There is limited published data on antibiotic use in neonatal units in resource-poor settings.This study sought to describe antibiotic prescribing practices in three neonatology units in Kigali, Rwanda.A multi-center, cross-sectional study conducted in two tertiary and one urban district hospital in Kigali, Rwanda. Participants were neonates admitted in neonatology who received a course of antibiotics during their admission. Data collected included risk factors for neonatal sepsis, clinical signs, symptoms, investigations for neonatal sepsis, antibiotics prescribed, and the number of deaths in the included cohort.126 neonates were enrolled with 42 from each site. Prematurity (38%) followed by membrane rupture more than 18 hours (25%) were the main risk factors for neonatal sepsis. Ampicillin and Gentamicin (85%) were the most commonly used first-line antibiotics for suspected neonatal sepsis. Most neonates (87%) did not receive a second-line antibiotic. Cefotaxime (11%), was the most commonly used second-line antibiotic. The median duration of antibiotic use was four days in all surviving neonates (m=113). In neonates with negative blood culture and normal C-reactive protein (CRP), the median duration of antibiotics was 3.5 days; and for neonates, with positive blood cultures, the median duration was 11 days. Thirteen infants died (10%) at all three sites, with no significant difference between the sites.The median antibiotic duration for neonates with normal lab results exceeded the recommended duration mandated by the national neonatal protocol. We recommend the development of antibiotic stewardship programs in neonatal units in Rwanda to prevent the adverse effects which may be caused by inappropriate or excessive use of antibiotics. Infection is responsible for approximated 35% of all neonatal deaths In resource-rich settings, antibiotic stewardship is recognized as a critical patient safety and quality initiative to combat unnecessary antibiotic use to optimize clinical outcome while minimizing the harmful consequences of antimicrobial useThe Rwanda Neonatal protocol advocates for the firstline empirical treatment of neonatal sepsis with Ampicillin and Gentamicin This study sought to describe antibiotic prescribing practices (antibiotic used and duration) in three Neonatology Units in Kigali, Rwanda. Secondary objectives were to describe the all-cause mortality, frequencies of risk factors for sepsis, and clinical features of sepsis in the recruited patients.Study design: A multi-center, cross-sectional study. Reporting of this study has been verified in accordance with the STROBE  checklist Study sites: The study was conducted in three hospitals in Kigali, namely; University Teaching Hospital of Kigali (UTHK), Rwanda Military Hospital (RMH) and Kibagabaga District Hospital (KDH) Participants: Inclusion criteria were neonates admitted in neonatology units at UTHK, RMH, and KDH who were given a course of antibiotics during their admission to the neonatal unit (i.e. neonates admitted directly from maternity units). Neonates who were admitted to other units and/or from outside hospitals, i.e. neonates from the community, were excluded. Subjects were opportunistically recruited by the principal investigator (PI) between August to December 2017. The Principle Investigator (PI), was a pediatric resident, based in Kigali, who would intermittently visit the study sites, and recruit patients available at that time point. The PI then followed-up these patients, collecting the necessary data during the admission. No data on non-recruitment was taken.Outcomes: The primary objective of the study was to describe antibiotic prescribing practices, predefined as antibiotic used and duration of antibiotic use. The duration was described in days of antibiotic used. To take into account for the amount of time neonates spent as inpatients, a second descriptor for antibiotic duration was used, namely the Antibiotic-Use-Ratio (AUR). AUR was pre- defined as the number of days an infant was exposed to one or more antimicrobial agents divided by the total length of hospital stay Data-collection: A data-collection tool was designed specifically for use in this study and was reviewed at the University of Rwanda (UR) pediatric academic team for content validity. This data-collection tool was piloted on the case-files of five neonates to ensure the feasibility of use. Data were collected prospectively from patient files (note-review) onto a paper version of the data-collection tool, recruited between 2nd August and 22nd December 2017. Ethical clearance was gained to question parents if any data was missing from the patient file, however this was not required.Data management: Data were then entered into Epi-data before analysis using Statistical Package for the Social Sciences (SPSS) version 24.Sample size:Goal sample size was 42 neonates from each site powered to identify a difference of 2 days between district and tertiary hospital duration of antibiotic use, with 95% confidence (2-sided) with 80% power and a ratio 2:1 for tertiary:district hospital sites.Statistical analysis: For categorical data, ordinal outcomes were analyzed with Chi-square. For cells smaller than five, Fischer's exact test was employed. For continuous data, means were compared with Student's t-test or ANOVA dependent on group size. Non-normally distributed data were described using medians and compared using the Mann-Whitney non-parametric test.Characteristics of recruited participants: One hundred and twenty-six neonates were enrolled with 42 neonates from each study site . There were significantly different prescribing habits between the hospital sites regarding the duration of antibiotic use and in the antibiotic to the length of stay ratio (ALR) . SurviviChoice of antibiotic: Ampicillin and Gentamicin (84.9%) were the most commonly used first-line antibiotics for suspected neonatal sepsis . Most neMortality in recruited patients: [A1]Overall mortality, in recruited patients, at all three sites was 10% with no significant difference between the sites. Sepsis was the cause of death in 77% of deaths .Klebsiella spp (n=1); Staphylococcus aureus (n=2); Coagulase-negative staphylococcus (n=1); E. coli (n=3); Non-specific “Gram-negative bacilli” (n=3); Non-specific “Gram-positive cocci” (n=1).Causative organisms: Two of the three sites (UTHK and RMH) have microbiology laboratory facilities and therefore, can perform blood cultures. Seventy-eight (93%) neonates had a blood culture performed in the sites with these facilities. Of these, 11 (14%) had a positive blood culture (seven gram-negative and four gram-positive). The following organisms were reported: Frequencies of risk factors, and clinical features of sepsis[A2]: Prematurity was the most common risk factor for sepsis (38%) followed by prolonged rupture of membranes (25%) . NeonateThis study aimed to describe antibiotic prescribing practices in three Neonatology Units in Kigali, Rwanda. We found that the median duration of antibiotics was four days in surviving neonates with 85% receiving ampicillin and gentamicin as first-line antibiotics. The median duration of antibiotics is consistent with other reported studies The mean number of risk factors for each neonate was only 1.2, which might suggest that antibiotics were being used too frequently when significant risks were not present. However, this is speculative as this study did not include infants who did not receive antibiotics, and some risk factors may not have been thoroughly documented in the case-files. The evaluation of asymptomatic neonates for sepsis is controversial, but several studies have shown that application of risk stratification can result in decreases in empiric antibiotic use The most frequently used combination of empirical antibiotics was ampicillin and gentamicin, reflecting the recommendations of the Rwandan national protocol. However, a 2016 study of 128 positive neonatal blood cultures at UTHK in Rwanda, found zero percent sensitivity to ampicillin with 13% sensitivity to gentamicinOne of the three hospitals in this study did not have a microbiology laboratory. However, even with the lack of access to blood culture, this hospital (KDH) gave shorter courses of antibiotics. Concerns about the reliability of blood cultures  can lead to prolongation of antibiotic treatment. Also, delay in reporting negative blood culture results causes clinicians to continue antibiotic treatment while the results are pending. Automated blood culture systems have been shown to identify >94% of bacteria within 48 hours of incubation Neonates received a median of four days, three days, and 3.5 days despite a negative blood culture, CRP, or both . AntibioThis study had a number of limitations. Data was collected from the patient records. Therefore the data was reliant on the completness and accuracy of the patient files. CRP results were only reported as positive or negative, without specifying the quantitative values for a positive CRP. This could impact the duration of antibiotics used as antibiotics can be discontinued if the positive CRP value is low or trending down. In addition, this study is not powered to assess if antibiotic choice and duration have an impact on mortality.Governmental bodies, hospitals, and individual clinicians should do more to standardize antibiotic use to avoid site-dependent variation in prescribing. Antibiotic resistance is a public health emergency and, currently, it is an under-researched area The median antibiotic duration for neonates with normal lab results exceeded the recommended duration by the national neonatal protocol. Based on this finding, we recommend the development of antibiotic stewardship programs, in neonatal units, in Rwanda to prevent the adverse effects which may be caused by inappropriate or unneccesarily prolonged use of antibiotics.


