kidney disease. In this report, we describe the case of a patient who presented with interstitial pneumonia and was diagnosed with IgG4-tubulointerstitial nephritis and IgG4-related kidney disease. Treatment with prednisolone was initiated soon after diagnosis and the patient responded well.Immunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disease characterized by extensive lymphoplasmacytic infiltration of IgG4-positive cells in various organs.2. Initial laboratory and diagnostic workup revealed blood urea nitrogen 18 mg/dL , creatinine 0.98 mg/dL , estimated glomerular filtration rate 56 mL/min/1.73 m2 , calcium 9.4 mg/dL , total protein 9.1 g/dL , albumin 3.6 g/dL , alkaline phosphatase 60 IU/L , aspartate transaminase 27 IU/L , alanine transaminase 11 IU/L , total cholesterol 182 mg/dL , triglyceride 175 mg/dL , WBC 11.5×103/μL , RBC 3.97×106/μL , hemoglobin 12.5 g/dL , platelets 200×103/μL , eosinophils 3% , and urinalysis negative for protein, RBC, and cell casts. Urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine 17.1 IU/gCr  and urinary β2 microglobulin 371 mg/L . Antineutrophil cytoplasmic antibodies screening was found to be negative, with low C3=68 mg/dL, low C4=7.4 mg/dL, and negative for anti-SSA, anti-SSB, anti-RNP, Scl-70, anti-Sm, and ds-DNA antibodies. Antinuclear antibodies (ANA) antibodies were found to be ×1280. Hyperglobulinemia was determined with an IgG level of 3719 mg/dL  and an IgG4 level of 1290 mg/dL . Rheumatoid factor (≤15 IU/mL) was elevated at 24 IU/mL, and KL-6 (<500 IU/mL) was significantly increased at 623 IU/mL. Computerized tomography (CT) revealed bilateral ground-glass and reticular opacities predominantly in the lower and peripheral portions of the lungs -produced Castleman’s disease and autoimmune disorders., The discrepancy between these findings can be owing to the presence or absence of contrast-enhanced CT, which is necessary within renal function tolerance. Ga-67 scintigraphy and FDG-PET have been reported to be useful for its diagnosis. However, contradictory to the present case, positive accumulation in the kidney during Ga-67 scintigraphy has been reported to be only 11%. Another useful method of analysis for IgG4-related kidney disease is T2-weighted and diffusion-weighted MR imaging.Similar to the present case, approximately 30% of the patients diagnosed with IgG4-related kidney disease do not show any abnormality on a CT scan. In contrast, previous reports indicated that approximately 70% of patients with IgG4-related kidney disease show some kind of abnormality. The ground-glass opacity and diffuse reticular patterns potentially suggest lymphocyte and plasma cell infiltration of the alveoli and interstitium. Bronchial wall thickening pattern indicates plasma cells infiltration of the bronchial vascular bundles, alveoli, and interstitium. Finally, nodular sclerosing inflammation of the bronchial glands was prominently observed to be associated with the nodular pattern. However, in some lymphoproliferative diseases other than IgG4-related diseases, similar findings are seen on chest imaging or histopathology, and it is difficult to differentiate them from respiratory involvement of IgG4-related diseases, suggesting that respiratory involvement of IgG4-related diseases should be diagnosed comprehensively from the clinical picture, imaging findings and pathological aspects. Furthemore, relatively good response to corticosteroid has been reported for the treatment of IgG4-related lung lesions. Although we did not perform a lung biopsy in the present case, the CT findings of diffuse reticular and bronchial wall thickening confirmed pulmonary involvement in IgG4-related diseases.CT imaging findings of the lungs in IgG4-related diseases have been classified into four types: ground-glass opacity, diffuse reticular, bronchial wall thickening, and nodular patterns., Furthermore, our previous reports also indicate that the inflammatory cytokines play a potentially pivotal role in the development of renal fibrosis. T helper cells type 2 (Th2) and regulatory T cells (Tregs) have been reported to be involved in IgG4-related tubulointerstitial fibrosis. Treg cells can increase the regulatory cytokines, such as transforming growth factor-β (TGF-β), which has also been identified in renal fibrosis signaling., However, many aspects of this disease, especially complications caused by interstitial pneumonia, remain unclear with limited reports on this disease type; hence, further studies are warranted.Inflammatory cytokines, such as IL-5 and tumor necrosis factor (TNF)-α, reportedly correlate with IgG4-related diseases.et al. showed that the induction of prednisolone led to rapid improvement in renal function and serological abnormalities 1 month after the initiation of therapy, and that maintenance therapy with low-dose prednisolone successfully resulted in long-term suppression of disease activity in 43 Japanese patients with IgG4-related kidney disease.The optimal treatment for IgG4-related kidney disease has not been established; however, most patients, including the one in the present case, respond to prednisolone. SaekiSimilar to the present case, even in patients without diagnosis of renal localized IgG4-related disease, favorable outcomes can be achieved with the same treatment modalities as those employed for the patients diagnosed with the disease.IgG4-related kidney disease is an emerging disease with recently identified pathological features. Generally, patients respond rapidly to prednisolone and present a relatively favorable prognosis. The present case of IgG4-related kidney disease associated with interstitial pneumonia provides a novel rationale for its pathophysiology.Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.The study protocol for the patient record review was reviewed and the need for approval was waived by Institutional Review Board of Osaka Medical and Pharmaceutical University, as a retrospective review of patient data did not require ethical approval in accordance with local guidelines. The authors have revised appropriately.Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?PartlyIs the background of the case’s history and progression described in sufficient detail?YesReviewer Expertise:diabetic kidney diseaseI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This case report presents an IgG4-related disease complicated by pulmonary involvement. The association with pulmonary lesions is discussed as a novel finding.Are there any other findings besides imaging that can be evaluated in relation to steroid therapy? Physical examination, walking distance, oxygen saturation, pulmonary function tests, and even other blood tests would be acceptable.Can you discuss more about IgG4-related diseases and pulmonary involvement? For example, the classification and frequency of interstitial pneumonia, the prediction of steroid response, and whether the findings are predictive of recovery of renal function. Please allow me to ask the following questions to improve the paper and make it more meaningful to the reader:Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?PartlyIs the background of the case’s history and progression described in sufficient detail?YesReviewer Expertise:kidney disease, acute kidney injury, chronic kidney diseaseI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. The quality of microscopy findings of renal biopsy seems to be poor.Please describe in more detail how to differentiate normal IP from IgG4-related lung disease in the absence of lung biopsy findings.Please describe any differences from previous reports in cases of IgG4-related renal and respiratory disease.This case report is well written. However, I suggest the authors to respond to the following comments:Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?PartlyIs the background of the case’s history and progression described in sufficient detail?YesReviewer Expertise:diabetic kidney diseaseI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. This case report focuses on the topic that interstitial pulmonary diseases are a rare complication of IgG4-related diseases. As the authors acknowledge, lung biopsy was required for showing IgG4 cells infiltration in interstitium of lungs, and therefore the pathological association between lung and kidney may not be evident. This reviewer was curious about changes in KL-6 after steroid treatment.Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?YesIs the background of the case’s history and progression described in sufficient detail?YesReviewer Expertise:CKDI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Key messageSevere hypereosinophilia may be a modifying factor in IgG4-related disease.Dear Editor, IgG4-related disease (IgG4-RD) is a fibroinflammatory disease characterized by elevated serum IgG4 levels and organ enlargement . The patient tested negative for ANA, MPO-ANCA, and PR3-ANCA. Serum levels of C3 and C4 were significantly decreased . The patient’s bone marrow biopsy results did not indicate haematologic disease, and chromosomal abnormality was not found.  kidneys . Further kidneys . In addi kidneys . Based o kidneys . In addiWe concluded that the patient’s symptoms were attributable to the overlap of IgG4-RD and hypereosinophilia. He was treated with a 3 day course of CS pulse therapy , followed by oral prednisolone , after which his fever disappeared. In addition, improvements were noted in fever, eosinophilia, liver involvement and renal involvement.This patient showed severe eosinophilia , persistent fever and acute multi-organ involvement. Previous research has indicated that patients with IgG4-RD often show a mild to moderate degree of eosinophilia . TherefoThe patient’s pathological and PET/CT findings suggested IgG4-RD. However, considering his atypical findings of IgG4-RD, the pathology of our patient seemed to indicate the presence of composite factors in addition to IgG4-RD. Although our patient had no history of allergies before hospital admission, he experienced anaphylactic shock immediately before treatment with CSs. This event and the high elevation in serum eosinophil count suggest an overlap of IgG4-RD with hypereosinophilia. Thus, we hypothesized that over-activation of allergic reactions by unexpected causes can occur in patients with a chronic course of IgG4-RD, which might consequently lead to severe eosinophilia and simultaneous acute multi-organ involvement accompanied by fever.The present case suggests that clinicians should consider the existence of modifying factors, such as hypereosinophilia, when patients present with atypical IgG4-RD, even if pathological and imaging findings are consistent with those of IgG4-RD. Few cases of IgG4-RD associated with severe hypereosinophilia and/or eosinophilic ascites have been reported , 8. The


Multiple transformations—referred to as “waves” in a panoply of recent public health and law enforcement publications—have rendered North American drug markets increasingly toxic since the early 2010s. The introduction of exceptionally potent synthetic sedatives and stimulants is initiating a new generation of drug injectors into co-use of opioids and methamphetamine, catapulting rates of deadly overdoses and infectious diseases. Drawing on extensive participant-observation research in Philadelphia (2007-present) and Tijuana (2018-present), we document the experience of street-based drug users across these two North American cities to focus on regional shifts in narcotics supplies and endpoint user preferences. We link the dramatic proliferation of fentanyl, methamphetamine, xylazine, and Mexican white powder heroin to: 1) pre-existing drug supply networks on the western and eastern coasts of the North