An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis.2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography.We quantified blood glucose levels and binding of the dopamine D11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[ This exImaging studies using a variety of methods have repeatedly found alterations in subcortical dopamine (DA) functioning in patients with SCZ, and the degree of dopamine dysfunction is related to the severity of positive as well as negative symptoms .An important aspect of brain dopamine is its role in mediating goal-oriented behavior. Glucose is the most important energy source for the brain. Thus, when food supply is scarce, mechanisms of glucose homeostasis and brain dopamine transmission must closely interact in attributing salience to perceptional stimuli and in reinforcing patterns of behavior that support an efficient exploitation of environmental energy sources. Disturbances in goal oriented behavior underlie many symptoms of SCZ. A disrupted interaction between brain dopamine signaling and glucose homeostasis thus is a candidate mechanism for better understanding the pathogenesis of SCZ.Increased dopamine signaling in the basal ganglia has been associated with improved metabolic functioning in healthy subjects . Accordi2/3 receptor agonist radioligand (+)-[11C]-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphthooxazin-9-ol ((+)-[11C]-PHNO) in healthy volunteers (HV) and drug-naïve patients with first episode psychosis (FEP) in SCZ or schizophreniform disorder using positron emission tomography (PET). Since (+)-[11C]-PHNO, is highly sensitive towards fluctuations in brain dopamine levels, (+)-[11C]-PHNO non-displaceable binding potential (BPND) values are to a large part a reflection of extracellular DA levels  was approved by the Ethics-Committee of the Medical University of Vienna and Austrian federal regulatory authorities. Forty-one HV and 29 FEP patients were recruited between 2013 and 2017. Patients were recruited at in- and out-patient units of the General Hospital of Vienna. All participants gave written informed consent before entering the study. Patients with FEP were judged as being competent to fully understand scope, risks, and inconveniences of study procedures by treating psychiatric specialists who were not involved in the study.2.2Participants were not required to fast before PET scans but rather to spend the day and hours prior to scanning according to their custom. Subjects were instructed to refrain from drinking alcohol for at least 24 h before PET scanning. If applicable, participants were asked to consume caffeine and nicotine within usual limits on the day of PET scanning.11C]-PHNO. Radiosynthesis was performed as described previously (68Ge source. All scans were corrected for decay to the time of radioligand injection. T1 and proton density (PD) weighted 3 T magnetic resonance images (MRI) were acquired for PET image co-registration and delineation of regions of interest (ROI).PET images were acquired on a GE Advance scanner  with a spatial resolution of six mm full-width at half-maximum (FWHM). Emission data were acquired over 90 min after bolus-injection of 302 ± 79 MBq (mean ± SD) (+)--PHNO BPND values. One cluster of particularly strong effect size was located in a midbrain region corresponding to the ventral tegmental area . A large cluster was located bilaterally in the ventral striatum and the ventral pallidum .Analysis of parametric maps (sex entered as variable of no interest) revealed two clusters of strong effects of the interaction between blood glucose levels and diagnosis on (+)--PHNO for assessing the relationship between brain dopamine signaling and glucose homeostasis in HV and drug-naïve patients with FEP. We observed strong positive correlations between blood glucose levels and subcortical (+)-[11C]-PHNO BPND values in HV. Since (+)-[11C]-PHNO BPND values are primarily reflecting brain extracellular dopamine levels, our data indicate that in HV, extracellular dopamine levels are high when blood glucose levels are low and vice-versa -[11C]-PHNO BPND values in HV but not in patients with FEP. A highly significant effect of diagnosis on the correlation between blood glucose and BPND values was revealed by the linear model analysis. The difference in the relationship of blood glucose and BPND values between HV and FEP patients was not only strong enough to offset the physiological positive correlation but resulted in a net negative correlation in FEP patients. The ROI analysis yielded analogous results with the effect being most pronounced in the right SN/VTA ROI. This is in line with the parametric maps analysis. However, the lack of association in the VST ROI as well as the generally lower levels of significance may be attributed to the heterogeneous behavior of the VST and GP which notably display regional specialization better captured by a voxel-wise approach In summary, for the first time, we show a differential relationship between blood glucose and D2/3 receptor availability in HV and medication naïve patients with FEP.We initially described two clusters of interaction between blood glucose levels and the (+)-[2/3 receptors availability in medication naïve FEP patients provides the unique possibility to study disease-specific phenotypes unaltered by antipsychotic medication. (+)-[11C]-PHNO is a D2/3 receptor agonist radioligand. It is sensitive towards competition with extracellular dopamine and allows for reliable estimation of binding potentials not only in neostriatal areas and the pallidum but also in the SN/VTA  and mTOR , where dopamine D2/3 receptor activation inhibits AKT phosphorylation which in turn decreases activation of mTOR. Phosphorylated AKT induces translocation of dopamine transporters on the cell surface, in turn reducing the dopaminergic tone -[11C]-PHNO was found to correlate positively with BMI -[11C]-PHNO is largely determined by extracellular dopamine levels being more susceptible to fluctuating on endogenous dopamine concentrations and preferential binding to D2/3 receptors in a high affinity state. Thus, notwithstanding slight differences in the physiological processes captured by the two methods, this supports the interpretation of our data, as low binding of [11C]raclopride (low receptor availability), and high binding of (+)-[11C]-PHNO (low levels of extracellular dopamine) would reflect a decrease in dopamine transmission, and vice versa. In our data, adding BMI as a covariate in the parametric maps analysis did not impact the results. This may be due to the narrow range of BMI values in our study population. There was a trend towards a higher rate of smoking in patients with FEP. This is in-line with previous investigations, where patients with SCZ consistently display higher rates of smoking than healthy controls -[with BMI . These scontrols . The acucontrols . In the  results . There w results . While ts in SCZ .. The VSsychosis .5In summary, our data give strong and robust indication of a disease-specific phenotype in SCZ, as the physiological interdependency of dopamine signaling and glucose homeostasis appears to be disturbed in medication naïve patients with FEP. Perturbation of the dopamine-insulin interplay in the brain may be a fundamental aspect of schizophrenic psychosis. It appears as though dopamine, physiologically necessary for movement and volition and typically associated with a catabolic state, and insulin signaling, typically excreted after the ingestion of food and associated with rest and an anabolic state, do not interact in a canonic way in FEP patients. The physiological relationship between dopamine signaling and glucose homeostasis is perturbed in FEP patients, possibly reflecting an underlying pathogenic alteration linking these seemingly unrelated aspects of schizophrenic psychosis.Ulrich Sauerzopf: Data curation, Formal analysis, Investigation, Validation, Visualization, Writing - original draft. Ana Weidenauer: Data curation, Formal analysis, Investigation, Project administration, Validation, Writing - review & editing. Irena Dajic: Data curation, Formal analysis, Writing - review & editing. Martin Bauer: Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Writing - review & editing. Lucie Bartova: Data curation, Investigation, Validation, Project administration. Bernhard Meyer: Data curation, Investigation, Software, Validation. Lukas Nics: Data curation, Investigation, Resources, Validation, Writing - review & editing. Cecile Philippe: Data curation, Investigation, Resources, Validation, Writing - review & editing. Sarah Pfaff: Data curation, Investigation, Resources, Validation, Writing - review & editing. Verena Pichler: Data curation, Investigation, Resources, Validation, Writing - review & editing. Markus M. Mitterhauser: Methodology, Resources, Validation, Supervision, Writing - review & editing. Wolfgang Wadsak: Conceptualization, Project administration, Methodology, Resources, Validation, Supervision, Writing - review & editing. Marcus Hacker: Project administration, Resources, Supervision, Writing - review & editing. Siegfried Kasper: Resources, Supervision, Writing - review & editing. Rupert Lanzenberger: Resources, Supervision, Writing - review & editing. Lukas Pezawas: Resources, Supervision, Validation, Writing - review & editing. Nicole Praschak-Rieder: Conceptualization, Data curation, Supervision, Validation, Writing - review & editing. Matthäus Willeit: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing - review & editing.This project was funded by the Vienna Science and Technology Fund , the Austrian Science Fund , the Anniversary Fund of the Austrian National Bank (Grant number. 16723), the Medical Scientific Fund of the Mayor of the City of Vienna (Grant number 15189), all granted to M.W.Without relevance to this work, M. Willeit declares to having received speaker honoraria and consulting fees from Janssen-Cilag Pharma GmbH, Austria. Without relevance to this work, W. Wadsak declares to havingreceived speaker honoraria from GE Healthcare, research grants from IpsenPharma, Eckert-Ziegler AG, Scintomics and ITG. WW is a part time eployee ofCBmed Ltd . and is a member of advisory boards of Amgen, Chieri and Sanofi-Aventis. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. S. Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP OrphanPharmaceuticals AG, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. U. Sauerzopf, A. Weidenauer, I. Dajic, M. Bauer, L. Bartova, B. Meyer, L. Nics, C. Philippe, S. Pfaff, V. Pichler, M. Mitterhauser, L. Pezawas and N. Praschak-Rieder have no conflict of interest to declare.