MET·HCl = 0.66), we observed a slight enhancement in the dissolution properties compared with pure HTZ (1.21-fold). The same analysis for the solid forms of MET·HCl-CTZ (χMET·HCl = 0.33 and 0.5) showed an enhancement in the dissolved amount of CTZ accompanied by a slight improvement in solubility. From these dissolution profiles and saturation solubility studies and by comparing the thermodynamic parameters (ΔHfus and ΔSfus) of the pure drugs with these new solid forms, it can be observed that there was a limited modification in these properties, not modifying the free energy of the solution (ΔG) and thus not allowing an improvement in the dissolution and solubility properties of these solid forms.The mechanochemical synthesis of drug–drug solid forms containing metformin hydrochloride (MET·HCl) and thiazide diuretics hydrochlorothiazide (HTZ) or chlorothiazide (CTZ) is reported. Characterization of these new systems indicates formation of binary eutectic conglomerates, i.e., drug–drug eutectic solids (DDESs). Further analysis by construction of binary diagrams (DSC screening) exhibited the characteristic V-shaped form indicating formation of DDESs in both cases. These new DDESs were further characterized by different techniques, including thermal analysis (DSC), solid state NMR spectroscopy (SSNMR), powder X-ray diffraction (PXRD) and scanning electron microscopy–energy dispersive X-ray spectroscopy analysis (SEM–EDS). In addition, intrinsic dissolution rate experiments and solubility assays were performed. In the case of MET·HCl-HTZ (χ Pharmaceutical cocrystals are multicomponent crystalline entities composed of an active pharmaceutical ingredient (API) and a coformer in a defined stoichiometric ratio ,2,3. TheReplacement of the coformer by another API yields the formation of drug–drug cocrystals (DDCs) ,7, speciThe benefits found in the preparation of DDCs ,7, DDESsThus, when monotherapy is no longer efficient for T2D, the simultaneous utilization of two or more drugs depending on the clinical profile of the patient seems to be a more appropriate approach ,41. Metfint 12.5-fold more than HTZ crystalline and 2.2-fold better than the PM HTZ-atelonol [Within the family of thiazide diuretics, chlorothiazide (CTZ) is a poor water-soluble drug (0.2 and 0.4 g/L at pH 4 and 7), exhibiting a plasma half-life of 45–120 min . Furtheratelonol .Taking this into account, we are interested in the preparation of drug–drug solid forms containing MET·HCl  , in the TM  or Toronto Research ChemicalsTM  and were used as received. The solvents were purchased from TecsiquimTM  and were used as received.All the pharmaceutical reagents were purchased from Tokyo Chemical Industry AmericaTM 7 Fritsch  device. MET·HCl  was ball-milled with HTZ  or CTZ  in a 1:1 stoichiometric ratio. For every LAG experiment 100 μL of solvent were added. The solvents used were, hexane, acetone, acetonitrile, and water. Stainless steel bowls of 20 mL containing 10 stainless steel balls (10 mm diameter) were used. The NG or LAG were carried out at 600 rpm for 30 min. The physical mixtures (PM) were prepared by mechanical shaking MET·HCl  with HTZ  or CTZ  in a 1:1 stoichiometric ratio for 5 min using a Vortex Genie 2 Scientific IndustriesTM  (velocity of shaking 5).NG or LAG solvent-screening for the preparation of the solid forms was performed using a Planetary Micro Mill PulverisetteA simultaneous thermal analyzer Netzsch STA 449 F3 Jupiter was used. The samples were placed (2–4 mg) in sealed non-hermetic aluminum pans and scanned at a heating rate of 10 °C/min from 30–400 °C under a dry nitrogen atmosphere.TM 7 Fritsch at 600 rpm for 2 h. The DSC determinations proceeded at a heating rate of 10 °C/min using the thermal analyzer Netzsch STA 449 F3 Jupiter. Binary phase diagrams were constructed by plotting the melting temperatures from the different compositions (onset), and the second endothermic event as the liquidus (Tonset) in function of the mole fraction of MET·HCl. Tammann diagrams were constructed by plotting ΔHfusion from the different stoichiometric ratios as a function of the mole fraction of MET·HCl. Some samples were occasionally analyzed at a heating rate of 2 or 5 °C/min to improve the viewing accuracy on some thermal events.The determination of the eutectic points was made by means of construction of binary phase and Tammann diagrams ,65. Diffositions , considePXRD experiments were carried out in a Bruker D8 Advance diffractometer with Bragg-Bretano geometry, Cu Kα radiation (1.54060 Å) and Linxeye detector. Each sample was measured by a continuous scan between 5–60° in 2θ, with step time 151.19°/min and step size of 0.0198°. The Rietveld refinements were carried out using the program Fullprof suite to calculate the final crystal lattices of the different outcomes . Deposit1H 300 MHz, 13C 75 MHz and 15N 30 MHz). SSNMR measurements were carried out on a 4 mm rotor double resonance CP-MAS probe at 5–6 kHz spinning rate with a cross-polarization contact time of 2 ms and delay of 5 s. In addition, HMBC and HSQC experiments were carried out in a Bruker Avance III 500 . Solution NMR measurements were carried out on a 4 mm broadband probe with two channels; the heteronuclear channel can be tuned 31P (202 MHz) until 107Ag (27 MHz), with Z-axis gradients. CTZ and HTZ were dissolved in d6-DMSO for the HMBC and HSQC experiments (15N experiments we used NH3(l) δ = 0 ppm as internal reference and glycine (δ = 38 ppm) as secondary standard. The chemical shifts assignment in the 15N-SSNMR experiments presented in 1H, 13C and 15N [6-DMSO and D2O for MET·HCl have been previously reported [15N-SSNMR spectra for MET·HCl we noted the presence of 4 signals as well as the reported NMR solution [13C CP-MAS assignation of CTZ [Solid-state NMR (SSNMR) spectra were recorded in a Bruker Avance II 300 spectrometer  and MET·HCl-HTZ 1:1 (χMET·HCl = 0.5), A JEOL  scanning electron microscope (SEM) model JSM-6510LV was employed to examine the morphology of the solid forms (MET·HCl-CTZ 1:1 (χ2. The dissolution rates were determined with a Wood’s apparatus according to the USP XLI. Dissolution profiles were made in 0.1 N HCl for each batch. Experiments were carried out in triplicate at 37 °C under constant stirring (50 rpm) in a constant volume of 900 mL. For CTZ and the different MET·HCl-CTZ compositions, IDR determinations were made using a HPLC Agilent 1100 with an automatic injector (DE116471) under the following chromatographic conditions: mobile phase of H3PO4 0.025 M and acetonitrile (80:20) with a flow of 1 mL/min and using a Zorbax SB-C18 column with dimensions of 4.6 mm × 150 mm with particle size of 5 µm at a wavelength of 272 nm. For HTZ and the different MET·HCl-HTZ compositions, IDR determinations were performed using a UV-VIS spectrophotometer ) at the wavelength of 272 nm.We determined the IDR constants under physiological conditions. The experiments were performed using tablets, prepared with a hydraulic press at a total force of 180–200 kg/cmAn excess amount of powder (eutectics or pure drug) was weighed (approximately 33.3 mg) and dissolved in a vial with a fixed volume of water (1 mL 0.1 N HCl). The vial was magnetically stirred for 72 h at 37 °C. After the equilibrium time, an aliquot was passed through a 0.45 µm filter and properly diluted and quantified through HPLC (Agilent 1260 infinity II) using a calibration curve. The experiments were made in triplicate.The preparation of the solid forms was performed by ball-milling of MET·HCl with CTZ or HTZ (1:1) using neat grinding (NG) or liquid assisted grinding (LAG) ,62,63,64Analysis by PXRD  of the aP21/c) and CTZ , indicating the coexistence of two solid-phases as a conglomerate of separated components, both APIs keeping their own lattice, being more like a non-continuous single-phase than a eutectic solid. According to Cherukuvada and Nangia, “eutectic solids lack a distinct unique lattice arrangement from the individual components and retain the cohesive interactions in solid solutions” [P21/c) and HTZ , both constituents retaining their own lattice. Hence, no effect of the polarity of the solvent was found for the LAG solvent-screening in both solid forms, the quantitative percentage ratios for the lattice structures between the APIs remaining constant in all cases.Based on the Rietveld refinements  for MET·lutions” ,20. Simifus (197.8–203.2 °C) compared with the parent APIs. In addition, for the PM the endothermic event exhibits two overlapped peaks (209.5 and 218.28 °C), clearly indicating that the different products obtained on the LAG solvent-screening are not PMs, since they only exhibit a single endothermic peak and not separated melting events for the individual components [The products obtained through the LAG solvent-screening were also analyzed by DSC. PMs were prepared combining MET·HCl with HTZ or CTZ in a 1:1 stoichiometric ratio, and analyzed by the same technique. mponents .fus compared with the pure MET·HCl or HTZ  of MET·HCl-CTZ 1:1 or MET·HCl-HTZ 1:1, SSNMR experiments were performed. Atom numbering for MET·HCl, CTZ and HTZ for 13C and 15N nuclei are shown in So far, we have seen that according to PXRD results, homosynthons predominate over the heterosynthons. In this regard, Cherukuvada and Nangia explained that “through different spectroscopical and PXRD analysis, eutectic solid phases and solid solutions have close similarity with their pure constituents” . Thus, u13C-SSNMR experiments, it can be observed that there are no significant Δδ of the pure APIs compared with the new solid forms MET·HCl-CTZ 1:1 or MET·HCl-HTZ 1:1  compared with MET·HCl (232.9 °C) [13C is observed compared with the original APIs (2NH2) catemer chain of HTZ cannot be interrupted by the amide group of ATL. In addition, for MET·HCl-CTZ 1:1 or MET·HCl-HTZ 1:1 apparently the non-self-complementarity (shape mismatch) of the initial components promotes the lack of formation of heterosynthons [Through -HTZ 1:1 . The mins in CTZ . This is32.9 °C) . A similnal APIs . Once agsynthons ,21,82.13C-SSNMR spectra of pure CTZ , lacking signals for C5′, C9′ and C10′ which were not observed, probably due to lack of efficient cross polarization 1H-13C.The pure CTZ  exhibit 15N-SSNMR experiments, for the APIs MET·HCl, CTZ or HTZ and the solid forms of MET·HCl-CTZ 1:1 or MET·HCl-HTZ 1:1  against the mole fraction of MET·HCl (χMET·HCl) at all examined compositions (fusion) against the mole fraction of MET·HCl [Thus, binary diagrams b were coositions . Tammann MET·HCl ,31. For The depression in the melting point, giving place to the characteristic V-shape in the binary diagram, indicates that a true eutectic composition has been found ,64,86. CMET·HCl = 0.5 (molar ratio 1:1), the formation of a true eutectic composition with a Teut = 198.78 °C occurs. Further, the Tammann’s triangle confirmed that at χMET·HCl = 0.5 is a true eutectic point  (MET·HCl = 0.66 (molar ratio 2:1), a higher value  was observed, with this composition not a genuine eutectic point, due to the appearance of a second peak (liquidus) caused by the presence of unreacted or excess components.A typical V-shaped graphic for MET·HCl-CTZ b indicatsolidus) , only exMET·HCl = 0.5 (molar ratio 1:1), with Teut = 169.9 °C since a single endotherm was observed. Once again, according to Tammann’s triangle the highest value of ΔHfus  (MET·HCl = 0.66 (molar ratio 2:1). However, this is an inaccurate determination because both endotherms (solidus and liquidus) almost form a single peak. Thus, composition χMET·HCl = 0.5  gives place to the true eutectic composition.In the case of