Urinary tract infection (UTI) afflicts millions of patients globally each year. While the majority of UTIs are successfully treated with orally administered antibiotics, the impact of oral antibiotics on the host microbiota is under close research scrutiny and the potential for dysbiosis is a cause for concern. Optimal treatment of UTI relies upon the selection of an agent which displays appropriate pharmacokinetic-pharmacodynamic (PK-PD) properties that will deliver appropriately high concentrations in the urinary tract after oral administration. Alternatively, high local concentrations of antibiotic at the urothelial surface can be achieved by direct instillation into the urinary tract. For antibiotics with the appropriate physicochemical properties, this can be of critical importance in cases for which an intracellular urothelial bacterial reservoir is suspected. In this review, we summarise the underpinning biopharmaceutical barriers to effective treatment of UTI and provide an overview of the evidence for the deployment of the intravesical administration route for antibiotics. UTIs remain one of the most common bacterial infections, affecting 150 million patients globally each year . AlthougUTI is also commonly associated with the use of urinary drainage catheters. Globally, catheters are a very common and increasingly used clinical tool. A National Health Service England survey from across the entire system of its users found 12.9% of patients were catheterised . SimilarUTI, alongside respiratory infection, is among the most common reasons why antibiotics are prescribed in primary care . HoweverClostridioides difficile. Antibiotic use is also associated with a reduction in gut microbiota species diversity, which can be detrimental, for example by perturbing the complex network of interconnected metabolic activity over which the microbial community presides [While antibiotics can be effective in treating acute UTI in three quarters of patients, their use has detrimental effect on the homeostasis of the host microbiota when it is exposed directly to these drugs, which in turn adversely harms human health via effects on nutrients, metabolism, pathogen resistance, and other processes . Recent presides .Escherichia coli 83972 can protect recurrent UTI patients from infection {Loubet, 2020 #1808}. Moreover, as far back as 1997, Smith and colleagues noted that prior antibiotic treatment (either for a UTI or some other infection) in young women actually increased the risk of cystitis (bladder infection) [Less well understood is the effect of antibiotic treatment in the bladder itself. Although long assumed to be sterile, a number of years of careful work by multiple labs have established that the healthy bladder, which is open to the environment, contains a commensal ‘urobiome’ that differs significantly from the infected state ,20,21,22fection) . Costellfection) . ClinicaAntibiotic choice in UTI treatment is largely empirical, with the consistent aim of either killing or stalling the growth of the causative uropathogen. For over six decades it has been appreciated that in the treatment of kidney infection (pyelonephritis), antimicrobial activity against the infecting organism in the urine during the course of treatment was essential for successful eradication of bacteriuria . HoweverThe physiological role of the urinary system is to filter the blood, retrieving key metabolic substrates while selectively disposing of metabolic by-products and other solutes that may otherwise pose a toxicity risk to the body. Together with the liver, the renal system serves as the major clearance route for metabolic by-products and xenobiotics. Following administration of any drug, including antibiotics, there is potential for metabolism in the liver. Hepatic metabolic transformations typically produce metabolites that are more polar in nature that the parent antibiotic, which can be achieved through direct chemical modification of the antibiotic structure through Phase I metabolism . These chemical transformations are often coupled with metabolite conjugation to polar moieties such as glucuronic acids and sulfates in a process termed Phase II metabolism. Ultimately, the purpose of Phase I and II metabolic processes is to endow the drug with physicochemical features  that make it liable to renal excretion.Many antibiotics, including those indicated for UTI, are principally cleared in their chemically unmodified, active form via the renal route. This results in high antibiotic concentrations in the urine, which often surpass those detected in the blood plasma. Therefore, optimised pharmacotherapy of UTIs can be achieved by careful selection of the antibiotic agents according to their pharmacokinetics as well as their antibacterial activity against the causative organism.Antibiotic efficacy is principally dependent upon the relative free concentration in the relevant tissue fluid in relation to the minimum inhibitory concentration (MIC) against the pathogen in question. Consider the concentration–time profile of a typical antibiotic after oral administration .When considering the optimal therapy for UTI, one should consider the PK/PD of the drugs under selection. To avoid the emergence of AMR, it is imperative that the dose magnitude and dosing schedule are appropriate to achieve drug concentrations above the MIC for the suspected pathogen. There are three basic PK/PD parameters that correlate well with antimicrobial efficacy in vitro and in vivo .(1)The length of time for which the antibiotic concentration surpasses the MIC: T > MIC(2)max) and the MIC: Cmax/MICThe ratio between the peak antibiotic concentration (C(3)The ratio between the under the plasma concentration–time curve (AUC) and the MIC: AUC/MICmax/MIC. Other antibiotics, such as the fluoroquinolones, which are typically reserved for more severe/resistant infections, display concentration-dependent activity and their efficacy is well predicted by AUC/MIC [For the majority of antibiotics used to treat UTIs, antibacterial efficacy is time-dependent and therefore the optimal PK/PD parameter is T > MIC. In contrast, aminoglycosides, which are delivered exclusively by parenteral routes for severe UTIs, display concentration-dependent activity and are therefore best assessed by the parameter, C AUC/MIC . Notably AUC/MIC .One can estimate the time course of antibiotic appearance in the primary urine by studying the drug plasma concentration–time profile. However, the dynamic processes of renal filtration, bladder filling, and voiding render the precise prediction of antibiotic concentrations in the urinary tract extremely challenging. A comprehensive understanding of the PK/PD of antibiotics active against UTI can therefore be appreciated fully only after direct measurement of urinary antibiotic concentrations.max values of 2.2 and 268 mg/L, respectively, representing approximately 100× higher ciprofloxacin concentrations in urine. The ratios of urinary and plasma antibiotic concentrations for some antibiotics commonly used in UTI are shown in Detailed published data comparing plasma and urinary concentrations of long-established antibiotics are relatively scant. Nonetheless, for some of the well-established, first-line antibiotics for UTI, there are comparative plasma and urinary PK profiles available (reviewed in ). FigureIn recent years, a small number of new antibiotics have been approved for specific indications. For example, plazomicin is a next-generation aminoglycoside that was derived from sisomicin using a chemical approach that endows activity against resistant bacteria expressing aminoglycoside-modifying enzymes . It was The accumulation of an antibiotic in the renal and urinary system is dictated principally by a few key processes—the extent to which it is filtered through the glomerulus, how it is transported across the renal tubules, and its interactions with the urothelium when in the urine.u), is the fraction that is available for glomerular filtration. Approximately 20% of the plasma volume passing through the glomerulus at any given moment is filtered to produce primary urine which contains the majority of blood solutes, except most proteins. Thus, for most antibiotics which undergo extensive plasma protein-binding, renal clearance via glomerular filtration plays a minor role in drug clearance. Instead, a balance of active drug secretion into the renal tubules and passive tubular reabsorption are key determinants of renal disposition. For an overview of the role of renal drug transporters, we refer the reader to two excellent reviews [In the blood, all antibiotics undergo reversible binding to plasma proteins such as albumin. The extent of protein binding varies widely from e.g., 95% for ceftriaxone  to 2% fo reviews ,47.Taken together, these data indicate that it is feasible to achieve sufficiently high concentrations in the urinary compartment for many antibiotics. Nonetheless, recurrent, chronic, and severe infection caused by resistant bacteria represent an unmet clinical need that would greatly benefit from the development of innovative technologies for controlled and targeted delivery of antibiotics.Although multiple factors are thought to contribute, recurrent UTIs are considered to be, at least in part, the result of bacterial biofilm production or persistent intracellular bacterial colonies that are recalcitrant to eradication with antibiotics ,48. The AQP2 mRNA was undetectable in human bladder [14C labelled creatinine in the rabbit was approximately 5% per hour in the healthy bladder, rising to 22% in the inflamed bladder [The major biopharmaceutical challenge is that the primary function of the urothelium is to provide a barrier against the flux of solutes  and pathogens into the systemic circulation. The hypertonic nature of urine (300–900 mOsmolar) presents considerable osmotic and chemical gradients at the epithelial cell surface and highlights the critical protective role played by the urothelium to the maintenance of a safe equilibrium between the blood and urinary compartments. The barrier function of the urothelium to non-specific passage of solutes, particles, and microorganisms is principally presented by a restrictive paracellular pathway. A series of radiolabelled tracer studies on urothelial tissue from different species have demonstrated the permeability to several, small endogenous urinary solutes including water ,56, urea bladder . The dis bladder . The not bladder  and xeno bladder  was repo bladder ,67,68,69E. coli [The urothelium is stratified into three distinct cell layers, basal, intermediate, and luminal superficial (umbrella) cells. In humans, these superficial umbrella cells are protected by a crystalline lattice comprising four uroplakins—UPK1A, UPK1B, UPKII, and UPKIII—that adorn up to 90% of the umbrella cell surface . UPK1A aE. coli  and is rE. coli .The tightly-controlled differentiation of the urothelium produces a complex mucosal barrier that protects the underlying cells from the toxic effect of urine, but also poses particular challenges for intracellular drug delivery. The permeability of the urothelium is highly restricted with a demonstrably extremely low flux of electrolytes and non-electrolytes .Paracellular transport in the urothelium