ReDS values with a cutoff of 28% predicted a pulmonary capillary wedge pressure > 15 mmHg with sensitivity 0.70 and specificity 0.75. Conclusions: An electromagnetic-based engineering ReDS might be a potential tool to estimate cardiac pressure in patients with heart failure, including those with small physics.Background: Remote dielectric sensing (ReDS™) is an electromagnetic-based technology used to noninvasively measure lung fluid levels. The association between ReDS values and invasively measured hemodynamics, particularly among those with small physics, remains unknown. Methods: Consecutive patients with chronic heart failure who were admitted to our institute and underwent invasive right heart catheterization as well as simultaneous ReDS measurement at clinically stable conditions between September and November 2021 were prospectively included. The colinearity between ReDS values and pulmonary capillary wedge pressure was studied. Results: In total, 30 patients  years old, 13 men) were included. Median ReDS value was 26% . ReDS values had a moderate collinearity with pulmonary capillary wedge pressure (r = 0.698,  Patients with chronic heart failure are at risk for downstream morbidity without optimization of medical therapy. Furthermore, the use of novel engineering may offer further clinical benefit in those with persistent congestion, where quantification of intra-cardiac filling pressures can be estimated and used as a surrogate to tailor medical therapies Recently, remote dielectric sensing  system, which is a novel electromagnetic-based engineering to quantify lung fluid volume noninvasively, has been clinically introduced . One priHowever, the association between lung fluid volume quantified by ReDS and intra-cardiac pressures measured by invasive right heart catheterization, particularly among those with smaller physics, remains unclear . ClinicaConsecutive patients who were admitted to our institute for worsening heart failure and received right heart catheterization to assess hemodynamics after hemodynamic stabilization between September and November 2021 were included in this single-center prospective study. Patients with mechanical circulatory support, unstable clinical condition including cardiogenic shock, or too large of body habitus to wear the ReDS system were excluded. The local ethical review board assented the present study and all of the participants signed informed consent beforehand.Invasively measured hemodynamics, ReDS values, and plasma B-type natriuretic peptide levels were all measured on the same day for all of the participants. Hemodynamic data including pulmonary capillary wedge pressure (PCWP) were measured using right heart catheterization in a standard manner by the heart failure experts. All of the procedures were performed via external jugular vein. All data were obtained at an end-expiratory timing. The procedures were performed and the obtained data were read by clinicians who were blinded on patients’ ReDS values. ReDS values were measured just before right heart catheterization, as detailed below.ReDS engineering was previously detailed . In brieWe performed Shapiro-Wilks test for all of the continuous variables and confirmed their normal distribution. Variables with non-normal distribution were converted to common logarithm. Nevertheless, given small sample size, we exhibited all of the continuous variables as median and interquartile. Categorical variables were exhibited as numbers and percentages. The primary aim of the study was the quantify association between ReDS value and PCWP. Secondary aims included the association between ReDS value and other clinical parameters such as mean right atrial pressure and plasma B-type natriuretic peptide level.Correlations were assessed using Pearson’s correlation coefficient. The impact of ReDS value on the PCWP level was investigated by linear regression analyses adjusting for 4 potential confounders irrespective of their statistical significance . Receiver operating characteristics analyses with a Youden test were performed to determine the ReDS value which best estimated a PCWP > 15 mmHg.p values less than 0.05 were considered significant.All of the calculations were performed in SPSS Statistics 23.0 software  and two-sided In total, 30 patients were included. Detailed baseline characteristics are displayed in p < 0.001; p = 0.001; Median ReDS value was 26%  and median PCWP was 12  mmHg. There was a moderate correlation between the ReDS value and PCWP .There was a moderate collinearity between ReDS values and mean right atrial pressure  and those with body height ≤ 155 cm (N = 17), respectively,  there was a moderate collinearity between ReDS values and PCWP values irrespective of several potential confounders; (2) a positive correlation remained among those with small physics; (3) ReDS values moderately correlated with mean right atrial pressure and had a weak but non-significant correlation with plasma B-type natriuretic peptide levels.An accurate assessment of pulmonary congestion is challenging given the lack of proven techniques to quantify lung fluid levels in granular detail  Chest X-ReDS is a recently introduced engineering that quantifies lung fluid amount . In patiThere was a moderate collinearity between ReDS values and PCWP. Although we should not equate that the presence of lung volume as a direct representation of intra-cardiac pressure, the ReDS system might be a hopeful non-invasive alternative to estimate intra-cardiac pressures without performing right heart catheterization.Similar findings were reported by Uriel and colleagues . They prIn our study consisting of smaller physics, a cutoff ReDS of 28% was associated with PCWP > 15 mmHg, which represents another cut point of clinically significant congestion in patients with chronic heart failure . Of noteOur cohort differed from prior studies as it relates to body size: median body mass index in our study was 22.9 whereas the mean body mass index in the study by Uriel et al. was 28.1 . In theiWe should reference both the ReDS system and right heart catheterization for a comprehensive assessment of clinical congestion in patients with heart failure. Of note, there are several patients with discordance between the two values, which may be explained by the differences in pulmonary vasculature and lymphatics in patients with chronic heart failure that in turn may affect the balance of intravascular and extravascular fluid volume. For example, some patients with low cardiac output with hypovolemia would have high PCWP and B-type natriuretic peptide levels but low ReDS. Cardiac unloading would be a suggested treatment, whereas aggressive diuretics therapy would rather decrease preload and cause cardiogenic shock.This study was comprised of a small sample size. Of note, our cohort was non-Western patients with small body size. Systolic function was relatively preserved in most patients. Applicability of our findings to those with other races and/or advanced systolic heart failure remains unclear. The ReDS system cannot distinguish other lung-occupying lesions including pneumonia and malignancies. We performed right heart catheterization following medical stabilization. Patients with decompensated heart failure in the acute phase during a period of aggressive diuresis were not studied. The existence of pulmonary congestion is more clinically obvious rendering the use of this technique less necessary, whereas situations of unclear clinical assessment could benefit from the ReDS system. We included variables that were considered to be potential confounders in the multivariable model. Some uninvestigated confounders might have been missed.A non-invasive electromagnetic-based technology ReDS may be a hopeful procedure in estimating intra-cardiac pressures in patients with chronic heart failure, even among those with small body size.


Mycobacterium bovis and that is endemic to livestock populations in most Latin American countries. Traditionally, bTB control programs are costly and targeted to cattle, largely disregarding other species such as swine and wildlife. According to official services, in Argentina disease prevalence in pigs is comparable to that observed in cattle, suggesting the need for efficient control programs to manage the disease in both species. Additionally, extensive farming systems, which are commonly practiced in Argentina, allow the interaction between livestock and wildlife such as wild boar (Sus scrofa), which is considered a natural host of the disease. Here, we evaluated the bTB pigs- cattle interface, studying the dynamics of M. bovis isolates in the pig population and identifying farm-level epidemiological variables associated with the disease confirmation at slaughterhouses. Additionally, to assess the potential multi-host systems in the transmission of bTB, the molecular characterization of wild boar mycobacterial strains was included in the study, as this interaction has not been previously evaluated in this region. Multivariable logistic regression models were used to assess the association between farm-level epidemiological variables  and bTB confirmation in pig tuberculosis-like lesions samples. Results showed that when cattle were present, the odds of bTB in pigs decreased 0.3 or 0.6% for every additional sow when cattle were present or absent in the farm, respectively. Pigs shared 60% (18/30) of the genotypes with cattle and wild boar, suggesting transmission at the interface between pigs and cattle and highlighting the potential role of wild boar in bTB maintenance. These results provide novel information about the molecular diversity of M. bovis strains in pigs in Argentina and proposes the potential relevance of a multi-host system in the epidemiology of bTB in the region. The statistical models presented here may be used in the design of a low cost, abattoir-based surveillance program for bTB in the pig industry in Argentina, with potential extension to other settings with similar epidemiological conditions.Bovine tuberculosis (bTB) is a disease caused mainly by the  Mycobacterium bovis (M. bovis) is the most prevalent etiological agent causing bTB. In developing countries, bTB is often a neglected disease with reemergence periods in domestic animals, wildlife, and humans, thus representing a public health concern  is a widely spread disease that causes far-reaching economic losses through direct impact on animal health, restrictions to trade, confiscation and destruction of meat, and costs associated with the implementation of control programs . Mycobac concern , 3. Beca coexist .Sus scrofa domestica) are susceptible to different mycobacteria, mainly those species included in the Mycobacterium tuberculosis complex (MTC) and in the Mycobacterium avium complex (MAC). In countries in which infection is endemic, M. bovis is the most frequently reported Mycobacterium in pigs , axis deer (Axis axis), gray fox , brown rat (Rattus norvegicus), opossum , and wild boar (Sus scrofa), no studies have been conducted to assess the epidemiological role of these species as reservoirs hosts . Contrarily, this program does not include swine, where bTB confirmation relies entirely on meat inspection at the abattoir, which arguably leads to an underestimation of Worldwide, several studies have addressed the association between bTB infection and farm-level epidemiological variables in livestock –19, but With this background, an observational  analytic study was conducted under the hypotheses that: (1) the interface between pigs and cattle plays an important role in the dynamics of bTB in Argentina, and (2) wild boar may act as key maintenance host for bTB in the region.M. bovis confirmation in TBL samples detected during slaughter. Additionally, the diversity and frequency of spoligotypes was investigated to elucidate potential bTB transmission among pigs, cattle, and wild boar at the interface between these species. Results presented here will contribute to the evaluation and design of surveillance programs for bTB in swine of Argentina.The aim of this study was to evaluate the dynamics of mycobacteria in the pig population and to identify farm-level epidemiological variables associated with The studied samples were collected from slaughtered