American subcontinent; 2) material characteristics of local heroin supplies in pre-fentanyl opiate markets (Mexican black tar vs. Colombian off-white powder heroin); and 3) racialized repression/incarceration of drug sellers and users on both sides of the Mexico-US border. The article combines economic and medical anthropology to develop an ethnographically-informed political economy approach to an urgent public health challenge among street-based drug users with the highest overdose mortality rates in the US Northeastern Rust Belt and the Northwestern Mexican borderland metroplex anchored by Tijuana. It foregrounds street users’ experiences in real time amidst rapidly shifting narcotics supply chains, linking market-driven logics of profit-seeking to the war on drugs’ prohibitionist policy context, highlighting increasing toxic impacts on vulnerable sectors across regions. Multiple transformations—referred to as ‘waves’ in a panoply of recent public health and law enforcement publications : 2—have Firstly, decades-old paradigms and practices of narcotics prohibitionism circumscribe the evidential basis and analytical scope of scholars and service practitioners in both public health and the social sciences. Law enforcement agencies produce flawed, belated surveillance reports on drug markets while restricting access to their raw data and criminalizing the efforts of independent researchers to collect information via participant-observation methods. Street-level police officers habitually harass social science ethnographers and public health outreach workers near open-air narcotics markets, detaining them for questioning and sometimes brutalizing and arresting them . Law enfSecond, researchers become understandably wary of sensationalist media and are reluctant to document the socioeconomic organization of narcotics markets. Some scholars mistakenly assume that detailed knowledge about drug economies plays a key role in policing and in the criminal justice system, and warn drug researchers that their findings may inadvertently contribute to punitive interventions. Internal review boards evaluating qualitative, non-clinical research on ‘human subjects’ regularly subject studies of drug markets to non-sequitur ‘ethical’ logjams, further deterring participant-observation research on criminalized practices. Longstanding intellectual traditions linked to humanism, liberalism, and even Marxism continue to steer scholars away from the study of criminalized practices as if they were undignified or ethically suspect.selling, mixing, adulteration, and transportation are relinquished to criminal justice agencies, especially the Drug Enforcement Administration (DEA) and local police forces. In other words, public health has been relegated to downstream management of individualized pathologies, while law enforcement agencies monopolize the upstream assessment of narcotics supply chains.A long-term effect of these dynamics is that mainstream public health and social sciences research on illegal drug use in the United States has narrowed its analytical scope to the realm of individual drug use behaviors. More specifically, the prevailing line of analysis in these fields revolves around micro-behaviors to be altered through the provision of services, information and silver-bullet technologies to individual users. Meanwhile, key questions of political and public health import concerning drug Yielding this upstream terrain to law enforcement agencies has proven disastrous for drug users and sellers alike. Despite a historically unprecedented explosion of powerful synthetic substances across North America in the 2010s and 2020s, the DEA has repeatedly bungled testing and supply monitoring and delayed or forbidden dissemination of its data. Due to its longstanding, racialized hypercriminalization of the petty dealer, the DEA exaggerates the responsibility of retail sellers for toxic adulteration of the product they sell e.g., : 7–8. ThPublic health, the humanities, and the social sciences have not pushed back against these developments with sufficient vigor or imagination. For example, at what level of the supply chain does fentanyl and/or xylazine enhancement actually take place? Public health should already have robust answers to this question instead of having passively ceded this terrain to law enforcement’s punitive logics. Anthropologists and other scholars with expertise in participant-observation methods and political economy analysis could significantly expand the reach of harm reduction by more systematically analyzing drug sales and supply chains in addition to users’ vulnerabilities and pharmacological preferences. Drug retailers represent an untapped potential conduit for population-level, structurally and culturally competent, micro-community-based, supply-level harm reduction priorities. The current division of labor in the production of knowledge about drugs, however, has forestalled unconventional interventions that would incorporate systemic knowledge of the socioeconomics of drug markets.This article brings together the study of macro and micro drug supply chains and the analysis of endpoint drug consumption by combining participant-observation ethnography and a close reading of the often inaccurate, always outdated, publicly available DEA surveillance data. We combine the tools of medical and economic anthropology to examine the recent shifts in the drug markets of two sentinel cities: Philadelphia and Tijuana, where we have long-term ethnographic and epidemiological collaborations.Most of the recent changes in North American narcotics markets involve the displacement of agriculturally produced substances such as poppy-sourced heroin and coca-bush sourced cocaine by the synthetic sedatives and stimulants fentanyl, xylazine, and methamphetamine. Drawing on team-based, participant-observation research