This research presents a systematic review focusing on rituximab's therapeutic applications in immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a rare condition characterized by immune-mediated systemic inflammation and tissue fibrosis, as well as the clinical features of IgG4-RD. While the disease commonly affects organs such as the bile ducts, lymph nodes, retroperitoneum, pancreas, and salivary glands, it can potentially involve other organs. This intricacy often leads to diagnostic challenges due to clinical overlaps with cancer, infections, and other autoimmune disorders.The diagnosis of IgG4-RD necessitates a comprehensive approach involving laboratory tests, imaging studies, and clinical assessments. Symptoms can vary, ranging from lymphadenopathy to jaundice, affecting multiple organs. Although elevated blood IgG4 levels and findings of tissue involvement and fibrosis on imaging can be suggestive, they lack the specificity for a definitive diagnosis. Early diagnosis is crucial for initiating corticosteroids and immunosuppressive to prevent further damage from IgG4-RD. This study highlights the therapeutic role of rituximab in managing this condition.Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, the research identifies and evaluates relevant literature across various electronic databases, including PubMed, ScienceDirect, and Google Scholar. This review includes 14 selected publications, comprising three systematic reviews, three observational studies, four narrative reviews, and four case reports. The study design ensures a comprehensive evaluation of rituximab's potential efficacy in treating IgG4-RD and its associated clinical characteristics. Based on this study, it can be concluded that IgG4-RD can potentially be treated with rituximab, particularly in cases of relapse and maintaining remission. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare disorder characterized by IgG4-positive plasma cell infiltration and tissue fibrosis due to immune-mediated systemic inflammation . It is aThe lymph nodes, bile ducts, retroperitoneum, pancreas, and salivary glands are typical sites of involvement; however, it may affect almost any organ system . ClinicaIgG4-related disease is still relatively under-recognized and often misdiagnosed due to its diverse and overlapping clinical manifestations, which can mimic a variety of other conditions . This diIn addition to the typical organ involvement mentioned, such as the bile ducts, retroperitoneum, pancreas, and salivary glands, IgG4-RD has been found to affect an expanding array of organ systems, including the thyroid, lung, kidney, and even the central nervous system . This wiRituximab is a monoclonal antibody that targets a specific protein called CD20 found on the surface of B cells. It is primarily used in the treatment of several autoimmune disorders and certain types of malignancies, particularly B-cell lymphomas and leukemia. Rituximab works by binding to CD20-positive cells and leading to the destruction of B cells, which play a crucial role in immune responses and the production of antibodies. Rituximab helps suppress unwanted immune responses by reducing the number of memory B cells in circulation.Rituximab has emerged as a promising therapeutic option for IgG4-RD in recent years, showing the potential in inducing and maintaining remission. Rituximab, a monoclonal antibody that targets CD20-positive B cells, has demonstrated efficacy in various autoimmune conditions . Its mecMethodsStudy ObjectiveThis study seeks to provide a detailed analysis of the effects of rituximab in IgG4-RD and its clinical characteristics. Our purpose of the study is to evaluate rituximab’s use in treating IgG4-RD while also pinpointing any blind spots in our knowledge. This comprehensive literature evaluation also examines the commonly associated clinical features of IgG4-RD.Study DesignThe studies selected for evaluation were thoroughly filtered using inclusion and exclusion criteria. Additionally, the studies were chosen based on their relevance to the research's objectives, including keywords such as "IgG4-related disease," "rituximab," and "glucocorticoids." The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were used to conduct this systematic review -10.Inclusion and Exclusion CriteriaThe inclusion criteria of this research include studies that analyze the effect of rituximab on IgG4-RD and its clinical characteristics. This encompasses diverse study designs  reporting on clinical outcomes, adverse events, response rates, and other relevant factors. These studies must be published in English within the last 10 years (2013-2023) and exclusively involve human participants.The criteria for exclusion involve the removal of studies involving animals, in vitro experiments, or phase 1 clinical trials. Additionally, studies that do not focus on rituximab or IgG4-RD, those lacking adequate data regarding clinical features or treatment effects, studies not in English, and those scoring below 70% in quality assessment are also to be excluded.Data ExtractionThree databases, including PubMed, Science Direct, and Google Scholar, were used to retrieve the data from the studies necessary for this research. The information that was collected consists of research specifics , patient specifics , clinical outcomes , clinical features, and adverse events.Search StrategyPubMed, Science Direct, and Google Scholar were the three electronic databases combed for relevant articles. Keywords “rituximab,” “glucocorticoids,” and “IgG4-related disease” will all be part of the search approach. Only articles written in English that were published before May 6, 2023, will be included in the search. When research studies from the chosen databases were combined and duplicates were removed, the search technique yielded a total of 323 results. The field searches utilized in the process were meticulously chosen based on the keywords used in the previous literature and through Medical Subject Headings (MeSH), depending on the database used.The records were initially examined based on the titles and abstract, and irrelevant studies were excluded. Microsoft Excel  was used for duplicate removal and organizing each reference in the order. EndNote citation manager  was used to convert and organize references to the desired format. The outcomes of the search strategies are unambiguously illustrated in Table Risk of Bias in Individual StudiesThe quality and risk of bias of included studies are assessed using appropriate tools such as the Newcastle-Ottawa Scale for observational studies , Scale fResultsWe conducted a systematic review to explore rituximab's therapeutic use in IgG4-RD and its clinical features. After a comprehensive search of relevant literature, we identified 22 studies that met our inclusion criteria. These studies were published between 2013 and 2023 and encompassed various aspects of IgG4-RD and rituximab treatment. We started with 104 potentially relevant research, assessed the quality of 22 publications, and ultimately included 14 in our systematic review since they matched our inclusion criteria. A total of 14 publications were used to produce the study's findings: three systematic reviews, three observational studies, four narrative reviews, and four case reports. No other resources were added. The summary of the study selection and study designs is presented in an organized manner in Figure Quality AssessmentTwo independent reviewers screened the titles and abstracts of retrieved articles and did a quality assessment check to identify potentially relevant studies. We conducted a comprehensive evaluation of all studies that could meet the criteria for inclusion. To ensure accuracy and fairness, any discrepancies that arose were addressed either by reaching a consensus or consulting with an impartial third reviewer. This approach allowed for a comprehensive evaluation of the systematic review, resulting in relevant data. The quality appraisal score for each study is shown in Table The table includes studies that were categorized by the type of study and the evaluation tool to assess their quality. Each study has the average score in percentage given by author 1 and author 2 and the combined average score of both authors.Narrative reviews: These studies provide an overview or update on IgG4-RD. The average scores range from 54.17% to 83.33%, indicating moderate to high quality.Systematic reviews: These studies systematically evaluate the existing literature on IgG4-RDs. The average scores range from 43.75% to 82.59%, indicating moderate quality.Observational studies: These studies observe and analyze IgG4-RDs in real-world settings. The average scores range from 81.25% to 87.50%, indicating high quality.Case reports: These studies present individual cases of IgG4-RD and their treatment outcomes. The average scores range from 81.25% to 93.75%, indicating high quality.Clinical featuresThe IgG4-RD is recognized as a multi-organ fibroinflammatory disorder with a wide range of affected organs. The involvement of glands, such as salivary and submandibular glands, lymphadenopathy, and epithelial edema, which are essential clinical markers for diagnosis. Additionally, autoimmune pancreatitis is common in IgG4-RD characterized by pancreatic enlargement, lymphoplasmacytic infiltrates, and fibrosis. This condition often presents with jaundice and biliary strictures, indicating the potential involvement of the biliary tract. The clinical features of IgG4-RD described in Table Additionally, IgG4-RD can also affect the orbit resulting in ophthalmoplegia, proptosis, ocular edema, and vision impairment. Dermatological involvement presents complexity to the disease presentation with manifestations such as erythema, nodules, plaques, masses, and eczema. The kidneys are also critically affected by this disease, often leading to tubulointerstitial nephritis, renal masses, and reduced kidney function. This autoimmune disease can also involve the respiratory system and may contribute to asthma, bronchitis, pulmonary nodules, pleural effusion, and interstitial lung disease.In summary, the studies we examined in our