pigs originated from 135 farms located in the main productive areas of Argentina, including the provinces of Buenos Aires, Córdoba, Santa Fe, and La Pampa. A few (3%) samples came from other secondary production provinces such as San Luis, Entre Ríos, and Santiago del Estero. Farms of origin were representative of the two major production systems in Argentina; specifically, 77% of the studied farms were small pig producers and had <1,000 pigs, whereas the remaining 23% were intensive pig producers with 1,000–4,000 pigs.n = 191). Between 20 and 29 samples were collected annually at each of the four visits. Tissue samples were stored at −20°C until bacteriological and molecular analyses were conducted. Samples were collected after meat inspection by SENASA and according to national regulations; therefore, no ethical consent approval was required.Special permits for accessing abattoirs were issued by the official authorities . Samples were collected at four annual visits to a large abattoir in the province of Buenos Aires during an 8-year period (2010–2017). Lymph node sections (~4 × 4 cm) with TBL were collected from slaughtered pigs , and epidemiological data related to each farm were obtained from SENASA's official database. Farm-level epidemiological data included location (geographic coordinates), size , and co-existence with cattle. When multiple samples were taken from the same farm in different dates, only the one collected closest to date of epidemiological data collection were considered for the statistical analysis.M. bovis were considered as cases , whereas M. bovis-negative samples were considered as controls. Multivariable logistic regression was used to assess the association between farm-level epidemiological variables and the confirmation of TB-TP. First, the linearity assumption for continuous predictor variables was checked following Hosmer and Lemeshow (n = 133).TBL samples characterized and confirmed as Lemeshow . FollowiLemeshow  for eachc values within 2 units of distance were also considered as competing models. Akaike weights (wiAICc) were calculated and interpreted as the probability that a model was the best-fitting given the data and the set of candidate models. The strength of evidence in favor of one model over the other was obtained by dividing their wiAICc. Within each model, variable importance was assessed by evaluating the increment in AIC value if the single term was dropped.Model selection was streamlined by generating models including all possible combinations of variables using the R package “MuMIn” . Here, oFirst-order spatial effects were investigated by including the location of each farm in the final model, as “latitude,” “longitude,” and their interaction term. Second-order spatial effects were assessed using scan statistic  in the RThe association between TB status and independent variables was assessed by estimation of the odds ratios (OR) and their 95% confidence intervals (95% CI). The OR for the interaction term was calculated and interpreted following Hosmer and Lemeshow . The preM. bovis-negative samples) , sensitivity (proportion of correctly classified TB-TP), and specificity (proportion of correctly classified samples) . In all www.mbovis.org). The spoligotypes obtained in this study and those previously reported for pigs in Argentina  were TB-TP and 61 (32%) were TB-negative (included negative cultures and MAC positive cultures). In the TB-TP samples, 6.92% (9/130) exhibited co-infections with MAC species. Of the 61 negative TBL samples, 52 were culture-negative and nine were MAC culture-positive.Three competing logistic models were selected . Their cM. bovis isolates were classified in 15 different spoligotypes  spoligotype. The distribution of spoligotypes among pigs, wild boar, and cattle is shown in The 130 igotypes . Unique Despite significant improvement in the last 20 years, bTB and zoonotic TB (zTB) remains a major health challenge for many developing countries. One of the main goals of bTB national control programs is to decrease the incidence of zTB, an objective that can only be achieved through improving food safety and controlling bTB in domestic and wild animal reservoirs , 39.Our study suggests an association between bTB infection in pigs and cattle, through the analyses of the genotypes present in these species and farm-level epidemiological variables. The identification of farms at highest probability of being infected will allow the implementation of effective preventive and control measures in Argentina. Additionally, the diversity of spoligotypes detected in these species strongly suggests the possibility of bTB transmission between livestock and wildlife in this region.A large proportion 68%) of the collected TBL samples was confirmed as TB-TP. Studies conducted in Spain reported similar results, with over 63% of MTC isolates in TBL samples . In Sout8% of theMAC species were isolated in 9.1% 18/191) of TBL samples, similar to previous research in pigs in Argentina . In cont/191 of TThe association between farm-level epidemiological variables and bTB prevalence in pig systems has been assessed in other countries, such as Ethiopia and Norway , 42. In M. bovis, and 15 different spoligotypes were detected. Here, the most frequent spoligotype was SB0140, which is also the most frequent in Argentina, being detected in zTB and several host species  of its spoligotypes with pigs, suggesting a bTB spillover phenomenon between these species. Wild boar is widely distributed in Argentina, with large populations coexisting in vast areas with pigs and cattle . In ArgeHealth research and policy addressing wild boar diseases have received increased attention in recent years , 56; howSpoligotyping has limitations regarding its discriminatory power among isolates, and more accurate techniques, such as MIRU-VNTR or Whole Genome Sequencing, would be key to establish infection directionality under the epidemiological context presented here. Also, spatially explicit modeling of different spoligotypes over time might shed additional light on the potential for cross-species transmission of bTB, and specifically on the role of wild boar as reservoir and spillover host. A spatially broader sampling scheme including abattoirs from other geographical regions might reveal spatial patterns in the associations between farm-level epidemiological variables and TB-TP.In conclusion, the study here suggests an association between presence of cattle and increased odds for bTB in domestic pigs, and also, transmission between domestic pigs and wild boars in Argentina. Results contribute to understanding the epidemiology of bTB in Argentine swine. These results will ultimately contribute to the design and implementation of surveillance and control programs for the disease in Argentina and other settings in which the disease is endemic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SB: data curation, formal analysis, methodology, funding acquisition, writing—review, and editing. MM: data curation, methodology, writing-review, and editing. GC: formal analysis and methodology. MA: data curation and methodology. ME and MV: writing—review and editing. MZ, MC, and MW: methodology. AP: methodology, writing—review, and editing. LS: data curation, formal analysis, writing—review, and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Using an experimental vignette methodology, vets were randomly assigned across four conditions, to examine the effects of different contexts  on vets’ likelihood of prescribing antibiotics. Vets’ beliefs about different groups’ responsibility for causing and preventing AMR and vets’ values were also measured. Key findings were that context alone, values, and beliefs about groups’ responsibilities for causing AMR were not predictive of vets’ likelihood of prescribing antibiotics. However, vets’ beliefs about groups’ responsibilities for preventing AMR were predictive of an increased likelihood of prescribing antibiotics, when vets were exposed to the experimental condition of the vignette in which the vet–farmer relationship was under pressure. Farm vets also believed that different groups have different levels of responsibility for causing and preventing AMR. Results should be interpreted cautiously, given the smaller than planned for sample size, and the possibility for both false negatives and false positives. Further research is needed to explore how these findings could inform antimicrobial stewardship interventions in veterinary medicine.Antimicrobial resistance (AMR) is a pressing threat to public and animal health. There is evidence that antimicrobial prescribing and stewardship behaviors by veterinarians (vets) are influenced by non-clinical factors, such as psychological, social, and environmental factors. This study explored the role of context, beliefs, and values on vets’ antimicrobial prescribing decisions. UK-based practicing farm vets ( Antimicrobial resistance (AMR) represents a profound threat to human and animal health . AlthougThere is growing evidence that prescribers are influenced by a range of psychological, social, and environmental factors, although the volume of evidence varies, with a relative paucity of evidence about vets’ prescribing compared to doctors’ prescribing. Vets and doctors are influenced by psychological factors, such as emotions ,7,8, habDeveloping effective stewardship interventions, therefore, requires a good understanding of the various non-clinical factors that influence prescribing. In human medicine, a large number of studies using a range of methods have extensively researched and reviewed non-clinical influences on the prescribing behaviors of general practitioners ,23, hospIt is possible to experimentally explore the effects of different factors on prescribing using a vignette methodology ,43. VignIt is clear is that veterinary antimicrobial prescribing takes place in a complex and dynamic context, which can affect decision-making. For example, a vet’s prescribing can be influenced by economic factors ,47,48, fThis study was, therefore, designed to further understand the relative importance of some contextual factors, informed specifically by previous qualitative research in which farm vets reported they feel prevented from always practicing ‘ideal’ antimicrobial prescribing due to three key contextual factors: situational factors on the farm , farmer variability in personality and ability, and concerns for relationship management with their farmer clients . These fPrevious research conducted with vets  has identified the phenomenon of other-blaming for the problem of AMR, with vets generally expressing beliefs that their own prescribing behaviors contribute less to the issue of AMR than prescribing by other vets and doctors or usage by farmers and the public ,35,47,52This study, therefore, sought to measure farm vets’ beliefs about the level of responsibility that they, and other groups, have for both causing and preventing AMR. This was for two reasons; first, to assess whether such other-blaming would be evidenced again in a larger sample, using a different methodological approach, and second, as a way of attempting to quantify this other-blaming. Furthermore, given that those who engage in other-blaming may have reduced motivation to change their own behavior, as they do not perceive their own behavior to be a contributing factor to the problem of AMR, this study also sought to assess whether these beliefs about responsibility would be associated with vets’ likelihood of prescribing antimicrobials.The inappropriate use of antimicrobials can be considered a classic tragedy of the commons problem ,54; a coEnvironmental behaviors have been defined as “all types of behavior that change the availability of materials or energy from the environment or alter the structure and dynamics of ecosystems or the biosphere” . The useResearch has demonstrated that four values  have been consistently associated with environmental beliefs, intentions, and behaviors ,65,66,67When people experience a situation in which their different values conflict, they are likely to act in accordance with the more salient value, which is usually the value that is more strongly endorsed . It was,To summarize, three insights from