is restricted by the apical junctional ring (AJR) complex. The AJR is composed of the tight junctional complex (zonula occludens), the adherens junction, desmosomes, and the associated actomyosin ring. It is responsible for maintaining the integrity of the urothelial surface through cycles of bladder filling, extension, and voiding that is reported to see a greater than 50% increase in the cell perimeter during bladder distension . The tigThe amalgam of a highly restrictive paracellular and a uroplakin-reinforced transcellular barrier confers the urothelium with an ultra-low permeability profile, which supports its physiological role as an impenetrable liner for the conduits and repository of the urinary tract. From a drug delivery perspective, the challenges for effective antibiotic delivery are distinct for acute and recurrent infections. To treat acute infections, the challenge lies in achieving sufficiently high drug concentrations at the urothelial surface for efficient bactericidal activity. Recent work in the drug delivery field has provided advances in mucoadhesive formulations that could be adapted to antibiotic delivery platforms that provide sustained antibiotic release ,76,77,78The targeting of intracellular bacterial colonies in cases of recurrent UTI presents a considerably greater challenge . To eradRecently, Gonzalez et al. examined the extent of dose-dependent intracellular antibacterial activity of ceftriaxone, ciprofloxacin, and azithromycin, using amikacin as a non-cell-penetrant control . They deFor the most effective treatment, the ideal scenario would be to deliver the right drug, at the right dose, at the right time, to the right target and nowhere else, to maximise safety and efficacy while minimising drug burdens and, hopefully therefore, overall treatment costs. Direct drug-targeting technologies are used extensively to minimise confounding pharmacokinetic variations to provide best quality treatments e.g., eye drop formulations, metered dose inhalers, skin creams/ointments, and intra-tissue injections. Bladder cancer adjuvant chemotherapy and intra-detrusor botulinum toxin injections exemplify the usefulness of direct-to-bladder delivery.In 2018, Pietropaolo and colleagues  publisheBased on this evidence, an intravesical drug-delivery approach shows promise and has generated the interest of patients, clinicians and scientists alike. However, a better delivery system needs to be developed. Drug delivery through standard drainage catheters is fraught with infection risks and handling challenges, especially with patient self-administration. To date, none of the available catheters are certified for this purpose, and pharmaceutical companies will not produce products for delivery through unlicensed devices if there is a licensed alternative treatment. Therefore, an unmet need in the field is for properly designed devices to deliver drugs directly to the urothelium to attempt to prevent and treat UTI.Looking ahead to the future of intravesical treatments for UTI, some have attempted to make antibiotic instillations more efficient through the deployment of nano-sized delivery platforms aiming to permit intracellular drug accumulation via the internalisation of drug-loaded particles through endocytosis (64). For example, Brauner et al.  created Given how antimicrobial resistance will only increase globally, however, there have been attempts to move beyond antibiotic instillations in the treatment of UTI. Leitner and colleagues , for exaE. coli, which is responsible for host–cell binding and contributes to biofilm formation. Liu and colleagues [E. coli and S. aureus in an in vitro cell culture infection model, and against E. coli in experimentally-infected mice treated intravesically. While promising, the mice needed surgery to introduce the laser treatment, so more refinements in technique would be needed to make this a less invasive option in humans. As a final example, Iyer and colleagues [E. coli.A number of groups are exploring the use of functionalized antimicrobial particles suitable for intravesical treatment of UTI. For example, in an in vitro cell culture infection model system, Khanal et al.  coupled lleagues  took a plleagues  created Antibiotics remain the primary treatment for UTI. However, with increasing AMR and in the face of growing evidence of microbiota disruption following systemic antibiotic administration, there is a growing need to better target antibiotic therapies, alongside the development of new non-antibiotic alternatives. In complex cases of UTI, intravesical antibiotic delivery holds the potential to better resolve these infections by enabling the presentation of antibiotic concentrations far in excess of those achievable via the systemic route. By virtue of the negligible urothelial permeability, which prevents drug permeation into the systemic circulation, this route would also logically pose little threat to non-urothelial microbial communities including those residing in the gut which are crucial to overall health. Impediments to the successful exploitation of this route include the availability of licensed administration devices and drug formulations that can be safely and effectively delivered to the urinary tract. Only with appropriate investment in these technologies and the performance of clinical trials in the appropriate patient populations can we properly appraise the potential of intravesical therapy for UTI.


Little is known about clinical outcomes in patients with EOPC, and age at diagnosis is not considered in current treatment guidelines. In our manuscript titled “Resected Early-Onset Pancreatic Cancer: Practices and Outcomes in an International Dual-Center Study” we investigate clinicopathologic features as well as outcomes of patients with EOPC undergoing resection.2Similar to other tumor entities including colorectal cancer, the incidence of early-onset pancreatic cancer (EOPC) affecting individuals ≤ 45 years of age is on the rise.In a dual-center study between Heidelberg University Hospital and Johns Hopkins Hospital, we present the largest series of patients with EOPC after surgery. We demonstrate that oncologic outcomes of patients with EOPC are excellent in stage I tumors, with a median overall survival of 70 months and reaching a median survival of 29.5 months even in locally advanced disease (T4N0/1). Classical prognostic factors of resected pancreatic cancer, including AJCC tumor stage, pN stage, and margin status, were confirmed. After upfront surgery, 85% of patients with EOPC received adjuvant chemotherapy, a noticeably higher rate than reported after average-onset pancreatic cancer. However, in both centers a trend toward neoadjuvant treatment was observed, although preoperative staging of tumors remained constant.3 Dedicated prospective studies comparing oncologic outcomes as well as patient-reported outcomes between EOPC and average-onset pancreatic cancer are necessary to assess if a more aggressive treatment including aggressive systemic therapy and extended resections should be recommended in treatment guidelines for patients with EOPC.A number of questions remain and need to be addressed in future research efforts. First, the contributions of hereditary pancreatic cancer and of molecular aberrations in the etiology and biology of EOPC need to be investigated. On a larger scale, the rising incidence of pancreatic cancer affecting individuals ≤ 45 years of age demands further attention from epidemiological scientists to investigate the associations of macroenvironmental risk factors in EOPC carcinogenesis. A comprehensive assessment of molecular characteristics may identify potentially actionable EOPC-specific vulnerabilities for which novel personalized systemic therapies are emerging.


Clostridioides difficile infection (CDI) treated with vancomycin.To investigate the role of previous antibiotic therapy in the risk of recurrence after a Multicentre observational study. Patients with a CDI episode achieving clinical cure with oral vancomycin and followed up 8 weeks were included. Previous antibiotic exposure up to 90 days was collected. Multivariate analysis of predictors of recurrence adjusted by the propensity score (PS) of being previously treated with each non-CDI antibiotic was performed.P = 0.01], whereas higher rates were seen in those treated with cephalosporins in the last month . In multivariate analysis controlled by the inverse probability of treatment weighting by PS, receiving ≥5 days of piperacillin/tazobactam in the last month as the last antibiotic regimen prior to CDI was independently associated with a lower risk of recurrence  whereas exposure for ≥5 days to cephalosporins (versus piperacillin/tazobactam) was associated with an increased risk .Two hundred and forty-one patients were included; 216 (90%) had received systemic antibiotics. Fifty-three patients (22%) had a CDI recurrence. Rates of recurrence were lower in those treated with piperacillin/tazobactam in the last month when compared with those not receiving piperacillin/tazobactam [3 (7%) versus 50 (25%); Recent use of piperacillin/tazobactam might be associated with a lower risk of CDI recurrence, while recent use of cephalosporins might promote an increased risk. These findings should be considered when treating hospitalized patients. Clostridioides difficile infection (CDI) is the leading cause of nosocomial infectious diarrhoea and one of the most prevalent healthcare associated infections.2 Antimicrobial exposure is one of most relevant individual factors associated with CDI development.3 Previous studies have shown that the risk of CDI is driven by the duration of antibiotic exposure but also by the specific class of antimicrobial agent received.4–8 In this sense, the risk of CDI seems to be higher after exposure to cephalosporins, carbapenems, quinolones and clindamycin when compared with other antibiotic regimens.6–8 Timing of exposure to antibiotics plays also an important role, as the higher risk seems to be concentrated in the first 90 days after antibiotic exposure.5 In this sense, the impact of antibiotics administered in the 60 days prior to admission seems to be more relevant than those administered during the index hospitalization in patients with healthcare associated CDI.8 In addition to direct patient exposure to antibiotics, the influence of antibiotic use on the risk of CDI may also operate at aggregate levels .9 Previous studies have shown that limiting hospital use of high-risk antibiotics is associated with a substantial decline in CDI.10–12 For the above-mentioned reasons, the implementation of antimicrobial stewardship programmes is one of the most important strategies to diminish the burden of CDI within hospitals.13–15 However, following discontinuation of CDI therapy, up to 15%–25% patients will experience a first recurrence of CDI,13–15 the risk of recurrence being progressively higher in subsequent recurrent episodes.17 Besides its clinical implications, the economic burden of recurrent episodes is substantial, mainly derived from increased length of hospital stays and readmissions.18 Importantly, cost-effectiveness models have shown that cost-effectiveness of CDI treatments are mostly affected by patient responses during their initial