MET·HCl-HTZ b, the trsolidus)  was for In addition, PXRD experiments  and RietMET·HCl = 0.5 were analyzed by scanning electron microscopy energy–dispersive X-ray spectroscopy SEM–EDS (MET·HCl = 0.5) was EDS Cl: 11.49 and S: 9.00 and calculated Cl: 15.37 and S: 13.90 (MET·HCl = 0.5) it was EDS Cl: 14.49 and S: 14.97 and calculated Cl: 15.37 and S: 13.90  and MET·HCl-HTZ (χMET·HCl = 0.5) (MET·HCl = 0.5) or MET·HCl-HTZ (χMET·HCl = 0.5) are not a continuous single crystalline solid and the APIs are physically separated [Furthermore, the EDS mapping shows the distribution of O and S atoms in the region of interest for both MET·HCl-CTZ (χl = 0.5) , where ieparated . This pheparated , when sueparated .According to the SEM micrographs, the morphology and texture observed in both solid forms are as solid phases with low crystallinity .MET·HCl = 0.5) and MET·HCl-HTZ (χMET·HCl = 0.5) solidified in a faceted manner (irregular microstructure) [By itself, binary eutectic solids exhibit a microstructure-level periodicity different of the original pure crystalline components ,91. Durionstant) ,93 obserregular) . In our J/mol·K)  (Table 2ructure) ,93.fus(excess) with the experimental ones can be used to differentiate whether a eutectic mixture or a PM has been obtained [component = mole fraction of either component):Furthermore, a comparison of the determined values of ΔHobtained . Thus, tfusion(excess) values were observed for both solids MET·HCl-CTZ (χMET·HCl = 0.5) and MET·HCl-HTZ (χMET·HCl = 0.5): −84.90 J/g and −110.05 J/g, thus indicating that DDESs were formed instead of PMs [Based on the above, negative ΔHd of PMs .int values for both thiazides. Thus, IDR experiments were carried out only for the solid phases MET·HCl-CTZ and MET·HCl-HTZ with compositions of 1:1 (χMET·HCl = 0.5), 1:2 (χMET·HCl = 0.33) and 2:1 (χMET·HCl = 0.66), since these proportions are closer to the true eutectic points determined. int values found and Due to the fact that CTZ and HTZ are the limited-water soluble drugs, in this study we only focused on the Kint value determined (0.076 mg/min·cm2) is close to that reported for crystalline HTZ (0.098 mg/min·cm2) [int value of MET·HCl [MET·HCl = 0.66 showed an increase of 1.21-fold compared with pure HTZ, however the compositions χMET·HCl = 0.33 and 0.5 exhibited a decrease in the dissolution rate (0.76- and 0.77-fold). This decrease in the release behavior of HTZ can be attributed to the great excess of HTZ compared with MET·HCl, limiting any probable enhancement during dissolution [MET·HCl = 0.33 and 0.5 showed an increase in the amount of CTZ dissolved (1.31 and 1.65-fold) compared with pure CTZ. However, in the case of MET·HCl-CTZ χMET·HCl = 0.66, it exhibited an increase of 6.06-fold. This should be taken with caution, since this Kint value presented a high standard deviation  was observed, suggesting an enhancement in the amount dissolved of the thiazides. However, there was also a slight increase in the ΔHfus compared with the original components, which affected the ΔG, leading to a limited modification in the amount dissolved, because ΔG tends to be more positive. In the case of the solid forms with composition χMET·HCl = 0.33, both parameters remain almost unchanged, reflecting a limited modification in the amount dissolved: ΔHfus (limited modification in the intermolecular interactions) and ΔSfus (poor dispersibility). On the other hand, in the case of the DDES HTZ:atelonol (0.3:0.7), a 10-fold improvement of the % release of HTZ (phosphate buffer and pH = 7.4) was observed [fus values for both solid forms MET·HCl-CTZ and MET·HCl-HTZ led us to conclude that a limited modification in the intermolecular interactions occurred after the solidification of the DDESs compared with their parent components.The Kmin·cm2) . In a pr MET·HCl . Specifisolution . In addieviation . This isnd ΔHfus . Usuallylubility ,97. Thuslubility . Globallobserved . Haneef MET·HCl = 0.33, 0.5 and 0.66 improved 1.51-, 1.48- and 1.44-fold respectively, and for MET·HCl-HTZ χMET·HCl = 0.33, 0.5 and 0.66 increases in the solubility were 1.11-, 1.13- and 1.36-fold, respectively. Considering again the DDES HTZ:atelonol (0.3:0.7), an improvement in the solubility of HTZ by 14-fold was reported. The poor modifications in the solubility observed in the solid forms MET·HCl-CTZ χMET·HCl = 0.33, 0.5 and 0.66 and MET·HCl-HTZ χMET·HCl = 0.33, 0.5 and 0.66 is attributed to the limited alteration of ΔG in the solution.According to the saturation solubility studies , all theMET·HCl = 0.5 for both solid forms. In general, it has been reported that DDESs have a lower melting point than their original components, and that these solid forms have high free energy, greater molecular mobility and weaker intermolecular interactions [fus and ΔSfus, compared with the original constituents, despite the fact that a considerable decrease in Tfus values is observed.Thus, this paper describes the mechanochemical preparation of the DDESs MET·HCl-CTZ and MET·HCl-HTZ by NG or LAG. Analyses by means of binary diagrams (DSC screening) allowed the determination of the true eutectic points at the composition of χractions ,91,93,99Hence, this study represents a thorough characterization of two DDESs containing MET·HCl and CTZ or HTZ. This shows that despite an active research history describing organic solid eutectics , when re


IntroductionThe Accreditation Council for Graduate Medical Education (ACGME) requires annual reporting of resident scholarly activities. However, this can be time-consuming for both residents and residency leadership and may not contain the most accurate or up-to-date information. This study sought to determine whether Google Scholar could adequately identify resident publications when compared with their ACGME self-report.MethodsThis was a cross-sectional study comparing resident Google Scholar publications with their ACGME self-reported data from 2018 to 2020. Manuscripts were only included if they were published prior to June 30, 2020, and while the participant was a resident at Rush University Medical Center. We did not count articles published prior to beginning residency. We independently collected data from the residents' self-report and Google Scholar profiles and compared the results. We assessed the overall concordance between data. When a discordant publication was identified, it was reviewed in full and discussed with the resident to ensure that it was correctly attributed to the resident. Data were presented primarily as descriptive statistics including percentages.ResultsOf 24 (96%) residents, 23 created Google Scholar profiles. There were 22 total publications. Google Scholar was concordant with self-report in 18 (78.3%) instances and discordant in five (21.7%) cases. In all five residents (n = 9 publications), the discordant publication was correctly identified by Google Scholar despite not being reported by the resident in their ACGME self-report.ConclusionWe found that resident Google Scholar accounts resulted in the identification of publications that had not been previously reported on their ACGME self-report without missing any relevant publications. The Accreditation Council for Graduate Medical Education (ACGME) stipulates that all residents participate in some form of scholarly activity prior to graduation from their residency program . This prA freely available repository of scholarly work, which can accurately track published works in real time, could be beneficial to address this challenge. Google Scholar is one such search engine that allows anyone to search for scholarly work among numerous sources, including articles, theses, books, and abstracts . An indiThis article was previously presented as a meeting abstract at the 2021 Society for Academic Emergency Medicine Scientific Assembly on May 13, 2021.This cross-sectional study sought to compare Google Scholar with resident ACGME self-report to assess the degree of concordance with regard to publications. The study was conducted at a three-year, urban, academic emergency medicine residency program with 12 residents per postgraduate year (PGY) . Between August and October 2020, we asked all residents to create an account in Google Scholar using their university email. Residents were guided through the process with a brief online tutorial. After all accounts were created, we compared their publications listed in Google Scholar with those self-reported in their ACGME surveys for 2018-2020. Manuscripts were only included if they were published while they were currently a resident at Rush University Medical Center. Manuscripts published prior to residency or that had not yet been published as of June 30, 2020  were excluded. Only postgraduate year (PGY) 2 and 3 residents were eligible for inclusion, as PGY 1 residents had not officially started residency until July 1, 2020. This study was deemed exempt by the Rush University Medical Center institutional review board. The authors do not have any conflicts of interest to declare.We collected the resident name, resident PGY level, and individual PubMed identification numbers from the ACGME research tracking report for all manuscripts that met the inclusion criteria. We then independently obtained this data using their Google Scholar profile. The resulting publication data from both the self-report and Google Scholar accounts were compared. A resident’s Google Scholar profile was deemed "concordant" with their ACGME self-report if all included publications in Google Scholar were the same as those in their ACGME report. A resident’s Google Scholar profile was deemed "discordant" if one or more publications were present in only one resource . When a discordant publication was identified, it was reviewed in full and discussed with the resident to ensure that it was correctly attributed to the resident.Data were presented primarily as descriptive statistics including percentages. Statistical analyses were performed using Microsoft Excel, version 16.45 .A total of 23 out of 24 (96%) residents created Google Scholar profiles, comprising 11 PGY 2 residents and 12 PGY 3 residents. One PGY 2 resident did not create a Google Scholar profile and was excluded from the study. That resident had no prior publications. All residents completed an ACGME self-report. Thirteen residents had a total of 22 publications . Six publications were reported in the 2019-2020 ACGME self-report, and seven publications were reported in the 2020-2021 ACGME self-report. Google Scholar identified an additional nine publications not listed in either ACGME self-report.Google Scholar was concordant with ACGME self-report data in 18 out of 23 (78.3%) instances and discordant in five (21.7%) cases (Table Our findings suggest that Google Scholar can adequately identify resident publications. This can have important time-saving implications for residents and residency leadership alike. Emergency medicine residency programs are required to submit an annual report to the ACGME, while many programs also are responsible for creating institution-specific annual program reports . Having Importantly, using Google Scholar requires a small time commitment at the beginning of the year to set up the account and help troubleshoot any issues. However, we found that using the online tutorial substantially reduced the time involved and most residents were able to easily create their accounts. Additionally, this is only a data aggregation tool, so it is important to train residents on how to best utilize this. While all publications in Google Scholar were correctly linked to the resident, we recommend residents check their profile at least once per year to remove any publications that have been misattributed to them.Our study has several important limitations. First, our study included a select group of emergency medicine residents at a single institution. Additional studies are needed to determine whether these findings are consistent in other institutions and among other specialties. We did not perform additional searches via PubMed or other search engines, so it is possible that additional publications may have been missed by both the ACGME self-report and Google Scholar, although we expect the risk of this is low . This stIn summary, we found that the creation of resident Google Scholar accounts resulted in the identification of publications that had not been previously reported on their ACGME self-report. This may help reduce the burden on resident physicians and program leadership for reporting scholarly efforts. Future research should assess this among faculty and use other online profile tools.