previous research with vets have informed this current study. Firstly, vets report being influenced in their prescribing decisions by contextual factors. Secondly, vets hold differing beliefs about who is responsible for causing and preventing AMR and they engage in other-blaming for AMR. Thirdly, vets exhibit ambivalence towards tackling this issue, which may further influence their prescribing decisions and stewardship behaviors. Finally, it is also proposed that vets’ values may be associated with their prescribing.The primary aim of the study was, therefore, to use an experimental vignette to explore whether farm animal vets’ antibiotic prescribing decisions were influenced by context. Secondary aims were to explore whether 1) vets held different beliefs about how responsible different groups were for causing and preventing AMR and 2) whether vets’ prescribing was also influenced by their beliefs about who has a responsibility for causing and preventing AMR, and by their values. The experimental hypotheses were:The primary hypotheses predicted that vets’ prescribing would be influenced by the context of the decision.Hypothesis 1a. Vets provided with contextual information will be more likely to prescribe antibiotics, compared to the control condition ;Hypothesis 1b. The likelihood of prescribing antibiotics will differ between the three different contextual  conditions. The four vignette conditions were control , economics , farmer (farmer under work pressure), and relationship (vet-client relationship under pressure).Secondary hypotheses predicted that vets would believe different groups had different levels of responsibility for causing and preventing AMR, and that these beliefs would be related to their prescribing.Hypotheses 2a, 2b. There will be a difference in the level of responsibility that vets believe different groups have for (a) causing AMR and (b) preventing AMR;Hypotheses 2c, 2d. Vets’ beliefs about which groups have responsibility for (c) causing AMR and (d) preventing AMR will be associated with vets’ antibiotic prescribing.Additional secondary hypotheses predicted that vets’ prescribing would also be associated with the values they more strongly endorsed.Hypotheses 3a, 3b. Vets who are (a) more hedonic and (b) more egoistic will be more likely to prescribe antibiotics;Hypotheses 3c, 3d. Vets who are (c) more altruistic and (d) more biospheric will be less likely to prescribe antibiotics.mdn) = 33, interquartile range (IQR) = 12); in total, 17 participants declined to provide their age. The year in which they qualified was reported by 91 participants, who had been qualified for between 1 and 44 years . See Participants were 97 farm animal vets from across the UK. Gender and ethnicity were disclosed by 91 participants . The age of 80 participants ranged from 23 to 69 years  and 0.97 (S = 0.04); see Baseline differences were assessed using Fisher’s exact test or Pearson’s chi-square test for categorical variables and using one-way independent ANOVAs or the Kruskal–Wallis test for continuous variables. The associated p-values for these models ranged from 0.26 (S = 1.94) to 0.75 (S = 0.42), suggesting prescribing was not associated with these demographic variables. See To confirm that demographic variables did not influence prescribing, a total of six bootstrapped hierarchical multiple regressions were conducted, with vignette condition entered in block one and the demographic variable of interest entered in block two . The associated p-value, S-value, and small effect size suggest there was no meaningful difference overall between conditions of the vignette on the likelihood of prescribing antibiotics, F  = 1.64, p = 0.19, S = 2.40, partial η2 = 0.05  was that contextual information would influence vets’ prescribing, such that participants in the three experimental conditions would be more likely to prescribe antibiotics compared to those in the control condition . The second experimental hypothesis (1b) was that the likelihood of prescribing antibiotics would also differ between the three different experimental conditions. These hypotheses were tested using a one-way independent ANOVA. Mean likelihood of prescribing antibiotics was highest in the relationship condition, followed by the farmer condition, and lowest in the control condition, but the associated 0.05 see . Both nup-values suggest there were meaningful differences in vets’ beliefs about the level of responsibility between groups for both causing AMR, 2χ(5) = 130.06, p < 0.001, S = 9.97, and preventing AMR, 2χ(5) = 100.51, p < 0.001, S = 9.97. In terms of both causing and preventing AMR, participants believed that human medics had the most responsibility and companion animal vets had the least responsibility. Differences between beliefs about all groups were explored using pairwise comparisons  were that vets would believe that different groups had different levels of responsibility for causing and preventing AMR, with higher scores indicating greater responsibility . Based on the remaining associated p-values , there were no meaningful differences in responsibility for causing AMR between farmers, medics, and the public/patients, or between farm vets, companion animal vets, and pet owners, suggesting that participants believed the former three groups are equally more responsible for causing AMR, and the latter three groups are equally less responsible for causing AMR.Regarding cause beliefs, farm vets believed themselves to be less responsible for causing AMR than farmers, human medics, and the public/patients , but less responsibility for preventing AMR than human medics  participants did not believe their own levels of responsibility differed from those of farmers, public/patients, and pet owners. Beliefs about companion animal vets differed from all other groups , suggesting participants saw this group as having the least responsibility for preventing AMR when compared to the responsibilities of the other five groups.Regarding prevent beliefs, farm vets believed themselves to have more responsibility for preventing AMR compared to companion animal vets  or preventing AMR (hypothesis 2b) were, therefore, rejected. Farm vets did differ in their beliefs about which groups had greater or lesser responsibility for both causing and preventing AMR, with human medics believed to have the most responsibility and companion animal vets the least responsibility.The fifth and sixth experimental hypotheses  were that participants’ beliefs about farm vets’ and other groups’ responsibility for causing or preventing AMR would be associated with the likelihood of prescribing antibiotics. These hypotheses were tested using two bootstrapped hierarchical multiple regressions.n = 89; see p-values for the effect of condition alone on prescribing (model one) was not meaningful overall, F  = 1.81, p = 0.15, S = 2.74, although it should be noted that the relationship condition had p = 0.059, S = 4.08. Adding beliefs about which groups have responsibility for causing AMR (model two) improved the overall model somewhat, F  = 1.74, p = 0.095, S = 3.40, , with small associated p-values for the relationship condition  and beliefs about the public/patients causing AMR . This model explained 16.5% of variance in the sample (7.0% in the population).In the first hierarchical regression  suggested that any effect was not meaningful overall, F  = 1.53, p = 0.21, S = 2.25, although the relationship condition was potentially meaningful, p = 0.068, S = 3.88. Adding beliefs about which groups have responsibility for preventing AMR (model two) improved the model, F  = 2.21, p = 0.030, S = 5.06, , with this model explaining 20.3% of variance in the sample (11.1% in the population), and the associated p-values suggest model two is meaningful overall. In this model, based on the p-values, most of the measures of beliefs about different groups having responsibility for preventing AMR were not meaningful individual predictors, although beliefs about the public/patients causing AMR could be potentially important, t (78) = 1.87, p = 0.065, S = 3.94. The associated p-value for the relationship condition in this model also suggests it is an important predictor of prescribing, t (78) = 2.24, p = 0.028, S = 5.16. Taken together, these results suggest that when beliefs about all groups being responsible (or not) for preventing AMR were included in the model, exposure to the relationship condition was meaningfully associated with an increased likelihood of participants’ prescribing antibiotics.In the second hierarchical regression  was therefore retained, but the null hypothesis that prevent beliefs would not be associated with prescribing (hypothesis 2d) was rejected. Participants were more likely to prescribe antibiotics in the relationship condition, once their beliefs about groups’ responsibilities for preventing AMR were taken into account.r = 0.45, p < 0.001, S = 9.97) and vets’ altruistic and biospheric values were also positively correlated . Altruistic values did not correlate with hedonic  or egoistic values  and biospheric values did not correlate with hedonic  or egoistic values .As a group, vets endorsed altruistic values most strongly, and egoistic values least strongly see . In linen = 92; see p-values for the effect of condition on prescribing (model one) continued to suggest this effect was not meaningful overall, F  = 1.94, p = 0.13, S = 2.94; however, as with models presented above, the p-value associated with the relationship condition was low, p = 0.050, S = 4.32. Adding the values subscales (model two) did not meaningfully improve the model, F  = 0.87, p = 0.53, S = 0.92 . Therefore, vets’ likelihood of prescribing antibiotics was likely not influenced by their values and the null hypotheses for 3a, 3b, 3c, and 3d were retained.The seventh and eighth experimental hypotheses  were that vets who were more hedonic or more egoistic would be more likely to prescribe antibiotics. The ninth and tenth experimental hypotheses  were that vets who were more altruistic or more biospheric would be less likely to prescribe antibiotics. These hypotheses were tested using a bootstrapped hierarchical multiple regression. In this regression , farmer (farmer under work pressure), and relationship (vet-client relationship under pressure). The study also measured vets’ beliefs about which groups have more or less responsibility for both causing and preventing AMR and measured vets’ values.The key findings were that context alone did not appear to meaningfully influence the likelihood that vets would prescribe an antibiotic, nor did vets’ values or their beliefs about which groups have responsibility for causing AMR, at least in this sample of farm vets. Adding vets’ beliefs about which groups have responsibility for preventing AMR did, however, appear to result in a more meaningful overall model; furthermore, in this model, exposure to the relationship condition (but not the economic or farmer conditions) appeared to be an important predictor for increased likelihood of prescribing, suggesting that the prescribing context may be more influential for some people, depending upon their beliefs. In other words, once vets’ beliefs about responsibility for preventing AMR were taken into account, those vets who were exposed to a hypothetical situation where their relationship with the farmer may be under some pressure were more likely to prescribe antibiotics than vets exposed to clinical information only, a situation where the farm is under financial pressure, or a situation where the farmer is under work pressure.These findings, therefore, suggest the nature of the vet’s relationship with their farmer client may be a particularly important factor in terms of antimicrobial prescribing and stewardship behaviors. What is not clear from the present study is exactly what it is about the relationship being under pressure that resulted in vets being more likely to prescribe antibiotics. It may be that when vets feel they have a better quality relationship with a farmer, they feel more able to resist prescribing antimicrobials in clinically ambiguous situations. Alternatively, it may be that if vets feel less secure in their relationship with a farmer, they are more likely to prescribe antimicrobials