among street-level drug sellers and injectors in both Philadelphia (2007–present) and Tijuana (2018–present), we reinterpret US local, state, and federal forensic drug monitoring reports from 2013–2022 to analyze how synthetic sedatives and stimulants, in combination with the fleeting supremacy of Mexican white powder heroin from 2014–2019, have transformed narcotics markets across the subcontinent—especially the US Northeastern Rust Belt and the Northwestern Mexican borderland metroplex anchored by Tijuana.Our findings link the dramatic proliferation of fentanyl, methamphetamine, xylazine, and Mexican white powder heroin to: 1) pre-existing drug supply networks on the western and eastern coasts of the North American subcontinent; 2) material characteristics and consumption logistics of local heroin supplies in pre-fentanyl opiate markets (Mexican black tar vs. Colombian off-white powder heroin); and 3) racialized repression, deportation, and incarceration of drug sellers and users on both sides of the Mexico-US border. We offer what we believe to be the first data-driven rebuttal to the DEA’s thesis that fentanyl adulteration takes place predominantly at the level of street retail. In sentinel distribution cities with open-air drug markets like Philadelphia, fentanyl enters the street supply at the level of local wholesale—two steps upstream from the level of street retail sales.The first major transformation in the last decade began in 2012/2013, when the synthetic opioid fentanyl entered heroin supply chains as a potency-enhancing adulterant . FentanyA second, simultaneous transformation received surprisingly little attention outside of relatively obscure and often inconsistent US Drug Enforcement Administration’s (DEA) annual reports monitoring wholesale and retail drug markets. Having reached the levels of quality and solubility to which heroin users had become accustomed in the eastern half of the United States, Mexican powder heroin supplanted Colombian heroin as the principal poppy-sourced opiate sold in that region between 2014 and approximately 2019 .A third change, occurring unevenly throughout the 2010s but accelerating in 2015, has involved the diffusion of highly potent, low-cost Mexican crystal methamphetamine across North America . This poFinally, starting in the late 2010s, several US cities with large, segregated Puerto Rican neighborhoods such as Philadelphia and parts of Connecticut witnessed the appearance of a new opioid enhancer, the veterinary tranquilizer xylazine . Known aThese shifts are having devastating economic and health impacts on the most vulnerable actors across the North American narcotics production and supply chain—notably, small farmer producers, unemployed polysubstance-using consumers, and racialized street retail sellers. They have been churned into profitably expendable fodder as a result of the ‘war on drugs.’ Critical medical anthropologists, geographers, and public health scholars have shown that prohibitionist interventions such as crop eradication programs in Mexico and South America fomented the shift by wholesale drug producers to fentanyl and methamphetamine production labs, paralleling the global industrialized for-profit logics of the legal economy . SynthetA key underexamined feature of the US war on drugs is the renunciation by state institutions to any active role in the quality control of public consumables. Heroin’s potency-enhancing adulteration with xylazine and synthetic fentanyl analogues serve as a vivid illustration of how drug prohibitionism has fomented a toxic regulatory regime negatively impacting laborers and consumers while enhancing capital accumulation. In the United States, Latin and African American street dealers (labor) are subject to incessant punitive policing and mass incarceration, while the investors and purveyors of wholesale narcotics at the local, regional, and international levels, including the financial institutions laundering narcotics profits  are left relatively untouched. Even a superficial skim of the US government’s official reports confirm that the narcotics seized by US law enforcement agencies are a mere drop in the bucket compared to the exorbitant quantities of narcotics reaching North American endpoint consumers annually. Most ironically, a complex machinery of financial regulation allows the profits from illegal narcotics sales to enter the banking system at relatively minimal economic cost or legal risk .Adulteration and potency enhancement are only one set of pharmacological marketing and production practices characterizing the ‘fourth wave’ of synthetic sedatives and stimulants. In addition to adulteration, this article will elaborate on other key practices—including diversification, substitution, counterfeiting, refinement, and supplementation—giving structural shape and political economic logic to US drug markets and shifting street-user preferences during the late 2010s and early 2020s. We link descriptions of each relevant substance to users’ accounts of their experience with those substances and discuss their public health impact. The article is divided into four sections, one for each substance . The first three sections contain two subsections, one for each of the two cities where we have conducted the most extensive, long-term participant observation.By far the least reported transformation in North American drug markets over the last decade was the displacement of Colombian powder heroin by Mexican powder heroin east of the Mississippi River between 2014 and approximately 2019. This change is also the most poorly understood. Inconsistent DEA data reports and faulty DEA testing and categorization methods since 2014 delayed awareness of the implications of this shift for both the US and Mexico by almost a decade. As early as 2011, the DEA’s annual Heroin Domestic Monitoring Program report