The Ullmann reaction has been reported to be the first cross-coupling reaction performed by using a transition metal catalyst. This reaction has been initially considered as the copper-catalyzed homocoupling of aryl halides, leading to the formation of symmetrical biaryl compounds via the generation of novel C–C bonds. Although this reaction has been extensively studied in recent decades and valuable results have been achieved, there are still considerable efforts focused on the development of novel catalytic systems, mild reaction conditions, and extended substrate scope. The mechanistic aspects of the Ullmann homocoupling reaction have also been investigated, as related to the introduction of new sustainable strategies and green procedures. The application of recyclable heterogeneous catalysts has been found to overcome most of the limitations associated with the harsh reaction conditions of the original Ullmann reaction. More recently, copper-based catalytic systems have also been replaced by palladium nanoparticles, ionic palladium species, gold nanoparticles, and palladium–gold bimetallic systems. In this review, current results reported on the Ullmann homocoupling reaction are discussed, with an emphasis on the development of novel catalytic systems, which can be efficiently used under heterogeneous conditions. Carbon–carbon (C–C) bond formations through cross-coupling reactions belong to the most versatile and useful procedures applied in synthetic organic chemistry. These reactions are typically performed by using transition metal catalysts ,2,3,4,5.Transition metal complexes applied as homogeneous catalysts are generally sensitive to moisture, oxygen, and high temperature. The instability of such complexes restricts their catalytic applications, as they often require inert atmospheres, deoxygenated solvents, and special reaction conditions. It has also been pointed out that these catalysts are difficult to remove from the reaction mixtures ,21. The The aim of the present paper is to review the recent progress on the application of novel catalytic systems developed for the Ullmann homocoupling reactions performed under heterogeneous conditions. Emphasis has been laid on the utilization of catalytically active copper, palladium, gold, and bimetallic particles.0-catalysed cross-coupling reactions, transformations including C–C bond formation, such as the Ullmann homocoupling reactions, have been predominantly carried out by using copper catalysts  on graphene oxide (GO) as a support material has been carried out by Balakrishna et al. [2 atmosphere. The synthesis procedure was based on a condensation reaction between the methoxysilane groups of the Pd complex and the hydroxy groups of GO. The resulting composite material, denoted as PdII-PNP-GO was characterized by FTIR spectroscopy, solid-state 31P NMR, SEM, TEM, XPS, and ICP-AES techniques, which confirmed that the Pd complex was successfully immobilized on the surface of GO. XPS studies also gave evidence that the oxidation state of Pd in the composite material was +2 . The catalytic performance of PdII-PNP-GO with a Pd loading of 2.8 wt% was investigated in the Ullmann homocoupling reactions of substituted aryl chlorides and a substantial catalytic activity was experienced, as the corresponding biaryl compounds were produced with high yields. The results are shown in The immobilization of homogeneous catalysts on solid support materials by different methods including encapsulation, coordination, and ion interaction, has been found to exert a beneficial effect on the recovery and reuse of these catalysts ,65,66. Ca et al. . ImmobilRecycling studies, effected for the homocoupling of 3-chlorotoluene, indicated moderate stability of the catalyst, as related to a gradual decrease in activity observed on repeated applications .N-heterocyclic carbene (NHC)-based organometallic polymers has been found to result in the formation of efficient catalysts, applied in C–C coupling reactions [2 .The incorporation of Pd nanoparticles in eactions ,70. Receeactions . In a thII-NHC polymer, for which the Pd loading was not reported, was applied as a catalyst in the Ullmann homocoupling reactions, for a limited scope of aryl halides, as shown in The PdN,N-dimethylformamide (DMF) has been found to exert a beneficial effect on C–C coupling reactions catalyzed by metal nanoparticles [4 to preheated DMF, followed by reflux at 150 °C for 2 h. The resulting yellow solution was found to contain Au nanoparticles, for which the mean particle diameter was 2.5 nm, as revealed by HRTEM measurements. PXRD studies also confirmed the formation of monodispersed Au0 nanoparticles, for which the lattice fringes were consistent with those of metallic gold and corresponded to the lattice spacing of the (111) crystal plane of face-centered cubic Au0 particles.As related to its considerable polarity, wide solubility range, and reducing ability, articles . In ordearticles , Lang etarticles . The Au 0, indicated by 4f7/2 signals at 84.7 eV and 88.3 eV. In this study, the homocouplings of iodobenzenes were carried out delivering substituted biphenyls in prolonged treatments (48 h), providing moderate to excellent product yields in most cases -MCM41 from a mixture of a magnetic Fe3O4 colloid, sodium silicate, and cetyltrimethylammonium bromide (CTABr), followed by calcination. This material was functionalized by 3-mercaptopropyl-trimethoxysilane, followed by the addition of the precursor HAuCl4, applied in a methanol solution. The Au loading of the product, Au0-α-Fe2O3/MCM-41, was reported to be 6.44 wt%. Structural characterization of the sample, performed by N2 sorption, SEM, and TEM measurements, indicated the formation of ordered mesopores and a uniform size distribution of the gold nanoparticles of 2–3 nm. Further, XRD patterns revealed the formation of Au0 nanoparticles with an fcc structure [3PO4 as a base, as displayed in So far, there have been rather few reports on the Ullmann homocoupling reactions catalyzed by gold nanoparticles ,76. The tructure . The samFor the reactions of substituted aryl iodides, the biaryl products were obtained with good to excellent yields. On the other hand, the transformation of aryl bromide did not take place, even at an elevated reaction temperature of 150 °C and a prolonged reaction time of 24 h. After reaction, the catalyst could be readily separated and recovered by an external magnet. Recycling of the magnetic nanocatalyst was investigated for the homocoupling reaction of 4-iodoacetophenone. It was found that the catalyst displayed high stability and could be reused without a significant decrease in activity . On the other hand, the reaction mechanism proposed by the authors cannot be fully justified.2 sorption, TGA, XRD, XPS, and SEM/EDX measurements. XRD studies indicated the formation of a novel crystalline phase, corresponding to the Cu-Fe mixed oxide and TGA analysis confirmed that a phase transformation of LDH to a mixed metal oxide took place at 400 °C. XPS patterns revealed that the binding energy of the Cu 2p3/2 level was 934.4. eV, indicating the formation of a CuO phase, whereas the binding energy of the Fe 2p3/2 core level appeared at 712 eV, which was related to the presence of iron oxide. It was therefore suggested that CuO-FeIII-MMO consisted of a crystalline CuO phase, doped with FeIII ions, derived from the LDH precursor. The results obtained for the Ullmann homocoupling reactions of aryl halides, performed for a limited scope of reactants, are shown in A mixed metal oxide obtained from a Cu-Fe layered double hydroxide (LDH) via thermal decomposition has been reported to be an efficient ligand-free catalyst for the synthesis of biaryls through the Ullmann homocoupling reaction . The Cu-It was found that the transformations of aryl iodides and bromides afforded good yields for the biphenyl products, whereas the reactions of chlorides and fluorides did not take place, even at prolonged reaction times. Recycling studies, effected for the reaction of 4-iodoanisole, indicated that the catalyst could be reused without an appreciable decrease in activity .2 and OH groups, which readily form chelate complexes [2 mixture was first prepared from an acetic acid solution of chitosan and a silica colloid, followed by the addition of Zn powder and a Na2PdCl4 solution under stirring. The mixture was subsequently dried to form membranes, which were purified by soaking in a NaOH solution and dried at 60 °C. The product was characterized by N2 sorption, FTIR, XRD, XPS, SEM, and HRTEM measurements. Structural investigation revealed that the surface of the membrane had an open macroporous structure, whereas the cross-section of the membrane had fewer pores with smaller sizes. XRD patterns displayed characteristic diffraction peaks of Zn0 and Pd0 particles and XPS spectra revealed two significant peaks at binding energies 337.5 and 335 eV, corresponding to Pd 3d5/2 signals, which indicated that the Pd species were both in zero-valent and divalent states. The catalytic activity of the Pd0/PdII-Zn0-CS/SiO2 sample was investigated in the Ullmann homocoupling reactions of aryl iodides, performed in a DMSO-ethylene glycol solvent mixture at 120 °C, by using 5 mol% of catalyst. The results are indicated in Chitosan (CS), considered the second most important natural polysaccharide after cellulose, has been used as a support material of transition metal catalysts, as related to its significant amount of NHomplexes . In a reomplexes . A CS/Si0/PdII-Zn0-CS/SiO2 membrane catalyst exhibited a high catalytic activity. This finding may be associated with the incorporation of the active species into SiO2. Specifically, the generation of the porous structure of the CS/SiO2 matrix resulted in improved diffusion properties and high thermal stability. In addition, the active metal species were well distributed in the support. Catalyst reuse was explored in the homocoupling of iodobenzene in a five-run test with easy recovery. Results show a 10% drop-in activities, which is rather significant . This phenomenon is certainly attributed to the loss of Zn content (7.1%), resulting in the deterioration of the CS/SiO2 matrix. Note also the significant Pd leaching of 8.6 wt%.As shown in Palladium-catalyzed Ullmann reactions have been used not only for the coupling reactions of simple organic molecules but also