Thyroid cancer (TC) is the most common neck malignancy. However, a large number of publications of TC have not been well summarized and discussed with more comprehensive methods. The purpose of this bibliometric study is to summarize scientific publications during the past three decades in the field of TC using a machine learning method.Scientific publications focusing on TC from 1990 to 2020 were searched in PubMed using the MeSH term “thyroid neoplasms”. Full associated data were downloaded in the format of PubMed, and extracted in the R platform. Latent Dirichlet allocation (LDA) was adopted to identify the research topics from the abstract of each publication using Python.A total of 34,692 publications related to TC from the last three decades were found and included in this study with an average of 1,119.1 publications per year. Clinical studies and experimental studies shared the most proportion of publications, while the proportion of clinical trials remained at a relatively small level (5.87% as the highest in 2004). Thyroidectomy was the lead MeSH term, followed by prognosis, differential diagnosis, and fine-needle biopsy. The LDA analyses showed the study topics were divided into four clusters, including treatment management, basic research, diagnosis research, epidemiology, and cancer risk. However, a relatively weak connection was shown between treatment managements and basic researches. Top 10 most cited publications in recent years particularly highlighted the applications of active surveillance in TC.Thyroidectomy, differential diagnosis, genomic analysis, active surveillance are the most concerning topics in TC researches. Although the BRAF-targeted therapy is under development with promising results, there is still an urgent need for conversions from basic studies to clinical practice. Thyroid cancer (TC) is the most common neck malignancy and is on the rise to become the fourth leading type of cancer worldwide . During Natural language processing (NLP) is a series of machine learning methods for human language analyses. Among these methods, the Latent Dirichlet allocation (LDA) is most usually used to analyze scientific publications by identifying specific themes and dividing documents into these themes –6. In adThe present study is aiming at summarizing scientific publications of TC in the past three decades. Moreover, by detailedly analyzing the research topics using a machine learning method, we are hoping to provide insights into scientific developments, recognize areas with declining interest, and more importantly, reveal potential future research foci in the field of TC.Scientific publications focusing on TC from 1990 to 2020 were searched in PubMed using the MeSH term “thyroid neoplasms” on January 26, 2021, limited by the language of English. Full associated data were downloaded in the format of PubMed, and extracted in the R platform using the package “Bibliometrix”,  .The visualizations were achieved by R platform and Excel, while the network was constructed by Gephi (hi.org/) . All theA total of 34,692 publications related to TC from the last three decades were found and included in this study with an average of 1,119.1 publications per year. As shown in A total of 1,595 MeSH terms with 3,459,152 times of occurrence were included in detailed MeSH term analyses.MeSH terms concerning the age of the study population were initially investigated Figure 3In order to acknowledge the role of TC treatments, we further identified the top 10 MeSH terms associated with TC treatments except for thyroidectomy  scan, and ablation therapy. In the cluster of diagnosis research, differential diagnosis, cytology of fine-needle aspiration (FNA), and ultrasound-guided fine needle aspiration biopsy (US-FNAB) were the top three studied topics. Strong connections were shown between these two clusters, especially between differential diagnosis and tumor recurrence. The cluster of epidemiology and cancer risk covered a relatively small proportion of topics, however having high connectivity with the cluster of treatment management and the cluster of diagnosis research. Moreover, cancer cell proliferation and apoptosis, BRAF mutation, expression analyses of cell lines and tissues accounted for the main part of the basic research cluster. Notably, the topic of follicular adenomas and follicular thyroid carcinoma (FTC) also had a great significance in the basic research cluster, which was strongly connected with the cluster of diagnosis research. However, the rest of the basic research cluster showed a relatively poor connection with other clusters, suggesting that there may be an urgent need for conversions from basic researches to clinical treatments.Additional attention was put on recent top-cited publications. The top 10 most cited original researches from 2016 to 2020 were searched, while review, guidelines, and epidemiological papers were excluded. The results are listed in For the very first time, the present study comprehensively investigated 34,692 scientific publications concerning TC during the past three decades using a machine learning method. The number of publications in TC expanded rapidly, however with a small proportion of clinical trials. The most concerning topics of TC researches were thyroidectomy, differential diagnosis, genomic analysis, active surveillance. Furthermore, the results of LDA analyses also indicated a potential need for conversions of novel therapeutic targets from basic researches to treatment management. The top 10 most cited papers also covered these hot topics.There is no doubt about the predominant role of thyroidectomy in the field of TC treatment. With the increasing incidence of TC, thyroidectomy is subsequently increasing . RecurreDifferential diagnosis and US-FNAB were the main topics in the diagnosis research cluster. In fact, differential diagnosis always plays as the central issue in diagnosing TC, with US-FNAB as an extremely important method. US-FNAB is simple, safe, and reliable, providing the most definitive information for differential diagnosis. In most of the medical centers in the world, cytology results from US-FNAB are reporting using six categories of the 2017 updated Bethesda classification system . HoweverThis study highlighted topics of thyroidectomy, differential diagnosis, genomic analysis, translational researches in the field of TC. Meanwhile, the top 10 most cited papers seemed to concern consistent fields. Moreover, the overtreatment issue and the active surveillance were particularly raised by most cited papers. These studies showed a large proportion of papillary thyroid cancer did not need surgical intervention. However, the problems mainly lie in effective methods to sort out the patients who need immediate surgery, and a unified standard to suggest surgery to patients who suffer from progressed lesions. The overtreatment issue may be simultaneously settled when the problems are solved. Additionally, the results of the present study showed a lack of high-quality RCT, and there was only one non-randomized study in the top 10 most cited papers. Although TC holds a relatively higher incidence than most other cancer types, most TC patients do not need any treatments other than surgery. The rest minority with advanced diseases can be further divided into several subtypes with potentially different therapeutic needs due to various pathogenic mechanisms, such as poorly differentiated TC, anaplastic TC, radioactive iodine refractory TC, etc., causing the difficulties of therapy developments, as well as a relatively small number of trial candidates in each subtype. It may be the reason for lacking high-quality researches.There were also some limitations in this study. Firstly, only PubMed was chosen for this bibliometric research because of the high quality and comprehensive information of publications, while other databases were also available. Secondly, the MeSH term was used for searching publications, which might restrict the comprehensiveness of our search. Lastly, some publications were tagged with multiple publication types. Although the publication type was manually adjusted with double-check, it might still cause inaccuracy.Thyroidectomy, differential diagnosis, genomic analysis, active surveillance are the most concerning topics in TC researches. Although the BRAF-targeted therapy is under development with promising results, there is still an urgent need for conversions from basic studies to clinical practice.The original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author.Result, Discussion, and Conclusion sections. FX and WW drafted the Methods sections. FX, XL, and LY edited the manuscript. All authors read and approved the final manuscript. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.All authors made substantive intellectual contributions to this study to qualify as authors. XL and FX conceived the design of the study. FX modified the design of the study. ZZ, FX, WW, and LY performed the study, collected the data, and contributed to the design of the study. ZZ, LY and BJ analyzed the data. ZZ and LY drafted the This work was supported by the National Natural Science Foundation of China (grant No. 82073262) and the Hunan Province Natural Science Foundation (grant number 2019JJ40475).