review offer valuable insights into how rituximab affects IgG4-RD and its clinical characteristics. Lymph nodes, pancreas, and salivary glands are found to be the most commonly involved organs. However, the current evidence indicates that rituximab is a promising treatment option, but additional high-quality research, including randomized controlled trials, is required to determine its effectiveness, optimal dosage, and long-term results.Therapeutic use of rituximab in IgG4-related diseaseThe studies in our review covered a wide range of topics related to IgG4-RD and rituximab, including disease introduction, safety, efficacy, diagnostic, and treatment workup. According to the available evidence, rituximab could be a treatment of choice for IgG4-RD. However, it is important to acknowledge that the studies included in this analysis differed in their design, patients they involved, treatment plans used, and duration for follow-up. Due to this variability in studies, it becomes challenging to draw definitive conclusions.Among the included studies, several explicitly focused on rituximab treatment in IgG4-RDs. They examined the efficacy and safety of rituximab as a monotherapy or in combination with other medications. One study by Wang et al. investigated the combination therapy of leflunomide and glucocorticoids for remission in IgG4-RDs . AnotherThe findings from the included studies demonstrate that rituximab showed promising results in treating IgG4-RDs. It was associated with improved clinical outcomes, including remission induction, relapse prevention, and reduced disease activity. Furthermore, rituximab was generally well-tolerated, with only a few reported adverse events. The findings from these studies are included in Table Based on the selected studies, the advantages of using rituximab as a treatment for IgG4-RD are presented below.Efficacy and Tolerability of RituximabRituximab has shown promise in achieving remission and reducing relapse rates in IgG4-RD . It has Rituximab vs. GlucocorticoidsRituximab and glucocorticoids are both commonly utilized treatments for several autoimmune and inflammatory conditions. Glucocorticoids are the first line of treatment in most autoimmune disorders, including IgG4-RD. Although, rituximab is often considered when glucocorticoids alone fail to induce remission . CombinaRituximab vs. Other Immunosuppressive AgentsRituximab was the most often utilized therapy after glucocorticoids when compared with other treatment options for IgG4-RD. Rituximab is considered a treatment option when immunosuppressive agents are ineffective or not well-tolerated . It has In summary, rituximab appears to be a promising therapeutic option for IgG4-RDs, offering both efficacy and tolerability. It has shown potential benefits over glucocorticoids and other immunosuppressive agents, particularly in cases where these treatments have not provided adequate results.DiscussionRituximab's mechanism of action, targeting CD20-positive B cells and modulating the immune response, aligns with the underlying immunopathology of IgG4-RD ,24. It hThis medication is administered intravenously and it is typically given in multiple doses spread over several weeks or months. Common side effects include infusion-related reactions , heightened susceptibility to infections due to reduced B cell count, and potential long-term impacts on the immune system's ability to combat new infections. As with any medical intervention, patients should consult their healthcare providers to determine the most suitable course of action based on their specific medical situation.Recently, rituximab has shown promise as a treatment for IgG4-RD. The study conducted in 2019 shows a comprehensive analysis of the safety and effectiveness of rituximab for the treatment of immune-mediated illnesses such as IgG4-RD . A signiMaintenance treatment with rituximab for IgG4-RD has also been studied for its potential benefits. Wolfson and Hamilos  highlighRituximab has shown potential in the management of IgG4-RD, although the best therapy method is still up in the air. As Brito-Zerón et al. pointed out, further research is needed to create standardized treatment regimens after they comprehensively examined the therapeutic approach to IgG4-RD . In a neThe findings from the systematic review by Choi et al. and the prospective study by Wang et al. consistently support the efficacy of rituximab in inducing remission and controlling disease activity in IgG4-RDs ,29. OtheMoreover, Wallace et al. identified rituximab as a predictor of disease relapse in IgG4-RDs . This suRituximab use has demonstrated potential as both an induction and maintenance therapy for IgG4-RD, particularly in non-responsive cases. It has shown efficacy in inducing remission and improving clinical outcomes. Monitoring blood IgG4 levels during treatment could aid in predicting disease recurrence. However, refining treatment protocols, optimizing rituximab dosing, and identifying predictors of response require additional investigation.IgG4-RD often impacts multiple organ systems and has a variety of clinical characteristics, which often complicates its diagnosis and treatment. The diagnostic features of IgG4-RD include elevated serum IgG4 levels, eosinophilia, malignant lesions, and proliferation of IgG4-positive plasma cells. This disease can affect any organ, such as the pancreas, lacrimal glands, orbits, retroperitoneum, salivary glands, lymph nodes, lungs, kidneys, and others.Diagnostic tools including MRI, PET, and CT scans may demonstrate evident signs of fibrosis in the tissue and edema, consequently helping in early diagnosis and to identify the organs that are impacted. However, these diagnostic methods are not definite but they can still aid in early diagnosis of this complex disease. Due to the disease's broad symptomatology and tendency to resemble other autoimmune conditions or malignancies, physicians have to maintain a high index of suspicion.IgG4-RD is recognized by characteristic histopathological markers, including lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis, and an abundance of IgG4-positive plasma cells. These features aid in distinguishing the disease from others and play a pivotal role in its diagnosis. Figure The clinical manifestations of IgG4-RD have been examined in several research. A study in 2017 outlined the diagnostic and therapeutic process for IgG4-RD, stressing the significance of spotting the disease's multi-organ involvement and signature histological features . Al-MujaThe disease also presents as organ-dependent clinical symptoms, like in autoimmune pancreatitis, patients may experience abdominal pain, jaundice, and weight loss. There can be mucus gland involvement, which can present as xerostomia and sicca syndrome. Chest discomfort, dyspnea, and cough could be symptoms of respiratory tract involvement. A multidisciplinary approach is needed for accurate diagnosis because each afflicted organ system may present with different symptoms.Clinical similarity of IgG4-RD with other conditions, such as malignancies, granulomatous diseases, and even Sjögren's syndrome, might result in an incorrect diagnosis. The uncommon nature of this condition and the lack of clear clinical indicators frequently result in a delayed diagnosis. When patients report recurring symptoms or unclear multi-organ involvement, clinicians have to assess IgG4-RD as an alternative diagnosis.IgG4-RD is known for its relapsing-remitting nature. Even with treatment, patients can experience disease flares that necessitate close monitoring and prompt adjustments in management. The clinical features of relapses may mimic the initial presentation or manifest as exacerbations of pre-existing symptoms, emphasizing the need for rigorous follow-up care.Relapse prediction in IgG4-RD is important for guiding treatment decisions. Elevated blood IgG4 levels were one of the indicators of illness recurrence after rituximab therapy was discovered . MonitorIt is important to note that the clinical features can vary depending on the organs affected by IgG4-RD. Additionally, individual cases may present with unique manifestations. Therefore, a comprehensive evaluation of clinical and laboratory findings is necessary for accurate diagnosis of IgG4-RD.ReportingThe findings of this systematic review are presented in compliance with PRISMA guidelines. A clear and comprehensive representation of the findings is used, and suitable tables or figures are provided to illustrate the essential findings and conclusions from the studies that have been included.Ethical considerationsAs this review is solely based on previously published studies, there is no need for ethical approval for this study. Additionally, there will be no gathering or examination of patient-specific data, ensuring their privacy and confidentiality. The study's focus solely on published literature ensures adherence to ethical standards without compromising data security.In conclusion, based on the extensive analysis of literature and studies presented in this review, we affirm that rituximab holds considerable promise as a remarkably effective treatment for IgG4-RD, particularly in cases of relapse and maintaining remission. Despite variable responses observed in some cases, rituximab's overall impact on reducing IgG4 levels, mitigating disease relapse, and sparing the need for high-dose steroids presents a favorable patient profile. Studies reveal that rituximab has shown a superior response when used in combination with other medications to treat this disease. IgG4-RD often targets multiple organs, such as the lymph nodes, pancreas, and salivary glands. Rituximab has emerged to be an effective treatment option with a relatively good safety profile for treating the clinical symptoms associated with this autoimmune disease. This review suggests that, although glucocorticoids remain the first line of treatment for IgG4-RD, rituximab has the potential to become one of the major treatment options for IgG4-RD. Further clinical trials and studies are warranted to maximize its use and determine the long-term benefits of rituximab in IgG4-RD treatment.