episodes.19 Thus, the optimization of CDI management at the initial episode with the aim of preventing recurrences is essential.Current first-line options for treatment of CDI, which include the use of fidaxomicin or vancomycin, achieve clinical cure after the end of therapy in at least 80% of patients.C. difficile spores in the intestinal tract.3 Due to this, exposure to systemic non-CDI antibiotics has been associated not only with CDI development but also with an increased risk of recurrence.20–22 However, a recent meta-analysis found that there was insufficient evidence for a role of non-CDI antibiotics in recurrence.23 Additionally, there is scarce information on whether the risk of CDI recurrence varies depending on the specific class of antibiotics received previously to the initial CDI episode. As the impact of different systemic antibiotics on intestinal microbiome might differ, it is reasonable to speculate that the risk of recurrence could be also influenced by the specific class of antibiotic that induced CDI. A case–control study conducted in acute and long-term care Veteran Affairs facilities found that prior use of several antibiotic classes  was associated with an increased risk of CDI recurrence.21 However, a relevant limitation in that study was that the majority of patients were treated with oral metronidazole, which is no longer a first-line option for CDI therapy.25Recurrence of CDI has been attributed to a lack of recovery of intestinal microbiome diversity following CDI treatment and the persistence of Our objective was to investigate the role of previous systemic antibiotic therapy in the risk of recurrence after an initial CDI episode treated with vancomycin.The ICD-ANCRAID-SEICV cohort  is a prospective multicentric cohort recruiting all consecutive adult patients with a new diagnosis of CDI from 15 hospitals from Spain since October 2020. Besides, since 2018, all CDI cases diagnosed at the coordinator centre of the cohort  have been prospectively followed up under a structured protocol of care, including data collection, and were used for the present analysis.Patients were included in this study provided that they met the following inclusion criteria: (i) diagnosis of CDI; (ii) treatment of the CDI episode with a standard regimen of oral vancomycin; (iii) achieved clinical cure at the end of therapy with vancomycin; and (iv) completed a minimum follow-up of 8 weeks after the end of CDI treatment. Patients with a previous episode of CDI in the preceding 8 weeks and those who received adjuvant therapy with bezlotoxumab were excluded.26 and ESCMID recommendations27 by the presence of diarrhoea and a positive laboratory assay for C. difficile toxin A and/or B in stools or a toxin-producing C. difficile organism detected in stools by means of a PCR method. According to ECDC criteria, a CDI episode was classified as healthcare-associated CDI (HA-CDI) if the onset of symptoms occurred on Day 3 or later following admission to a healthcare facility or within 4 weeks of discharge from a healthcare facility.26 Among HA-CDI cases, analyses were also performed considering only hospital-onset healthcare facility-associated (HO-HCFA) CDI cases as defined by IDSA.25 Clinical cure was defined as resolution of diarrhoea with maintenance of resolution for the duration of therapy and at least 48 h after the end of treatment.24 Recurrence was defined following ESCMID and IDSA criteria25 as the reappearance of symptoms within 8 weeks after a previous episode, provided the symptoms from the previous episode resolved after completion of initial treatment.CDI diagnosis was established following the ECDCC. difficile by immunochromatography . We assessed discrepancies by detecting C. difficile toxin genes by real-time PCR .The algorithm employed for the microbiological diagnosis of CDI was based on the sequential qualitative detection of glutamate dehydrogenase and toxin A and B from Data from systemic antibiotic exposure up to 90 days previous to CDI diagnosis were collected. Antibiotic consumption prior to CDI diagnosis was collected by means of electronic clinical records, which are linked with in-hospital and community electronic prescriptions modules by a unique patient identifier. For each antibiotic, exposure was recorded as ‘yes’ or ‘no’ irrespective of treatment duration, provided that at least 48 h of treatment was completed. Patients with multiple courses of antibiotics were not excluded. Sensitivity analysis restricted to patients with a single course of antibiotic and those with exposure to antibiotics in the last 4 weeks before CDI diagnosis was also performed. A sensitivity analysis considering exposure to individual antibiotics of at least 5 days duration was also performed. Non-CDI antibiotics were defined as those not currently considered as treatment options for CDI in ESCMID clinical practice guidelines .27 number of bowel movements at diagnosis, persistence of diarrhoea at Day 5 of CDI treatment, exposure to non-CDI systemic antibiotics in the previous 90 days including the specific antimicrobial agent, concomitant antibiotic at CDI diagnosis and antibiotic use after CDI diagnosis.The primary outcome variable of the study was the emergence of CDI recurrence. The possible association between the primary outcome and the following variables was assessed: age, sex, setting of infection, diabetes, active neoplasm, immunosuppression, chronic kidney disease, cirrhosis, bowel inflammatory disease, Charlson comorbidity index, major surgery in the previous 3 months, living in a long-term facility, hospitalization in the last year, treatment with proton pump inhibitors (PPIs) in the last 3 months, severity of the CDI episode according to IDSA criteria,t-test or the Mann–Whitney U-test, depending on whether a normal distribution was proven or not. Chi-squared and the Fisher tests were used for comparisons between categorical variables. Variables with a P value less than 0.2 on univariate analyses were entered in a logistic regression model, which also included age and sex. In order to control potential confounding bias due to differences between patients with previous exposure to different antibiotic classes showing univariate associations, propensity score (PS) analysis was performed. Thus, in the subcohort of patients who received systemic antibiotics prior to CDI, a PS for receiving a specific antibiotic agent was calculated using a non-parsimonious multivariable logistic regression model in which all potential predictors of receiving a specific antibiotic agent were included. The ability of the PS to predict the observed data was calculated by the area under the receiver operating characteristic curve (AUROC) with 95% CI. The performance of the PS was assessed by examining density plots. The PS was used in two ways: (i) as a covariate in a multivariable logistic analysis; and (ii) to form an inverse probability of treatment weighting (IPTW) subcohort. Differences were considered significant for P values ≤0.05. OR and the respective 95% CI were calculated. Data were analysed using IBM SPSS 24.0 version .Continuous variables were expressed as median (IQR) and categorical variables as frequencies (percentage). Continuous variables were compared by means of the Student’s This study was designed and performed according to the Declaration of Helsinki and was approved by Hospital Universitario de Valme Ethics Committee (Ref. 1254-N-20).JAC-AMR Online, summarizes the disposition of patients with the reasons for exclusion. Table Seven hundred and forty-seven patients were diagnosed with CDI in the participant hospitals during the study period. Of those, 403 (54%) were excluded as they received initial treatment with regimens other than vancomycin. Figure Two-hundred and sixteen (90%) patients had received systemic non-CDI antibiotics in the previous 3 months Table . Of thosFifty-three patients 22%) had a CDI recurrence during follow-up. Table 2% had a P = 0.3). When considering the specific antibiotic agent, recent exposure to piperacillin/tazobactam was associated with a lower risk of recurrence. Thus, 3 out of 41 (7%) patients who received piperacillin/tazobactam in the last month had a recurrence, while this was observed in 50 (25%) patients without recent exposure to piperacillin/tazobactam (P = 0.01) (Table P = 0.03] (Table Forty-four out of 190 23%) patients with exposure to antibiotics in the last 30 days and 4 out of 23 (17%) with antibiotic exposure in previous 3 months but not in the last 30 days developed a recurrence (% patient1) Table . On the 3] Table .P = 0.02). With respect to cephalosporins, 20 out of 66 (30%) patients with an exposure for ≥5 days within the last month had a recurrence whereas this occurred in 33 out of 175 (19%) remaining patients (P = 0.05).We repeated the same analysis but considering only exposures to piperacillin/tazobactam or cephalosporins of at least 5 days duration during the last month. By this approach, recurrence was seen in 3 out of 38 (8%) patients with an exposure to piperacillin/tazobactam for ≥5 days in the last month whereas it was seen in 50 out of 203 (25%) of the remaining patients . With respect to cephalosporins, 8 (31%) out of 26 patients had a recurrence whereas this occurred in 10 (15%) out of 66 treated with other options (P = 0.08). Recurrence rates were similar for those receiving quinolones and those receiving options other than quinolones .In order to control for the possible confounding effect in patients receiving multiple courses of antibiotics, we further analysed the impact of the specific class of antibiotic on recurrence in 92 patients who underwent a single course of antibiotic in the last 3 months. A single course was defined if no change of antibiotic was made within the entire duration of antibiotic therapy. One (14%) out of seven patients treated with piperacillin/tazobactam had a recurrence, whereas this was seen in 17 (20%) patients treated with other options (P = 0.8). The rates of CDI recurrence among those who received antibiotics after CDI was 32% (17/53) versus 22% (28/128) in those not receiving antibiotics after CDI (P = 0.1).Exposure to antibiotics during the first 8 weeks after the end of CDI therapy and before recurrence could be assessed in 181 patients. Of these, 53 (22%) patients received antibiotics after CDI. Eight (28%) patients among those whose last antibiotic regimen prior to CDI was piperacillin/tazobactam received antibiotics during the first 8 weeks after CDI, whereas this occurred in 16 (35%) of those recently treated with cephalosporins and 16 (25%) of those previously treated with other options .A multivariate analysis including variables prior to CDI diagnosis to identify the independent predictors of CDI recurrence was performed. The independent predictors of CDI recurrence in the overall study population were age, male sex and recent exposure to cephalosporin-based antibiotic course (versus a piperacillin/tazobactam course)  receiving ≥5 days of piperacillin/tazobactam as the last antibiotic regimen; (ii) receiving cephalosporins for ≥5 days as the last antibiotic regimen; and (iii) other antibiotic regimens. First, a PS for receiving ≥5 days of piperacillin/tazobactam as the last antibiotic regimen in the last 30 days by logistic