for the synthesis of complex organic molecules such as pharmaceuticals, polymers, and alkaloids ,84. As d06Pd0-resin [4 and H2PdCl4, followed by stirring for 2 h. The final catalyst was obtained by reduction with NaBH4. This synthesis process was performed with different Au–Pd ratios  with a total metal loading of 2 wt%. Various instrumental methods  were used to collect useful pieces of information on the catalyst structure. According to EXAFS and CO adsorption measurements, bimetallic alloys were formed (particle size of 2–4 nm) with palladium islands separated by gold atoms. DRIFTS and EXAFS studies indicated that the Au–Pd single-atom structure is generated in the case of Au/Pd ≥ 4. Accordingly, the best yields and selectivities in chlorobenzene homocoupling were obtained with Au6Pd and Au20Pd, for which the TON values were 643 and 1148, respectively. The catalytic performance of the Au06-Pd0-resin single-atom catalyst was investigated in the Ullmann homocoupling reactions of various aryl halides and high to excellent yields were obtained .It was suggested that the active sites of the reaction were isolated PdH-imidazolium hydrogen sulfate (MPIHS) [2AuCl4 and Na2PdCl4 with NaBH4. N2 sorption isotherms of the samples indicated the formation of uniform mesoporous structures. The synthesis of the mesoporous carbon-stabilized bimetallic nanoparticles (Au0-Pd0-NMCI-2) was performed by the addition of NaPdCl4 and Na2AuCl4 to an aqueous suspension of the support material, followed by reduction with NaBH4. The total loadings of Au and Pd in the catalyst were 0.085 and 0.238 mmolg−1, corresponding to 0.157 wt% Au and 2.53 wt% Pd, respectively. XPS patterns displayed binding energies 335 and 340 eV, corresponding to Pd0, as well as 84 and 88 eV, corresponding to Au0, which confirmed that both metals were in zero oxidation states.Karimi et al. fabricated nanofibrillated mesoporous carbon support derived from the ionic liquid 1-methyl-3-phenethyl-1 (MPIHS) . In a ca0-Pd0-NMCI-2 clearly showed that the nanoparticles consisted of an Au–Pd alloy and not a mixture of Au and Pd species. The catalytic performance of the sample was investigated in the Ullmann homocoupling reactions of aryl chlorides and bromides (TEM analysis revealed that the metal particles were uniformly distributed over the surface of the support material. It was also established that the ratio of Au:Pd was 4:1 and the absence of any surface plasmon absorption peak related to the pure Au nanoparticles in the DRIFT-UV spectrum of Aubromides , and sig0 nanoparticles and PdII complexes immobilized on solid support materials, has clearly gained increasing importance. Heterogeneous Pd catalysts offer versatile applications, and their beneficial effect has been confirmed by their enhanced performances, as compared with those of copper-based catalysts. Furthermore, Pd-based catalytic systems can be employed under milder reaction conditions and for a broader substrate scope. In this respect, promising results have also been achieved for the utilization of gold nanoparticles and bimetallic systems, for which future prospects can be anticipated. Successful efforts have been made on the development of ligand-free catalysts and mild reaction conditions, including lower temperatures and/or green solvents, which give rise to the introduction of environmentally friendly procedures.The Ullmann homocoupling reaction has been found to play an important role in organic syntheses and medicinal chemistry and can be widely employed for the preparation of biologically active compounds and pharmaceuticals. Although copper-mediated Ullmann homocouplings have remained the subject of extensive studies, the application of Pd-based systems, including PdDespite the substantial progress reported for the investigation of the Ullmann homocoupling reaction so far, limitations in terms of substrate scope, catalyst efficiency, stability, and reuse still exist. For the transformations of aryl chlorides and fluorides, increased reaction temperatures, high metal loadings, and extended reaction times are required. Therefore, it may be suggested to introduce more efficient catalytic systems, which would also be suitable for practical applications. As the recent development of copper-catalyzed homocoupling reactions is far behind those promoted by Pd-based systems, it is also desirable to develop more sophisticated and more reactive copper catalysts, which may also be employed under mild conditions. Moreover, copper-catalyzed asymmetric coupling reactions still remain a challenge, which should be addressed by further studies.In summary, a future perspective would be the development of improved catalytic systems with novel ligands, anchoring species, and/or support materials, which could be more efficiently used under milder conditions for an extended substrate scope, including less active chlorobenzene and fluorobenzene derivatives. The results reported for catalyst recycling also need considerable improvement and therefore the design of novel catalysts with enhanced activities and stabilities would also be appreciated.


Current patterns of preventive antibiotic prescribing are encouraging the spread of antimicrobial resistance. Recently, the Spanish Society of Implants (SEI) developed the first clinical practice guidelines published to date, providing clear guidelines on how to prescribe responsible and informed preventive antibiotic therapy (PAT) based on the available scientific evidence on dental implant treatments (DIs). The present document aims to summarise and disseminate the recommendations established by this expert panel. These were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were analysed using the Scottish Intercollegiate Guidelines Network (SIGN) checklist templates and ranked according to their level of evidence. They were then assigned a level of recommendation using the Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). Guidelines were established on the type of PAT, antibiotic and dosage of administration in the placement of DIs without anatomical constraints, in bone augmentation with the placement of DIs in one or two stages, placement of immediate DIs, sinus elevations, implant prosthetic phase, as well as recommendations in patients allergic to penicillin. Therefore, the PAT must be adapted to the type of implant procedure to be performed. Dental implants (DIs) are the most predictable therapeutic option in the total or partial replacement of missing teeth; however, around 0.7–3.8% of them fail . These fAntibiotics are used for longer periods than other drugs in dentistry, such as anaesthetics, analgesics, anti-inflammatories or anxiolytics, among others, which increases the risk of adverse reactions, such as allergies that can cause life-threatening complications ,10 or toThe current evidence is very limited. Despite this, it has been shown that for every 24–50 healthy patients treated with PAT, early failure will be avoided in one patient ,14,15,16Antimicrobial resistance causes more than 33,000 deaths per year in the European Union (EU)  and the Recent surveys ,23,24 inFor the elaboration of the consensus report document, a group of 12 expert dentists and stomatologists was carefully selected for their extensive knowledge on the subject. It also benefited from the assessment of three external reviewers who participated as independent evaluators and the validation of the following Scientific Societies: Spanish Society of Implants (SEI), Spanish Society of Gerodontology (SEGER), Portuguese Society of Implantology and Osseointegration (SOPIO), Latin American Oral Implantology Society (SIOLA) and the International Federation of Oral Implantology (FIIO), which includes the following scientific societies: Colombian Dental Implant Association (SOCI), Mexican College of Oral and Maxillofacial Implantology (CMIBM), Chilean Society of Oral and Maxillofacial Implantology, Brazilian Academy of Osseointegration (AMBROSS) and Peruvian Association of Integral Oral Implantology (ASPIOI).This consensus report was structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .The study aimed to answer the following PICO  questions based on the PRISMA guidelines :The secondary objective was to determine the type of PAT, type of antibiotic, dose and posology recommended in these cases according to the available scientific evidence.The studies were evaluated by two authors, determining the quality of the scientific evidence using the Scottish Intercollegiate Guidelines Network (SIGN)  checklis1++: High-quality meta-analyses, systematic reviews of clinical trials (CTs) or high-quality CTs.1+: Well-conducted meta-analyses, meta-analyses of CTs or well-conducted CTs with low risk of bias.1-: Meta-analyses, systematic reviews of CTs or CTs with a high risk of bias.2++: High-quality systematic reviews of cohort or case-control studies. Cohort or case-control studies with a very low risk of bias and a high probability of establishing a causal relationship.2+: Well-conducted cohort or case-control studies with low risk of bias and with a moderate probability of establishing a causal relationship.2-: Cohort or case-control studies with a high risk of bias and a significant risk that the relationship is not causal.3: Non-analytical studies, such as case reports and case series.4: Expert opinion.After having catalogued each of the pieces of evidence that respond to the initial (PICO) question, the recommendation is made by incorporating a Grade of Recommendation based on the GRADE   was used as the search engine for the available evidence. Its elaboration was carried out from January 2020 to February 2021. The reference list of the included studies was also reviewed for possible inclusion.A preliminary search was conducted to define the scope and objectives of the consensus report. This search determined the eligibility criteria of the studies to be included given the available evidence for each procedure related to the placement of DIs. The objective was to gather the studies with the best evidence. If there was a limited amount of scientific literature for a given treatment, we moved down the pyramid of evidence and, if no related studies were found, we evaluated those carried out on teeth whose results could be extrapolated. Thus, the search was individualised for each DI treatment as follows: AND (antibiotics OR preventive antibiotics OR antibiotic prophylaxis).