as they wish to avoid either a potentially challenging conversation with the farmer or avoid the risk of displeasing the farmer by refusing antimicrobials. Nonetheless, the findings suggest that the more comfortable or confident a vet feels in their relationship with a farmer, the more likely it is that they will engage in responsible antimicrobial prescribing.Relationships between prescribers and their patients or clients do seem to be important influences on prescribers’ treatment decisions ,11,14. TIt, therefore, seems reasonable to propose that enabling vets and doctors to more quickly establish good communication and trusting relationships with clients and patients could be useful in driving antimicrobial stewardship behaviors. Indeed, junior dairy vets have recognized the importance of rapidly building trust with farmers, and have expressed a desire for more senior vets to facilitate this development of trust between junior vets and farmers . One wayIn addition to exploring the effects of context on farm vets’ prescribing, this study also set out to explore farm vets’ beliefs about which groups hold more or less responsibility for both causing and preventing AMR. The results identified that farm vets believe that farmers, human medics, and the public  have greater responsibility than themselves for causing AMR. In terms of preventing AMR, farm vets believe they have more responsibility than companion animal vets, but less responsibility than human medics. These quantitative findings support the conclusions from previous qualitative research that farm vets do take some ownership and level of responsibility for antimicrobial stewardship, but that they also shift the responsibility for AMR and further stewardship onto other groups . Indeed,Reducing this other-blaming between different groups of antimicrobial prescribers and users may be an important area of intervention, potentially positively impacting on on stewardship behaviours of individuals, or at least on their motivation to critique and consider changing their behavior. For example, there is evidence that vets and farmers feel stigmatized and blamed for AMR by others ,86, whicFinally, this study also measured farm vets’ values and assessed whether these were associated with vets’ likelihood of prescribing antimicrobials. Values were measured in this study because values have been associated with the likelihood of engaging in a range of pro-environmental behaviors ,65,66,67This study aimed to recruit farm vets from across the UK and this was achieved, but no claims are made for the representativeness of this sample for farm vets currently practicing in the UK; indeed, a comparison with 2019 data from the Royal College of Veterinary Surgeons (RCVS)  indicatep < 0.05 as the threshold for statistical significance). Nonetheless, as with any results based on a single inferential test with what is arguably an arbitrary threshold .The experimental vignettes contained the following additional text, presented at the end of the clinical information:You are familiar with this farm business and know that it has been having real financial difficulties for quite some time now.[Economics].You know this farmer is well trained and usually diligent, but he says his herdsman who usually manages the cows day-to-day has recently resigned and has yet to be replaced. It is obvious that the farmer is run off his feet and keeping an eye on this cow is likely to be a low priority for him right now.[Farmer].You have known this farmer for a while and the last time you visited him it was quite tense, and he wasn’t happy with some of your decisions. As you are examining the cow, you hear the farmer grumbling.[Relationship].The outcome measure was how likely participants would be to prescribe systemic antibiotics in each condition. After reading the vignette, participants were presented with the following instructions:Below are some common treatment options that vets might recommend in this scenario. Thinking about your own day-to-day practice, please indicate to what extent you would be likely to recommend each of the following options in the above scenario.very unlikely) to 5 (very likely). The treatment options were (i) systemic antibiotics, (ii) cortico-steroids, (iii) isolation from other animals, (iv) provide highly palatable diet, (v) no treatment, (vi) non-steroidal anti-inflammatories, and (vii) other. The order in which the treatment options were presented in the list was randomized to control for any order effects.Participants then indicated for 7 treatment options how likely they would be to recommend each option, using a Likert scale from 1 , or if you chose ‘other’ please elaborate” and “Please briefly describe your reasons for this course of action”. Participants were asked to provide their age, gender, and ethnicity; they were also asked about their veterinary experience .opposed to my values) to 7 (of supreme importance), to indicate to what extent they endorse certain values . For the data analysis, responses to these subscales were recoded as ranging from 1 to 9.Values were measured using the value orientation scale, which has been extensively used in environmental psychology and has been validated across different countries ,64,65. Tcontributes not at all) to 5 (contributes very much). Both scales were piloted to check for clarity and meanings of items with the same vets and psychologists who piloted the vignette.Beliefs about which groups of stakeholders have responsibility for causing AMR and responsibility for preventing AMR were measured using two 24-item scales that were developed for this study see . These sThe responsibility for causing AMR scale measured the extent to which farm vet participants think the behavior of different groups (including themselves) contributes to increasing rates of AMR. Statements presented for each group included a mix of statements about antibiotic use, biosecurity, and infection prevention and control (IPC) practices. Example items that participants were asked to rate are: “The number of antibiotic prescriptions that GPs write”, “Levels of compliance with infection control protocols in companion animal veterinary practices”, and “Farmers using antibiotics to compensate for issues with husbandry”.The responsibility for preventing AMR scale measured the extent to which participants think all groups are equally responsible for preventing AMR. Statements are focused on what members of each group could do differently to help reduce selective pressure for AMR. Example items that participants were asked to rate are: “Members of the public taking antibiotics as instructed by their doctors”, “Pet owners accepting that their animals don’t always need antibiotics”, and “Farm animal vets adopting antibiotic stewardship policies”.α) were calculated for all measures and are reported in Cronbach’s alphas  around 2 weeks after the study was launched. The initial drop-out rate was 40%; participants were either not progressing beyond the consent form or were only completing some of the demographics information. In total, 3 key changes were made: the information sheet was edited to be more succinct, the consent form was altered so participants only had to agree to one global statement at the end of the form , and the demographic questionnaire was moved to the end of the study. After these changes were implemented the drop-out rate reduced to 24%. All randomizations were performed using the Qualtrics software. Participants were randomly allocated to the control and experimental vignette conditions; randomization was not stratified or performed in blocks. As the design was between-subjects, allocation to condition was not revealed to participants; however, allocation to condition was not blinded to the experimenter during data analysis. To control for order effects, the order of treatment options presented after the vignette was randomized, as was the order of presentation for all scale items within each scale. Additionally, the order of presentation of the responsibility for causing AMR and responsibility for preventing AMR scales was also randomized, to control for any potential contamination between the 2 scales.Missing data were not imputed; cases with missing data were excluded pairwise in all analyses . The ‘forced entry’ option was used in Qualtrics for all items in the main measures, meaning that missing data only occurred when participants declined to continue the survey; there were no missing data for individual items on completed measures. Data analysis was conducted using IBM SPSS Statistics version 24.Baseline checks of group differences (to check randomization to conditions) were performed using Pearson’s chi-square test and Fisher’s exact test for categorical variables and one-way independent ANOVAs and Kruskal–Wallis tests for continuous variables. The impact of context (vignette condition) on the likelihood of antibiotic prescribing was tested using a one-way independent ANOVA. Differences in beliefs about different groups’ responsibility for causing or preventing AMR were tested using Friedman’s ANOVAs, followed by pairwise comparisons. The impact of demographics, beliefs, and values on prescribing were tested using bootstrapped hierarchical multiple regressions. All regressions were conducted using the ‘Enter’ method and dummy variables were created for categorical variables.p-values, 95% confidence intervals, and effect sizes, the S-value  is also reported. The S-value is the base-2 logarithmic transformation of the p-value, which transforms the p-value into a measure of information  against a test hypothesis; the greater the S-value, the less compatible the observed data are with the test hypothesis [S-value to nearest integer) [S-value of 2 (meaning there are 2 bits of information against the test hypothesis) indicates that the observed test statistic is about as surprising as tossing two heads in two fair coin tosses, whereas an S-value of 10 would indicate the test statistic is about as surprising as tossing 10 heads in 10 fair coin tosses.To aid interpretation of results, in addition to reporting pothesis ,106,107.integer) ,106,107.A favorable ethical opinion for the study was granted by the University of Surrey’s Ethics Committee (Reference: UEC/2017/105/FHMS). Participants were provided with an information sheet and written informed consent was provided by participants before commencing the study. Participation was voluntary and participants could withdraw at any point until they completed the survey; as data collected were anonymous, there was no mechanism for identifying and removing responses from individual participants. To enter the optional prize draw, participants provided an email address after they completed the survey; email data were stored separately from the study data. The study was not pre-registered but has been reported in line with guidelines for experimental and cross-sectional studies: the Consolidated Standards of Reporting Trials (CONSORT) checklist  and the The key findings from this online experimental vignette and cross-sectional survey were that, once their beliefs about various groups’ responsibility for preventing AMR were taken into account, farm vets exposed to a hypothetical scenario in which their relationship with a farmer was under pressure were more likely to prescribe antimicrobials than farm vets in other contextual conditions. Farm vets’ values and their beliefs about various groups’ responsibility for causing AMR were not associated with their likelihood of prescribing antimicrobials. This study also found that there were differences in farm vets’ beliefs about how responsible different groups are for causing and preventing AMR, adding to previous evidence that farm vets at least partially locate the problem of AMR and the responsibility for antimicrobial stewardship with other groups. Results should be interpreted cautiously given the smaller than planned for sample size and given the risk for both false negatives and false positives as discussed in the limitations. Further research is needed to explore whether these findings can be replicated in different samples, and to examine how these findings could inform antimicrobial stewardship interventions in veterinary medicine.