regression analysis was done. To calculate the PS, variables included in the logistic regression were age, sex, setting of infection, neoplasm, chronic kidney disease, Charlson comorbidity index, cirrhosis, inflammatory bowel disease, living in a long-term facility, immunosuppression, severity of the episode and previous CDI episode. The AUROC for PS was 0.78 (95% CI: 0.70–0.86). A multivariate logistic regression model including PS as a covariate was then performed  out of 3041 isolates tested in 17 studies being resistant to this drug.29 Apart from its in vitro activity, piperacillin/tazobactam might achieve sufficient concentrations in the intestinal tract to inhibit C. difficile colonization during therapy. In line with this, in a study comparing the frequency of asymptomatic rectal carriage of toxigenic C. difficile among patients receiving piperacillin/tazobactam with that of patients receiving antibiotics lacking activity against C. difficile, such as cephalosporins or ciprofloxacin, patients receiving piperacillin/tazobactam were less likely to be asymptomatic carriers than those receiving non-inhibitory antibiotics or patients without active antibiotic therapy but with prior exposure within 90 days.30 This might be relevant, as the persistence of C. difficile spores in the gut can play a role in the recurrence of CDI. 31A remarkable finding in our study was the lower rate of recurrence that was seen in those recently exposed to piperacillin/tazobactam when compared with patients treated with other classes of antibiotics, specially cephalosporins. As described for other agents, previous exposure to piperacillin/tazobactam had been associated with an increased risk of a first episode of CDI.C. difficile within the gut is still a challenge. A relevant study recently published in Nature has confirmed that enterococci enhance C. difficile pathogenesis as they reshape the metabolic environment in the gut, favouring C. difficile colonization, toxin production and virulence.32 According to this new evidence, the differences in spectrum of activity against enterococci between piperacillin/tazobactam and cephalosporins might explain the different impact on CDI recurrence observed in our study. A reasonable hypothesis is that the disruption of gut microbiome induced by piperacillin/tazobactam might be less deleterious than that induced by cephalosporins or other options, as piperacillin/tazobactam might preserve against enterococci dominance in the microbiota, promoting a gut environment less prone to CDI recurrence. However, the effect of antibiotics on intestinal microbiota might differ not only due to the differences between the spectrum of antibacterial activity, but also according to the pre-treatment composition of the microbiota, the dose of antibiotics, the duration of the exposure or pharmacodynamics factors such as biliary excretion or faecal concentrations.33 Besides, it has been questioned if the measured activities of CDI antibiotics in vitro in a very well-defined environment against pure cultures of C. difficile represent what occurs in vivo in the intestinal tract with the presence of various other bacterial species and metabolites.34 Prospective analyses of faecal microbiota composition after CDI, adjusting for previous non-CDI antibiotic exposure, would be very informative to confirm or refute our observations.Clarifying the role of the microbiome and its interactions with 22 as treatment with concomitant antibiotics other than those given to treat CDI has been associated with an increased risk of treatment failure and recurrent CDI.20 However, in many circumstances, antibiotic therapy is clinically indicated and therefore impossible to stop at CDI diagnosis. There is a lack of evidence regarding which antibiotic agents are preferable in the case that concomitant systemic antibiotic cannot be stopped. Although most experts advise selecting agents among those that are less frequently implicated in antibiotic-associated CDI,22 evidence supporting this practice is lacking. Moreover, a recent systematic review found that neither non-CDI antibiotic use prior to the primary CDI nor concomitant non-CDI antibiotics used during the primary CDI episode appeared to be convincing predictors for recurrent CDI.23 Our results raise the question of if it should be considered to give preference to piperacillin/tazobactam, when this is a suitable option, rather than other agents such as cephalosporins in those diagnosed with CDI and needing concomitant systemic antibiotics. Although the observational design of this study does not allow us to give a strong recommendation on this, our data should be taken into account in the complex process of daily antimicrobial stewardship decisions when caring for patients with healthcare-associated infections at high risk for CDI development.Classically, discontinuation of the inciting antibiotic agent as soon as possible has been considered an important step in the management of CDI,35 Besides, we also analysed the impact of the last antibiotic course. All the approaches show concordant results, suggesting that recent exposure to piperacillin/tazobactam when compared with cephalosporins was associated with a lower risk of recurrence. These findings were also seen when non-CDI antibiotic regimens were also evaluated taking into account treatment duration, as a dose–response association between community-acquired (CA)-CDI risk and antimicrobials has been previously suggested.5 Thus, we performed a sensitivity analysis restricted to patients with a recent exposure to piperacillin/tazobactam or cephalosporins of at least 5 days that yielded the same results. Finally, our findings only apply to patients undergoing treatment with a standard course of vancomycin as other treatment options were excluded, with the aim of avoiding confounding bias due to the lower rates of recurrence that are achieved with fidaxomicin or the use of bezlotoxumab. Future research should confirm our findings in patients with CDI treated with other options.Our study has some limitations. First, this is an observational study and the indication of previous systemic antibiotics were made by the caring physicians. Thus, observed associations between antibiotic classes and CDI recurrence might not imply causality as selection bias might have occurred. To avoid this, we performed multivariate analysis adjusted by the PS of receiving each specific drug. Second, patients with multiple antibiotic courses were not excluded, to assure that the real-life population with CDI was analysed. However, determining the role of each antibiotic agent in those receiving multiple ones is challenging and prone to confounding bias. To solve this, we performed several sensitivity analyses as those restricted to patients receiving a single antibiotic course and to antibiotics received in the last month. The selection of this interval was based on previous studies showing that the risk of CDI is highest during non-CDI antibiotic treatment and for up to 1 month after discontinuation.In summary, recent exposure to piperacillin/tazobactam prior to CDI diagnosis might be associated with lower rates of CDI recurrence when compared with the use of cephalosporins. While awaiting further confirmatory data, this information should be incorporated to guide clinical decisions from an antimicrobial stewardship perspective.dlad033_Supplementary_DataClick here for additional data file.


The overuse and inappropriate use of antibiotics pose a grave threat to public health, contributing significantly to the accelerated development of antimicrobial resistance (AMR) and increased rates of morbidity and mortality, making it a leading cause of death globally. To examine the relationship between demographic variables and knowledge, attitudes, and behaviors concerning antibiotic use, a survey-based cross-sectional study was conducted involving 1158 individuals. The questionnaire included two sections: in the first section, participants’ socio-demographic characteristics were analyzed; the second investigated knowledge, attitudes, and behaviors concerning antibiotics utilization using a total of 36 questions. Descriptive statistics were used, and then a multiple linear regression analysis (MLRA) using three models was carried out. In Model I, knowledge about antibiotics exhibited correlations with smoking habits and educational attainment. In Model II, attitudes were significantly associated with gender, smoking habits, age, education, relationship status, and knowledge. In Model III, behaviors related to antibiotics were correlated with educational attainment, having children, knowledge, and attitudes. Implementing tailored public health programs could be a cost-effective intervention to enhance behaviors associated with antibiotic use in the general population. This study offers valuable insights into the determinants of knowledge, attitudes, and behaviors regarding antibiotics in the general population. Overuse and inappropriate use of antibiotics pose a serious threat to public health, animal health, environmental health, and global economic development ,2,3,4,5,The overuse of antibiotics, exacerbated by the impact of the COVID-19 pandemic , presentMoreover, antibiotic overuse is a leading cause of death worldwide, particularly in low- and middle-income countries ,15,16,17The inappropriate use of antibiotics is often associated with inadequate knowledge and awareness regarding their proper use, both among healthcare providers and patients ,21. ThisTo effectively tackle the challenge of antibiotic overuse, it is crucial to raise awareness among healthcare providers and the general public about the dangers of antibiotic misuse and the importance of responsible antibiotic use ,23.Numerous ongoing studies utilize the KAP model to explore the underlying reasons for inappropriate antibiotic use. These studies focus on assessing knowledge about antibiotic use, understanding attitudes towards antibiotics, and examining practices related to antibiotic consumption.For instance, several studies have focused on measuring the knowledge, attitudes, and behaviors of medical students towards antibiotics. Although some studies show encouraging results, many highlight a lack of knowledge regarding the importance of correct antibiotic use and prescription ,29,30,31Numerous studies have investigated the knowledge and attitudes of the general population in various countries, revealing notable differences: some studies have indicated low levels of knowledge regarding the proper use of antibiotics and a high prevalence of self-medication, raising significant concerns about antibiotic practices ,34,35,36In Italy, there is limited research on the knowledge and attitudes of the general population regarding antimicrobial drugs. Only one study has been conducted, and it highlights a concerning lack of knowledge among the population ; in factThe objective of this research is to assess individuals’ understanding, perspectives, and practices pertaining to the proper utilization of antibiotics. By accomplishing this, it becomes possible to identify effective interventions and strategies that can help address the problem of antibiotic resistance. Through comprehensive evaluation, valuable insights can be