Due to its high water solubility, large hydrophobic cavity and distinct 1H NMR fingerprint {Pd84}Ac is an ideal molecule for exploring supramolecular behaviour with small organic molecules in aqueous media. Molecular visualisation studies highlighted potential binding sites between {Pd84}Ac and these species. Nuclear Magnetic Resonance (NMR) techniques, including 1H NMR, 1H Diffusion Ordered Spectroscopy (DOSY) and Nuclear Overhauser Spectroscopy (NOESY), were employed to study the supramolecular chemistry of this system. Here, we provide conclusive evidence that {Pd84}Ac forms a 1 : 7 host‐guest complex with benzyl viologen (BV2+) in aqueous solution.Polyoxopalladates (POPs) are a class of self‐assembling palladium‐oxide clusters that span a variety of sizes, shapes and compositions. The largest of this family, {Pd 84}Ac) is shown to act as a water‐soluble inorganic host encapsulating organic guests in a Russian Doll fashion. NMR analysis including 1H NMR, Diffusion Ordered Spectroscopy (DOSY) and Nuclear Overhauser Spectroscopy (NOESY), as well as ESI‐MS, was used to study the supramolecular chemistry of this system providing conclusive evidence that {Pd84}Ac forms a 1 : 7 host‐guest complex with benzyl viologen (BV2+) in aqueous solution.The largest anionic polyoxopalladate ({Pd With its hydrophobic cavity, multiple binding sites, high water solubility and charge of −70 this nano‐wheel is an excellent candidate for studying host‐guest chemistry.[N,N′‐dialkyl‐4,4′‐bipyridinium salts) such as benzyl viologen (BV2+) are well‐known for their strong redox, electrochromic and photochromic properties.[84}Ac, by investigating its interaction with benzyl viologen, BV2+  are a class of large, self‐assembling inorganic structures formed by the condensation of metal oxides, usually under acidic conditions.2, 3 F+ Figure , and cha84}Ac has D7d symmetry and is composed of 14 {Pd6} repeating units: {Pd6(μ4‐O)2(μ2‐O)(CH3CO2)2(PO4)3}. In each {Pd6} building block six palladium atoms are linked by μ4‐O oxo ligands, capped by two phosphate ligands which are on the outer surface of the sub‐unit and bridged by a single phosphate group. One acetate ligand points into the centre of the cavity and one sits on the outer surface. The outer ligands point perpendicular to each other and lie on alternating faces of the {Pd6} sub‐units minimising steric hindrance. The arrangement of these ligands on the internal surface of the nano‐wheel creates pockets with an electro‐positive nature. The 1H NMR displays a single set of well‐resolved peaks for the carboxylate ligands on the inner and outer rim of {Pd84}Ac. The inner −CH3 protons, I, are represented by a peak at 2.53 ppm whilst the outer −CH3 protons, II, resonate upfield with a broad peak at 1.86 ppm, Figure S5. Hydrolysis occurs on a slow time‐scale relative to the NMR measurement, therefore an equilibrium exists between charge separated (i.e. free) acetate ligands and those bound to palladium centres and there is correspondingly three distinct resonances in the spectrum for the bound ligands (I and II) and the free ligands.I and II arises from the subtle variance in their respective chemical environments. The internal carboxylate ligand methyl tails are near each other compared to those on the outer face. There is a single μ2‐O connecting two Pd atoms on the inner surface on the nano‐wheel and two phosphate groups capping the sub‐unit on either side. The outer surface of the nano‐wheel has only a single phosphate which bridges each {Pd6}. These dissimilarities make the internal surface slightly more electro‐positive than the external surface corresponding to the slight downfield shift of the inner −CH3 due to the de‐shielding effect caused by this electronic environment.{Pd84}Ac, with its acetate ligands on the inner and outer surface is a richly hydrophobic environment that is filled with water molecules when it exists alone in solution. Enthalpic hydrophobic interactions occur in systems where there is a single organic (often apolar) guest molecule in aqueous solution within a cavity.[84}Ac molecule are in close proximity to one another we predict that the binding event of a single guest would enhance the possibility of further binding through π‐π‐stacking between guest species. This process is known as positive cooperativity and a number of such supramolecular host‐guest systems have been reported using NMR, UV/Vis and calorimetry.[Supramolecular systems rely on a variety of non‐covalent bonds to stabilise the interaction: electrostatic interactions, van der Waals forces, π‐effects and the hydrophobic effect.a cavity.37, 381H NMR titration experiment involving sequential addition of 0.18 mM solution of BV2+ in D2O to a 0.18 mM solution of {Pd84}Ac in D2O shows the formation of a large supramolecular host‐guest complex  in the solid state. ESI‐MS of this precipitate, shown in Figure S10 & Table S12, shows a trend in charge:guest ratio which allows us to suggest that this precipitate represents a {Pd84} : BV stoichiometry of 1 : 8. This implies that after encapsulation of seven guests the 8th equivalent of BV replaces an exo bound cation, initiating precipitation of the complex.The 84}Ac and benzyl viologen. During complexation the chemical environment of BV2+ protons changes, which has consequences on the chemical shift (Δδ) of each proton. In this system the guest experiences an overall de‐shielding effect with Hα, Hβ and Hγ moving downfield whilst Hδ is unchanged. The change in chemical shift was plotted for each guest proton, separately, and is found in Figure 2+ guest species interacting with {Pd84}Ac molecular visualisation was completed using WebLab ViewerLite 3.7, Figure without computational optimisation or energy minimisation. These visualisation models suggest it is possible for seven BV2+ molecules to sit inside the hydrophobic cavity of {Pd84}Ac, each being held in one of the pockets by interaction of the pyridinium protons, Hα Hβ, and the inner ligand of the host, I. The benzyl rings (associated protons denoted Hγ) at either end of the guest flank and wrap around the torus of the nano‐wheel. This is likely aided by the flexible sp3 hybridised methylene, Hδ, which links these rings to the central, rigid and cationic viologen platform.The method of continuous variation was used to evaluate the binding stoichiometry between {Pd1H DOSY NMR is used to provide information about the tumbling rate of molecules in solution. It is a well‐established method in host‐guest chemistry to highlight differences in diffusion rates when guest species are bound to a host molecule compared to that of when it is moving freely.[2+ guest and {Pd84}Ac host tumble at an average rate of 401 pm2 s−1 and 207 pm2 s−1, respectively when they are alone in solution. In a 1 : 7 solution of the two components there is a significant decrease in the average diffusion coefficients for BV2+ to 144 pm2 s−1 and {Pd84}Ac to 113 pm2 s−1. This decrease in rate of tumbling is evidence to show that the BV2+ is interacting with another component which slows its motion through solution. The similarity in diffusion coefficient for both host and guest components when they are together in solution suggests that they are bound together and have formed a supramolecular system. It is interesting to note that there is a slight variation in diffusion coefficient for the protons on BV2+, corroborating nicely with the molecular visualisation data. Hα and Hβ are tightly bound within the internal pockets of the POP, interacting strongly with the methyl groups on internal acetate ligands. These two protons have smaller diffusion values than Hγ and Hδ meaning they are moving slower through solution. The methylene Hδ protons are bonded to a flexible sp3 carbon atom and so their motion is likely to be marginally faster. Benzylic protons, Hγ, sit exposed to the outer environment and therefore experience faster motion, and a larger diffusion coefficient.2D g freely.55, 561H‐1H NOESY NMR is used to determine through‐space interactions occurring between host and guest on complexation. Couplings from host to guest, and guest to host were observed between inner ligand −CH3 of {Pd84}Ac and all four guest resonances; Hα, Hβ and Hγ and Hδ, Figure 2+ resonances and the outer ligand −CH3 group, II. It is clear from the 1H NMR titration data  that guests interact exclusively within the cavity of {Pd84}Ac and not on the outer surface, therefore couplings to outer ligand −CH3 of{Pd84}Ac, II, are not expected.84}Ac@nBV2+, led us to investigate the possibility of further encapsulation by another species within the cavity created by the lining of the organic guest molecules. The development of supramolecular systems which include unfunctionalised C60‐fullerene is of great interest due to the unique properties of the carbon allotrope, but has often been limited to the C60‐fullerene hosting a single atom or small molecule , as opposed to another larger molecule hosting C60‐fullerene.