The exploitationof sunlight as a clean, renewable, and distributedenergy source is key to facing the energetic demand of modern societyin a sustainable and affordable fashion. In the past few decades,chemists have learned to make molecular machines, that is, syntheticchemical systems in which energy inputs cause controlled movementsof molecular components that could be used to perform a task. A varietyof artificial molecular machines operated by light have been constructedby implementing photochemical processes within appropriately designed(supra)molecular assemblies. These studies could open up new routesfor the realization of nanostructured devices and materials capableto harness, convert, and store light energy. The work done by machinesis used to accomplish tasks that frequently involve conversion intoanother form of energy. A typical example is an electrically poweredpump employed to transfer a mass of water uphill; the electrical energyinput is converted into mechanical work (movement), which in its turnis transformed in gravitational potential energy.1 following early conceptual discussions of physicistRichard Feynman2 and engineer Eric Drexler,3 it was proposed that the notion of device andmachine can be transferred to the molecular scale.5 In brief, a molecular device can be consideredas an assembly of a defined number of molecular components designedto execute a function upon appropriate external stimulation. A molecularmachine is a particular class of molecular device where the functionis achieved by means of the mechanical movement of its molecular components.6Macroscopicmachines are assemblies of different parts that worktogether to execute a function. In the context of research on supramolecularchemistry, which deals with “the organized entities of highercomplexity that result from the association of two or more chemicalspecies held together by intermolecular forces”,8 Owing to the progress of chemicalsynthesis, supramolecular systems composed of a significant numberof molecular components capable of self-assembling in a predeterminedfashion can nowadays be designed and prepared. Assemblies in whichdistinct molecular components are held together by covalent or coordinationbonds, as in grids, racks, arrays, or dendrimers, or even mechanicallyinterlocked with each other, as in rotaxanes and catenanes, can alsobe constructed.7 Although such systemswould not fall into the original definition of supramolecular speciesgiven in the previous paragraph, it was pointed out that they canexhibit a supramolecular behavior with regard to their physicochemicalproperties and the related emerging functions.6 The common element of all these species is their multicomponentnature, that is, the fact that they consist of molecular units linkedby means of interactions that span from weak electrostatic forcesto strong covalent bonds.Supramolecular chemistryis an area of chemistry closely relatedto biology that has expanded intensely over the past 40 years.10 The supramoleculararchitectures of the biological world are certainly the main and provenexamples of the feasibility and usefulness of nanotechnology.11 Their efficiency constitutes a strong motivation for engaging inthe realization of artificial molecular devices. The bottom-up constructionof sophisticated devices and machines such as those found in nature,however, is currently a prohibitive task. Therefore, chemists havesought (i) to build much simpler systems, without mimicking the complexityof biological structures,12 (ii) to understandthe principles and processes underlying their functioning,13 and (iii) to address the challenges inherentin the interfacing of these systems with the macroscopic world, particularlyconcerning energy supply14 and informationexchange.15The impetus to build molecular devicesand machines comes in alarge part from the extraordinary advances in molecular biology, thanksto which we are beginning to comprehend the secrets of the naturalnanomachines that underpin life.17 This is also true in nature, where living systems utilize sunlightphotons as both energy quanta in photosynthesis and as informationelements in vision-related processes.18Molecular devices andmachines, similarly to their macroscopiccounterparts, need to be fed with energy and to exchange signals withtheir environment  1. Such aThis short review is aimed at highlighting thepotential of artificialmolecular machines to harvest, convert, and utilize light energy toperform tasks. We first recall a few basic concepts of molecular machinesand the implications of their light-driven operation. Then, we describea number of selected examples that illustrate the strategies exploredand the prominent results obtained in the field. Limitations, openproblems, and future directions are discussed in the final part.2A molecular machine canbe defined as an assembly of a discretenumber of molecular components that exhibit controlled mechanicalmovements in response to an external stimulus. Molecular switchesand motors are classes of molecular machines, which, as pointed outin the 21 and edited books24 and in several excellent reviews.31 The high scientific value of this research, and its potential toenable revolutionary applications in several areas of technology andmedicine,38 was recognized in 2016 by the award of the Nobel in Prize in Chemistryto Jean-Pierre Sauvage, Fraser Stoddart, and Ben Feringa “forthe design and synthesis of molecular machines”.39During the past four decades,the application of an engineeringmentality to research in synthetic, physical, and analytical chemistryhas led to the development of a large variety of artificial molecularmachines and motors, utilizing a wide range of molecular and supramolecularspecies, both manmade and of biological origin. The key concepts,most significant achievements, and perspectives of such systems havebeen discussed in a few monographs2.140 The observation of biological nanodevices, infact, reveals that molecular machines should not be considered simplyas shrunken versions of their macroscopic counterparts.9 While the latter are made of hard and rigid materials and can relyon temperature differences to operate ,molecular machines are made up of soft components and must operateat a constant temperature (determined by the environment), because,as noted by Feynman in his historic speech on what later became knownas molecular nanotechnology,2 heat flowsvery quickly at the nanoscale. Indeed, most biomolecular motors inour body—for example, myosin and kinesin—are poweredby an exergonic chemical reaction, ATP hydrolysis, that happens atconstant temperature.The design and constructionof artificial molecular machines requires knowledge of the chemical–physicalprinciples that govern the functioning of the natural versions.–8 W, that is, at least 8 orders of magnitudegreater than the power supplied by the chemical reaction that powersa biomolecular motor.41 In other words,the problem of making molecules move in a controlled manner resemblesthat of riding a bike during an earthquake; since the latter cannotbe stopped, the sole viable solution is to exploit the shakes to moveforward. This is in fact what biological molecular motors do; theyexploit an external energy source to bias random Brownian motion,thus rendering the movement in a given direction more likely thanthat in others.Due to the tiny mass of molecules, gravityand inertial effects are negligible on the molecular scale, whereviscous forces arising from intermolecular interactions (includingthose with solvent molecules) dominate. A distinctive feature of themolecular scale with regard to motion is the fact that objects ofnanometer size are subject to the incessant and random agitation causedby thermal energy (Brownian motion). The second law of thermodynamicsstates that such a movement—which is unavoidable, unless atabsolute zero—cannot be harnessed to produce useful work. Undernormal conditions, Brownian motion has a disruptive effect on themovement of molecular species; it can be estimated that the thermalnoise power to which a molecule is subjected at ambient temperatureis 1040From this discussion, it is clear that accomplishingcontrolledand directional movements at the molecular scale is a challengingobjective, and a careful design of the systems and their stimuli-inducedtransformations—keeping in mind the phenomena mentioned above—isrequired.2.242 Sunlight is typicallyconverted into high energy chemicals by photosynthetic processes;44 these species are subsequently transformed into appropriate “fuels” which are utilized in the end to power all biologicalfunctions, including those involving movements.Althoughsunlight is the primary energy source for all living systems, thedirect conversion of light energy into motion is quite rare in biologicalsystems; an example is bacteriorhodopsin, wherein photoisomerizationtriggers conformational changes that ultimately make protons passacross a membrane.Chemical fuelsare particularly suited to meet the daily energy needs of living organismsbecause they can be conveniently stored, transported, and processed.A device that exploits chemical energy, however, will require freshreactants to be available at every step of its functioning cycle,and waste products will be concomitantly generated. The progressiveaccumulation of this “waste” will compromise the functioningof the device, unless it is removed, as happens both in our cellsand in internal combustion engines. It is clear that the need to disposeof waste products poses considerable problems in the design and constructionof artificial molecular machines driven by chemical inputs. On theother hand, it is well known that light energy inputs can cause reversibleand “clean” endergonic reactions.45 First of all, if the absorption spectrum of the species of interestis known, the amount of energy supplied can be carefully controlledby means of the wavelength and intensity of the exciting light. Theenergy of photons can be transferred to molecules without “wiring”them to the source; the only requirement is that the matrix is transparentat the excitation wavelength. Other properties of light, such as polarization,can also be