gained, leading to the development of targeted initiatives aimed at promoting responsible antibiotic use and combatting the rise of antibiotic resistance.This observational cross-sectional research was carried out from May 2022 to August 2022 by administering questionnaires to the adults of the metropolitan city of Naples in the South of Italy, with a population of 909,048 . Some 15The questionnaire was submitted to the respondents from Monday to Friday between 10:00 a.m. and 8:00 p.m. in order to prevent oversampling nonworking people. Before beginning the questionnaire, each respondent was informed that the study was being undertaken on behalf of the “Federico II” University of Naples. Furthermore, participants were informed about the nature, scope, and methods of the study. Additionally, the respondents were informed that their involvement was entirely voluntary, that all information gathered would be handled anonymously and confidentially, and that they might discontinue their participation at any moment without explanation. Before proceeding with the interview, verbal informed consent was obtained. There was no incentive to take part or finish the survey. The study was conducted in accordance with the Helsinki Declaration, and ethical approval was acquired in accordance with local regulations.The survey was developed by a commission of health professionals. The appropriateness and usefulness of questions was analyzed during a meeting, and questions considered not appropriate or useful for the study objectives were either removed or replaced ,46. Accop < 0.05, and to estimate significance of both the beta coefficient and coefficient of determination in order to determine how the results of present study vary in relation to independent variables.The collected data has been processed using the STATA MP v14.0 statistical software program . The analysis consists of a first part, in which descriptive statistics were used, and a second part, in which a multiple linear regression analysis (MLRA) was conducted using dependent and independent variables to evaluate their correlation. MLRA allows us to evaluate the statistical significance of the regression model within values of (1)Knowledge about the proper use of antibiotics (Model 1);(2)Attitudes on the use of antibiotics (Model 2);(3)Behaviors related to the use of antibiotics in daily life (Model 3).Three models of MLRA were considered:p-values were less than or equal to 0.05.The dependent variables  were calculated by adding the scores from the respective questions (questions with inverted responses were encoded in reverse). Gender ; age, in years; level of education ; single ; career, and smoking  were all included as independent variables in all models. In Model 2, we included knowledge in the independent variables, and in Model 3, we included knowledge and attitudes in the independent variables. In the study, attitudes and knowledge were treated as indices rather than scales, implying that each observable variable  is critical in causing the related latent variables (attitudes and knowledge). All statistical tests were two-tailed, and results were statistically significant if the The attitudes of the respondents towards the use of antibiotics are presented in In The findings of a multiple logistic regression analysis (MLRA) using three models are shown in This study underscores the critical importance of addressing antibiotic overuse and misuse to combat antimicrobial resistance and its global health implications. The findings, derived from a comprehensive survey-based study involving 1158 individuals, highlight the intricate relationship between demographic variables, knowledge, attitudes, and behaviors related to antibiotic use. Therefore, this research provides a foundation for implementing effective public health programs aimed at improving antibiotic-related behaviors in the general population, ultimately contributing to a healthier and more informed society.In the results presented in Furthermore, this research has consistently shown a positive correlation between non-smoking habits and knowledge regarding antibiotics. Individuals who do not smoke exhibit greater awareness and understanding of health risks associated with antibiotic use ,51. HoweThe second piece of evidence, as shown in Consistent with previous research ,48, thisAnother result of this study was the association between older age and attitudes regarding antibiotics, which is consistent with previous research ,39,57. TOverall, this study highlights the importance of considering age as a factor when examining people’s attitudes towards antibiotics, as this can help healthcare professionals to better understand how to communicate with different age groups about appropriate use of antibiotics. Previous research has demonstrated that evidence-based interactive health literacy programs designed specifically for older adults have been effective in enhancing knowledge and skills related to health decision-making .Furthermore, the study revealed a noteworthy association between knowledge and attitude, suggesting that knowledge regarding antibiotics may contribute to the development of positive attitudes. This finding is consistent with previous studies in which the relationship between attitudes and knowledge has been assessed ,62. PossIn Furthermore, this study identified a relationship between individuals’ education levels and their behavior regarding the use of antibiotics. This finding is not surprising, as previous research has also reported a similar connection between education and antibiotic use . It is pAdditionally, this study revealed a noteworthy association between a higher level of knowledge and attitudes about antibiotics and the adoption of healthy behaviors, in contrast with other studies ,38. Our The findings of this study should be interpreted with caution due to several limitations that need to be considered. One major limitation is that the study relied on self-reported behaviors obtained through questionnaires not validated previously, which could have led to social desirability bias, in addition to the fact that answers may be subjective. However, the study attempted to address this issue by ensuring participant anonymity and confidentiality. Another potential limitation is the possibility of selection bias, because the sample selection was not random, as certain individuals or groups may have been excluded from the study; thus, the results could be affected by reliability problems. Confounding bias is also a possibility, if there were other variables that influenced the results but were not accounted for in the analysis. Moreover, the study’s small sample size relative to the population of Naples limits the generalizability of the findings. Furthermore, while the use of a KAP-based questionnaire was helpful in capturing knowledge, attitudes, and practices related to antibiotics, it may not have captured all the factors that influence antibiotic-related beliefs and behaviors. Furthermore, while every effort was made to ensure the accuracy and reliability of our data, it is essential to acknowledge the potential limitations of this study. First, the sample size, though representative of the target population, may have limited the generalizability of our findings. Second, the absence of a long-term follow-up restricts our ability to draw conclusions about the sustainability of the observed effects. Thirdly, no statistically significant differences were found in the subgroups of the sample; however, these results may be influenced by the numerosity of such subgroups. Lastly, although an adjusted analysis would have provided a more robust approach to the methodology of this study, our research design and resources constrain us from conducting further analysis. These limitations should be considered when interpreting the results and designing future research endeavors in this area.The appropriate use of antibiotics is a pressing concern that demands immediate attention. The findings of this study underscore the vital role of knowledge and attitudes in promoting the proper use of antibiotics and reducing the spread of AMR. It is important to recognize that misconceptions and preconceived notions regarding antibiotics and their effects persist among the general public, indicating the need for the continuous evaluation and improvement of such campaigns to ensure their effectiveness ,66.To effectively address the issue of antibiotic overuse and promote appropriate antibiotic use, the implementation of comprehensive antibiotic stewardship programs is crucial, aiming to mitigate overuse and encourage responsible practices . ConsistVarious channels, including social media, television, and newspapers, as well as the engagement of healthcare professionals, can be used effectively to distribute information about the proper use of antibiotics ,62.In conclusion, promoting appropriate antibiotic use requires a multifaceted approach that includes robust antibiotic stewardship programs, continuous evaluation of national campaigns, and the utilization of insights from research and activities aimed at both the general public and healthcare professionals. By implementing these strategies, we can strive to mitigate antibiotic overuse, combat antibiotic resistance, and safeguard the effectiveness of these essential medications. Ultimately, these efforts can contribute to reducing the overall burden of resistant microbes and AMR, promoting the well-being of humans and all other living beings.This research provided valuable insights into the impact of demographic factors, educational attainment, knowledge, attitudes, and behaviors on antibiotic use in the general population. However, it is important to acknowledge and address the limitations inherent in the study’s cross-sectional design when interpreting the findings, as the selected respondents may not fully represent the wider population. Additionally, relying on self-reported behaviors may be susceptible to limitations related to memory and social desirability bias.The research emphasizes the interplay between knowledge, attitudes, and behaviors, and reveals that knowledge plays a crucial role in influencing attitudes and behaviors related to antibiotic use, as evidenced by the fact that individuals with greater knowledge exhibit more positive attitudes and engage in more responsible behavior. These findings underscore the importance of addressing misconceptions and promoting accurate knowledge about antibiotics to drive positive behavioral change. Furthermore, specific demographic factors were identified as influencers of attitudes and behaviors related to antibiotic use.These significant findings, which were the intended aim of the study, have noteworthy implications for public health policies, providing valuable insights for targeted interventions and campaigns, recognizing the need to tailor educational initiatives to different demographic groups in order to promote accurate knowledge and to encourage positive behaviors. These behaviors will play a crucial role in reducing antibiotic overuse and preserving the effectiveness of antibiotics, thereby mitigating the threat of AMR. By acting now, we can ensure the continued efficacy of antibiotics for future generations.