[60‐fullerene are even more sought after due to their potential application in biology, but this brings synthetic challenges.60‐fullerene is 7 Å. Therefore we hypothesise that the C60‐fullerene would sit on the edge of this cavity created by the BV2+ guests as opposed to sitting directly inside the secondary cavity, Figure S22. This is more likely due to the Rebek limit of 55 % which suggests that supramolecular inclusion is only possible when the guest species is ≤55 % of the diameter of the space it is intended to occupy.13C NMR experiments of {Pd84}Ac, BV2+ and C60‐fullerene revealed shifting and broadening associated with supramolecular complexation, Figure 60‐fullerene has a strong and characteristic resonance at 143.6 ppm in toluene‐d8. This solvent was chosen due to the poor solubility of C60‐fullerene in most organic solvents, despite its similar resonance to the aromatic benzyl viologen guest species. A solvent system of 5 : 2 D2O : toluene‐d8 was employed to aid solvation of the C60‐fullerene and because the polyoxopalladate is only soluble in aqueous solution. 1H‐13C HSQC NMR was carried out on seven equivalents of BV2+ in this solvent system to show that the peaks are distinguishable from one another, Figure S14. 13C NMR experiments were carried out on the three‐component system as well as a variety of appropriate controls and all spectra were calibrated in alignment with toluene‐d8 solvent peaks. The inner and outer acetate ligands of {Pd84}Ac have two associated resonances for the carboxylate and methyl components. The inner ligand resonates at 187.4 ppm and 23.3 ppm, respectively, whilst the outer ligand resonates at 185.9 ppm and 22.5 ppm, respectively as shown in Figure S20b. On addition of BV2+ or C60‐fullerene to the polyoxopalladate there is no significant change in these shifts. The benzyl viologen guest species  has eight distinct peaks in the spectrum‐ 150.4 ppm and 145.6 ppm for C1 and C2, 132.4 ppm for C3, 130.3 ppm, 129.8 ppm and 129.4 ppm for C4, C5 and C6, 127.2 ppm for C7 and 65.4 ppm for C8. The benzyl viologen sees a slight change in shift for all resonances when it is in the presence of the polyoxopalladate, Figure 60‐fullerene seen in Figure 60‐fullerene is added to the {Pd84}Ac and BV2+ there is a change in chemical shift for BV2+. C1 is unchanged whilst C2 shifts downfield to 146.4 ppm (Δ 0.8 ppm) and C3 moves downfield to 133.3 ppm (Δ 0.9 ppm). C4, C5 and C6 are the carbon atoms associated with the benzyl rings on the BV2+ guest species, on addition of the C60‐fullerene to the pre‐formed supramolecular complex these resonances significantly broaden and C6 and C7 become slightly lost to the solvent peaks. However, using 1H‐13C HSQC NMR it is possible to distinguish these resonances from one another and to be sure they originate from the guest species rather than the solvent system‐Figure S15, S16 and S17. C8 is significantly shifted to 65.4 ppm (Δ 1.0 ppm). The binding of C60‐fullerene to the secondary cavity is most likely to be on the surface that is created by the benzyl rings of the guest which protrude from the cavity. Therefore, C3 and C8 are anticipated to be the most strongly affected by the addition of the C60‐fullerene, a hypothesis backed by the data.Formation of the supramolecular polyoxopalladate complex, {Pdullerene.59, 601H and 13C NMR chemical shifts as well as 1H NMR DOSY and NOESY data show the location of the interaction, definitively, to be on the internal surface of the nano‐wheel and to be driven by the hydrophobic effect and electrostatic forces between the sub‐units of the anionic polyoxopalladate and the cationic guest. Encapsulation of unfunctionalised C60‐fullerene inside this supramolecular complex was confirmed, similarly, by 13C NMR. This represents an interesting and biologically relevant system for potential application in biomedicine and catalysis.Work on supramolecular systems has focussed on organic macrocycles and their interactions with other molecules in organic solvents. Limitations of these systems include their lack of biological mimicry and the number of guest species that can be incorporated into them. Here we present a system with 7 guest molecules bound into symmetrical pockets of a nanoscale polyoxopalladate which is stable in water. The authors declare no conflict of interest.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


Composite beam theory was previously developed to establish an analytical solution for determining the transfer length of prestressed fiber-reinforced polymers (FRP) tendons in pretensioned concrete members. In the present study, a novel finite element (FE) modeling approach is proposed to provide further verification of the developed analytical method. The present FE model takes into account the friction coefficients obtained from pull-out tests on the FRP tendons and prestressed concrete members. Convergence analysis of two numerical simulations with different mesh densities is carried out as well. The results demonstrated that the transfer length predicted by the fine FE model with a friction coefficient of  Along with the strikingly rapid development of composite materials in the field of civil engineering, the applications of fiber-reinforced polymers (FRP) in strengthening concrete structures have attracted more and more attention. CFRP has higher mechanical properties, excellent fatigue resistance, corrosion resistance, and creep resistance. BFRP and GFRP have relatively low prices and wide sources. However, their long-term performances in service environments may degrade ,2,3. TheComposite beam theory, proposed by Granholm  in 1949 As an important numerical technique, FEA has been widely used to study the behavior of prestressed concrete beams ,29,30. MOne of the most compelling advantages of FEA over other analytical solutions is that a simulation associated with fewer assumptions may be closer to the corresponding experimental outcomes. In addition, visualizations of the pre- and postprocessing of FEA can help engineers easily find vulnerabilities in the design. Despite some obvious advantages, mesh convergence is a critical issue that must be taken into account in the process of developing FE models. In this work, a comparative study is conducted between numerical simulation with fine and coarse meshes to illustrate the effect of mesh density on convergence. Another noteworthy point is that the concrete model used for numerical simulation is based on the linear elastic assumption. Although the concrete damaged plasticity (CDP) model from Abaqus  has ofteIn order to provide convenient use in engineering practice, the key technical challenge of this study is to develop a general form of the governing equations specifically for FRP-strengthening concrete members in terms of composite beam theory. Taking account of the empirical bond–slip relationship between FRP tendons and the concrete matrix, governing differential equations are derived in terms of the equilibrium of axial force acting on each element as well as the balance of the overall bending moment. Using the FEA commercial software Abaqus , a compaUnderstanding the nature of bond behavior plays a critical role in assessing how the prestress force is transferred from the prestressing FRP tendons to the concrete. A large amount of research ,30,34,35Friction can be defined as a relationship that is responsible for transmitting the shear and normal forces between contacting bodies, i.e., prestressing tendons and the surrounding concrete matrix. According to the commercial FE program Abaqus , frictioterature ,35. Howeterature  reports It is worth mentioning that the current work using FEM to estimate the transfer length is based on the friction coefficient specifically for FRP tendons in pretensioned prestressed concrete members. Previous studies on finite element analysis ,29,30 ofFor another description of the bond-behavior model, the local bond stress–slip relationship al model  developeal model ,37,38,39P) model , the modP) model . The BEPFor the mBEP model, terature ,5,7,23. Thick-wall cylinder theory  depends (1)Linear elastic constitutive behavior and small displacement are applied to each component in the developed analytical models;(2)FRP’s bending resistance is negligible compared to that provided by the concrete member;(3)Slender beams are considered and therefore Euler–Bernoulli beam theory can be applied to each component of a composite structure, and, therefore, the shear deformation is neglected through the cross section of the concrete beam and FRP components, respectively.The following assumptions and limitations are specifically proposed for FRP-strengthening concrete members using the general approach of composite beam theory:A differential element of the composite beam is composed of the concrete and FRP, as illustrated in As mentioned above, the analysis of the behavior of FRP-strengthening concrete members is based on partial composite action. To some extent, this means that relative movement between FRP and the surrounding concrete, namely slip Thus, Equation (9) indicates that the slip In terms of the As a result, the governing equation relevant to the axial force is generated in the form:The known external moment Furthermore, it can be observed that the slip The reason for this change is that the structural behavior is limited to