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Severe or life threatening infections are common among patients in the intensive care unit (ICU). Most infections in the ICU are bacterial or fungal in origin and require antimicrobial therapy for clinical resolution. Antibiotics are the cornerstone of therapy for infected critically ill patients. However, antibiotics are often not optimally administered resulting in less favorable patient outcomes including greater mortality. The timing of antibiotics in patients with life threatening infections including sepsis and septic shock is now recognized as one of the most important determinants of survival for this population. Individuals who have a delay in the administration of antibiotic therapy for serious infections can have a doubling or more in their mortality. Additionally, the timing of an appropriate antibiotic regimen, one that is active against the offending pathogens based on in vitro susceptibility, also influences survival. Thus not only is early empiric antibiotic administration important but the selection of those agents is crucial as well. The duration of antibiotic infusions, especially for β-lactams, can also influence antibiotic efficacy by increasing antimicrobial drug exposure for the offending pathogen. However, due to mounting antibiotic resistance, aggressive antimicrobial de-escalation based on microbiology results is necessary to counterbalance the pressures of early broad-spectrum antibiotic therapy. In this review, we examine time related variables impacting antibiotic optimization as it relates to the treatment of life threatening infections in the ICU. In addition to highlighting the importance of antibiotic timing in the ICU we hope to provide an approach to antimicrobials that also minimizes the unnecessary use of these agents. Such approaches will increasingly be linked to advances in molecular microbiology testing and artificial intelligence/machine learning. Such advances should help identify patients needing empiric antibiotic therapy at an earlier time point as well as the specific antibiotics required in order to avoid unnecessary administration of broad-spectrum antibiotics. Enterococcus (VRE), Klebsiella species resistant to β-lactams, or carbapenem-resistant Acinetobacter species were associated with a higher risk of in-hospital death compared to susceptible microorganisms . I–9. I5–9]Despite multiple analyses emphasizing the need for appropriate antibiotic treatment, documented rates of appropriate therapy in chart audits have not improved. Some suggest that relying on ORs to describe the burden of inappropriate therapy have not sufficiently motivated clinicians to change behavior. Therefore, Vazquez-Guillamet et al. shifted the emphasis from reliance on ORs to making the burden of inappropriate therapy much more tangible for the bedside provider. Specifically, they determined the number needed to treat (NNT) with appropriate therapy to save one life . In overWhy does inappropriate therapy persist in clinical practice? In part, there may be delayed recognition of sepsis. More likely, the issue lies with the clinician. Looking at the factors associated with inappropriate therapy, the strongest variable related to failure to prescribe appropriate therapy relates to the prescriber not considering the presence of antibiotic resistance. With escalating rates of antibiotic resistance, the strongest factor independently associated with inappropriate therapy has been infection due to a resistant pathogen. In other words, the central factor propelling inappropriate therapy is failure to realize a patient’s risk factors for infection with an antibiotic resistant pathogen.When initiating antimicrobial treatment in ICU patients, the choice of agents is most often empirical based on the site of infection, clinical severity and patient comorbidities . AnotherStaphylococcus aureus, VRE and ceftriaxone-resistant Gram-negative bacteria (GNB) when none of these were isolated) occurred in 8405 (67.8%) cases. The adjusted odds ratio for in-hospital death was 1.27 (1.06–1.4) when comparing unnecessarily broad-spectrum and not unnecessarily broad-spectrum initial antibiotic therapy. Unnecessarily broad antibiotic therapy was also associated with increases in acute kidney injury and Clostridium difficile infections.Rhee et al. conducted a multicenter cohort study of 17,430 adults with sepsis and positive clinical cultures [Although it is difficult to ascertain with certainty the presence of an MDRB infection before pathogen identification and susceptibility testing, several factors can help clinicians in guiding broad-spectrum therapy , 19. TheIn patients colonized with extended-spectrum beta-lactamase (ESBL) producing GNB, carbapenem use increased from 69 to 241 per 1000 patient-days in patients who will not develop an ESBL infection and only 7.5% of infection-related ventilator-associated complications could be attributed to ESBL GNB in ESBL colonized patients , 21. AmoPseudomonas aeruginosa [Besides the use of broad-spectrum antibiotics, combination antibiotic regimens  can help provide appropriate initial coverage while avoiding the systematic use of empiric carbapenems, providing that the patient is at low risk of infection with ESBL GNB . The benruginosa , 27.Candida was an independent risk factor for hospital mortality (OR 2.09) [Candida [There is considerable clinical evidence that delayed initiation of appropriate treatment is associated with increased mortality in patients with invasive fungal infections (IFI) , 28–30. OR 2.09) . Similar[Candida .Candida treatment is frequently based on risk scores with very low positive predictive values that inevitably lead to unnecessary, expensive and sometimes toxic antifungal administration [Candida biomarkers  have emerged to assist clinicians in de-escalating unnecessary empirical therapy [The findings that a delay in initiating appropriate treatment is associated with increased mortality , 30, hasstration . Despitestration , 39. Acc therapy , 39. A s therapy , thus peAspergillus PCR and 1,3-β-D-glucan assay) along with computed tomography, should always be performed and treatment should be revised and eventually withheld if the diagnosis of fungal infection is not confirmed [Regarding other IFIs , no consensus exists about the exact timeframe for starting empirical therapy outside of neutropenic patients . Howeveronfirmed .Antimicrobial de-escalation (ADE) refers to early modification of empiric antimicrobial therapy in order to prevent the emergence of antimicrobial resistance by decreasing overall exposure to broad-spectrum agents. It is known that the risk of new resistance emergence increases for each day of additional exposure to antipseudomonal β-lactam antibiotics ranging from 2% for meropenem to 8% for cefepime or piperacillin/tazobactam . ADE is Many clinicians still are reluctant to modify initial broad-spectrum antibiotic regimens even when the practice is supported clinically and by microbiologic testing. To date, most studies have agreed on the fact that ADE is safe , 43. OneThe impact of ADE on resistance prevention has not been consistently demonstrated. In fact, few studies have specifically analyzed the effect of ADE on new antimicrobial resistance. One retrospective study of ADE did not find any prevention for the subsequent isolation of multi-drug resistant (MDR) pathogens in surveillance cultures or in ICU-acquired infections . Montravp = 0.052). Importantly, this study was not designed to draw definite conclusions about resistance emergence. In non-critically ill patients, a retrospective study that evaluated the safety of de-escalation of empiric carbapenems prescribed in an ESBL-endemic setting observed a significantly lower incidence of carbapenem-resistant A. baumannii acquisition in the group that underwent ADE [The DIANA study also did not demonstrate significant differences in the emergence of MDR pathogens following ADE . Howeverwent ADE . The ratADE is clearly feasible to carry out for both bacterial and fungal infections. ADE is safe and has been a recommended strategy in critically ill patients endorsed by an international position paper . Clinici TFREE > 4 × MIC) to 78.9% for a traditionally acceptable target (50% TFREE > MIC). These data suggest that many critically ill patients have inadequate antibiotic exposure as assessed by PK/PD endpoints.In addition to delivering timely appropriate antibiotic regimens, adequate drug concentrations at the infection site are needed to optimize clinical outcomes. The DALI study, a prospective, multicenter study, was primarily conducted to describe the frequency with which PK/pharmacodynamic (PK/PD) end points for β-lactam antibiotics were achieved in critically ill patients . Achieve2 in males and greater than 120 mL/min/1.73 m2 in females [2 [Many factors influence the PK of antibiotics in critically ill patients and may contribute to subtherapeutic exposures. Hypoalbuminemia, large-volume crystalloid administration, large pleural effusions or abdominal ascites that increase the volume of distribution for hydrophilic drugs, catecholamines, and renal replacement therapies can all significantly alter infection site concentrations of administered antibiotics . Another females . ARC has females , 57. How females –60. ARC  females . Altogetmales [2 .The most common strategy studied to adjust for altered PK parameters in critically ill patients and achieve greater time above the MIC has been prolonged or continuous infusions of time-dependent antimicrobials, including β-lactams, carbapenems, and vancomycin. While numerous observational studies have shown better clinical cure rates with prolonged or continuous infusion of β-lactams, two meta-analyses have failed to confirm these findings , 63. In n = 432) randomized, multicenter trial to date comparing continuous β-lactam infusions with intermittent infusions in critically ill patients with severe sepsis found no difference in alive ICU-free days, 90-day survival, or clinical cure 14 days after antibiotic cessation [The variability in outcomes between meta-analyses of prolonged or continuous antibiotic infusions is likely multifactorial but, in large part, a result of the lack of methodologic rigor and transparency as recommended by well-established standards for conducting such studies. Therefore the findings, both positive and negative, should be tempered by the presumed risk of bias . It is aessation .As the foundation of optimal sepsis care is fundamentally linked to the timing of key interventions, early recognition coupled with timely management strategies remain paramount to improving outcomes. Artificial Intelligence (AI) and Machine Learning (ML) are types of advanced mathematical models that combine computer science with statistical methods to yield highly accurate predictive models. These advanced computational tools can analyze enormous quantities of data to identify patterns from large, complex datasets. Sepsis, being a common entity with significant heterogeneity, combined with the large quantity of clinical data available, especially in the ICU, is a particularly attractive target for AI/ML-based analysis.As a result, over the past 10 years, there has been a relative explosion in the use of AI/ML in sepsis, particularly around predicting onset time, which if done correctly, can help identify patients with impending sepsis and reduce time to appropriate antimicrobial therapy. One of the earliest approaches used a simple recursive partitioning and regression tree to identify ward patients who may become septic . In thisWhile rapid molecular diagnostic tests are increasingly being developed to identify pathogens and antibiotic resistance patterns, their cost and availability preclude widespread deployment. Similarly, even though these tests are considered “rapid”, they still require time for sample collection, lab delivery, and specimen analysis, during which time, antibiotic therapy is usually not withheld. AI/ML may be able to help bridge this time gap, by predicting antimicrobial resistance patterns, further facilitating antimicrobial stewardship. In a recent analyses, McGuire and colleagues demonstrated that longitudinal clinical data could be harmonized to predict the risk of carbapenem resistance . In thisBeyond using AI/ML to predict onset time and antimicrobial resistance patterns, advancements in decision modeling are creating avenues for investigators to develop AI/ML algorithms to help determine optimal timing for fluid resuscitation and vasopressor initiation . In thisAs we look towards the future of AI/ML in sepsis care, there are many necessary barriers that need to be overcome before wide scale deployment is achieved. These include the need for larger, more integrated datasets, a harmonized definition of sepsis suitable for automated extraction, more robust explainability, and prospective algorithm validation with emphasis on end-user needs, expectations and clinical workflows –81.Time variables play an important role in the care of patients with life threatening infections. As Fig.