(a) human studies; (b) meta-analyses and systematic reviews; (c) articles published in English and/or Spanish, and (d) from 2010 to 2020.(immediate implant OR immediate implantation OR fresh extraction socket) AND  AND (antibiotics OR antibiotic prophylaxis OR clindamycin OR amoxicillin OR azithromycin OR erythromycin).(a) human studies; (b) meta-analyses and systematic reviews; (c) articles published in English and/or Spanish, and (d) from 2010 to 2020.(maxillary sinus lift OR maxillary sinus augmentation OR sinus lift elevation) AND (antibiotics OR antibiotic prophylaxis OR clindamycin OR amoxicillin OR erythromycin OR azithromycin OR metronidazole).(a) human studies; (b) no filters by study type; (c) articles published in English and/or Spanish. (d) No temporal restrictions were applied and (e) the search was updated to December 2020. AND  AND (antibiotic prophylaxis OR antibiotics).(a) human studies; (b) meta-analyses, systematic reviews and randomized clinical trials (RCTs); (c) articles published in English and/or Spanish, and (d) from 2005 to 2020. AND (antibiotics OR antibiotic prophylaxis) AND .(a) human studies; (b) meta-analyses, systematic reviews, RCTs, observational studies, multicentre studies, comparative studies, and clinical studies; (c) articles published in English and/or Spanish, and (d) from 2000 to 2020. AND .(a) human studies; (b) meta-analyses, systematic reviews, RCTs, observational studies, multicentre studies, comparative studies, and cohort studies; (c) articles published in English and/or Spanish. (d) The search was not temporarily restricted and was updated to December 2020.Data collection was conducted using a predetermined table designed in advance of the assessment of the resulting articles.For the evaluation of the scientific evidence, the articles were reviewed by two authors using the SIGN critical reading template. Disagreements between the two were resolved by the intervention of a third author.The recommendations for each of the questions asked are summarised below, providing recommendations on the type of antibiotic and dosage when possible:A large number of systematic reviews and/or meta-analyses on the effects of PAT administration on early DI failure and/or postoperative infections have been published in the last 10 years. Specifically, 11 studies were found that answered the established PICO question ,32,33,34mean = 0.08–0.45). More specifically, a significant benefit has been demonstrated in the use of preoperative antibiotics , 1+ [n = 2]), 1++ [n = 1]). These authors base their conclusions on the fact that PAT offers a modest reduction in early DI failure of 1.8–4% [In short, there is a tendency to recommend the routine prescription of PAT in these cases; however, a smaller number of authors consider that its use should be avoided in simple cases in healthy patients ,30,31,33f 1.8–4%  . However, not prescribing it could not be considered a wrong approach in certain cases (GRADE B).After evaluation of the selected articles, six articles with a level of evidence of 2++ were included. All were systematic reviews ,37,38,39p = 0.02), with all failures being early failures. A trend toward lower survival of immediate DIs was observed when PAT was not administered postoperatively (RR = 0.93). On the other hand, in both DI placement protocols (immediate vs. delayed), healing was adequate, except in one study [Cosyn et al.  reportedne study , where tLee et al.  concluden = 7) and human (n = 21) studies, none of which compared immediate DI placement with and without the prescription of PAT, so there is no control group with which to compare results. If only human studies are considered and all cases of immediate DIs are included, without distinction between the previous pathology or not, the failure rate is 1.7%. The total duration of PAT in the different studies was 6–14 days. The most frequent regimen was perioperative, although some studies carried out only pre-or postoperative PAT (LoE 2++).Chrcanovic et al.  conducteÁlvarez-Camino et al.  highlighn = 244 DIs), and in 15, only postoperative PAT, which lasted 5–7 days (n = 935 DIs). The remaining 14 studies prescribed perioperative PAT (one preoperative dose followed by 5–7 days postoperatively) (n = 665 DIs). To determine the DI failure rates associated with each regimen, they performed a multivariate analysis using the fixed-effect Poisson regression model, taking the preoperative prescription as a reference. In this way, they calculated the annual failure rate of DIs placed under preoperative PAT at 1.9%, postoperative at 0.5% and perioperative at 0.8% (p = 0.002). Therefore, single-dose preoperative PAT alone is not sufficient to maintain bacterial levels below the critical threshold during the healing period but prescribing them 5–7 days post-surgery may help to prevent complications that may lead to DI failure (LoE 2++).Lang et al.  conducten = 4), in those prescribed preoperatively 8% (n = 1) and perioperatively 0–2.6% (n = 2) (LoE 2++).Waasdorp et al.  did not The type of PAT and the guidelines used were not provided by all studies. From those that did provide these data ,36,38, iEvidence has shown an added benefit of perioperative PAT prescription in reducing early failure of immediate DIs. Despite this, studies have failed to recommend a specific type and dose of PAT and, therefore, pending further research, it is necessary to advise a specific guideline based on the extrapolation of the recommendations established in Endodontics, given the nature of the microbiota to be combated, advocating for the prescription of PAT with a loading dose, followed by a maintenance dose (GRADE D). It is recommended to administer the loading dose of 2 or 3 g of amoxicillin 1 h before surgery (GRADE B), followed by 500 mg/8h, during the 5–7 postoperative days (GRADE D). In case of confirmed true penicillin allergy, azithromycin 500 mg 1 h before followed by 250 mg/24 h, 5–7 days; clarithromycin 500 mg 1 h before followed by 250 mg/12 h, 5–7 days; or metronidazole 1 g 1 h preoperatively followed by 500 mg/6 h/5–7 days (GRADE D).The evidence related to PAT in sinus lifts is very limited. After searching, one study was found  that exaZinser et al.  evaluateCarreño-Carreño et al.  took micThe choice of the type of PAT should be made based on the sensitivity of the micro-organisms following an antibiogram. In the case of empirical prescription of antibiotics, which is done in routine clinical practice, amoxicillin/clavulanic acid, ampicillin or ciprofloxacin are recommended as the first choice, since the germs found are sensitive to these antimicrobials, while they have shown greater resistance to macrolides, fosfomycin or penicillin G  (LoE 2+)An expert panel recommended amoxicillin/clavulanic acid 875/125 mg every 12 h, starting one day before surgery, followed by the same schedule, every 8 h for 7 days. In patients allergic to penicillin, clarithromycin 250 g/12 h together with metronidazole 500 mg/8 h, starting one day before surgery, followed by the same regimen for 7 days  is advisKhoury et al.  (LoE 3) The use of topical antibiotics, such as metronidazole, has also been described. For this, 5 mL of a sterile 0.5% metronidazole solution (25 mg) is applied as follows: 3 mL to irrigate the sinus after membrane elevation and 2 mL to hydrate the graft, which is equivalent to 1/20 of a 200 mg tablet, reducing the possibility of antimicrobial resistance. This results in a significant decrease in the number of inhomogeneous areas of the graft over the next three months, leading to a more compact and higher quality graft. These air bubble gaps suggest an anaerobic bacterial activity that increases the risk of graft failure (“septic theory”)  (LoE 2+)The evidence suggests that the prescription of PAT does not reduce the failure rate of DIs placed at the same time as sinus lifts compared to not prescribing it. There is no evidence of their effect on the prevention of postoperative infections. Assuming that PAT does prevent them, their prescription should be based on prior cultivation (GRADE C); however, it is an impractical approach. Prescription of 2 to 3 g of amoxicillin 1 h before surgery would be sufficient in the absence of Schneider’s membrane perforation (GRADE B). In most cases, it is not possible to foresee this complication, so it is recommended to rely on the assumption that such a complication would occur. In this case, amoxicillin/clavulanic acid 875/125 mg/12 h, starting one day before surgery, followed by the same regimen, every 8 h for 7 days (GRADE D) is advised. In penicillin-allergic patients, ciprofloxacin 500 mg/12 h/9 days is recommended (GRADE D).Overall, few studies investigated the effect of PAT on the prevention of postoperative infections after GBR, with or without simultaneous DI placement, and early DI failure. After evaluation of the selected articles, one systematic review  and fourThe systematic review , rated wp > 0.05). The authors concluded that there is no evidence to recommend the routine prescription of PAT in these interventions. Infection of the grafted material leads to its total loss [Of the four RCTs included, three employed a preoperative antibiotic dose in both the test and control groups. The first  (LoE 1+)tal loss ,53 or patal loss ,57.Different studies have shown a reduction in the rate of postoperative infections in those cases where PAT was prescribed preoperatively compared to perioperatively (GRADE A). A single dose of 2 or 3 g amoxicillin 1 h before surgery is recommended to reduce the failure rate of single-stage DIs and to reduce the degree of bacterial contamination of the grafted bone particles in these cases, as well as in two-stage DIs (GRADE C).The search did not find any articles investigating the appropriateness of prescribing PAT for the second stage of DIs, so the information obtained from four studies on surgical procedures in periodontology was extrapolated. Of these, three ,59,60 hap < 0.05). However, only 0.170% of all surgeries experienced infectious complications and the NNT to avoid postoperative infection is 203, so the benefit of using PAT in these cases is considered to be of no clinical significance.Liu et al.  conducteOswal et al.  performeAn expert panel, the 10th European Workshop on Periodontology , concludAt present, PAT in the second DI stages, impression making and/or DI prosthetic placement does not seem to be justified (GRADE D).Five studies were found that answered the PICO question posed. All were observational and, in particular, four were cohort studies ,63,64,65The included studies only evaluated the effect of clindamycin as an alternative to amoxicillin in the placement of DIs in native bone, with or without the need for simultaneous GBR and/or sinus lifts and immediate DIs ,63,64,65p = 0.046) (RR = 3.64) [Salomo-Coll et al.  (LoE 2+) = 3.64) .p = 0.002), with an OR of 3.10. They also investigated the occurrence of postoperative infections, which was 0.6% in non-allergic and 3.4% in allergic patients, i.e., 6-times higher. Further, 12.3% of the DIs were immediate (n = 687), of which 91.7% (n = 630) were placed in non-allergic patients, with failure rates of 1%, while 8.3% in allergic patients, with failure rates of 10.5%, i.e., 10-times higher. The differences were due to a higher infection rate in “allergy sufferers”.French et al.  (LoE 2+)Wagenberg and Froum  conducteKhoury et al.  (LoE 3) A study  . Pending further studies, azithromycin 500 mg 1 h before surgery is recommended (GRADE C).Dentists are often faced with the dilemma of whether or not to prescribe antibiotics preventively in DI treatment, which is currently a controversial issue. Prescription has been accepted to avoid systemic bacteraemia , but alsThese recommendations  are inteTo date, the largest number of publications and the highest level of scientific evidence  refer to the prescription of PAT in healthy patients without anatomical conditions. Recent advances have been made in establishing recommendations for other DI procedures, such as bone augmentation with single- or two-stage DI placement , or the This consensus report presents several strengths, such as the searching process of studies and data extraction performed in duplicate. Furthermore, these recommendations were endorsed by several international societies, such as SEGER, SIOLA, SOPIO and FIIO (with their respective member societies). In addition, on 12 December 2021, they were endorsed by the General Council of Dentists of Spain.Nonetheless, these recommendations have limitations, such as the shortage of studies with control groups that allow a comparison between the groups, which is why the external validity of the results in this review should be confirmed with future studies.PAT is indicated for all types of implant surgical procedures, except for the prosthetic phase of DIs. The type of PAT, and its dosage, must be adapted to the type of implant procedure to be performed. Furthermore, the prescription of PAT shall in no way replace or relax the adoption of the necessary aseptic and sterile measures in surgical procedures.


Catharanthus roseus exhibited the highest number of citations (19), while Peltophorum africanum had 14 and both Carica papaya and Vachelia karoo had 12. In the mode of administration of the reported medicinal plant species, most of the plants are boiled and taken orally (48.22%), while other plant species are used as mouth washes (3.25%). Although there is reasonable in vitro activity of some of the plant species, validating the relevance of use, there is still a need to explore the mode of action of such plant species; isolated compounds and possible derivatives thereof are of paramount importance and need to be explored as well. Furthermore, toxicological aspects of such plant species need to be explored.The current work is aimed at generating the first inventory of South African medicinal plants used in the treatment of sexually transmitted and related opportunistic infections associated with HIV-AIDS. This is important in assisting researchers to access a list of plant species to evaluate for potential phytocompounds, as this area of research is greatly lagging in South Africa. A total of 335 medicinal plants from 103 families have been documented in the current work. The most represented families are Fabaceae (11.64%) and Asteraceae (6.27%). Herbs constitute 36.53%, trees 32.34%, shrubs 29.04%, climbers 1.80% and parasites 0.30%. It is worrying that on the plant parts used, the roots constitute 47.18%, while leaves and stem bark yield 16.62 and 15.01%, respectively.  Sexually transmitted infections (STIs) or venereal diseases (VD) are infections which are transmitted sexually from one partner to the other, through semen and/or blood. Such infections are treated with conventional drugs, which includes metronidazole, ciprofloxacin, ceftriaxone azithromycin and doxycycline . WorldwiIn recent times, researchers in Africa have developed an enormous interest in documenting medicinal plants traditionally used in many communities to manage and treat a variety of sexually transmitted infections ,15,16,17Neisseria gonorrhoea, Mycoplasma hominis, Mycoplasma genitallium, Chlamydia trachomatis and Klebsiella granulomatis and some important viruses such as Cytomegalovirus, HSV type-2, HSV-8, Hepatitis B and human immunodeficiency virus [Sexually transmitted infections are infections that are acquired mainly through sexual contact and involve exchange of fluids that may enhance reproduction of many species. Such infections are known to be caused by many bacteria, parasites, and fungi such as cy virus ,21. Pleasures of Venus”, “Strangury”, “The Clap”, “Les Clapiers”, “Rabbit huts” and “An issue of seed”, as described in the Book of Leviticus in Old Testament and named by the Greek physician Galen [The Clap” refers to a clapping sensation experienced by the infected penis, the male reproductive organ, that exudes pus. This disease was believed to be incubated in most women’s bodies, and men were believed to be victims while women were a cause. In the 16th century, mercury was injected into patients suffering from gonorrhoea as a form of treatment, while the insertion of catheter into the urethra with the intention of flushing the infection with a lot of warm water (at 45 to 50 °C) was also practiced in the 18th century [Gonorrhoea is one of the most known and prevalent STIs and has been present from ancient times. It is known for its unwanted discharge of a whitish semen and is commonly called “an Galen . The cla century . This wa century . In 1913Penicillin is one of the first antibiotics discovered back in 1929 by Sir Alexander Fleming from moulds, and it is still the greatest milestone in modern medicine . In 1950Arctopus monacanthus Carmich. ex Sond, synonym Arctopus echinatus L., in the treatment of common sexually transmitted infections such as gonorrhoea and syphilis by the early Cape dwellers dates to the Thunberg’s travels in the eighteenth century [The use of plants in treating many pathogenic infections against variety of microorganisms is ancient in Africa. However, such ethnobotanical data are not well documented, and this remains so to date . Further century . It is a century ,31 and tHuman immunodeficiency virus (HIV) remains the only incurable type of STI, which may result in several various infections within a human body and result in a syndrome. Such infections may result in many opportunistic infections, which may well be treated using both antibiotics and medicinal plants . It is iSince both the approaches in ancient times and the current Western methods of healing had some shortfalls, which may include the antimicrobial resistance of the microbes implicated as causative agents of sexually transmitted infections, the use of plant species is one of the solutions. Such plants are readily available, natural, socially acceptable to society and may well serve as the first line of defence against devastating human pathogens ,7,9.Data on medicinal plant species used in the treatment of sexually transmitted and related opportunistic infections, particularly associated with HIV-AIDS, were scrutinized using several search engines. A total of 63 studies were used to document the medicinal plants used in the treatment and management of sexually transmitted and related opportunistic infections. Such literature studies  and indiIn the current work, a total of 335 medicinal plants from 103 families Out of 335 medicinal plants reported in the current work, herbs constitute 36.53% , followeA similar trend has been reported in South African medicinal plant species used in mitigating pain and inflammation, which involves illnesses such as toothache, general pain, headache, swelling, back ache, stomachache, menstrual or period pains and the disturbance of normal functions of different body parts . KlopperCatharanthus roseus (L.) G.Don (19) yielding the highest number of citations followed by Peltophorum africanum Sond. (14), Carica papaya L. (12), Elephantorrhiza burkei Benth Hypoxis haemerocallidea Fisch., C.A.Mey. and Avé-Lall., Senna petersiana (Bolle) Lock, Ximenia caffra Sond. (11) and both Solanum panduriforme E.Mey. and Securidaca longipedunculata Fresen. Yielding 10 citations apiece. These plant species have also been reported in the treatment and management of many other human and animal infections. C. roseus is used in the management of diabetes, various types of cancers, hypertension and malaria, while P. africanum is recommended in the treatment and management of illnesses such as bilharzia, eye infections, joint and back pain, toothache, ascites and abdominal disorders, diarrhoea, dysentery, infertility, skin rashes and blisters and depression [A total of 29 medicinal plant species exhibited a number of citations ≥6 , with Capression ,102,103.Elephantorrhiza species [According to Tlakula , and Ran species . The tre species . Medicin species .Out of the 335 medicinal plant species reported in the current inventory, roots constitute 47.18%, followed by leaves (16.62%), stem bark (15.01%), whole plant (10.46%), bulbs (6.43%), fruits (4.02%) and then twigs at 0.27% . The prePreparation and mode of administration of medicinal plants reported to manage STIs and related infections are reported in The biological activity of some of the reported medicinal plants are reported . The in Helichrysum caespititium, Peltophorum africanum, Carica papaya, Grewia flava and Aloe ferox are amongst the plant species which yielded a noteworthy and potential antimicrobial activity against agents of STIs and related opportunistic infections. However, the mode of action of such medicinal plant species still needs to be explored. Furthermore, there