harnessed. Modern techniques and light sources providethe opportunity to limit excitation to very small spaces and extremelyshort times, whereas the irradiation of large areas and volumes enablesthe simultaneous stimulation of a huge number of individual nanomachines.Feeding artificialmolecular machines with light energy exhibitsfurther advantages compared to chemical or electrical stimulation.writing  and reading .15Because of the extremely small size of molecules, the observationof motion is not a trivial issue in research on molecular machines.In general, the movement of the component parts should cause readablechanges in some chemical or physical properties of the system. Photochemicalinteractions are also useful in this regard, because optical spectroscopicmethods  can provide informationon the state of the machine. Hence, similarly to natural systems,it is also true for artificial molecular machines that photons canplay the dual role of 46 A further element of interest about optical stimulation is thatthe use of reversible photochemical processes in appropriately designedmolecules can enable the development of motors that function autonomously,which means that they can repeat their functioning cycle under constantexperimental conditions as long as light is supplied. This resultis achieved by devising a mechanism based on a cyclic pathway thatleads the system through transient electronic and structural states, in which at least one of the steps is photoinduced. For instance,the operation of the machine could be based on a photoinduced sequenceof processes that involve electronically excited states, where thefinal deactivation of the system to the ground state provides an automaticreset that closes the cycle. Alternatively, the mechanical motioncould be related to the light-triggered switching between stable andmetastable states, as it happens in photochromic systems. In bothcases, once the system has performed one complete cycle, the successiveabsorption of another photon triggers a new cycle, and the processcan be repeated indefinitely at a frequency that depends on the timescale of the transformations comprised in the operating cycle (unlessirradiation is performed at such a low intensity that the flux ofincoming photons determines the reaction rate). These paradigms willbe conveniently illustrated with the case studies discussed in thenext section.The fact that photoinducedprocesses can directly bring about motionand generation of force, thus deterministically relating the energyinput with the “power stroke” of the device, is a remarkablefeature of light-driven molecular machines.50 and reviews.54In order to highlight the role of molecular machinesfor processinglight energy, and also for space reasons, in this review we deal onlywith cases in which the photochemical energy conversion is intrinsicto the molecular machine. Hence, systems and materials wherein thephotomechanical actuation at the basis of energy conversion and storagestems from bulk effects  are not discussed;interested readers can refer to specific recent articles33.155 These machines are based on rotaxanes, i.e.,mechanically interlocked molecules (MIMs)20 minimally composed of a macrocyclic ring encircling a molecularaxle endowed with terminal bulky groups to prevent dethreading. MIMsare very appealing platforms to develop molecular machinery for thefollowing reasons: (i) the molecular components, due to the lack ofstrong chemical bonds between them, can easily undergo rearrangements;(ii) the mechanical bond confines the intercomponent movements withina defined range and ensures the overall stability of the system; (iii)the population of a specific mutual arrangement of the componentsis determined by the strength of noncovalent interactions betweenthem; (iv) such interactions can be modulated by external stimulation.Molecular shuttles are certainlythe most popular realization ofthe molecular machine concept with artificial chemical species.34In a molecular shuttle, the ring component moves in a linear fashionalong the molecular axle, in a way that reminds the operation of anabacus. If there is no obstacle on the axle, Brownian motion willcause the ring to move back and forth in a random fashion. The simplestdesign of a controllable molecular shuttle—i.e., a system whereinthe position of the ring along the axle can be set by external stimulation—impliesthe presence of two different recognition sites (stations) on theaxle. The ring initially encircles the most efficient station untila chemical reaction, properly activated, changes the relative affinitybetween the ring and the stations, thereby causing the thermally drivenmovement of the ring to the other station according to the mechanismdiscussed in 56 and electron transfer57 havebeen widely employed to modulate the interaction of the ring withthe stations with the purpose of causing mechanical movements. A relativelydated but highly instructional example based on the reversible E-Z photoisomerization of azobenzene is rotaxane 1 . Upon isomerization to the Z form, inducedby irradiation with ultraviolet (UV) light, the encapsulation becomessterically impossible, and the β-CD macrocycle has to move towardthe alkyl spacer. Back Z → E isomerization, caused by exposure to visible light, is followedby the return of the ring at the original location. As the currentintensity associated with oxidation of the appended ferrocene unitdepends on its distance from the electrode, the position of the β-CDring along the axle could be determined electrochemically. Interestingly,this nanomechanical device exploits a shuttling motion to transduceoptical information (light input) into an electrical signal (currentoutput).Photoinduced reactions such as isomerizationtaxane 1 3, which59 the localchange in wettability of a surface, caused by UV irradiation and mediatedby ring shuttling in surface-bound rotaxanes, was exploited to movea small liquid drop up an incline, thereby using light energy to dowork against gravity at the macroscopic scale. In brief, the axleof the rotaxane contains a primary fumaramide and a secondary tetrafluorosuccinamidestations; the former one can be photoisomerized to the maleamide form,which has a very low affinity for the employed tetralactam macrocycle.Hence, in the dark, the ring encircles the fumaramide site, whileit is shifted to the fluorinated succinamide site upon UV irradiation.Interestingly, the photoinduced ring shuttling in this system leadsto exposure or concealment of the highly hydrophobic fluoroalkaneportion of the axle, thereby changing the surface tension. In thekey experiment, a portion of surface next to a 1.25 μL (4.16μg) diiodomethane droplet was exposed to light; the liquid wasattracted toward the irradiated area and thus moved across the surface.The droplet was transported for 1.38 mm up a 12° incline, resultingin 1.2 × 10–8 J of work done against gravity.Considering that the droplet subtends ca. 2 × 1012 rotaxane molecules and the photoswitching efficiency is 40%, eachmolecular shuttle contributes with 1.5 × 10–20 J, i.e., 9 kJ mol–1. It should be noted, however,that the droplet does not move as a direct consequence of amplifiedmolecular-scale movements and that similar results were obtained withsimple photochromic compounds deposited on surfaces.60In a related investigation,2  polypyridine complex, a p-terphenyl-type rigid spacer, π-electron-poor 4,4′-bipyridinium(Bpy) and 3,3′-dimethyl-4,4′-bipyridinium (Dmbpy) units,and a tetraarylmethane group as the terminal stopper  affords a triplet excited state which is sufficiently reductantand long-lived to transfer an electron to the Bpy site (step 2), incompetition with the intrinsic decay of the excited state (step 3).The reduced Bpy station becomes deactivated, and as a consequence,Brownian motion moves the macrocycle by 1.3 nm to reach the Dmbpyunit (step 4). This process competes with the back-electron transferfrom the reduced Bpy unit, still encircled by the ring, to the oxidizedphotosensitizer (step 5). Once the macrocycle has moved away fromits initial location, back-electron transfer from the reduced anduncomplexed Bpy to the oxidized Ru-based unit (step 6) regeneratesthe primary station by restoring its electron acceptor properties.As a consequence of such an “electronic reset”, thering moves from Dmbpy back to Bpy by Brownian motion (step 7). Thecycle is thus completed, and the rotaxane is ready to process anotherphoton.As illustrated in 62 Because of competition with undesirable energy-wastingprocesses , the overall quantum yield for ringshuttling (Φsh) was found to be only 2% in acetonitrileat 303 K. The free energy available for the shuttling, which, in principle,could be used to do mechanical work, was estimated from thermodynamicdata . As depicted inthe energy-level diagram in –1 in the forward movement and−8 kJ mol–1 in the backward one. Indeed,most of the photon energy is dissipated to transfer electrons acrossthe molecule. The fraction F of the excited stateenergy used to move the ring is about 9%, and the overall efficiencyof light-to-mechanical energy conversion, η = Φsh × F, amounts to 0.2%. Considering that thefull cycle is completed in 1 ms, the machine can potentially operateat a maximum frequency of 1 kHz and generate a mechanical power of3 × 10–17 W per molecule. While such low figuresappear disappointing, it should be noted that molecular shuttle 2 can utilize a free energy source (sunlight), and it is extremelystable and functions under mild environmental conditions (liquid solutionat room temperature).As it happens for macroscopic machines, the successfuloperationof this nanodevice relies on a proper synchronization of the processesthat contribute to its mechanism 4, a resu1 and 2 a fraction of theincoming light energy input is indeedemployed to move the ring, in the described experiments, the latteris not doing any mechanical work, as the energy is simply dissipatedin the solution due to the viscous drag of the solvent. Another crucialissue, common to all molecular switches and shuttles, is that thereset of the ring occurs by traveling backward along the same coordinateof the forward motion. At the molecular