elastic and small displacement, the constitutive relation is assumed to be linear, and each component of the composite beam has the same deflection Substituting Equation (15) into Equation (14) results in the expression for the bending moment as follows:Consequently, plugging 7 s0.337 :(22)s″ −It is critical to estimate the transfer length of prestressed concrete beams, not only because it affects the bending and shear strength of the structure, but also because it is valuable for designers to understand it for structural detailing. The effective prestressing force is transferred from the prestressed tendons to the concrete in the transfer zone, in which the distance is related to the transfer length. The conventional experimental investigation used to measure the transfer length mainly depends on the strain change in the concrete or the prestressed tendons before and after release. The determination of transfer length is implemented in terms of the strain distribution along the length of the beam using the 95% Average Maximum Strain (AMS) method. For the analytical solution, the proposed model relied upon a novel and theoretically pure composite beam theory developed specifically for pretensioned prestressed concrete members with FRP tendons, the details of which were provided in the previous work . Based oI) units :(25)s(x)Transfer length tionship  resultinExperimental studies on the transmission of prestressing force conducted by Nanni et al.  are utilC3D8R with eight-node linear brick is employed for modeling the concrete in Abaqus, which is a reduced integration element with hourglass control. The C3D6 element, which is a six-node linear triangular prism, is used for the FRP tendons. The geometries of these two elements are illustrated in In order to optimize the computing time and the results precision, the mesh around the FRP tendons is very refined, and the mesh density increases as the distance from the midspan increases. The quarter symmetry FE model of a pretensioned concrete beam with boundary conditions is represented in The interaction between the concrete and FRP tendons modeled by FE consists of three parts: tangential behavior, normal behavior, and cohesive behavior. According to the concept of the Coulomb friction model, as previously described, the tangential behavior between two contacting surfaces is defined in accordance with four different friction coefficients In order to investigate the dependence of nonlinear solutions obtained from the proposed FE model on the mesh size, two models with different mesh densities are simulated in Abaqus. By means of the solution technique of full Newton and automatic control of the time increment, the mesh convergence study is performed on the three-dimensional FE model of a pretensioned concrete beam using coarse mesh and fine mesh, respectively. The cross sectional and longitudinal views corresponding to both the fine and coarse models are shown in To further demonstrate the mesh convergence and the feasibility and accuracy of the 3D FEA solution, a comparison is made between the FE results and the strain profile from the experiment . Figure Based on the 95% AMS method, comparisons of transfer length predicted by the present FE models with measured results  are summFor further proving the performance of the application of composite beam theory on predicting the transfer length for prestressed FRP tendons strengthening pretensioned concrete members, the present FE model is used to compare with the previously developed analytical solutions. As can be seen from Since it is not possible to exactly match the values measured from testing, the local bond–slip relationship between the FRP tendons and the concrete is taken into account to predict the transfer length using closed-form solutions from Equation (26) in the analytical model. This results in an error between the predictions and the test values of 7% and 26% for high pretension (100% force release) and low pretension (50% force release), respectively. In this perspective, the accuracy of the transfer length obtained from the theoretical solution in terms of partially composite action is superior to that of the numerical simulation by using a Coulomb friction model based on FEA.In addition, extensive studies ,42 have terature , in whicterature  during tOn the other hand, it is obvious to see that a remarkable increase in interface slip occurs when the value of the friction coefficient decreases as shown in Through normalizing the parameters, the influence of the friction coefficient In analytical solutions using composite beam theory, the BEP expression is chosen as the bond–slip relationship Testing is considered to be the best way to predict a phenomenon and obtain necessary information. However, large-scale testing is time-consuming, expensive, and has many limitations. With this consideration, along with the need to further verify the accuracy and feasibility of the previously developed method, a three-dimensional FE model of pretensioned concrete members with prestressing FRP tendons was developed. Despite the numerous numerical research on reinforced concrete beams strengthened with conventional FRP bars, none of the existing studies considered the effects of friction coefficients on the transfer length. To bridge this gap in the literature, the different friction coefficients between FRP tendons and the surrounding concrete obtained by experimental studies are fully considered in this study. Based on the data reported from the pullout test, fine and coarse FE models were implemented for convergent analysis, respectively.A general form of the governing equations has been presented specifically for FRP-strengthening concrete members in terms of composite beam theory. Associating with the knowledge of the local bond stress–slip relationship Comparisons with the experimental data demonstrate good agreement, which indicates that the proposed FE model with fine mesh is acceptable. The measured transfer length for high pretension agrees with the prediction from the fine FE model with the friction coefficient Although friction plays a key role in the interaction between concrete and prestressed tendons, the slip-prediction comparisons show that if the adhesion and mechanical interlocking are ignored, the bond behavior cannot be accurately evaluated;The transfer-length prediction is strongly dependent on the adopted function form of the bond–slip relationship In addition, the general approach of composite beam theory, as the key innovation of this research, is derived for providing convenient use in engineering practice, specifically for FRP-strengthening concrete members. Lastly, a comparison between the analytical solution and the FE simulation is carried out and discussed. The main accomplishments and conclusions are as follows:Therefore, it is necessary to adopt a new method to describe the bond behavior between concrete and FRP tendons in the future FE simulation. In this process, adhesion, friction, and mechanical interlocking must be fully considered in order to provide more accurate predictions and facilitate engineering applications.


We piloted a pharmacist-led multidisciplinary penicillin allergy de-labelling (PADL) daily ward round to determine the opportunity for PADL in a UK hospital.A daily ward round, delivered by either an antibiotic pharmacist or a junior doctor, identified adult medical and surgical patients between 7 November 2022 and 31 January 2023 with a penicillin allergy (penA) record that was preventing first-line penicillin use. An allergy history was taken before risk stratifying likelihood of future harm from penicillin re-exposure and an allergy testing method was determined [de-label on history (DOH) or after direct drug provocation testing (DDPT)]. Following successful de-label, in agreement with the responsible clinician, the antibiotic was switched to a penicillin antibiotic.Of 7214 inpatients during the study period, 1133 (15.7%) had a penA record. Of 285 allergy histories taken, 105 (36.8%) met high-risk criteria, 45 (15.8%) met low-risk criteria eligible for DOH, 73 (25.6%) met low-risk criteria eligible for DDPT and we were unable to obtain a history from 62 (21.8%) patients. Of 45 low-risk patients eligible for DOH, 40 (88.9%) were de-labelled of which 24 (53.3%) were switched to a penicillin antibiotic. Of 73 patients with a low-risk allergy history eligible for DOC, 16 (21.9%) received DDPT, of which nine were switched to a penicillin antibiotic to complete their antibiotic course. Two DOH patients experienced harm (thrush within the first 5 days and delayed skin reaction after day 5), none of the DPTs had a reaction by day 5. The switches resulted in 170 DDDs of penicillin use (predominantly amoxicillin) and reduced alternative antibiotic use by 174 DDDs (predominantly meropenem and levofloxacin).Penicillin allergy de-labelling patient pathway delivered by pharmacists and junior doctors was safe and effective and well accepted by patients and the wider clinical teams. Further work is required to optimize and streamline these patient pathways to maximize patient and health system benefit.