is a need to explore the antimicrobial activity of the medicinal plant species reported in the current inventory Furthermore, fractions with MIC values ranging from 0.1 to 0.3 mg/mL possess moderate antimicrobial activity, while fractions with an MIC value >0.3 mg/mL are referred to as inactive. Judging by these standards, the extracts from Peltophorum afracanum butanol extract exhibited a noteworthy anti-HIV-1 activity, yielding IC50  values of 1, 3 and 4 µg/mL, respectively, in a MAGI CCR5 assay [50 values of 0.04 and 0.002 µg/mL against two different strains of HIV-1 and the highest selectivity index (SI). The higher the SI, the higher the safety margin [50 value of 3.5 μg/mL against the RNA-dependent DNA polymerase (RDDP) activity of RT by the methanol extract of the stem bark of Peltophorum africanum Sond. Furthermore, the gallotannin isolated from the stem bark inhibited the RDDP and RNase H functions of RT with IC50 values of 6.0 and 5.0 μM, respectively. HIV-AIDS continues to pose an unprecedented public health problem of enormous proportions to society worldwide, with no cure. Current treatment options for HIV-AIDS have not been satisfactory, and the quest for effective curative or preventive therapies goes on. Several countries have proposed the use of a wide combination of plant species . HoweverR5 assay . Furthery margin . It is iy margin ,118,121.y margin ,122. Elsy margin  reportedHypoxis haemerocallidea in a clinical trial for patients with cancer and HIV-AIDS resulted in anxiety, nausea, vomiting and diarrhoea and apparent bone marrow suppression [H. haemerocallidea in rats infected with HIV and found that the CD4 count of rats treated with phytosterols from the plant species had stable CD4 cell counts compared to placebo, a control drug, and that the mortality between the two groups was significantly different. In another study, 37 male tuberculosis patients treated with phytosterols in combination with TB drugs resulted in significant weight gain compared to those treated with drugs alone [The use of hypoxide isolated from pression ,124. Furpression . Elsewhepression  studied gs alone .Peltophorum africanum was evaluated for its cytotoxic effect against a plethora of human cell lines [50 > 1000 μg/mL [ll lines ,128. The00 μg/mL . Althoug00 μg/mL  reportedTerminalia sericea were found to be not cytotoxic to a variety of cell lines, including SC-1 fibroblasts, the EA.Hy926 endothelial hybrid, and Vero cell lines [in vitro toxicological studies [In addition to exhibiting a potent enhanced cell migratory activity of endothelial hybrid and fibroblast cells in vitro, various extracts from ll lines ,131. Alt studies ,112,113.There are a variety of plant-based mixtures sold over the counter used in the treatment of a variety of STIs and related opportunistic infections . However50 value of 0.18 mg/mL, while Combivir and Kaletra yielded IC50 values 0.06 and 0.30 mg/mL, respectively. It is possible that the plant mixture comprised high levels of betulinic acid, as Peltophorum africanum was a major ingredient. It is important to note that these reported plant-based mixtures are not available over the counter. Furthermore, the quantities of such plant materials are not reported, thereby making it difficult to evaluate the biological activity in vitro. Although the mixture exhibited potential ant-HIV-1 activity, there is a need to explore the in vivo activity to further ascertain the anti-HIV activity. This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, as well as the experimental conclusions that can be drawn.Elsewhere, a decoction made up of about nine medicinal plant species has been evaluated for anti-HIV-1 effects in vitro . The decThe information reported in the current paper was collected from a literature search using various computerized databases such as ScienceDirect, Scopus, Scielo, Scifinder, PubMed, Web of Science and Google Scholar. Additional information was further retrieved from various academic dissertations, theses and general plant sciences, ethnomedicine and other relevant ethnobotanical books. This was conducted following (covering from 1990 until December 2020) the guidelines by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . Key worhttp://www.theplantlist.org, accessed on 9 October 2022). The data were collected with help from library staff at the University of South Africa (Florida Campus). In the search engine, plant species with only genus name were omitted in the current work. To generate the inventory/data The papers, books and other sources used in the current work were screened for inclusion, ranging from 1990 to 2020, two decades. Papers appearing as duplicates, cited in abstract form or not in English were excluded . The tasCatharanthus roseus (19) and Peltophorum africanum (14) were the plant species with high citations from various literature sources. Several plants are used, in combination, to prepare medicines which are also available over the counter; however, the safety profiles of such medicines are still overlooked. Interestingly, these two species mentioned above further exhibited a potent antimicrobial activity against etiologic agents of sexually transmitted infections and some important microbes which are major causative agents of opportunistic infections such as Candida albicans and Staphylococcus aureus. A total of 29 recorded plants are relatively well known, given that they were mentioned by six or more sources in South Africa. In some cases, it was observed that important information such as preparation methods and recipes for a significant portion of identified plants were missing in the existing literature. This underscores the limited value of the existing fragmented nature of the ethnobotanical surveys in South Africa. To mitigate these challenges, adherence to the established guidelines and robust ethnobotanical research methodology remains essential for the development of a holistic inventory relating to remedies used for the treatment of STIs and related infections in South Africa. It is important to note that these medicinal plants may well serve as complementary and alternative medicine, particularly in remote rural areas without hospitals, to the available antibiotics which are under pressure due to antimicrobial resistance and the costs of various pharmaceutical products.There is enormous traditional knowledge on the use of medicinal plants in mitigating STIs and related infections in South Africa. In the current work, the first inventory of 335 medicinal plants was constructed and it is evident that their utilization for managing STIs and related infections remains a common practice in South African folk medicine. It is important to note that the recorded plants were utilized among the different ethnic groups. The most common species are from the family Fabaceae (11.64%). Herbs constitute 36.53%, followed by trees (32.34%), while


At present, although the early treatment of sepsis is advocated, the treatment effect of sepsis is unsatisfactory, and the mortality rate remains high. Shenfu injection (SFI) has been used to treat sepsis with good clinical efficacy. Based on network pharmacology, this study adopted a new research strategy to identify the potential therapeutic targets and key active ingredients of SFI for sepsis from the perspective of the pathophysiology of sepsis. This analysis identified 28 active ingredients of SFI based on UHPLC-QQQ MS, including 18 ginsenosides and 10 aconite alkaloids. 59 targets were associated with the glycocalyx and sepsis pathways. Based on the number of targets related to the pathophysiological process of sepsis, we identified songorine, ginsenoside Rf, ginsenoside Re, and karacoline as the key active ingredients of SFI for the treatment of sepsis. According to the cluster analysis of MCODE and the validation on the GEO dataset, LGALS3, BCHE, AKT1, and IL2 were identified as the core targets. This study further explored the therapeutic mechanism and the key active ingredients of SFI in sepsis and provided candidate compounds for drug development. Sepsis is a series of organ dysfunction syndromes caused by dysregulated infection response. In addition to systemic inflammatory response and infection of the primary lesion, severe patients may also experience shock and multiple organ failure . AlthougTalinum paniculatum (Jacq.) (hongshen) and Aconitum carmichaeli Debx (fuzi). In clinical treatment, SFI has been widely used to treat a variety of diseases including sepsis [α, reduce the inflammatory response, and inhibit apoptosis by downregulating the MEK and ERK signaling pathways [Shenfu injection (SFI), derived from the traditional Chinese medicine (TCM) Shenfu decoction, is extracted from g sepsis , 4, shocg sepsis , and heag sepsis  with goog sepsis , 8, redug sepsis , and impg sepsis , 10, 11.pathways . Prelimipathways  in septipathways , and imppathways .Given the multi-ingredient, multitarget, and multiway characteristics of TCM, we use network pharmacology to describe its mechanism of action. Network pharmacology combines various disciplines including traditional pharmacology, systems biology, and computer technology . Studieshttp://www.ncbi.nlm.nih.gov/pubmed) was used to retrieve the main active ingredients of SFI in plasma. Through a search of the PubMed database, we found the latest research on UHPLC-QQQ MS (ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry) for SFI [http://herb.ac.cn/), a TCM database guided by high-throughput experiments and references, was used to retrieve the number of herbal medicines containing the main active ingredients of SFI to observe the specificity of the active ingredients [http://www.swissadme.ch) to calculate the physicochemical properties of the compounds and predict the drug-likeness by RO5 [https://tox-new.charite.de/protox_II) [The PubMed database ( for SFI . Based oredients . An idearedients . Therefos by RO5 . Compounotox_II) .https://pubchem.ncbi.nlm.nih.gov) was used to determine the canonical SMILES of the main active ingredients in SFI. Then, we input canonical SMILES into SwissTargetPrediction (http://www.swisstargetprediction.ch) [Homo sapiens,” to get the relevant targets of active ingredients. Among them, the screening standard of the targets were with probability>0.The PubChem database (tion.ch) , which chttps://www.genecards.org) is a comprehensive