noted in passing that Mexican powder heroin was ‘expanding… into markets traditionally dominated by SA heroin … in the eastern and midwestern US’ : 11. It This new heroin source-type was a significant technological innovation for Mexican producers, who formerly monopolized US markets west of the Mississippi with a visually distinct ‘black tar’ heroin formulation (gooey or waxy depending on temperature). Black tar continues to dominate most opioid markets in the western half of the United States, whereas Mexican powder heroin briefly overtook the eastern US until 2019 (assuming the DEA’s testing was accurate during those ‘MEX-SA’ dominated years).It is difficult to determine the exact moment when this change took place, but DEA reports claim Mexican powder heroin supplanted Colombian powder heroin east of the Mississippi by 2014. According to the DEA’s 2014 ‘Heroin Signature Program’ (HSP) report, based on data drawn from wholesale seizures (surpassing 1 kg) at the border and elsewhere throughout the country, Mexican powder heroin accounted for 58% (by weight) of the heroin analyzed by the program that year, whereas Colombian heroin had dropped to only 17% : 5. In cScholars, journalists, and government officials initially assumed that Mexican powder heroin was closely associated with fentanyl at the international wholesale level. DEA data on opioid confiscations from 2013–2020, however, show that Mexican powder heroin and fentanyl enter the United States along two distinct supply chains. In 2016, for instance, out of 395 large seizures of powder heroin analyzed by DEA’s HSP program, less than 2% contained fentanyl. None of the powder samples seized at Southwest border ports of entry contained any fentanyl : 10. On: 10. TheOur separate supply chain thesis is unambiguously substantiated at regional wholesale levels in the US Northeast. The DEA’s Philadelphia Field Division’s 2020 report detected no fentanyl in ‘all heroin seizures greater than five kilograms in Pennsylvania between 2017 and 2019’ : 5. LikeWhile DEA national and state-level reports repeatedly affirm that heroin’s adulteration with fentanyl occurs at the micro-retail street level  can elucidate the fuller range of circumstances driving such momentous transformations of the hemispheric heroin supply. The public health crisis and economic dislocations inflicted on the most vulnerable sectors among source-producers, transshipment points, and endpoint retailers and consumers have been overwhelming. For instance, it is likely that the highly refined form of Mexican powder heroin that transformed opioid markets in the eastern half of the United States requires smaller quantities of poppy paste for its production than traditional Mexican black tar. The crisis in poppy production in the Mexican states of Michoacan and Guerrero see  might haUsers and street sellers in Philadelphia are completely unaware that this particular change occurred. From 1991 to approximately 2014, heroin in the city remained almost exclusively Colombian origin. Nevertheless, users touted their product as ‘China white’ because of its slightly off-white powder appearance, consistent with Hollywood blockbuster film portrayals of 1970s–1980s Southeast Asian heroin. This imprinted loyal ‘brand recognition’ in opioid user nomenclature and mythology . It was For the first time since we started conducting research in Philadelphia, users in 2021 referred to heroin as ‘brown,’ a reference to Colombian off-white powder heroin that used to turn brown when mixed with water immediately prior to injection. The term ‘brown’ is now used interchangeably with the terms ‘heroin,’ ‘real heroin,’ and ‘dope-dope’ to differentiate ‘real’ heroin from the known adulterants fentanyl  and xylazine . The term ‘dope’ has become an ambiguous catchall term referring to heroin, fentanyl, and xylazine in any of their permutations. When asked in the spring of 2021 if they knew the origin of the ‘heroin’ they were injecting, users gave wildly varying answers ranging from Puerto Rico, Dominican Republic, and Colombia to distant China.The most surprising feature of the ‘fourth wave’ of synthetic opioids and stimulants has been the relative resilience of powder heroin in many towns and cities east of the Mississippi. It took five or six years for fentanyl to fully displace heroin from street drug markets in this part of the country. In the last DEA report listing municipal-level data (published in 2018 with data from 2016), 97% of Philadelphia’s retail samples were classified as ‘MEX-SA [Mexican powder heroin]’ with average purity of 64.7% : 15. ThiThe high purity levels of Mexican powder heroin in the Philadelphia opioid supply between 2014–2019 was reflected in users’ appreciation of the pharmacological effects of their ‘high’ during those years. Users reported ‘staying well,’ relaxedly free from opioid withdrawal symptoms, following habitual heroin injections for 7–8 hours, compared to 1–2 hours in other parts of the country such as the former mill towns of Massachusetts : 149. HeWhy did fentanyl not immediately supplant powder heroin in the opioid supply of cities like Philadelphia, Newark, and Atlanta? On the one hand, heroin simply continues to be a prized opiate. Veteran users of heroin in Philadelphia nostalgically describe the deep, holistic, full-body embrace of ‘brown,’ which offered them 8–12 hours of comfort before the onset of withdrawal symptoms. ‘I miss real heroin’ was still a common refrain in the spring of 2021. In addition, there is a competitive urban street-corner logistics to Philadelphia’s open-air drug market that fosters high quality levels in the retail supply. Street-based people who use drugs are concentrated in public spaces such as sidewalks, subway stations, and local parks. This urban logistics facilitates a robust information network sensitive to constant variations in corner-to-corner retail offerings. When asked how they select a particular corner to buy their drug of choice, a typical user replied: ‘We usually ask around like “what’s good” and “how long ago did you do it?” Because even if they give [free] samples in the morning and it’s good stuff, when you go back to buy it later it’s not always the same quality. So you’ve gotta ask everyone who’s doing it around you, “What’s good? What’s good?” and then “How long ago?” Depending on what they say, that’s where we go.’ This information network shapes demand, which in turn has a regulatory impact on supply, moderating local levels of adulteration.This collective regulatory impact remains limited, however, and no matter the romantic memories of ‘real’ 8–12-hour long heroin highs, fentanyl and xylazine pervade the contemporary heroin supply and are changing predilections for generational drugs of choice that also tend to be racialized. In mid-2021, users generally informed each other about which corner’s current supply most resembled heroin or ‘brown,’ versus which one was more ‘tranqy,’ versus ‘tranq-fentyn’ or ‘pure fent.’ Hence a statement by one user for an option that did not exist four years ago: ‘My favorite is tranq-fentyn with some brown.’The diversity of the opioid supply in Northwestern Mexico’s street markets distinguish them from US markets. While US markets are still loosely divided into a ‘black tar heroin’ West and a ‘powder dope’ East, street markets in Tijuana consistently offer both types, with white powder rising in popularity. Mexican users were initially unaware of the term fentanyl. Over the course of our fieldwork, the word ‘fentanilo’ became commonly used and often represented a term for sellers to advertise their product as having a high potency. Tijuana’s diverse supply may result from the city’s function as a major transit hub and storage zone for narcotics passing into the United States from different regions. Just as in the US, however, only powder heroin is habitually adulterated with fentanyl. On the contrary, black tar is a solid resin known as ‘goma negra’ that is logistically difficult to alter without transforming its color and consistency. While black tar has predominated for decades, white powder heroin, also known as ‘China white’ or ‘la china,’ arrived approximately in 2016. Users affirm that ‘la china’ has increased in potency and availability over the past five years.  In the street market, this powder is usually white, although it sometimes comes in shades of brown or even bright yellow or orange depending on cutting agents, processing methods, or dyes purposefully added for brand recognition.Healthcare providers link ‘China white’ to increased risk of overdose (OD) and soft tissue infections (abscesses). Tijuana injection drug users recognize the increased OD and other health risks, but simultaneously praise its psychoactive potency:china es muy mala, con la mitad de una 50 se puede doblar [with half a 50 peso bag you can overdose (50 pesos = US$2)]. The first time I used “la china”, I almost died. Well it’s not real China white, but that’s what they call it—it’s like fentanyl or some shit from the East Coast…I was surprised to see that when I got deported here [2 years prior]. But don’t get me wrong, that shit is strong, cause it’s just pure fentanyl or whatever. And it’s fun, I’m not going to lie. I’m fully into it now, it’s the only shit I use, unless they run out and I have to do black for a bit. And yeah, the China rots your body from the inside out, and that’s why you see all these people out here doblando [ODing] with flesh and bone hanging out, but the rush is just too good.’‘Man with goma I can do waaaaaay more, like almost 2 full [50 peso] bags. Pero la Marta, F, 45, injects opioids and methamphetamineStrong preferences are often expressed for both varieties of opioids. Older veteran drug users who have used black tar heroin for decades often prefer its psychoactive effects. They describe it as ‘more pure’ and ‘real heroin – not that fake crap [fentanyl].’ They also often claim it represents a safer choice, less likely to cause overdose and other health risks, including soft-tissue infection:doblando like twice a week…minimum! And plus, goma is just better. It’s got this better feeling to it…it’s a big difference. Yeah it’s more expensive, but it’s safer, and I’m not tryin’ to fuck around with that fake shit.’‘Look man, I’ve saved like 12 people with bloqueadores [Narcan] this year. And I’m always the one who has to do it, cuz I’m the one smoking black. But all these other fools out here are slamming china and Eduardo, M, 45, smokes and sniffs opioidsSeeking to maximize the psychoactive effect per peso spent on opioids, younger drug users typically prefer powder formulations. They universally describe ‘China white’ as the most potent option—even those who prefer black tar’s ‘warmer’ psychoactive embodied effects acknowledge ‘la china’s’ potency. It is usually described as shorter-acting, but some insist it staves off abstinence symptoms for just as long. This may reflect the distinct array and concentration of multiple fentanyl analogues (very short acting) that can be added into a base product of longer-acting poppy-based powder heroin. Although both varieties of opioids can be mixed with methamphetamine for a ‘speedy’ shot, China white is typically preferred for polysubstance use due to its superior solubility and ease of measurement and handling. Both can be smoked or injected, yet ‘goma negra’ is considered less wasteful to smoke because it releases psychoactive components efficiently when combusted.Unlike fentanyl or xylazine, Mexican methamphetamine entered the US market as a cheaper, autonomous product of purer and more potent quality than the stimulants formerly available in US inner-city street markets . It did not enter camouflaged as did the fentanyl