Clostridium difficile was variable depending on the antibiotic used (0.5% to 8%). Noteworthy serious AEs included hepatotoxicity due to beta-lactams (5% to 17%) or quinolones (3%); cytopenia’s related to linezolid (5%) and beta-lactams (6%); nausea under rifampicin, and renal failure under cotrimoxazole. Skin rash was found to rarely occur and was commonly associated with the use of penicillins or cotrimoxazole. AEs from prolonged antibiotic use in patients with DFI are costly in terms of longer hospitalization or additional monitoring care and can trigger additional investigations. The best way to prevent AEs is to keep the duration of antibiotic treatment short and with the lowest dose clinically necessary.The use of antibiotics for the treatment of diabetic foot infections (DFIs) over an extended period of time has been shown to be associated with adverse events (AEs), whereas interactions with concomitant patient medications must also be considered. The objective of this narrative review was to summarize the most frequent and most severe AEs reported in prospective trials and observational studies at the global level in DFI. Gastrointestinal intolerances were the most frequent AEs, from 5% to 22% among all therapies; this was more common when prolonged antibiotic administration was combined with oral beta-lactam or clindamycin or a higher dose of tetracyclines. The proportion of symptomatic colitis due to  Diabetic foot infections (DFIs) are the major cause of non-traumatic amputations globally and are only expected to increase in absolute numbers . The curThe international IDSA and IWGDF practice guidelines provide helpful recommendations for clinicians to improve the diagnosis of infectious disease, to classify the severity of infections, to promote antibiotic stewardship in the field of DFI, and to guide antibiotic therapy ,4,5. HowIn order to fill these clinical knowledge gaps, we performed a narrative review with an epidemiological focus, with the main aim to summarize the most frequent and most severe AEs reported in prospective trials and observational studies at the global level in DFI. Systemic antibiotics administered orally or intravenously have been shown to be effective in the treatment of DFIs; however, none have been shown to be superior to others . The choClinicians should individualize the choice of antibiotic agent based on the pathogen, its susceptibilities, patient comorbidities, potential drug–drug interactions, and contraindications. Although it is beyond the scope of this focused manuscript to report on all possible drug–drug interactions, Pseudomonas aeruginosa. However, these antibiotics do not cover bacteria stemming from skin commensals in DFO or methicillin-resistant Staphylococcus aureus (MRSA) [Beta-lactams are the most frequently used antibiotic class in DFIs for parenteral and/or empirical therapy . The pols (MRSA) . In acutWe first performed a literature search in the English language on the PubMed database for relevant prospective trials and observational studies related to DFIs. During the first search, the terms “diabetic foot” and “antibiotics” were used. This search retrieved 144 articles, with 22 studies selected for full text review. A second search was conducted using terms related to “soft tissue infection” or “skin-structure infection and antibiotics”, which resulted 1151 potentially relevant articles. Of these, 264 articles underwent full text analysis and 29 were included in this review. Two additional articles were found through non-electronic methods and included in this review. In total, we included 53 studies. Details of the articles are shown in From these included articles, we found the incidence of AEs varied between 2% and 30% for patients with DFI. The most common AEs were gastrointestinal in nature, covering 5% to 22% of all reported AEs. In the following text, we summarize the most common AEs in patients with DFI stratified against a variety of antibiotic classes through the accurate revision of the selected articles.Clostridium difficile colitis (CDI) was reported more frequently during beta-lactam therapy compared with other groups of antibiotic classes   to the hibiotics  and 2% tibiotics ,26). Othibiotics ,28. A syibiotics . The higibiotics . In addiibiotics .With regards to cephalosporins, only a small number of AEs are reported in the DFI literature. Diarrhea appears to occur less frequently with cephalosporins compared with other beta-lactams . Skin rash (1%) and hepatoxicity (0.5%)  were shoGastrointestinal perturbances were found as the most common AE occurring in between 3% and 12% of cases for imipenem/cilastatine (I/C) or meropenem treatments. Symptomatic CDI occurred at a rate of 8 to 9% during I/C treatment ,36. HepaAlthough gastrointestinal AEs are also the most frequently reported, quinolones show fewer AEs related to diarrhea when compared with beta-lactam therapy (4 to 5%) ,40. RareIn a landmark randomized clinical trial regarding the duration of antibiotic therapy for the conservative management of DFO, 27 (68%) of the DFI patients received rifampicin and 19 (48%) received rifampicin with levofloxacin. In this study, antibiotic-related adverse events were recorded in 16 patients (40%); 6 patients (30%) at 6 weeks of follow-up and 10 patients (50%) at the 12-week follow-up timepoint. The most common AEs found were gastrointestinal (nausea and vomiting), all attributable to rifampicin at the 12-week follow-up timepoint (10%) . RifampiGlycopeptides such as vancomycin are commonly associated with hypersensitivity reactions such as infusion reaction and rash, known as red-man syndrome, which is an expected histamine release with immediate skin rash (3–40%) ,53. InfuThese agents, both with nearly universal anti-Gram-positive activity, may cause potentially substantial toxicities  due to impaired mitochondrial protein synthesis and consecutive mitochondrial dysfunction. A common feature is the expected drop in serum platelet and hemoglobulin counts, which usually occurs two weeks after the start of treatment ,54. LineOur search revealed that no clinical trials or multicenter studies with the use of an aminoglycoside as a systemic antibiotic for DFIs were published. However, gentamicin was the most frequently used topical antibiotic agent for infected diabetic foot ulcers and also takes place as intraosseous deposits for chronic osteomyelitis in the diabetic foot and other orthopedic infections. When used as gentamicin sponges for infected diabetic foot ulcers, gentamycin showed no systemic AE and was very well tolerated ,64. HoweGastrointestinal symptoms are the most common AE in this antibiotic group. According to reports captured through our search, nausea and vomiting may occur up to 25% , 35% , or 40% (95% CI. 36–45%) of the time ,66,67. FAs widely experienced by many clinicians, some articles confirmed the potential for a worsening of transient kidney function in the laboratory with the combination of cotrimoxazole and cephalexin . Other rClostridium difficile. We found that the relation of CDI with clindamycin in monotherapy was around 1.7% for an average duration of 14 days [The most common AEs are gastrointestinal in nature, with few reported cases of pseudomembranous colitis due to  14 days . Recurrent misuse of systemic antibiotics is high in the adult population with DFIs . With loClostridium difficile may be a severe complication and is higher for beta-lactams (8–9%) than other antibiotics. More serious AEs were reported: hepatotoxicity due to beta-lactams may not be as rare (5% to 17%) and it is important to be aware of that for monitoring care. The hepatotoxicity of fluoroquinolones is generally lower (3%), and there is cytopenia related to linezolid (5%) or beta-lactams (5% to 7%), nausea and multiple drug interactions under rifampicin, and renal insufficiency under cotrimoxazole.Overall, gastrointestinal intolerances were the most reported AE, ranging from 5% to 22% among all antibiotic therapies, although this occurred most frequently during oral beta-lactam or clindamycin use and at the increasing doses related to tetracyclines. Symptomatic colitis due to Kidney function may be altered by a wide range of antibiotic agents. However, vancomycin (compared with other agents) showed a higher potential for reduced glomerular filtration, and monitoring levels for vancomycin could help to avoid toxicity for which a potential overdose may lead to dialysis. Furthermore, and despite that the selected studies could not prove this toxicity, the regular use of cotrimoxazole at high doses is associated with transient nephrotoxicity and metabolic acidosis  in serumHematologic disturbances occur regularly with linezolid when prescribed for more than 10–14 days, with fewer cytopenia cases with tedizolid compared with linezolid. This mechanism of inhibition of bacterial ribosomes also has an effect on the mitochondrial protein synthesis of human cells and causes mitochondrial dysfunction with a decrease in ATP in the bone marrow precursor cells that leads to myelosuppression. This is important to know to fix the data to request a control hemogram blood test if treatment is to be continued for a longer period of time, i.e., more than 14 days. Since tedizolid is administered once a day, it allows longer recovery periods from mitochondrial dysfunction and can mitigate the higher intrinsic toxicity compared with linezolid .Skin rash was shown to seldom occur and was typically related to use of penicillins or cotrimoxazole. We believe inguinal mycosis (intertrigo) is mostly recognized in only hospitalized patients and is therefore underreported in the literature. Severe cutaneous and systemic toxic reactions have been described, such as eosinophilic rash (DRESS syndrome) together with a systemic inflammatory response syndrome (SIRS) with beta-lactam drugs, clindamycin, and vancomycin. In addition, cotrimoxazole may also be a potential cause of SIRS. The Stevens–Johnson syndrome of severe skin