database that integrates various gene-centric data including genome, proteome, and transcriptome [http://bioinfogp.cnb.csic.es/tools/venny) was used to find common targets of SFI-related targets and disease -related targets, which are potential therapeutic targets of SFI involved in glycocalyx and sepsis pathways.GeneCards  which is a comprehensive system covering gene function classification, pathways, and statistical analysis [Homo sapiens” for functional classification to further analyze the mechanism of the targets on sepsis. The results were plotted by Microsoft Excel software .Functional classification of potential therapeutic targets of SFI active ingredients was performed by the PANTHER classification system  was used for PPI analysis and the results were visualized by Cytoscape 3.7.2. The organism was set to “Homo sapiens” and the minimum interaction score was set to 0.4. Afterward, we used the tool MCODE to cluster the PPI network and screen the core targets according to the degree value and the mcode node status.To identify the key targets related to sepsis pathophysiology, we put the obtained therapeutic targets for protein-protein interaction (PPI) analysis. The STRING 11.5 database  was used for data analysis and visualization of the results. P value <0.05 was considered statistically significant.In addition, the Gene Expression Omnibus (GEO) dataset was used for differential analysis of core target expression between sepsis patients and normal subjects to demonstrate the specificity of the core targets. We used “sepsis” as the keyword and “https://david.ncifcrf.gov/summary.jsp) [Homo sapiens”. The results with P value <0.05 were considered statistically significant and could be further analyzed.The DAVID 6.8 (ary.jsp)  was usedary.jsp) . In the https://tcmsp-e.com/). The molecular structure of the core targets in the PDB format was obtained from the RCSB PDB database (https://www.rcsb.org/), where the screening criteria for PDB crystal structures were determined according to the resolution of the protein and whether they have ligands. Therefore, we selected IL2 (PDB ID : 1M48) [Molecular docking could simulate the interaction of protein targets and small molecule compounds. AutoDock Vina_1.1.2 simulated the interaction of core targets with key active ingredients by using a semiflexible molecular docking model, and its docking results were evaluated by semiempirical free energy functions . Specifi : 1M48) , BCHE (P : 1M48) , AKT1 (P : 1M48) , and LGA : 1M48)  in the R : 1M48) , and theBased on a recent UHPLC-QQQ MS study , a totalThese analysis results showed that mesaconine, karacoline, songorine, hypaconine, fuziline, neoline, talatisamine, ginsenoside Re, benzoylhypaconine, and ginsenoside Rf complied with RO5, exhibited good pharmacological parameters, and could be used as active ingredients in SFI for further analysis.We input the canonical SMILES of the active ingredients of SFI into SwissTargetPrediction and got 129 targets. To explore the mechanism of action of the active ingredients in SFI in the treatment of sepsis, we screened the targets from a pathophysiological perspective. In the GeneCards database, we got 2777 targets involved in sepsis and 156 targets involved in glycocalyx. Afterward, we obtained 59 overlapping targets of SFI and diseases . The number of active ingredient targets associated with glycocalyx and sepsis is shown in The PANTHER classification system was used for the functional classification of potential therapeutic targets. 53 out of 59 potential targets could be functionally classified. The 53 SFI targets related to sepsis and glycocalyx were divided into 8 different categories according to the protein class . SpecifiThe obtained overlapping targets were entered into the STRING 11.5 database for PPI and visualized by Cytoscape 3.7.2. Not all targets in the sepsis pathway are related to glycocalyx, and there are 6 targets  of active ingredients not only related to glycocalyx, but also involved in the sepsis pathway. So, 59 therapeutic targets were constructed as a PPI network with 56 nodes, 191 edges, and an average degree of 5 . And, asThrough the clustering module analysis of MCODE, we obtained 2 gene clusters as shown in The chip datasets GSE134347 and GSE6535 from the GEO database were used to validate the differential expression of the core targets. Among them, the GSE134347 dataset contains 156 sepsis samples and 83 normal samples, and GSE6535 contains 12 sepsis samples and 17 normal samples. GraphPad Prism software was used for differential analysis and visualization of the results . ValidatP value < 0.05 in the enrichment analysis results could be further analyzed.To further analyze the synergistic mechanism of SFI in the treatment of sepsis, we used the DAVID 6.8 to analyze 59 active ingredient targets involved in sepsis and glycocalyx by GO biological function analysis and KEGG pathway analysis. Statistical differences with a P value <0.05. We showed the top 20 pathways based on the P value , 31 items of cellular component (CC), and 39 items of molecular function (MF). We demonstrated each of the top five functions of BP, CC, and MF , BCHE (PDB ID : 6EQP), AKT1 (PDB ID : 3OS5), and LGALS3 (PDB ID : 6Q17) with the key active ingredients; the lower the binding energy, the better the combination of the two. Studies have shown that affinity lower than −4.25 kcal/mol hasa certain binding force, the affinity lower than −5.0 kcal/mol has a good binding force, and the affinity lower than −7.0 kcal/mol has a strong binding force , 41.The We presented targets with the strongest affinity , and TabSepsis remains the most important cause of death in global healthcare despite numerous clinical and experimental studies. Sepsis involves not only inflammatory responses to infection but also nonimmune pathways which include cardiovascular, coagulation, and metabolism. At present, studies have found that glycocalyx can regulate leukocyte adhesion and the homeostasis of the vascular system. Sepsis promotes glycocalyx degradation, which could lead to microvascular thrombosis and enhanced leukocyte adhesion. The level of glycocalyx was correlated with the degree of organ dysfunction and mortality . Therefoα and IL-12 [cAMP is a common member of the second messenger family that regulates key physiological processes including metabolism and calcium homeostasis. Elevation of intracellular cAMP inhibits the production of inflammatory mediators such as TNF-nd IL-12 . Studiesnd IL-12  and its nd IL-12 . Calciumnd IL-12 . Among tnd IL-12 , 48. Calnd IL-12 ; calciumnd IL-12 . The accnd IL-12 . Moreovend IL-12 . And, send IL-12 .The PI3K-Akt signaling pathway regulates multiple essential cellular functions such as transcription, growth, and multiplication. Activation of the PI3K−Akt pathway inhibits inflammation , fights Aconitum carmichaeli Debx and its active ingredients have various effects including anti-inflammatory and analgesic, immune system, and energy metabolism [According to the analysis of ingredients and targets, we determined that songorine, ginsenoside Rf, ginsenoside Re, and karacoline were the key active ingredients of SFI. Among them, songorine and karacoline belong to aconite alkaloids, and ginsenoside Rf and ginsenoside Re belong to ginsenosides. Studies have shown that tabolism . At prestabolism . Ginsenotabolism  and imprtabolism . Ginsenotabolism . Ginsenotabolism .Among the functional classifications of therapeutic targets for SFI, the metabolite interconversion enzyme was the most abundant class. Among them, 8 targets are hydrolase, 4 targets are transferase, 3 targets are oxidoreductase, and 1 target is lyase. It can be seen that SFI participates in many key biological processes in the human body. In addition, in the metabolite interconversion enzyme, 5 targets are glycosidases, which are closely related to the conversion of the glycocalyx. Research supports that various glycosidases, including heparanase and hyaluronidase, are involved in the degradation of glycocalyx and play an important role in the pathophysiological mechanism of sepsis , 65–67.According to the cluster analysis of MCODE and the validation on the GEO dataset, we obtained four core targets of LGALS3, BCHE, AKT1, and IL2. LGALS3 is a carbohydrate-binding protein that affects angiogenesis by affecting VEGFR2 . InteracBCHE plays an important role in the inflammatory response  and coulAKT1 is critical for acute inflammation, mainly by regulating neutrophils and monocytes . In sepsThe molecular docking results of the core targets and the key active ingredients of SFI show that the two have a good binding ability, which further proves that the treatment of SFI for sepsis is based on anti-inflammatory, antioxidant, immune regulation, protection of endothelial cells, and improvement of the glycocalyx.This study adopted a new research strategy to explore and identify the key active ingredients of SFI from the perspective of the pathophysiology of sepsis, improving the accuracy of potential therapeutic targets for SFI in the treatment of sepsis. And we obtained the blood-introducing active ingredients of SFI according to the UHPLC-QQQ MS study, avoiding the use of public databases to screen out a large number of nonspecific ingredients.However, this study also has some shortcomings. First, based on the limitations of network pharmacology, we could not consider the effect of the SFI dose on disease. Second, the present network analysis is static, which contradicts the dynamic changes in the occurrence and development of the disease. Finally, although animal experiments and clinical studies have shown that SFI has an obvious therapeutic effect on sepsis, the research on the active ingredients of SFI is still insufficient, and further research on its adverse effects is required.Based on network pharmacology, this study explored the mechanism of SFI in the treatment of sepsis from the perspective of pathophysiology. Songorine, ginsenoside Rf, ginsenoside Re, and karacoline were identified as key active ingredients in SFI for the treatment of sepsis. LGALS3, BCHE, AKT1, and IL2 were identified as core targets for the potential treatment of SFI. We provide a new perspective for the study of TCM network pharmacology and candidate compounds for drug development. However, its clinical application still needs further research and confirmation.