Background: Defects of articular cartilage represent a common condition that usually progresses to osteoarthritis with pain and dysfunction of the joint. Current treatment strategies have yielded limited success in these patients. Stem cells are emerging as a promising option for cartilage regeneration. We aim to summarize the developmental history of stem cells for cartilage regeneration and to analyse the relevant trends and hotspots.Methods: We screened all relevant literature on stem cells for cartilage regeneration from Web of Science during 2010–2020 and analysed the research trends in this field by VOSviewer and CiteSpace. We also summarized previous clinical trials.Results: We screened 1,011 publications. China contributed the largest number of publications  and citations . The United States achieved the highest H-index (39). Shanghai Jiao Tong University had the largest number of publications (34) among all full-time institutions. The Journal of Biomaterials and Stem Cell Research and Therapy published the largest number of studies on stem cells for cartilage regeneration (35). SEKIYA I and YANG F published the majority of articles in this field (14), while TOH WS was cited most frequently (740). Regarding clinical research on stem cells for cartilage regeneration, the keyword “double-blind” emerged in recent years, with an average year of 2018.75. In tissue engineering, the keyword “3D printing” appeared latest, with an average year of 2019.625. In biological studies, the key word “extracellular vesicles” appeared latest, with an average year of 2018.9091. The current research trend indicates that basic research is gradually transforming to tissue engineering. Clinical trials have confirmed the safety and feasibility of stem cells for cartilage regeneration.Conclusion: Multiple scientific methods were employed to reveal productivity, collaborations, and research hotspots related to the use of stem cells for cartilage regeneration. 3D printing, extracellular vesicles, and double-blind clinical trials are research hotspots and are likely to be promising in the near future. Further studies are needed for to improve our understanding of this field, and clinical trials with larger sample sizes and longer follow-up periods are needed for clinical transformation. Its principal function is to provide a smooth, lubricated surface for articulation and to facilitate the transmission of loads with a low frictional coefficient which disperses the stress in the joint to protect it from defects . Howevere harvest. The potHuman embryonic stem cells (hESCs) are considered to be a promising cell source for cartilage regeneration because of their unlimited self-renewal capacity and multidirectional differentiation potential . As the The literature is the carrier of scientific progress. Bibliometric analysis uses mathematical and statistical methods to quantitatively and quantitatively analyse publications in medical databases, revealing the development history, research focus and future trends of a certain field. In addition, bibliometric analysis can implement comparisons between different countries or institutions by analysing the quality and quantity of previous research . As muchClinicalTrials.gov , the keywords were the same, and the limited condition was “completed study”. All data were obtained online, and no ethical certification was required. All searches were conducted on November 27, 2020, to avoid bias related to database updates.Web of Science is an important academic database worldwide that has been widely used in bibliometric analysis. We selected WoS as a data source for a comprehensive search on the utilization of stem cells for cartilage regeneration from 2010 to 2020. The search strategies were as follows: TS = (stem cell* OR SC) and (*cartilage or chondro*) and regenera* AND language: (English). The screening process is shown in Two authors (Demeng Xia and Jianghong Wu) independently screened and extracted all data from the final included articles, including titles, keywords, authors, institutions, journals, dates of publication, countries/regions, citations, H-index, etc. We then conducted analysis with Microsoft Excel 2016, CiteSpace version V and VOSviewer.Relative research interest (RRI) is an indicator of activity in a certain field, and RRI is defined by weighted publications per year (WPPY) in a certain field and all weighted publications per year in PubMed (AWPPY). We used Excel to calculate the RRI and to display the time curve. The impact factor (IF) was acquired in the newest edition of the journal citation report (JCR). The visualization software programs VOSviewer and CiteSpace are widely used in bibliometric analysis. We employed VOSviewer software to perform coupling analysis of nations and institutions, co-citation analysis of journals, and co-occurrence of key words. The average appearing year (AAY) was used to describe the relative novelty of keywords. We employed CiteSpace mainly to perform co-citation analysis of references.Depending on the inclusion criteria, a total of 1,011 articles related to stem cells for cartilage regeneration were included in the final analysis. According to the annual distribution of publications, although there was a slight decline in 2010–2011 (35–26 publications per year), 2014–2015 (65–46 publications per year) and 2018–2019 (166–146 publications per year), the overall trend of the publication output increased from 2010 to 2020 (34–271 publications per year). The trend of the RRI was similar, suggesting that the field of stem cells for cartilage regeneration is receiving more attention in general .According to the national distribution of publications, China (317 publications) is the most productive country, followed by the United States (203 publications), South Korea (107 publications), Japan (82 publications) and Germany (59 publications) . It is mIn terms of total citations, the top four countries are China , the United States , South Korea  and Japan . Singapore is not among in the top 10 productive countries (25 publications) but ranks fifth for total citations . The countries with the highest H-index are as follows: first, the United States (39); second, China (37); third, South Korea (29); fourth, Japan (21); and fifth, Italy (18) .The collaborations between countries are shown in The four institutions with the most publications are all located in China, and sequentially, they are Shanghai Jiao Tong University (34 publications), Peking University (27 publications), Sichuan University (26 publications), and Chinese PLA General Hospital (22 publications). The Chinese Academy of Science (21 publications) and National University of Singapore (21 publications) tied for fifth. The top 20 institutions with the most publications are listed in Biomaterials  and Stem Cell Research and Therapy  published the most studies, with 35 publications each. There were 34 articles on stem cell research for cartilage regeneration in Stem Cells International , 33 articles in Acta Biomaterialia  and 32 articles in Journal of Tissue Engineering Part A . The top 20 journals with the most publications are listed in Different journals include different fields of publication. Therefore, we performed a journal distribution analysis of publications on the use of stem cells for cartilage regeneration. The journals Biomaterials and Acta Biomaterialia have the closest relationship. As far as this field is concerned, journals with a high volume of publications also have high centrality  published in Stem Cells in 2014 is at a key node in the co-citation network  in all included publications. A total of 203 identified keywords were mainly divided into three clusters: ‘clinical study,’ ‘tissue engineering’ and ‘biological study’. In clinical studies, the keywords with the highest frequency were repair (273 times), articular cartilage (238 times), osteoarthritis (264 times), regeneration (222 times) and bone marrow (193 times). In tissue engineering, these words were chondrogenic differentiation (203 times), scaffold* (160 times), mesenchymal stem cells (152 times), tissue engineering (108 times) and bone (97 times). In biological studies, the words were differentiation (282 times), chondrogenesis (208 times), cartilage (196 times), tissue (191 times) and chondrocytes (186 times) . The annClinicalTrials.gov  is one of the most important databases of clinical studies conducted around the world, and it was developed by the National Library of Medicine (NML) and the U.S. Food and Drug Administration (FDA). ClinicalTrials could provide clinical trial information inquiry services of clinical trial information to the general public and could also provide clinical trial registration services to medical researchers and institutions. We used ClinicalTrials.gov to list the currently completed clinical studies on stem cells for cartilage regeneration  and YANG F  are the most productive. However, in terms of the number of citations, the data of Toh WS  are particularly attractive . He has doi:10.1002/stem.1634) not only had the largest number of citations , with 8 times , which h(second highest frequency keywords in tissue engineering clusters) and embedded cells , with 9 times . 3D prined cells . Biomateed cells . After bed cells . Synthetin vivo. In contrast, the application of stem cells in tissue engineering is more promising. According to current research, the mechanism underlying cartilage regeneration in stem cells is mainly attributed to direct differentiation of chondrocytes and paracrine secretion , with 12 times . Extracein vitro expansion, and intra-articular injection (The purpose of clinical trials is to repair damaged articular cartilage. The application of stem cells is expected to replace traditional medical treatment and achieve the goal of radical cures without undergoing such a major operation as joint replacement. According to current clinical trials, except for CARTISTEM, which uses commercial hUCB-MSCs, all othnjection . Subjectnjection . Howevernjection . NCT0187njection . Howevernjection . For exanjection . What’s njection . The lasThis study investigated publications on stem cells for cartilage regeneration extracted from the Web of Science database and discussed hot issues in this comprehensive and objective field. However, limitations are inevitable. First, we only enrolled publications in the language of English, which may cause some important non-English studies in this field to be overlooked. In addition, although keywords can reflect the subject of the article to a certain extent, the preferences of different authors when using keywords and the shortness of keywords will lead to bias in trend analysis.Overall, this study summarized and analysed the global research trends concerning the use of stem cells for cartilage regeneration. The annual output of related publications has grown remarkably, and stem cells have positive development prospects for cartilage regeneration. China and the United States have made the largest contributions in this field. 3D printing, extracellular vesicles, and double-blind clinical trials are research hotspots and which are likely to be promising in the near future. Clinical trials with larger sample sizes and longer follow-up periods are needed for clinical transformation.