In the critically ill, pulmonary vasodilators are often provided off label to intubated patients using continuous nebulization. If additional aerosol therapies such as bronchodilators or antibiotics are needed, vasodilator therapy may be interrupted. This study assesses aerosol systems designed for simultaneous delivery of two aerosols using continuous nebulization and bolus injection without interruption or circuit disconnection.-AIRE dual-port breath-enhanced jet nebulizer (BEJN) or two Aerogen® Solo vibrating mesh nebulizers (VMNs) were installed on the dry side of the humidifier. VMN were stacked; one for infusion and the second for bolus drug delivery. The BEJN was powered by air at 3.5 L/min, 50 psig. Radiolabeled saline was infused at 5 and 10 mL/h with radiolabeled 3 and 6 mL bolus injections at 30 and 120 minutes, respectively. Two adult breathing patterns (duty cycle 0.13 and 0.34) were tested with an infusion time of 4 hours. Inhaled mass (IM) expressed as % of initial syringe activity (IM%/min) was monitored in real time with a ratemeter. All delivered radioaerosol was collected on a filter at the airway opening. Transients in aerosol delivery were measured by calibrated ratemeter.One iIM%/h during continuous infusion was linear and predictable, mean ± standard deviation (SD): 2.12 ± 1.45%/h, 2.47 ± 0.863%/h for BEJN and VMN, respectively. BEJN functioned without incident. VMN continuous aerosol delivery stopped spontaneously in 3 of 8 runs (38%); bolus delivery stopped spontaneously in 3 of 16 runs (19%). Tapping restarted VMN function during continuous and bolus delivery runs. Bolus delivery IM% (mean ± SD): 20.90% ± 7.01%, 30.40% ± 11.10% for BEJN and VMN, respectively.Simultaneous continuous and bolus nebulization without circuit disconnection is possible for both jet and mesh technology. Monitoring of VMN devices may be necessary in case of spontaneous interruption of nebulization. In recent studies, our group has developed and assessed techniques for measurement of instantaneous aerosol delivery in a mechanical ventilation circuit to assess the effects of changing variables on drug delivery during continuous infusion and bolus delivery.8 The kinetics of routine bolus delivery of aerosols as well as more complex continuous infusion have been tested with different devices over a range of ventilator settings.Continuous nebulization of selective pulmonary vasodilator aerosols during mechanical ventilation has become a common off-label therapy used in clinical practice for the management of refractory hypoxemia associated with acute respiratory distress syndrome (ARDS), severe pulmonary hypertension and, more recently, with COVID-19.1 and a single breath-enhanced jet nebulizer (BEJN) prototype outfitted with a dual-medication port adaptor that is currently in development and awaiting FDA 510(k) approval. This study evaluates these two technologies during simultaneous delivery of two aerosols during continuous nebulization and bolus injection. The experimental setup tests configurations that do not result in interruption of nebulization or circuit disconnection over a clinically relevant period (4 hours).During continuous nebulization, coadministration of bolus therapy may require opening the ventilator circuit to add devices or disrupt continuous infusion resulting in clinical deterioration. Two nebulizer configurations have been proposed to avoid interruption of continuous nebulization: two stacked vibrating mesh nebulizers (VMNs) delivering two drugs, which have been previously reported in a case report® Solo VMN, which had been reported by Elnadoury et al.,1 but not tested, and a device designed specifically to provide both modalities in a simple single device . To our knowledge, this delivery method has not been previously tested. We hypothesized that either a single i-AIRE BEJN with dual-medication port adaptor or two stacked Aerogen Solo VMN can be used to deliver multiple aerosols simultaneously without interruption or circuit disconnection and that concurrent bolus delivery does not change the overall qualitative and quantitative behavior of the continuous infusion.Real-time measurements with minute-by-minute determination of aerosol drug delivery will test the kinetics of a drug bolus injected during continuous nebulization to determine potential effects on the nebulizer and reliability of continuous therapy. The purpose of this study was to test the function of delivery systems designed to deliver multiple drugs; the “index case” the stacked AerogenThe experimental setup is diagrammed in 2O, Resistance: 20.4 cmH2O/L/s). An inhaled mass (IM) filter  placed in the circuit distal to the endotracheal tube measured the aerosol particles that would be inhaled by a patient (IM) under similar conditions.The humidifier was operated in its invasive mode with default settings and the temperature display was allowed to reach 37°C before each experiment commenced. To complete the circuit, a closed suction system  and a 7.5-mm endotracheal tube  were connected to ventilate a pair of 1-L neoprene test lungs  positioned at the distal tip of the endotracheal tube at the level of the IM filter for measurements of radiolabeled aerosol accumulating on the IM filter per minute over 4 hours. Ratemeter counts per minute were calibrated against quantitative units, for example, microcuries (μCi) of radioactivity with a dose calibrator or gamma camera.Real-time measurement of aerosol delivery during mechanical ventilation was performed using a technique developed in our laboratory to assess the effects of changing variables on drug delivery during continuous nebulization.After a room background radiation measurement coincident with the start of nebulization was obtained, the investigator triggered 1-minute counts of radioactivity every 2 minutes on the IM filter for the first 10 minutes and then every 5 minutes thereafter for each 4-hour experiment. For each 4-hour experiment, there were ∼42 experimental observations per experiment with each of the three output slopes reflecting ∼7–15 data points that were used for analysis and to establish each relationship.The IM filter was changed at 90, 160, and 240 minutes, respectively, to avoid saturation. At the conclusion of the test run, a final 1-minute ratemeter count of the IM filter was made, followed by a measurement by gamma camera or dose calibrator to calibrate the ratemeter and to determine IM% for each data point.AIRE BEJNs molded with a dual-medication port adaptor  and five Aerogen Solo VMNs  were used in rotation for experiments. The experimental setup in AIRE located at the ventilator outlet on the dry side of the humidifier. For Aerogen Solo experiments, the stacked Aerogen VMN system, first described by Elnadoury et al.,1 is shown with two devices and two controllers, one nebulizer and controller designated for continuous infusion and the other nebulizer and controller designated for bolus delivery -radiolabeled normal saline was utilized for all experiments, previous studies have demonstrated that normal saline is a suitable surrogate for multiple water-soluble drugs10–14 and that common drugs such as bronchodilators and steroids can be safely mixed.15 For continuous infusion experiments, a solution containing 9 to 16 mCi of 99mTc was drawn into a 60 mL syringe to achieve 99mTc concentrations of 150 to 270 μCi/mL. For the bolus treatment experiments, 3 and 6 mL solutions containing between 470 and 1330 μCi were prepared for injection. Before the start of each experiment, the nebulizer was dry, empty, and free of radioactivity.Technetium-99m pertechnetate  to establish the initial charge. The total volumes of the prepared solutions were precisely measured to determine the initial radioactivity per unit volume. The time at which this initial charge was measured served as the baseline time for decay correction of the subsequent measurements obtained throughout the experiment.AIRE devices were energized: the i-AIRE BEJN driven by compressed air at 3.5 L/min, 50 pounds per square inch gauge , and Aerogen Solo VMN by each designated Aerogen controller. Ratemeter data were continuously monitored and recorded every 3–5 minutes (counts per minute [CPM]). After establishing continuous nebulization (over 30 minutes), the first bolus injection was made (3 mL) either into the bolus-designated Solo or via the dual-medication port adaptor of the i-AIRE . A p-value of <0.05 was considered statistically significant for all tests.This protocol was followed for each ventilator setting and pump flow. Eight 4-hour infusions were performed each with a 3 and 6 mL injected bolus. Data from this study were compared with results from a previous publication from our group9For graphs  and 5, tBlack lines were drawn through three slopes indicating periods of continuous infusion. Three and 6 mL bolus injections were performed at 30 minutes (3 mL) and 120 minutes (6 mL) as indicated by the horizontal red line passing through the point at 30 and 120 minutes, respectively. After a bolus was introduced, the graph shifted markedly during the bolus nebulization and the red line extended horizontally for the duration of the bolus delivery. The red perpendicular line extends to the data point where the bolus was consumed and the continuous infusion slope consistent with the original steady state was re-established. The blue horizontal line is drawn at the point where the infusion slope and the bolus introduction intersect providing quantification of the contribution of the continuous infusion to the bolus.AIRE BEJN and Aerogen VMN mean ± standard deviation (SD) ranged from 13.1% ± 0.3% to 34.9% ± 1.9% and 19.3% ± 2.8% to 44.9% ± 1.8%, respectively. Kruskal Wallis analysis comparing bolus data from current study to that of Lee et al.7:  (Data for bolus delivery  were exp= 0.056) .p = 0.533; 10 mL/h, DC 0.13: p = 0.933; 5 mL/h, DC 0.34: p = 0.667; 5 mL/h, DC 0.13: p = 0.667). Comparison of all slopes for both nebulizer technologies for all experimental conditions : p = 0.983   and 5. L = 0.983 .AIRE BEJN protocols were routinely completed without incident with a typical experiment shown in AIRE BEJN and Aerogen Solo VMN as well as the responsiveness of the system, when the VMN spontaneously stopped, was tapped and restarted.i-in vitro bench study and does not assess patient-related factors or define actual clinical aerosol delivery using these systems. Our data set the stage for clinical trials and support the case report of Elnadoury et al.1 who first modified a ventilator circuit using stacked Aerogen Solo VMN devices. Radioactive saline was measured in this study, not actual drug delivery. However; normal saline has been shown to be a suitable surrogate for multiple drugs.10–14 The observation period of 240 minutes may not describe long-term continuous nebulization on the order of days. Only two breathing patterns, chosen as the extreme of clinically relevant settings, and two pump flows were studied. This article serves as a detailed template for future studiesThis was an 16 This study was designed to test the behavior of simultaneous bolus injections superimposed on continuous drug delivery. Two different nebulizer configurations were tested. Data for the Aerogen Solo VMN quantified aerosol delivery using the method first proposed in the case report of Elnadoury et al.1 who illustrated the technique of stacking two Aerogen Solo VMN devices in a single circuit. These data were compared with a different technology, the InspiRx i-AIRE BEJN which received both the continuous infusion and bolus injection into the same chamber.This study demonstrates that it is possible to deliver two aerosols simultaneously to an intubated patient without interrupting the ventilator circuit. Aerosol delivery for continuous infusion as well as the individual bolus was quantified separately supporting the concept that the clinician can interpret a dose-response to a given treatment. Previous reports have provided detailed comparisons between the nebulizer technologies.8 did not tap to restart the VMN and did not detect overall differences in function. The VMN tends to deliver a higher average dose when it completely empties.8The real-time ratemeter tracings indicated that behavior was similar for both technologies. Devices were monitored quantitatively by the ratemeter and independently by visual inspection to ensure that they completely emptied during bolus delivery and did not fill during continuous infusion. If the VMN spontaneously stopped, it was tapped to restart facilitating complete emptying. The latter maneuver increased overall delivery resulting in small but significant differences in bolus delivery  between 16 Once the nebulizer reaches a steady state, what is dripped into the nebulizer is completely nebulized provided that the drop-by-drop rate (pump flow) does not exceed the nebulizer's output.16 For continuous therapy, the Aerogen VMN devices produced similar ratemeter traces to the i-AIRE BEJN  are delivered in a predictable manner. That is, the infusion was delivered at its prescribed rate and the bolus at the maximal output rate of the nebulizer. In a clinical situation, the infusion works in the background as the bolus drug is delivered. For both nebulizer types, all the drugs that are placed in the nebulizer are consumed and the nebulizer should not be filled during therapy. After the bolus was consumed the infusion slope returned to its prior continuous rate. This observation was confirmed by visual inspection. The real-time ratemeter technique allowed visualization of transients during nebulization, including interruptions in delivery due to spontaneous cessation of nebulization, as well as quantification of both the bolus and infused radioactive surrogate drugs.7 Mixing of drugs within a nebulizer could result in solution incompatibilities, but it is known that common drugs such as bronchodilators and steroids can be safely mixed.15 Our data support the use of the i-AIRE BEJN with dual-medication port interchangeably with two stacked Aerogen Solo VMN. Either of the two nebulizer technologies can be used to deliver multiple aerosols simultaneously and that concurrent bolus delivery does not change the overall qualitative and quantitative behavior of the continuous infusion.In the analysis of the dynamic changes in the output graphs seen during introduction of the bolus during stacked (VMN) or single (BEJN), results were similar regardless of delivery method and consistent with the observations of isolated bolus delivery by Lee et al.A clinician wishing to treat a patient with two drugs simultaneously might ask the following questions: When you inject the bolus, what happens? Does introduction of the bolus interrupt the infusion? Is bolus delivery using the current method different than conventional stand-alone bolus delivery? The current study demonstrates that treatment using the two drugs occurs independently and in the classic manner, the infusion runs continuously in the background at its prescribed rate evidenced by the slopes and the bolus would be delivered immediately as the nebulizer functions at maximum output. In conclusion, simultaneous multidrug delivery is possible and opens a broader spectrum of possibilities for aerosol delivery in the clinical setting.