sold ‘as heroin’ east of the Mississippi River . MexicanMexican methamphetamine, consequently, is poised to revolutionize street drug markets in the eastern half of the United States in coming years . The impRecent public health studies show that co-use of methamphetamine and opioids is growing rapidly across the United States . As we dConsistent with US patterns of segregation, these pathologies are unevenly distributed along the fault lines of race/ethnicity/indigeneity, gender, class, and sexual orientation . The higMexican methamphetamine took the Philadelphia open-air drug market by storm in 2020. A new meth user described the changes in May 2021:‘Methamphetamine just hit Philadelphia real hard this year. That’s like taken off. You got a totally different ballgame because now you got people who have been up for like 4–5 days, 6, 7, 8 days and they’re losing their mind, you know. They’re like talking to shadow people and by Day 7 they’re like siding with them, plotting and scheming with them. At first you really think it’s funny but it’s not. There’s guys out here that look like ballerinas. People can’t control their bodies, their movements, or what they do. Irrational thoughts turn into actions. You can’t tell yourself “No, don’t do it.” If you think something, your body just, your mind just does it. You know what I mean? Usually when you think bad things you just think bad things, but when a person’s been on meth for a while, when they think bad things they start doing bad things whether it’s like stealing from a friend or whatever. A lot of people are waking up in jail and they don’t remember what they did.’Mike, 28, White, opioid and methamphetamine injectorThe relative newness of methamphetamine outside LGBTQ+ venues in Philadelphia manifests in its uneven availability in open-air markets. While most sales spots in North Philadelphia/Kensington offer ‘dope,’ only about a third also offer methamphetamine. Users—predominantly Whites—list several reasons for their new methamphetamine ‘habits.’ Meth helps to counteract fentanyl’s contraction of the opioid high, providing users the necessary time and energy to find money to buy more ‘dope’ before the onset of overwhelming withdrawal symptoms:‘Fentanyl is so short-lived that we gotta get high every 6 hours. But sometimes, let’s say things were tough or whatever, if we were 10 hours in and you started getting sick, a nice shot of meth will hold you over for another 6 hours, as far as not being sick altogether. You just wouldn’t be as sick, I mean eventually it would turn against you but it would keep you feeling better to get up and make a move to make money.’Suzy, 24, White, opioid and methamphetamine injectorMethamphetamine meshes well with street-based users’ income-generating strategies, primarily trading sex for money (for women) and scrapping metal (for men). These are predominantly nocturnal activities:Mike: ‘Meth does its part too, because if you really don’t have the money, meth can keep you well for a little bit longer, it kind of will help you like, give you some time to gather up money to find some dope, you know what I mean? And you can stay up later, scheming to get money, or if you do your thing at night, boosting or whatever. I scrap, so a lot of my shit is nighttime stuff.’This relationship between opioid/sedative withdrawal symptoms and methamphetamine remains significantly underexamined in the field of public health. In cities with different supply chains  users reported being able to minimize long-term opioid withdrawal symptoms by using methamphetamine. In Philadelphia, however, users insist that methamphetamine injection provides only limited respite:Mike: ‘You’d be doubling down, basically. You’d be sending yourself to go into like The Hole, you know what I mean? Like you only get one extension [laughing]. That second one, you’re gonna be sketched in a hurry, you’re probably gonna be like… You’re gonna do something stupid or someone’s gonna help you eventually, like, it’s gonna go down.The second shot of meth isn’t like the first shot, as far as helping you. Now it’s like going against you. Now you’re kinda super wired and you’re like high and sick now, you know what I mean? You’re still not feeling as bad as you would have being dopesick, but like it doesn’t really like… Put it this way, you’re not even gonna want to do more meth. It’s gonna go down. You’re gonna figure it out [find a way to get more “dope”].’Fernando: ‘What if after those 6 hours you shot more meth?’Stimulant preferences differ across ethnic boundaries and manifest as forms of ‘intimate apartheid’ . The relglobos de cristal’ [methamphetamine balloons] are available for as little as 25 pesos (about US$1). It is widely available in conectas [sales points] across the city. For example, in extreme proximity to the US pedestrian border crossing, White US monolingual, English-speaking crystal meth consumers can be found smoking for hours on dilapidated couches in graffiti covered rooms. Entry-level workers in large US-owned maquiladoras (factories on the border producing numerous goods for export to the United States) reported using methamphetamine to help cope with long working hours and low wages that require many to work two or three jobs to make ends meet. It is commonly consumed by the friends, romantic partners, and other peripheral members of the opioid scene in Zona Norte [open-air markets near US pedestrian border-crossing]. Many local residents smoke methamphetamine for years before ultimately shifting to opioid- methamphetamine co-use.Methamphetamine is also used widely across Tijuana by numerous demographics, including regular consumers of street drugs and more casual recreational users. Cheap ‘cristal can also be an important, albeit low-cost, bargaining chip to negotiate a small taste from a more costly opioid shot prepared by others later on.Among the most marginalized, homeless opioid-using groups, especially Mexican deportees, who were the focus of our fieldwork, it was increasingly common (2018–2021) to mix small amounts of crystal methamphetamine into nearly every injection of ‘China white.’ However, the ratio of methamphetamine to opioids was small, often 1 part methamphetamine to 5–10 parts opioids. A typical user, consequently, might go through many bags of China white in a single day, while their globo de cristal might last several days. Chipping in a small touch of cristal claiming it ruins heroin’s soothing euphoria:Many reasons are given for the recent, widespread tendency to inject ‘speedies’ (injections combining opioids and methamphetamine). Many users report improved euphoria and increased delay of opioid withdrawal symptoms. Others assert that methamphetamine prevents opioid overdose, due to its stimulating effects. Nevertheless, a contingent of mostly older and exclusively black tar heroin consumers avoid ‘Nah man, I don’t touch that synthetic crap [methamphetamine]. I like my sleep. Plus, it ruins the high. Takes away all the relaxation and gives me anxiety. Look, I’ve been using heroin for over 30 years cuz I love the way it makes me feel. I know lots of people around here are using meth and switching to that fake China white stuff, but I don’t understand why you would want to ruin the best feeling in the world.’James, 55, male, White US monolingual English speaker, living in Tijuana for 20 years, injects only black tar heroinFentanyl has had a long, albeit intermittent, career in the US opioid supply . Its irrFentanyl has spread unevenly throughout the United States. It first proliferated on the East Coast , where iWhile fentanyl shipments from China were prominent in the initial stages of the ‘third wave,’ Mexican fentanyl production almost fully supplanted Chinese production in the mid-2010s : 14–18. Fentanyl is a particularly versatile product because it can act as an enhancer, a counterfeit, and a substitute for any other opioid, including heroin and opioid prescription pills. That said, experienced users throughout the eastern half of the United States have belatedly developed the ability to detect the presence (not the concentration) of fentanyl in the sedative supply through taste, texture, and quality and length of fentanyl’s initial opioid rush and subsequent high . There hFollowing 30 years of stability in heroin’s street retail price ($10/packet), adulteration with synthetic sedatives, primarily fentanyls but also xylazine, suddenly transformed the retail pricing structure of ‘dope’ in North Philadelphia in the late 2010s. ‘Dope’ packets dropped from $10 to $5 at most salespoints by mid-2021. From 2007–2018, ‘bundles’ of heroin  generally consisted of 10–14 $10 packets sold to street-level wholesale customers for between $100– $140. In mid-2021, ‘bundles’ of dope contained 16 ‘bags’ in postage stamp-sized glassine envelopes and only cost $80, sometimes discounted to $65–75. Meanwhile, the volume of retail bags remained constant at 0.03 grams : 54 but In 2021, a user gleefully described this 50% drop in the unit price:‘One street, Wind Street, they put nicks out [“nickles” or $5 bags] and they kind of spread like wildfire. I was used to getting 6 for $50, I get out of jail and go back to getting high and I couldn’t believe it. Bags were $5, I felt I was in like dope paradise.’Users’ celebration of ‘dope-paradise,’ however, is tempered by their recognition that the drop in prices also drives them to purchase more bags because they are now consuming opioids with a shorter metabolic half-life, requiring more frequent rounds of injection. Economically and pharmacologically, fentanyl in the mid-2010s—early 2020s evokes the sudden inexpensive access of crack in the mid- 1980s to early-1990s prompting profitable chronic consumption patterns .is also a respiratory depressant. Ethnographic and medical reports  while heavily sedated, and according to all users interviewed in the spring of 2021, more severe withdrawal symptoms. Even though its respiratory effects are weaker than fentanyl’s, xylazine  reports  reveal tg supply .In examining the recent, far-reaching changes to narcotics markets from the mid-2010s to mid-2021, in two very different cities on opposite sides of the North American subcontinent, this article seeks to shed light on underexamined features of the US ‘war on drugs.’ It argues for expanding the purview of social science and public health research beyond individual drug use behaviors to include other key actors and aspects of the wholesale-to-retail market supply chains. Social science researchers and public health practitioners are only just beginning to develop robust understandings of hemispheric, national, regional, local, and neighborhood-level supply chains. Translationally, they could leverage this knowledge to cultivate diverse applied strategies of non-punitive engagement with criminalized actors across narcotics supply chains to decrease harms. Public health and social scientists could innovatively transcend taboo “rule of law” hostilities against criminalized drug smugglers/sellers that bias most state officials, scholars, medical practitioners, service providers, and “human subjects” Internal Review Boards. We need to collect/analyze valuable complex upstream drug supply chain data to benefit vulnerable street-based drug consumers. By cultivating relationships with criminalized actors, a social science-informed public health could develop innovative upstream harm reduction interventions capable of regulating narcotics supplies and wresting resources and jurisdictional capacities away from the often incompetent, delayed, and ultimately punitive logics of law enforcement that promoted the inexpensive public availability of highly toxic synthetic street drugs across much of North America.