Blastocystis, remains largely unknown. Here we assessed the prevalence and diversity of Blastocystis in an elderly adult group that were in receipt of antibiotics (n = 86) and an equivalent non-antibiotic treated group (n = 88) using a PCR-based approach. This analysis revealed that although similar subtypes were present in both groups, Blastocystis was significantly less prevalent in the antibiotic-treated group (16%) compared to non-antibiotic treated controls (55%); Fisher’s Exact test, p < 0.0001). Given that antibiotics target structures and molecules of prokaryotic cells to kill or inhibit bacterial populations, the most likely explanation for differences in prevalence between both groups is due to secondary extinctions owing to the potential dependence of Blastocystis on bacteria present in the gut microbiome that were negatively affected by antibiotic treatment. Although further work is required to explore this hypothesis in greater detail, these data clearly show that Blastocystis prevalence in human populations is negatively associated with antibiotic treatment. This finding may be relevant to explaining patterns of variation for this microorganism in different human populations and cohorts of interest.Antibiotics can drive the rapid loss of non-target, phylogenetically diverse microorganisms that inhabit the human gut. This so-called “collateral damage” has myriad consequences for host health and antibiotic mediated changes to the gut microbiota have been implicated in the aetiology of many chronic diseases. To date, studies have largely focused on how antibiotics affect the bacterial fraction of the gut microbiome and their impact on non-bacterial members, including prevalent eukaryal species, such as  Clostridioides difficile associated disease (CDAD)  . Accordi studies .Blastocystis, remains largely unknown.To date, these studies have largely focused on how antibiotics affect the bacterial fraction of the community, with some exceptions . This foBlastocystis is a prevalent and diverse member of the human gut microbiota as well as many other animal hosts  and an equivalent non-antibiotic treated control group (n = 88).al hosts . In humaal hosts  are commal hosts . Althougmmensals . Howeverfunction . As suchuman gut . Howeverommunity . MoreoveBlastocystis prevalence and diversity from the ABX- group was taken from two previously published studies  . Our sam studies , howeverBlastocystis prevalence and perform allele barcoding were conducted using the primer pair RD5 and BhRDr according to standard protocol  and Blastocystis prevalence using Fisher’s Exact tests for these nominal variables. We tested for a significant difference in time (days) from last antibiotic dose and faecal sample collection between Blastocystis positive and negative individuals within the ABX+ group using an unpaired t-test. We tested for a significant difference in the number of antibiotics treatments received per individual between Blastocystis positive and negative samples within the ABX+ group using a Mann-Whitney test. ABX- and ABX+ group were further sub-divided into ABX- Blastocystis-, ABX-Blastocystis+, ABX+Blastocystis-, and ABX+Blastocystis- to test for significant differences in mean bacterial alpha diversity, for all four measures of this index, between these four groups using ANOVA and Tukey’s HSD post-hoc test. These statistical analyses were carried out using SPSS version 28.0.0.0. Statistical analyses of the 16S rRNA dataset was performed using the DESeq2 methodology  and negative in the ABX+ group , p = 0.250983. Similarly, there was no significant difference in the number of antibiotic treatments taken for Blastocystis positive  and negative individuals  within the ABX+ group, p = 0.785.A recent antibiotic history was also available for a subset of individuals in the antibiotic treated group (n = 54) and is provided in p < 0.001) in mean bacterial alpha diversity between the four subgroups e.g. ABX-/Blasto- (n = 34), ABX-/Blasto+ (n = 42), ABX+ Blasto- (n = 65), ABX+/Blasto+ (n = 12), see p < 0.05) between different subgroups based on alpha diversity measure, see Information on bacterial alpha diversity was calculated using an OTU dataset rarified to 5000 reads per sample from a previously generated 16S rRNA gene dataset  that wasBlastocystis the DESeq2 methodology was applied with adjustment for antibiotic usage. The abundance of two bacterial genera, Anaerosporobacter and Robinsoniella, both members of the Lachnospiraceae family of bacteria, were positively correlated with Blastocystis irrespective of antibiotic status. Conversely, the following bacterial genera; Bacteroides, Bilophila, Escherichia/Shigella, Parasutterella, Subdoligranulum, Clostridium_XlVb and Flavonifractor were significantly decreased in Blastocystis positive individuals, see To assess differences in microbiota composition between microbiota profiles with and without Blastocystis are common in human populations and estimates indicate that over 1 billion people worldwide carry this microorganism  and an equivalent non-antibiotic treated control group (n = 88). Although similar subtypes (STs) were present in both groups, our results clearly show that Blastocystis prevalence is significantly lower in the antibiotic-treated group compared to non-antibiotic controls.Protists, such as organism . Here weorganism , affectse.g. inhibition of cell wall synthesis, inhibition of protein synthesis and inhibition of nucleic acid synthesis. With the exception of three antimicrobials listed, it is clear that all antimicrobials in this study belong to classes that are deployed to target bacterial populations and their modes of action largely target features of bacterial cells that are absent in eukaryotes such as Blastocystis   . Consequ insects . Of note insects  - a scenBlastocystis is correlated with a higher microbial diversity and the presence of specific microbial taxa  and specific bacterial taxa e.g. Akkermansia (e.g. certain diets or other factors could independently promote the growth of particular microbes), difficulties with axenising cultures of Blastocystis  between the date of last antibiotic treatment and sample collection for those who were Blastocystis positive and negative within the ABX+ group. Interestingly we found no significant difference in the mean number of treatments taken between individuals that were Blastocystis positive and negative within the ABX+ group. We also did not find any significant difference in time between the date of last antibiotic treatment and sample collection between positive and negative individuals within the ABX+ group. These data are important, as they are linked to how microbiomes are affected by and recover following antibiotic perturbation. However, there is considerable inter-individual variation in both the effect of antibiotics on bacterial populations in the gut microbiome, as well as their ability to recover, and this variability in response is due to a range of factors including initial microbiota composition . For others, where Blastocystis was potentially affected by antibiotic treatment perhaps insufficient time had elapsed for their microbiome to recover to baseline to facilitate Blastocystis to recolonise. Alternatively, their microbiome may have recovered to an alternative state that did not facilitate recolonisation. The basis of these arguments centre on the idea that inter-kingdom interactions between bacteria and Blastocystis is the primary factor underpinning Blastocystis prevalence rates in the human gut, and as outlined there is strong data to support this assertion. However, the genetic and phenotypic diversity of Blastocystis is likely considerable  and Sulfamethaxazole (folic acid synthesis inhibition), that are used to treat a wide range of bacterial infections, resulted in Blastocystis clearance rates of 94.3% in positive individuals (n = 53)  antibiotics, 1 individual was in receipt of nucleic acid synthesis (NAI) inhibiting antibiotics, and 5 individuals were in receipt of protein synthesis inhibiting (PSI) antibiotics. The remaining individuals in the ABX+ group were in receipt of two or more types of antibiotic groups as follows; CWI and NAI antibiotics, n = 10, CWI and PSI, n= 6, NAI and PSI, n = 1, and finally 4 individuals were in receipt of all three antibiotic groups e.g. CWI, PSI and NAI classes. The breakdown of these groupings together with the number and timing of treatments individuals received are outlined in position . This, tiderable  and ther subunit  and cert subunit . Of note(n = 53) . Similar or both ”.Blastocystis is significantly less prevalent in an antibiotic treated group compared to non-treated controls. Although we do not have a precise explanation for this finding, the most likely reason is that reduced prevalence is due to the secondary extinction of Blastocystis, at least for some individuals. Although further work is required to better understand how Blastocystis interacts with and potentially depends on specific bacteria for colonisation and persistence in the human gut, secondary extinctions can occur in both mutualistic and antagonistic interactions and occur following ecosystem perturbation.Understanding how the human gut microbiota is affected by antibiotics is not only fundamental to our understanding of how microbiomes are structured and respond to perturbation, but also central to our understanding of how antibiotic mediated effects on the microbiota impact host health. Here, we show that The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Cork Clinical Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.PS conceived the study, performed the experiments and data analysis, and wrote the paper. IJ and PC performed data analysis and edited the manuscript. All authors contributed to the article and approved the submitted version.This research was funded by a Marie Curie Intra-European Fellowship to PS (Grant No. 328673).