We sought to examine local prescribing patterns for uncomplicated febrile UTI in children to guide development of a standardized treatment pathway aimed at reducing unnecessary 3rd CEP use.Concerns regarding antibiotic resistance have led many pediatricians to rely on 3a priori definition. Antibiotic selections were evaluated relative to urinalysis (UA), UCx, and bacterial susceptibilities to assess appropriateness of treatment. This project was certified by our institutional review board as quality improvement.We conducted chart review of children aged 2 mo.-18 yrs treated at our institution for uncomplicated febrile UTI between Oct 2021 – Oct 2022. Subjects were identified by abnormal urine culture (UCx) regardless of colony-forming units (CFU) and included if they met E. coli was most common pathogen (81%) followed by other Gram-negative bacteria (14%); susceptibilities were reported in 97% . Initial antibiotic selection was deemed inappropriate in 68% ; 39% received CRO/CDR unnecessarily. ≥5 white blood cells per high-power field was most associated with a confirmed UTI (P=0.004).61 subjects were included . CRO or CDR were most frequently given as initial in-house treatment (ED or inpatient) . 53% of subjects received ≥1 dose of CRO or CDR . 31% of subjects (68% in ED only) were identified as misdiagnosed with UTI . Providers relied on urine test strips rather than UA/microscopy in 38% of cases misdiagnosed UTIs. Of those with confirmed UTI, rd CEP use and antibiotic overuse in general were prevalent in our study. The biggest drivers were UA underutilization contributing to UTI misdiagnosis and failure to use UCx to de-escalate antibiotics. Our findings serve as a foundation from which to build a standardized treatment pathway for uncomplicated febrile UTIs that will improve antibiotic stewardship and reduce 3rd CEP use.Inappropriate 3Taylor Morrisette, PharmD, MPH, AbbVie: Advisor/Consultant|Basilea: Advisor/Consultant Ronald J. Teufel, II, MD, MSCR, Enanta Pharmaceaticals: Grant/Research Support|Health Resources and Servises Administration: Grant/Research Support|Moderna: Grant/Research Support|National Institute of Health: Grant/Research Support


We present the case of periaortitis which presented initially with left flank pain. A diagnosis of IgG4-related disease (IgG4-RD) was subsequently made and managed as such. IgG4-RD is rare, can be difficult to diagnose, and requires clinical, serological, radiological and pathological correlation, particularly given that serum IgG4 levels may be normal. Immunosuppression is the mainstay treatment for this chronic condition alongside regular rheumatology input. A 42-year-old female presented to the Emergency Department (ED) with several weeks’ history of gradually worsening left flank pain and vomiting on a background of feeling generally unwell for 6 weeks. She was afebrile and denied any change in bowel habit, visible hematuria or other urinary symptoms. Her past medical history included previous cauda equina syndrome secondary to a herniated lumbar disc which still caused intermittent right-sided symptoms. There was no other past medical history of note. Her sister had a diagnosis of systemic lupus erythematosus (SLE) but there was no other autoimmune family history. On examination, there was no abdominal guarding or peritonism but there was lower left costochondral junction tenderness on palpation. Initial investigations revealed microscopic hematuria (+++ blood on urine dipstick). Nephrolithiasis was suspected for which the patient proceeded to computed tomography (CT) of the kidneys, ureters and bladder (KUB). No radiopaque urinary tract calculi were identified but subtle periaortic inflammation  was suspThe serum erythrocyte sedimentation rate (ESR) was elevated . During the subsequent rheumatology review, the patient reported a 12-month history of intermittent submandibular gland swelling which lasted for weeks at a time and could affect one or both sides. She complained of xerostomia but no other symptoms of connective tissue disease. There was fullness in the right submandibular region but no lymphadenopathy. There was no synovitis, sclerodactyly, or evidence of a vasculitic rash.Subsequent position emission tomography-computed tomography (PET-CT) demonstrated intense activity  in the pA full autoimmune screen revealed nonspecific homogenous serum anti-nuclear antibody (ANA) positivity (++). All other results were negative, including the immunoglobulin  and infection screen (including syphilis and HIV testing), rheumatoid factor and anti-Sjörgen syndrome (ASS) autoantibodies. A submandibular gland ultrasound +/- biopsy was requested to assess for histological features characteristic of IgG4-RD as an additional aid to the diagnosis.Our patient was commenced on systemic steroid treatment  with gastric and bone protection. The submandibular swelling resolved following the commencement of steroids so biopsy was unable to be performed. A clinical diagnosis of IgG4-RD was favored and made in conjunction with the 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease Our patient reported an improvement in symptom burden following initiation of steroid treatment shortly after presentation. She was started on mycophenolate the following month as her first steroid-sparing disease-modifying antirheumatic drug (DMARD) with subsequent steroid weaning. Methotrexate, a second steroid-sparing DMARD, was introduced a month later. A repeat CT performed 1-year following the initial presentation demonstrated reduced infrarenal abdominal aortic soft tissue inflammation with no change in disease distribution consistent with immunosuppressive treatment response. The renal arteries and suprarenal abdominal aorta remained unaffected.The diagnosis of IgG4-RD is often made from the combination of clinical, serological, radiological, and pathological information given that biopsy is not often possible. Importantly, IgG4 levels may be normal in a large percentage of patients IgG4-RD has only recently been recognized as a unifying disease entity linking many previously considered discrete unrelated organ-specific fibroinflammatory conditions The incidence of IgG-RD is poorly understood given its very recent identification as a separate disease entity but also because it is often under- or mis-diagnosed Fibroinflammatory lesions characteristic of IgG4-RD can occur at almost any anatomical site Radiological examination is increasingly recognized as an important tool in the identification and diagnosis of IgG4-RD. In the appropriate clinical context, Identifying periaortitis, especially of the infrarenal aorta, should raise suspicion for IgG4-RD.IgG4-RD is treatable. Initiation of treatment early is advocated (sometimes urgently depending on the organ involved) when inflammation has not yet resulted in irreversible fibrosis and/or end-organ damage. If left undiagnosed and untreated, significant morbidity and even death can result. Glucocorticoid treatment is the mainstay of initial treatment given its quick action and high response rate in remission induction IgG4-RD is a rare but recently recognized unifying disease entity. It can be difficult to diagnose, especially when biopsy is not possible. Clinical, serological, radiological, and pathological correlation is required, and a large proportion of patients have normal IgG4 levels. Given that several conditions may present with flank pain or “renal colic,”, in the absence of imaging evidence of urolithiasis, the clinical picture should be reassessed with close liaison between clinical teams and radiologists.Guarantor of integrity of the entire study: MP; Study concepts and design: MP; Literature research: SS; Clinical studies: MP; Data analysis: n/a; Statistical analysis: n/a; Manuscript preparation: SS, MP; Manuscript editing: SS, MP.I, on behalf of all authors, confirm that written, informed consent for publication of this case was obtained from the patient.