In recent years, COVD-19 has made millions of death worldwide. When reviewing the death rate, we encountered a very notable difference in death rate of Iran and Iraq, which are two neighboring countries. Investigating the COVID-19 risk factors, parameters, such as ethnicity and vaccination, do not appear not to be affecting our observation. We also could not find important differences in mortality rate being under-reported in the two countries. In this letter, we tried to discuss the possible effect of Iraq pre-COVID-19 mass gatherings on the death rate. The authors would like to highlight the effect of immune system on COVID-19. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The new respiratory disease has spread widely throughout the world during the last year and made important changes in the lifestyle across the world. About 6,400,000 deaths have been officially reported so far from this disease [Vaccination: when measuring all vaccine doses (including boosters), so far, total dose equal to about 172% of Iran's population has been injected in Iran, while this share is only 43% in Iraq [COVID-19 variant: Although we could not find strong evidences detailing dominant strains of COVID-19 as a function of time in the two countries; apparently, no important variation in the dominant strain may be detected .Management protocols: both countries have tried to follow the WHO suggested protocols for management of COVID-19 .Wearing face mask: we could not find data about number of people who wear face mask in Iraq during the last years. However, in Oct 2020, an Iraqi official declared that only 20% of Iraqis were wearing masks , while i3, respectively [Air pollution: based on the data provided by international association for medical assistance to travelers, the annual mean concentration of PM2.5 for Iran and Iraq is 39 and 62 µg/mectively .Underlying diseases: from a report by WHO , 10.3% of Iranians and 13.2% of Iraqis  suffer fObesity, physical inactivity and smoking: prevalence of obesity in Iran 25.8% ) is less%  is lesEthnicity: in our case, due to the linguistic, religious, and geographic commonalities of the two neighboring countries as well as economic, commercial, cultural, and religious exchanges throughout the history, we cannot predict notable variation in ethnicity of Iranians and Iraqis. Additionally, from COVID-19 registry system in Ahvaz University of Medical Sciences , by 22-Aug-2021, the death rate per 1MP was 1466 , relativAge: looking into the demographic information of the two countries, Iraq is a substantially younger country (median age 21.2 years) in comparison with Iran (median age 31.7 years)—percentage of people above 55 in Iraq is also considerably less than that of Iran  .Looking into the literature, various reasons have been reported as risk factors for the disease. Here, we try to provide a discussion of their possible effects on the mortality rate of the two countries. The authors appreciate that providing an extensive comparison is a very complicated task and many confounding variables may influence our assessment. However, to the best of our knowledge, an acceptable comparison has been provided here:Comparing the factors mentioned above, the only risk factor which we could find favoring the lesser death rate in Iraq is age. Although age is a very important risk factor, by studying the age in other countries, this single factor cannot address the huge difference between the mortality rate of Iran and Iraq. For instance, Kuwait, an Arab country with median age 29.7 years, has death rate close to Iraq  gathered in Karbala city in 2016, of which about 20% came from other countries . This nuThe severe form of COVID-19 is developed following excessive inflammatory responses and cytokine storm. Dysregulation of immune system through alleviation of T cells, increasing of IL-6 level, as well as reduction of B cells and natural killer (NK) cells has been reviewed in COVID-19 . The autA second effect from the mass gatherings in Iraq is the change in the microbiome profile of the Iraqis. The microbiome may play critical role in the training and development of major components of immune system . One mayTo conclude, this commentary argues that the Iraqis might have become more resistant to SARS-CoV-2 through their social behavior, especially mass gatherings. At this point, anticipating future viral pandemics, we would like to raise the question by Ghanaemi and Yoshioka that are we "losing our immunity when we need it the most" ?


We assessed the imprecision and compared the results to those obtained on existing instruments in the central laboratory. We found that the within-lab coefficients of variation (CV) were very low (<2%) or low (2–5%), except for creatinine and PT . For almost all the parameters, the results were strongly (R2 = 90–95%) or very strongly (R2 > 95%) correlated with those of the existing laboratory instruments, and the biases were very low (<2%) or low (2–5%). However, correlations of the PT and INR measurements with existing instruments were lower (R2 = 86.0% and 89.7%), and biases in the Po2 (7.9%), creatinine (5.4%) and PT (−6.6%) measurements were higher. The i-STAT Alinity appeared as a convenient device for measurements of numerous parameters. However, clinicians should interpret Po2, creatinine and PT results with caution.Many Point-of-Care devices have been released over the past decade. However, data regarding their analytical performances in real-world situations remains scarce. Herein, we aimed to assess the analytical performances of the i-STAT Alinity system. We conducted an analytical performances study with the i-STAT Alinity device using cartridges CG4+ (pH, Pco Point-of-Care (POC) testing is defined as testing performed near or at a patient’s bedside instead of in a conventional central laboratory . POC tesThanks to advances in technologies and the miniaturization of electronic devices, just in minutes, novel POC analyzers are now able to measure a large number of parameters from a small blood sample. Indeed, beyond a simple blood gas analysis with basic chemistry and hematology, measurements such as renal, cardiac or inflammatory biomarkers and coagulation tests are now available ,5,6,7. THowever, most of the POC users are clinicians, nurses or midwives with limited technical training. Therefore, biologists should assess POC analyzer precision remains equivalent to those obtained in central laboratories to ensure the proper diagnosis, management of patients and concordance of the threshold values for therapeutic decision making . Thus, aIn this study, we aimed to assess the analytical performances of the i-STAT Alinity system simultaneously for a large panel of analyses, including blood gas, lactate, sodium (Na), potassium (K), ionized calcium (iCa), glucose, urea, creatinine, hemoglobin (Hb), hematocrit (Ht), prothrombin time (PT) and international normalized ratio (INR). Moreover, we aimed to assess the ability of the i-STAT Alinity device to be used for the management of vitamin K antagonist (VKA) therapy and the classification of patients with chronic kidney disease (CKD).2 and partial pressure of oxygen or Po2 and lactate); CHEM8+  and PT/INR (PT and INR). During the study period, whole blood samples drawn from inpatients were randomly screened after routine blood gas analyses or PT/INR measurements. A single operator (M.L.), trained in the use of the i-STAT Alinity system, performed the analyses. We carried out the prospective analytical performance study of the i-STAT Alinity POC device in the Biochemistry and Hematology Laboratories of Montpellier University Hospital, France, between August, 2019 and February, 2020 using the following cartridges: CG4+  for both the laboratory blood gas and the i-STAT measurements (except for coagulation). Lithium heparin, sodium citrate and no additive  blood collection tubes  were used, respectively, for the urea and creatinine measurements in the central laboratory, PT and INR measurements in the central laboratory and for PT and INR measurements on the i-STAT device.2 by direct potentiometry; Po2 and lactate by amperometry and calculating the bicarbonate, base excess, total CO2 (Tco2) and O2 saturation (So2) in two minutes; (2) the i-STAT CHEM8+ cartridge measuring Na, K, Cl, iCa, Tco2 and urea by ion-selective electrode potentiometry, creatinine and glucose by amperometry after the enzymatic reaction; hematocrit by conductometry and calculating the anion gap and hemoglobin in two minutes and (3) the i-STAT PT/INR cartridge measuring PT and INR by amperometry after enzymatic reactions in five minutes. The i-STAT Alinity system is an easy-to-use portable blood analyzer that delivers test results in a few minutes. This POC system uses a single-use disposable cartridge containing microsensors, a calibrator and a waste container. The calibration solution is stored in a sealed cartridge and automatically released to perform a one-point calibration just before the sample analysis. The entire fluid path is also stored in the sealed cartridge and requires less than 100 microliters of whole blood introduced either from a heparinized blood gas syringe, a capillary or a neutral tube with a tip applicator. In this study, we focused