toxicity is not described in our focused review on DFIs, but clinicians should also be aware of this severe complication of antibiotic therapy, it being more frequent with sulfonamides and beta-lactams.All systemic antibiotic agents in diabetic patients with a poor glycemic control and classically with macerated inguinal regions due to overlapping abdominal fat tissues may produce fungal skin infections during or shortly after the antibiotic therapy . However, we found data regarding this clinically frequent observation to be sparce. One article attributed an overall incidence of 2% and 4% concerning all antibiotic classes ,19, and The musculoskeletal system was an uncommonly described AE, despite the fact that the risk of tendinopathies is a hallmark of fluoroquinolones; however, the published literature was not related to that of the selected DFI articles. Regarding the risk of quinolone-related tendon pathology, it is reported in the literature as a rare adverse event in 0.5–2% of cases treated with fluoroquinolones .With regards to neurological AEs, headache or insomnia is frequently described for many antibiotics. The incidences of such conditions are higher with quinolones, whereas seizures, confusions, or hallucinations are commonly associated with beta-lactam agents. Seizures are related to the beta-lactam ring, which binds to GABA receptors and alters ionic conduction. The most frequent neurological disturbances  occur with 3rd–4th generation cephalosporins (high with cefepime) and imipenem. A switch to early oral therapy by other agents or a therapeutic drug monitoring of the serum cefepime level in elderly patients with impaired renal function can be an option to reduce neurological AEs in patients with DFI. In our review, within the low frequency of seizures due to carbapenems, imipenem was the most common causative agent. Of note, monobactams (aztreonam) are less involved in neurological events .The main limitation of this review is the restriction to scientific publications in the English language only and to articles specifically targeting DFI antibiotic therapy. It is clear that the same antibiotic agents might represent other AE in other patient populations with fewer co-morbidities inherent to the DFI patient population. Such an expanded review would be beyond the scope of this article. Likewise, we excluded the problem of additional costs specifically related to the antibiotic-related AEs during the treatment of DFI (for which there are no specific data available) and we purposely skip the discussion of antimicrobial resistances in the management of DFI, which many clinicians would indicate as the most important adverse problem. However, the resistance problem is not a classical or random ‘adverse event’ of antibiotic therapy. It is a systematic flipside of each prolonged antibiotic administration in human and veterinary medicine. Articles on antimicrobial resistances in DFI treatment already exist and would complicate the content and structure of this manuscript.In October 2022 we searched PubMed using two distinct MeSH terms for studies relating to antibiotic-related AEs in DFI. We searched for relevant titles and abstracts with the search terms “antibiotics” AND “diabetic foot”. Our second search included the search terms “antibiotics” AND (“skin-structure infection” OR “soft tissue infection”) NOT (“skin grafting” OR “psoriasis” OR “tumor” OR “hematologic disease”). In both searches we included clinical studies, clinical trials, clinical trial protocols, multicenter studies, and randomized controlled trials that were published in the English language with adult patients 19 years and above between January 1990 and September 2022. We calculated 95% confidence intervals for proportions following the Clopper–Pearson approach.In preparing this narrative review, we adhered to key applicable items for narrative reviews from the PRISMA statement .We included randomized controlled trials (RCTs), nonrandomized or quasi-randomized controlled trials, and observational studies  from January 1990 to September 2022 in the English language. We included studies of people with diabetes mellitus (type 1 or 2) with any type of foot wound (ulcers of neuropathic or ischemic etiology) and with DFI (osteomyelitis or soft-tissue infections). All patients included in the selected studies had to be treated with systemic antibiotics  with well-described reports of adverse effects.We excluded studies that evaluated infections other than soft-tissue infection or osteomyelitis at the same time as DFI, studies that lacked data on antibiotic-related AEs, studies that included a case series with less than 30 diabetic patients, and studies that reported on topical antibiotics.There is a clear need for greater antibiotic stewardship in the clinical management of DFIs given the increasing worldwide incidence and the increased use of antibiotic therapies that lead to an increase the days of hospitalization and higher complications for patients. Epidemiological understanding of antibiotic-related AEs is considered the cornerstone of every stewardship program and cannot be limited to only the acquisition of resistances and costs. The medical complications that arise from some AEs are not negligible.The proportion of AEs in patients during or shortly after antibiotic therapy for DFI was shown to be as high as 30%. The risks and benefits of prolonged antibiotic use must be considered in each clinical situation, and knowledge of the most common and most severe AEs is useful for the clinician to be aware of the presentation of these AEs. A proven method to protect against such AEs is to reduce the duration of antibiotic treatment with lowered dosages as deemed clinically necessary. As mentioned by the stewardship program, clinicians should have an understanding of possible AEs and inform patients in cases where longer antibiotic therapy is deemed necessary.


In this paper, fluorinated compounds based on sulfolane, cyclopentanone, and gamma-butyrolactone are studied computationally, focusing on their applicability in electrochemical devices and acid–base-related studies. Candidates for solvents with (1) high polarity, (2) good electrochemical stability, and (3) low basicity were searched for. Some of the compounds are studied here for the first time. Electrochemical stabilities, dielectric constants, boiling points, basicities, and lipophilicities were estimated using DFT and COSMO-RS methods with empirical corrections. The effect of fluorination on these properties as well as the bond parameters was studied. The possible synthesis routes of the proposed compounds are outlined. Some molecules display a combination of estimated properties favorable for a solvent, although none of the studied compounds are expected to surpass acetonitrile and propylene carbonate by the width of the electrochemical stability window. Compatibility with the electrode materials also plays a role, as some compounds that perform well with metal anodes may be incompatible with graphite anodes or vice versa.Most properties that make an excellent electrolyte solvent are also needed in studies of strong acids and creating strongly acidic systems: high dielectric constant and solvation ability prevent undesirable interactions between ions, and a low reactivity allows for a wider choice of components. Low basicity is a necessary property for the study of strong acids, as the basic nature of the solvent has a leveling effect on the dissociation of acids and hinders differentiating their strengths. A sufficiently high boiling point is important for safety and retaining stable concentrations.An ideal solvent hardly exists, as some of the listed properties are correlated in such a way that achieving two within the optimal range is difficult. The solvent’s ability for specific solvation, on the one hand, promotes salt solubility and ion separation; on the other hand, it usually comes with more pronounced acid–base properties and higher viscosity. For these reasons, protic solvents are generally unsuitable for the above-mentioned purposes. Most solvents currently used in nonaqueous electrochemistry are dipolar aprotic: carbonates, ethers, esters, and nitriles ,2,8.▪Higher oxidation resistance due to a lower HOMO energy ,18, but ▪Lower flammability or even fire-suppressing properties ,19,20.▪Higher dielectric constant, if the F atom is placed in the right position to increase the dipole moment of the molecule.▪Lower basicity and higher acidity.▪Higher viscosity due to an increase in molecular mass and hydrogen bond donicity ,11,13, aFluorination can enhance some of the desirable characteristics of solvents, which, however, comes at the cost of some simultaneous undesirable changes. A variety of fluorinated compounds have been explored as solvents or electrolyte components for electrochemical devices, either experimentally ,12,13,14Most of the time, fluorinated  compounds are less reactive than their nonfluorinated analogs. However, in some cases, fluorination increases reactivity ,16,22. FIn this work, we choose three scaffold compounds—sulfolane (SL), cyclopentanone (CP), and gamma-butyrolactone (GBL)—to be modified by fluorination and the addition of double bonds and characterize the obtained molecules in the context of electrochemistry and studies of strong acids. The studied structures are shown in Of the parent compounds, SL and GBL are used as electrolyte components ,8. SL haThe available literature data  show thaAnother potentially problematic aspect is the reactivity of the unsaturated compounds, which can limit their usability in harsh conditions and in combination with other reactive species. Most solvents that are typically used in electrochemical devices are composed of saturated molecules because double bonds compromise stability. However, unsaturated compounds can be used as electrolyte additives. They may be required to have a lower stability than the main solvent in order to react and form a film on the electrode surface ,33,34.