Pancreatic adenocarcinoma (PDAC) is the most common pancreatic cancer and is associated with poor prognosis, a high mortality rate, and a substantial number of healthy life years lost. Surgical resection is the primary treatment option for patients with resectable disease; however, only 10–20% of all patients with PDAC are eligible for resection at the time of diagnosis. In this context, neoadjuvant therapy has the potential to increase the number of patients who are eligible for resection, thereby improving the overall survival rate. For patients who undergo neoadjuvant therapy, computed tomography (CT) remains the primary imaging tool for assessing treatment response. Nevertheless, the interpretation of imaging findings in this context remains challenging, given the similarity between viable tumor and treatment-related changes following neoadjuvant therapy. In this review, following an overview of the various treatment options for PDAC according to its resectability status, we will describe the key challenges regarding CT-based evaluation of PDAC treatment response following neoadjuvant therapy, as well as summarize the literature on CT-based evaluation of PDAC treatment response, including the use of radiomics. Finally, we will outline key recommendations for the management of PDAC after neoadjuvant therapy, taking into consideration CT-based findings. Pancreatic cancer is the tenth most common cancer in the United States, with an estimated 64,050 new cases in 2023. While it is only the tenth most common cancer, it is the third leading cause of all cancer-related deaths in the United States, being responsible for an estimated 50,550 deaths in 2023 ,2,3. MorOf all pancreatic cancer types, pancreatic ductal adenocarcinoma (PDAC) type accounts for the majority of cases 85–90%) . PDAC is5–90% . PFor the staging, restaging, and follow-up of patients with PDAC, diagnostic imaging remains the primary tool, with contrast-enhanced computed tomography (CT) being the most commonly used imaging modality for the local assessment of PDAC. In the primary staging setting, imaging is indicated to classify the tumor as resectable, borderline resectable, locally advanced, or metastatic ,12. In tIn this review, following an overview of the various treatment options for PDAC according to its resectability status, we will dive into the imaging-based assessment of PDAC following neoadjuvant therapy. Specifically, as CT remains the primary imaging modality for the evaluation of PDAC, we will describe the key challenges regarding CT-based evaluation of PDAC treatment response following neoadjuvant therapy, as well as summarize the literature on CT-based evaluation of PDAC treatment response, including the use of radiomics. Finally, we will outline key recommendations for the management of PDAC after neoadjuvant therapy, taking into consideration CT-based findings.Treatment plans for PDAC should be made following a comprehensive evaluation, including primary staging of the disease and assessment of the patient’s overall health status. At primary staging, PDAC is classified as a resectable disease, borderline resectable disease without metastases, locally advanced disease, or metastatic disease. Accuracy in the primary staging setting is crucial, as disease staging significantly affects treatment decisions. Guidelines for the management of pancreatic cancer have been published by the National Comprehensive Cancer Network (NCCN) in the United States . Of noteSurgery is the primary treatment option for patients with resectable PDAC. The goal of surgery is to obtain R0 resection, which entails the complete resection of the primary tumor and regional lymph nodes, since positive margins are associated with poor long-term survival ,17 Figu. After sConsidering the complexity of borderline resectable PDAC, multidisciplinary discussion between medical oncologists, radiologists, surgeons, and radiation oncologists is especially necessary to determine the best treatment strategy. Treatment options include upfront surgery as well as neoadjuvant chemotherapy with or without radiation therapy. It is also advisable to refer borderline PDAC patients to participate in a clinical trial, as clinical trials offer the opportunity to undergo innovative treatment approaches, new drug combinations, and emerging therapies that can potentially improve patient outcomes.The goal of neoadjuvant therapy is the downstaging of the tumor, which improves the likelihood of an R0 surgical resection, thereby prolonging survival rates; in this way, neoadjuvant therapy can also identify patients with rapid progression and poor response to treatment ,22. WhilGiven the various neoadjuvant strategies, molecular profiling at diagnosis and the evaluation of the immune environment are emerging as potential tools to personalize neoadjuvant strategies. Encouragingly, combining neoadjuvant therapy with immunotherapy has shown promise to improve patient outcomes, particularly in the context of localized disease .For patients with locally advanced PDAC and poor performance status, treatment options include best supportive care or palliative care  . For patFor patients with metastatic PDAC, treatment options include systemic chemotherapy , targeted therapy, or palliative care. Treatment for these patients is aimed towards managing the disease and improving their quality of life. The choice of treatment will depend on the patient’s performance status, the extent of the disease, and the patient’s treatment response.For the evaluation of treatment response following neoadjuvant therapy in patients with PDAC, CT remains the most commonly used imaging modality as it offers several advantages over the other imaging modalities, including higher spatial resolution and multiplanar reconstruction capability . HoweverTo identify pertinent articles and studies, a comprehensive search strategy was employed. Utilizing the PubMed database, the following search terms were used: “Pancreatic Adenocarcinoma”, “CT Imaging”, “Neoadjuvant Therapy”, “Radiomics”, and “Resectability”. Boolean operators  and quotation marks were strategically applied to optimize the search results. The search was performed without a specified date limit to encompass the breadth of the available literature. Subsequently, the results were reviewed, and relevant articles were selected for inclusion in the study, providing a foundation for the literature review and background of this research endeavor.Only a few studies have assessed the use of semantic CT imaging features  to evaluate treatment response following neoadjuvant therapy in patients with PDAC . To dateSemantic CT imaging findings that have been investigated include tumor size, volume, diameter, or attenuation, including those assessed according to RECIST criteria ,36,38,39p < 0.01 for both)  .p < 0.001 and p = 0.001, respectively). However, in Cassinotto et al. [Regarding tumor attenuation, Marchegiani et al.  found tho et al.  and Wagno et al. , attenuaRegarding vascular contact/involvement, Cassinotto et al.  demonstrp = 0.01). Jang et al. also found that regression or stability of the NCCN resectability status after neoadjuvant therapy was associated with improved recurrence-free survival (Low contrast enhancement of the soft tissue contacting the artery (≤46.4 HU) was shown by Jang et al.  to be assurvival .p = 0.01), leading to increased disease-free survival and overall survival.Amer et al.  classifiFinally, Kim et al.  used theAs can be seen above, the use of semantic CT imaging features in the assessment of treatment response and resectability in PDAC after neoadjuvant therapy remains limited. Meanwhile, radiomics has emerged as a valuable tool that involves extracting and analyzing quantitative imaging features from medical images, offering the potential to enhance treatment response assessment . In the Radiomics enables the quantitative assessment of subtle spatial variations pertaining to pixel intensities and distribution within radiological images; in this way, radiomics has the potential to provide insights into pathologic changes in the tumor and surrounding regions beyond what can be perceived by the naked eye alone ,43. Give(a)Pre-execution: In this step, the research team determines the study design, the involvement of human subjects, the imaging modalities that will be used, and the clinically relevant endpoints that will be studied. This step aims to determine the feasibility of the study, including ensuring that sufficient high-quality data will be obtained.(b)Data curation: In this step, clinical data, imaging data, and other relevant metadata are collected and managed according to the needs of the study. Of note, image anonymization is a key aspect of data curation; proper image anonymization is not only crucial to maintaining patient/participant privacy, but it is also an essential characteristic of high-quality data.(c)Image segmentation: In this step, tumors, peritumoral or tumor subregions , 2D regions of interest, or 3D volumes of interest are segmented, whether manually, automatically, or semi-automatically. This step aims to provide a representative area or volume to be assessed.(d)Image pre-processing: This step involves the application of a filter, normalization, resampling, and/or thresholding, aiming to increase standardization and/or improve image quality.(e)Feature extraction: In this step, different classes of features are extracted from the segmented area or volume, including morphological features , first-order or histogram-based features , and second-order textural features .(f)Feature selection: In this step, from all the extracted features, those features that are stable, informative, and non-redundant are selected for model building.(g)Model building: Model building is a crucial step, in which a radiomic model is developed using the selected radiomic features to enable realistic and accurate diagnosis, prognosis, or response prediction. During this step, the comparison of the performance of the radiomic model against that of clinically used tools is helpful for determining the added value of the radiomic model.(h)Validation: This step involves assessing the performance and generalizability of the developed radiomic model by applying it to an independent dataset, ideally from a different institution. This step ensures model robustness and effectiveness before potential real-world implementation.While radiomics is a promising tool, to date, only a few studies have assessed the utility of CT-based radiomics , for the assessment of PDAC treatment response after neoadjuvant therapy . These sp = 0.0046) and that kurtosis was indicative of tumor downstaging [p = 0.001). Kim et al. [Most studies involved manual segmentation of the pancreatic tumor. In Chen et al., radiomic features that were associated with a good pathologic response included changes in the mean histograms of CT number, standard deviation, skewness, and kurtosis . Nasief nstaging  investigm et al.  also invOne study by Rigiroli et al.  involvedThe precise pathologic correlates of the radiomic features that constitute the machine learning classifiers are not entirely known. The major limitations of these studies include their retrospective nature, rendering them prone to selection bias. Additionally, the number of subjects included in these studies are relatively small. Prospective studies with larger cohorts are warranted for further validation.NCCN guidelines recommend that after neoadjuvant therapy, if there is no evidence of metastasis, the determination on whether to perform surgical resection after neoadjuvant therapy in patients with PDAC should be made through multidisciplinary discussion, taking into account imaging findings, cancer antigen (CA 19-9) levels, and clinical symptoms . RegardiFor tumors classified as resectable or borderline resectable tumors at primary staging, exploratory surgery should be considered if there is no definite progression on imaging, and CA 19-9 levels either decreased or remained unchanged. Surgery may also be indicated if the portal vein or superior mesenteric vein are involved following neoadjuvant therapy, but are in the presence of patent vessels for vascular reconstruction proximally and distally to the site of the vessel involvement. Even in the presence of slightly increased perivascular soft tissue thickening, surgery may still be considered if this finding is accompanied by other signs of clinical improvement, such as an increased performance status and reduced symptoms .Locally advanced tumors at primary staging can be considered for exploratory surgical resection following neoadjuvant therapy if there is significant clinical improvement, markedly decreased CA 19-9, and no definite tumor progression on imaging. Moreover, it is essential to have a comprehensive discussion with the patient regarding the advantages and disadvantages of the surgery. If the decision to proceed is made, it should be performed at highly specialized centers.-CT is currently not sufficiently accurate to predict R0 resection.-Imaging frequently underestimates resectability following neoadjuvant therapy.-Favorable imaging findings after neoadjuvant therapy include partial regression of tumor contact with peripancreatic vessels, a mild fat-stranding perivascular halo in place of solid tumor contact with a vessel, and reduction in tumor size according to RECIST 1.1 guidelines.-Surgery after neoadjuvant therapy should be considered even if imaging findings are unchanged from those at primary staging.-CT is more accurate for evaluating venous involvement than for arterial involvement after neoadjuvant therapy. Decreased venous stenosis or decreased contour deformation indicates improved venous involvement.In addition to the NCCN guidelines, the American Journal of Roentgenology Expert Panel Narrative Review  presenteIn conclusion, this review presents the current state of CT-based assessment of PDAC treatment response after neoadjuvant therapy and emphasizes the potential of radiomics as a complementary tool for CT-based assessment. While the current literature is lacking in studies investigating the added value of radiomics to improve the accuracy and reliability of CT-based assessment after neoadjuvant therapy, it is expected that more studies will be conducted in the future, including multicenter, prospective studies which are urgently needed to pave the way for the integration of radiomics into clinical practice, ultimately benefitting many patients with PDAC.