level, this means that anyeffect performed on the environment during the forward movement  would be undone by thebackward step. Such a problem could be circumvented by coupling theshuttling motion with another process that desymmetrizes the operationcycle.63 A more insightful discussion onthis aspect can be found in refs .3.271 The transport must be active, that is, intrinsicallyperformed by the motor using its energy source, without relying onexternal concentration differences; in principle, it should take place against a concentration gradient. In fact, molecular pumpsare energy transducers capable of converting the energy input of thedevice into a chemical potential; in other words, they can use anexternal energy source to generate a nonequilibrium state.72 Conversely, passive transporters simply facilitatethe system to relax to equilibrium by moving a cargo down a concentrationgradient. The controlled transport of molecular and ionic substratesacross biological membranes, that define and separate compartments,is a fundamental task for living organisms.9 The constructionof artificial molecular species capable of performing such a functionis motivated not only by the high basic science value but also bythe potential for technological and medical applications.74 Such an endeavour can take significant advantage from the approachespursued in the making of artificial molecular machines.77Molecular pumps can be defined as linearmotors in which a molecularsubstrate is directionally transported with respect to the motor component.78 By defining the axle as the “track” of the machine,the ring component may be directionally moved—that is, transported—alongthe track. It should be noted, however, that in a homogeneous solutionnone of the molecular components are connected to a fixed referencesystem, and only relative movements can be considered. Hence, thedistinction between the “transporting” and “transported”components becomes purely conventional. Three classes of pumps weredescribed so far;79 in the first one, thering and axle components of a pseudorotaxane complex undergo unidirectionalthreading and dethreading. It can be envisioned that the ring becomesassociated with the axle by passing over a specific extremity of thelatter; successively, the ring dissociates by exiting from the oppositeside rotaxane architectures.iteside 6a. Pumpsiteside 6b. A thiiteside 6c.76 Conversely, in the semirotaxane and dual pump cases,the macrocycle(s) can be pumped energetically uphill along the axle,which thus acts as a “reservoir” of ring(s) in a metastablestate. Therefore, chemical energy can, in principle, be stored inthe system, even in homogeneous solution. Artificial molecular pumpsof the second and third kind are only available powered by chemical81 or electrochemical83 inputs.In all cases, the pumping cycle can be repeated, resulting in thepassage of successive rings along the axle in the pseudorotaxane speciesor in the accumulation of more than one ring on the axle in the semirotaxaneor dual pump classes. In the former case, the threading–dethreadingcycle can produce a net effect only if the transport involves spatiallyseparated “departure” and “arrival” compartments.This result could be achieved, for example, by a membrane that providesthe boundary of the compartments and the fixed support for the “transporting”component of the pump.84Supramolecularpumps of the type shown in 85 consists of thearomatic crown ether 3 and the nonsymmetricmolecular axle 4  the complex becomes less stable and(ii) the threading barrierat the Azo end is dramatically increased, making the Cp end the kineticallypreferred extremity for the transit of the ring. As a result, thepseudorotaxanes undergo partial dethreading, and in doing so, therings must escape from the Cp end  andbackward (counterclockwise) rate constants shows that, on average,the pump functions in the “wrong” direction once every160 cycles. This figure is related to the nonstandard free energychange of the system (ΔG) upon performing directionalcycling, i.e., the energy stored in the reaction network under dissipativenonequilibrium conditions.40 ΔG, which also corresponds to the maximum amount of inputenergy that can be converted into useful work, was found to be −12.6kJ mol–1 at 20 °C, that is, about 25% of theenergy provided by ATP hydrolysis.85 Consideringthat 430 photons of 365 nm (326 kJ mol–1) are requiredto complete a cycle, the upper limit for the energy conversion efficiencyis η = 12.6/(430 × 326) = 9 × 10–5. Such numbers show that the system is able to exploit only a tinyfraction of the input light energy because, not surprisingly, mostof the energy is wasted into heat in excited-state vibrational relaxationprocesses.The performance of the pump could be assessed bycomputer simulationsof the cycle shown in 94 These results highlight the robustness and flexibility of this approach,whose appeal is further increased by its minimalist design, structuralsimplicity of the components, ease of preparation, stability, andreversibility.More recently, the same behavior was observed withmodified ringand axle components, provided that the key mechanistic elements depictedin 3.3E-Z photoisomerization arounda C=C double bond in overcrowded chiral alkenes.95 Let us consider the progenitor of the series(5 in P) or left handed (M), a total of four stereoisomers exist for each enantiomerof 5  are irreversible, i.e., unidirectional.The tendency of the methyl substituents to adopt a less stericallydemanding, energetically favorable axial orientation is the drivingforce for the directional rotation in the helix inversion. As shownin 5 ata sufficiently high temperature (60 °C) results in repeated rotations,and thus, the motor can operate autonomously under the supply of lightenergy.94At the molecular level, the construction ofrotary motors—i.e.,machines that use energy to perform repeated unidirectional 360°rotations of one component with respect to the others—is particularlychallenging because of the unidirectionality requirement. Artificialmolecular rotary motors fueled by light were first obtained by exploitingthe ies5 in 8 to desc96 and were exploitedin various ways to control functions and perform tasks.97 A key feature of these compounds is that thelight-driven unidirectional rotation observed in a fluid solutionis preserved when the motors are deposited on macroscopic or nanostructuredsurfaces, embedded in membranes, and incorporated in hard or softmaterials.36 The robustness of the motor function is indeed one of the main reasonsfor the widespread use of these species in the search for applicationsof artificial molecular machines. Light-driven rotary motors basedon different classes of molecules98—forexample, imines,99 indigos,100 and catenanes101—have also been investigated.Overcrowded alkene rotarymotors have evolved impressively overthe past 20 years67 In recent years, the ability of covalent polymers embedding molecularmachines to collect and amplify movement from the nanometer to themacroscopic scale was demonstrated.70The integration of molecularmachines and motors with polymer chainshas long been proposed as a promising strategy for harnessing thepotential of the former to perform work.102 Compound 6  was copolymerized with the azide-terminateddiarylethene derivative 9  and macroscopic  scales.104 The case studies discussedhere show that a most critical point in this regard is the designedand effective integration of the molecular devices with their environment,in order for the input energy, part of which is used to produce directedmotion at the molecular scale, to result in an effect on the surroundingswhich ultimately causes a sizable free energy change of the systemor material.Although artificial molecular machines cannot (yet) rival theirbiological counterparts in terms of complexity and efficacy, theyare not limited to the blueprint established by nature. For example,the molecular machines described in this review are powered by light—afact that is uncommon for biological devices but is highly advantageousfrom a technological viewpoint. Investigations focused on the useof artificial molecular machines for converting and storing energyare currently a rarity, and theoretical formulations describing nonequilibriumthermodynamics of photochemical reaction networks have just startedto appear.106 At the micro- and macroscopic scales, strategies are required toorganize molecular machines at interfaces, on surfaces, or in materials,such that the synchronous and cumulative activation of a large numberof molecular devices allows the amplification of the effects of nanoscalemotion up to larger scales.107 Clearly,a substantial research effort will be necessary to learn how to introducemolecular machines in complex structured matrices and get them towork, either individually or collectively, in a predictable and reliableway.Such a goal can be accomplished at different lengthscales. Atthe molecular level, energy conversion and storage with molecularmachines requires a precise coupling of mechanical and chemical processesand the ability to generate nonequilibrium states that can persistover time as long as energy is supplied.109 or near-infrared110 light would be extremelyappealing to make active polymeric materials, such as those shownin Another open problem is the exploitation of visible ornear-infrared(IR) photons, which constitute the largest part of the Sun’soutput power that reaches the surface of Earth, in the place of highenergy, potentially harmful ultraviolet ones. A handful of artificialmolecular machines powered with visible light are available (see,e.g., In conclusion,research in the past few decades has shown thatthe manifold characteristics of the interaction between light andmolecules, together with the progress made in synthetic, supramolecular,and systems chemistry, can enable the realization of molecular machine-basedsystems with the potential for breakthroughs in energy conversionand storage. Indeed, the study of molecular assemblies that can harnesssolar energy in the form of UV, visible, or IR light is of fundamentalimportance to develop sustainable processes and materials arisingfrom nanotechnology.