on 3 of the 17 cartridges available: (1) the i-STAT CG4+ cartridge measuring pH and PcoThe imprecision of this cartridge-type POC was tested through the measurement of two levels of control material (Abbott i-STAT TriControl) over the course of one day at one site, by the same operator (M.L.) with one lot of test cartridges. The internal precision study was performed with duplicates of each sample tested five times a day on 2 i-STAT Alinity devices.2, Po2, lactate, sodium, potassium, chlorine, ionized calcium, glucose, hemoglobin and hematocrit were compared to those obtained using the ABL90 Flex Plus blood gas analyzer . The results for urea and creatinine were compared to those obtained by enzymatic methods on a Cobas 8000 instrument using a c702 module . The PT and INR measurements were compared to those determined using an ACL TOP 700 analyzer .Anonymized whole blood samples were tested on the POC i-STAT Alinity instrument using one lot of cartridges: CG4+, CHEM8+ and PT/INR. The i-STAT Alinity system results were compared to those obtained on existing instruments in central laboratories. The results for pH, PcoThe Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was used to calculate the estimated glomerular filtration rate (eGFR), and patients were classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines .An INR value between 2.0 and 3.0 was considered the target for patients treated with VKA according to the 2020 European Society of Cardiology (ESC) Guidelines for the diagnosis and management of atrial fibrillation .2) or were evaluated in an old study (pH). The Royal College of Pathologists of Australasia (RCPA) database [The means, standard deviations (SD) and coefficients of variation (CV) for each level of control were determined in the imprecision study. Multiple sources of analytical performance goals were considered for comparison purposes . The datdatabase  for the database  for imprThe Passing–Bablok regression analysis was used to compare the results of the POC i-STAT Alinity instrument with those obtained with existing laboratory instruments. The scatter of differences was visualized by means of Bland–Altman plots . Agreement between the analyzers for CKD staging based on creatinine values was assessed by Cohen’s kappa test. Taking into account that CKD stages are ordered and for how far apart the two analyzer measurements are, a weighted kappa was calculated . Cohen’sThe same analysis was conducted to assess the agreement between the analyzers for the management of patients treated with VKA based on INR values.® software .Data analysis and statistical calculations were performed using XLSTATThe imprecision study results are summarized in The within-lab CVs were very low (≤2.0%) or low (2.0–5.0%), except for low values of creatinine and high values of PT, in which the CVs were at 5.2% and 6.3%, respectively. In addition, the CV values for these parameters were above the desirable values expected for the central laboratory instruments.We analyzed excess whole blood from 49 patients ) collected in a heparinized syringe and 45 serum samples in lithium heparin collection tubes. In addition, 46 blood samples collected in no additive collection tubes  and citrate collection tubes were taken from 46 patients ).The results of the Passing–Bablok regression and Bland–Altman studies are reported in 2 = 90–95%) or very strongly (R2 > 95%) correlated with the existing laboratory instrument measurements, and the biases were very low (<2.0%) or low (2.0–5.0%) for almost all the parameters. However, the PT measurements and INR calculations with the iSTAT Alinity instrument showed a lower correlation with the existing laboratory instrument measurements: R2 at 86.0% and 89.7%, respectively . The percentage of agreement between the Cobas 8000 and i-STAT Alinity for CKD staging was 84.4%, with a crude Cohen’s kappa at 0.807 . Given that misclassified patients only had one stage difference , the weighted kappa was estimated at 0.926.The correlation of classification for patients with eGFR ≥ 60 mL/min/1.73mA comparison of the INR results obtained with the POC i-STAT Alinity and the ACT TOP 700 instruments in 46 patients showed that only four of them would have had different management for their VKA treatment .The percentage of agreement between the ACT TOP 700 and the i-STAT Alinity for management of the VKA treatment was 84.4%, with a crude Cohen’s kappa at 0.831  and a weighted kappa estimated at 0.850. These results underlined the good agreements between the devices for CKD staging and the management of VKA treatment in clinical settings.2, creatinine and PT/INR measurements were associated with higher imprecision and/or biases in comparison with the existing methods. However, the clinical impact in patients with hypoxemia, CKD or treated with VKA seemed limited.We reported herein the results of an analytical performances study of the i-STAT Alinity system for blood gas, lactate, electrolytes, glucose, urea, creatinine, hematocrit, hemoglobin and PT/INR measurements. Overall, the analytical performances in real-world situations were in agreement with the manufacturer specifications, including the creatinine and INR levels. In addition, POC testing with i-STAT Alinity reached desirable imprecision in the measurement of almost all parameters, and almost all these measurements were well corelated with the existing instruments in central laboratories. Nevertheless, the PoA growing number of POC analyzers are released and offer increasingly wide analysis panels at the bedside instead of in a conventional central laboratory. Among them, the i-STAT Alinity system is an easy-to-use portable blood analyzer allowing the performance of rapid diagnostics at the POC in a hospital, or even home, setting. Unsurprisingly, the use of POC testing is increasing ,2,3; howIn order to compare the analytical performances of the i-STAT Alinity with the other systems, we performed a deep review of the literature on similar commercial devices see . This re2, bicarbonate, lactate, electrolytes, glucose, hematocrit and hemoglobin tests [2 and creatinine  measurements were above the goals defined by the SFBC [2 [Our results are in accordance with previous studies that reported very good and good precision and correlation with the existing methods for pH, Pcoin tests ,4,19. Inin tests ,16. On tthe SFBC , except 2, which is generally assumed as an alert threshold, in particular, for contrast nephropathy and numerous drug dosage regimen adjustments. This point should be highlighted, since POC testing devices are intended for EDs and imaging departments in order to fluidify patient care rather than for nephrology departments or dialysis centers.Most importantly, we found a positive average bias (5.4%) in the creatinine tests versus the Roche isotopic dilution mass spectrometry (IDMS) calibrated enzymatic assay performed in the central lab. As previously described , this wa2 measurements that was not reported in other studies evaluating the analytical performances of i-STAT Alinity [2 measurements mainly impacted the highest value of Po2 (above 150 mmHg), which limited its clinical importance [We also reported a 7.9% bias in the Po Alinity ,4,19. Th Alinity . Interesportance ,24 and hportance . In the portance ,26.To the best of our knowledge, this study was the first to analyze the performance of i-STAT Alinity for PT/INR testing. Schober et al.  recentlyIn this work, we confirmed, in real-life situations, that the i-STAT Alininity technical performances reported by the manufacturer remained applicable and that the analytical performances were close to those of the central laboratory instruments. More importantly, this POC device had good clinical performances providing sufficiently reliable results for therapeutic decision making. Thus, our results showed that i-STAT Alinity can meet the critical therapeutic needs of patients in the ED or ICU and that the device was as easy to use, as testing can be performed by nurses or physicians searching for a POC device with a wide range of analyses.We must acknowledge some limitations to this study. First, we did not assess the linearity, interference and reproducibility of the i-STAT Alinity analyzer. However, previous studies have reported good linearity  and reproducibility (one run per day of each control level for 14 days) for all the parameters except for PT and INR . Second,2, base excess, bicarbonate, lactate, electrolytes, glucose, urea and hemoglobin measurements. However, the analytical imprecision did not meet the international recommendations for central laboratory devices showing bias in the measurements of Po2, creatinine, hematocrit and PT/INR. The i-STAT Alinity system could be an effective POC testing device for triage at patients’ bedsides in the ED or in the ICU; nevertheless, clinicians should interpret the results of the Po2, creatinine, hematocrit and PT/INR with caution. Further studies are mandatory to assess the capability of such a device to improve patient management and prognosis in real-life settings.The i-STAT Alinity system, a handheld, portable, POC blood testing device, has shown adequate imprecision and comparable accuracy to the existing laboratory methods for pH, Pco