▪Electrochemical stability windows (ESWs) were estimated via the calculated oxidation and reduction potentials in gas phase and DMSO, or approximated via the differences of the gas-phase HOMO and LUMO energies .▪εr) and boiling points (BP) were computed with the COSMO-RS method with empirical corrections.Dielectric constants (▪trG°(H+)), basicity in acetonitrile (pKaH(MeCN), corresponding to the pKa of the protonated molecule), and gas-phase basicity (GB) of the solvents.Basicities were characterized via the predicted Gibbs energies of the transfer of a proton from water to the studied solvent  values, and solubilities were computed on the assumption that the compounds are liquid at room temperature .The results of the computations, together with some values from the literature, are presented in The bond parameters were analyzed in a similar manner to ref. . As expeIt was found that, in all studied compound groups, α-fluorination weakens the bond between the fluorinated carbon and electronegative group and reduces its bond order. At the same time, it can strengthen other bonds. Also, a slight strengthening of the C=O and S=O bonds was observed. In sulfolanes , the bonSimilar effects were observed for cyclopentanone derivatives . α-fluorIn GBL derivatives , α-fluorSL-A0). For several compounds, the geometries of the oxidized/reduced species were broken up or rearranged during the geometry optimization step of the computation, hinting at the low stability of these species (such geometries were not used for further computations). It can be seen that, first, solvation in DMSO does not significantly change the stability trends compared to the gas phase  are presented in as phase , and secas phase .The computations show that fluorination (both number and position of F atoms) has a relatively small effect on the compound’s propensity to oxidation or reduction, compared to the significant drops in reduction stability that accompany the additions of the double bond(s) adjacent to the polar group . The structural variations in the studied molecules influence reduction more than oxidation. Most studied molecules have lower reduction stabilities than MeCN, PC, and DMSO. None of the compounds have resistance to oxidation that is superior to MeCN, although in this respect, many outperform DMSO, and several GBL group compounds outperform PC. As the addition of fluorine tends to lower both HOMO and LUMO levels in the studied compounds, the net effect of fluorination can be both positive and negative, depending on the structure. In most studied cases, however, fluorination slightly narrowed ESW.εr values in the SL group are within the prediction uncertainty. A similar situation is observed with the boiling points of fluorinated compounds: an increase in CP, a decrease in GBL, and small and inconsistent changes in SL. ∆trG°(H+) values are invariably increased by fluorination, and the effect of F atoms appears to be more or less additive. Lipophilicities (expressed as octanol/water partition coefficients) are notably higher for fluorinated GBL and SL derivatives, but the effect is weaker and less consistent in the CP group. A more pronounced increase in the dipole moment of CP likely counters the lipophilicity-inducing effect of the F atoms. The patterns of pKaH(MeCN) match the inverted patterns of ∆trG°(H+). Each F atom decreases the basicity by 2.5–3 orders of magnitude.As seen in GBL-B1a vs. GBL-B1b, and GBL-C1a vs. GBL-C1b). While the differences in εr, BP, and logPo/w matched the differences in molecular dipoles (GBL-B1b and GBL-C1b have lower dipole moments), the differences in basicity can be attributed to differences in electron delocalization: GBL-B1b and GBL-C1a, where F is located at the sp3 carbon, are less basic than their isomers, where F is conjugated with O atoms.The differences between the positional isomers of the fluorinated compounds were rather insignificant in SL and CP groups and only became notable in GBL-type scaffolds with double bonds (SL-A0), 1,1-dioxide-2,3-dihydro-thiophene (SL-B0), 3-sulfolene (SL-C0), and 1,1-dioxide-thiophene (SL-D0) are widely available compounds whose synthesis originates either from alkenes (with the insertion of SO2) [2O2 as an oxidizer) [SL-A2, SL-C2), thiophenes (SL-D1) [SL-B1, SL-B2) as precursors. Additionally, fluorination using a gaseous F2/N2 mixture of parent compounds has been employed (SL-A1) [SL-C1 could be prepared similarly. The preparation of the tri-fluorinated analogs SL-A3, SL-B3, and SL-C3 could be challenging by the abovementioned methods because the respective fluorinated alkene and thiophene are not available and their preparation methods have not been published.Sulfolane ( of SO2) , from thxidizer) ,45,46, oxidizer) ,48. Thei (SL-D1) , or fluo (SL-A1) . PerhapsGBL-A0) can be fluorinated using F2/N2 gas [GBL-A1a and GBL-A1b. The deoxyfluorination of hydroxy-γ-butyrolactone is also a well-established procedure [GBL-A2 was not described, but the preparation could be considered from 2,2-difluorobutanedioic acid [GBL-B1a [GBL-B1b [GBL-B2 by the isomerization of fumaroyl fluoride seems to be rather complicated [GBL-C0) derivatives have not been published; however, synthesis from fluorinated precursors or double bond migration could be employed [γ-Butyrolactone  is fluorinated to obtain a mono-fluorinated derivative (CP-A1) using different fluorinating agents  [CP-A2 is a readily available  compound. Its synthesis methods have not been published, but synthesis from difluoro adipic acid esters may be possible [CP-B1a is prepared using F2/N2 gas [Cyclopentanone  ,62,63. Cpossible . Cyclope2/N2 gas . MethodstrG°(H+) values as estimates of solution basicity , and dielectric constant and HOMO-LUMO gap as a first estimate of electrochemical stability. As expected, sulfolanes  surpass the other groups in terms of a favorable combination of properties: ESWs are estimated to be wide, BP and εr are relatively high, and basicities are medium to low. CP are the least suitable main solvent candidates given their relatively high basicities, low boiling points, and εr and HOMO-LUMO gaps. Some of GBL derivatives (series A and B) look promising with wide ESW, high εr, and medium basicity.The problem when choosing suitable solvents for nonaqueous applications involving electrochemistry and/or strong acidity is that many beneficial solvent properties are correlated with unfavorable ones. Therefore, trade-offs have to be found. The presence of double bonds (subgroups B–D) is expected to significantly increase melting points and decrease reduction stability, making the respective compounds less likely to be suited for the role of main solvent and more eligible for the role of reactive electrolyte additive.SL-C2 and CP-B2) could not be removed by reoptimization and were ignored. Gas-phase properties were computed with the Gaussian 16 Rev. A.03 software . The geooxG and ∆redG) for molecule S in the gas phase were computed from the lowest-energy conformers at the M06-2X/6-311+G** level of theory, as follows:Oxidation and reduction free energies (∆solvG) were calculated as the differences of the free energies of the molecules in DMSO and in the gas phase, computed at M06-2X/6-31+G* .Solvation free energies   and intrGB values were computed with the G4MP2 method .εr, pKaH, ΔtrG°(H+), BP, logPo/w values, and solubilities. The geometries of all conformers and protomers of the studied solvents were optimized at the BP86/TZVP level of theory in an ideal conductor (COSMO model), followed by single-point energy calculation at the BP86/def2-TZVPD level of theory with the Fine cavity parameter. Vibrational spectra were computed to ensure that the obtained geometries correspond to energy minima. Solvent properties were computed from the obtained surface charge distributions using the COSMOtherm software (release 2023) [The COSMO-RS method was used for computing se 2023)  using alse 2023) .COSMO-RS  ,74,75,76SMD is an implicit solvation model based on solute electron density . The soltrG°(H+): This property is used as the basicity estimate of the solvents and is defined as the Gibbs energy change i the following process (Equation (5)):trG°(H+) values of the process for several solvents were computed with the COSMO-RS method and correlated with the values from ref. [Sres refers to the overall regression standard deviation . Given the large value of Sres, the predicted ∆trG°(H+) values can be considered only semiquantitative. The liquid state of the solvent was assumed in all calculations.∆rom ref.  : The accuracy of dielectric constant estimates by the COSMO-RS method was assessed using the set of 20 solvents presented in Dielectric constant  and semiquantitative at εr > 35 (RMSE > 10). The semiquantitative nature of the prediction at high εr values is not a problem because εr values above 35 are certainly suitable for the purposes of this study; thus, knowing the accurate εr value is not critically important.To verify the reliability of the approach, redicted . The resKaH: The pKa and pKaH values predicted by COSMO-RS are usually biased, yet well correlated with the respective experimental data. With a lack of suitable experimental data to evaluate or correct the basicity values in acetonitrile (pKaH(MeCN)), we suggest that these values be used for semiquantitative comparison between structurally similar compounds rather than to access absolute basicities.pPo/w: COSMO-RS is known to predict the octanol–water partition coefficients very well, with some rare exceptions [logceptions ,80. The Mutual Solubility with Water: The reported accuracy estimates for the aqueous solubility predictions by COSMO-RS vary by solute type and the parametrization used. The expected error for liquid solutes is 0.3  log unitNote on Viscosity Computations: COSMO-RS predicted the viscosities of a set of typical electrolyte solvents with a mean absolute deviation of 0.22 cP and a good correlation between the predictions and experimental data . However