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Open lower limb fractures are common injuries, and the occurrence of infectious complications after open fractures is a usual problem. The rate of surgical site infections (SSIs) and the nature and resistance of the germs responsible for SSIs remain poorly described. Our aim was to describe the bacterial epidemiology of SSIs after surgical management of an open lower limb fracture. We conducted a retrospective monocentric cohort study from 1 January 2012 to 31 December 2020 based on the analysis of inpatient records in a non-university hospital of Ile de France region. All patients who underwent surgery for an open lower limb fracture were included. A total of 149 patients were included. In our population, 19 (12.7%) patients developed an SSI. Of these 19 patients, the sample was polymicrobial in 9 (47.4%) patients. In 9 (45%) cases, the samples identified a group 3 enterobacteria, Enterobacter cloacae being the main one in 7 (36.9%) cases. Staphylococci were identified in 11 patients, with Staphylococcus aureus in 9 (47.4%). All Staphylococcus aureus were susceptible to methicillin, and all enterobacteria were susceptible to C3G. Among all SSI, 10 (58.8%) contained at least one germ resistant to amoxicillin/clavulanic acid (AMC). The SSIs rate was 12.7%. The main pathogens identified were Enterobacter cloacae and Staphylococcus aureus. The presence of early SSI caused by group 3 Enterobacteriaceae renders current antibiotic prophylaxis protocols inadequate with AMC in half the cases. Open fractures of the lower extremity are common injuries after high-energy trauma. They require urgent surgeries of Altemeier contamination class 3 or 4 depending on the time to surgery. Altemeier contamination classes 3 and 4 correspond to contaminated and septic surgeries, respectively . GustiloThe severity of infection, Gustilo classification, smoking, diabetes, time to antibiotic therapy initiation, and shorter duration of antibiotic prophylaxis have been identified as risk factors for the occurrence of postoperative infections ,7.Antibiotic prophylaxis for surgery has proven to be effective in reducing surgical site infections ,8. RecomAccording to the French recommendations of the Société Française d’Anesthésie Réanimation (SFAR) , antibioStaphylococcus aureus), Enterobacter spp. (on average 20–30%), Pseudomonas spp., and enterococci (56% according to Glass) . Ca. CaStaphOur study has many limitations. Its monocentric nature leads to a bias related to local epidemiology, which is different according to regions and countries. Our institution is located near the forest of Fontainebleau, where many sports activities at risk of serious trauma, such as horse riding, quad biking, and mountain biking, favor soil contamination. It is likely that centers located in strictly urban areas do not present the same type of trauma.Our results suggest a failure of the antibiotic prophylaxis strategy with amoxicillin/clavulanate for the prevention of SSI after open limb fractures. These results call for a multicenter prospective cohort study that would allow the confirmation of the results of our study, which would argue in favor of antibiotic prophylaxis with piperacillin-tazobactam in case of land contamination for open fractures.The rate of postoperative infections in all open lower limb fractures was 12.7%. The presence of early SSI due to group 3 Enterobacteriaceae suggests that current antibiotic prophylaxis protocols using amoxicillin/clavulanic acid are not effective in half of the cases, warranting a re-evaluation of the protocols and a discussion on the possible use of piperacillin-tazobactam. Our data calls for prospective multicenter studies.


IntroductionAntimicrobial resistance is a serious problem to solve for the public health authorities at the global level, particularly in developing countries like India. One of the possible reasons for antimicrobial resistance could be the inappropriate or overuse of antibiotics. The Indian government started the National Action Plan on Antimicrobial Resistance to promote rational use of antibiotics in our country. This study was conducted with the objective to monitor antibiotic use in public health facilities of Puducherry which is a union territory of south India.MethodsTotal 900 prescriptions were prospectively collected from the 10 public health facilities  over the period of one year to analyse antibiotic use. ResultsWe found that 36.66 % of prescriptions contained at least one antibiotic. Our result shows that antibiotics were more commonly prescribed from the access category. Upper respiratory tract infections was the most common indication for which antibiotic was prescribed in primary health centres. In the tertiary care teaching hospital, half of the antibiotics were prescribed for cough, followed by pharyngitis (20 %).ConclusionsA high proportion of antibiotics were prescribed for viral infections. Using antibiotics unnecessary can increase the cost of treatment as well as risk of antibiotic resistance. The Department of Medical Services, Puducherry should take initiative to ensure the successful implantation of the National Action Plan on Antimicrobial Resistance. Data of this study can be used to provide educational intervention for all drug stake holders such as physicians, pharmacists and policy makers to promote rational use of antibiotics. Antimicrobial resistance (AMR) is a serious problem to solve for the public health authorities at the global level, particularly in developing countries like India. Worldwide deaths directly attributable to AMR are 700,000 per year, which is further projected to increase to 10 million by the year 2050 if current trends continue. The estimated cumulative loss of economic output from AMR by 2050 would amount to 20-35 trillion US dollars . One of A multi-country survey conducted by the WHO  revealed widespread public misunderstanding about antibiotic usage and resistance. The survey highlights for India are of concern and revealed that three quarters (75%) of respondents thought incorrectly that colds and flu can be treated with antibiotics. and only 58% knew that they should stop the antibiotics only when the course is completed as directed. More than three quarters (76%) of respondents reported taking antibiotics within the past 6 months and 90% said they were prescribed or provided by a doctor or nurse [It has been observed that restricting misuse of antibiotics reduces resistance . In 2017India is coming forward to resolve the problem of AMR by implementing the National Action Plan on antimicrobial resistance (NAP-AMR) and improve the use of antibiotics by doctors, consumers and health institutions . The IndPublic health facilities remain the main source of health care services for the majority of the population. However, there is a paucity of studies regarding antibiotic use in public health facilities. Therefore, we conducted this study to monitor antibiotic use in public health facilities of Puducherry which is a union territory of south India. The data of this study will provide the scenario of antibiotic use in Puducherry public health facilities and could help to provide educational intervention for various stakeholders like prescribers, pharmacists, drug suppliers, and policymakers to promote rational use of antibiotics. A cross-sectional study was conducted to monitor antibiotic use in public health facilities of a union territory of South India. This study was conducted for a period of one year (from March 2019 to February 2020) in Puducherry. Pondicherry is a union territory of India and consists of four small districts: Puducherry, Karaikal, Yanam and Mahe. Puducherry district is the largest among the four and more representative of Pondicherry. Puducherry district has an adequate number of public health facilities functioning under both central  and state government . A sample of 10 public health facilities was selected based on their geographical location. The sample included nine PHCs  and one tertiary care teaching hospital. These nine PHCs were selected randomly based on their geographical location  and number of PHCs present in each direction . Thus, we selected a total of nine PHCs . Out of the nine PHCs, seven PHCs are functioning under state government and two PHCs are functioning under the central government. In the tertiary care hospital, the OPD (Outpatient Department) unit of the medicine department was included, as it is more representative of a PHC set up in India.For antibiotics prescribing, we collected a total of 900 prescriptions. We included all patients visiting the outpatient departments of the selected health facilities. Pregnant women and patients with psychiatric illness were excluded from this study. To avoid seasonal bias, data were collected in three quarters . In each quarter, 30 prescriptions were prospectively collected from each health facility to reach a total of 900 prescriptions in a year. Around 50-100 patients visit PHC on a single day. Therefore, 10 consecutive prescriptions were collected in the middle of the clinic day to reach the sample size of 10 per day for three days in a week to get 30 prescriptions per season from each health facility.Data collection was done by qualified personnel having a Pharm.D (Doctor of Pharmacy) degree. Proper training was given for data collection prior to the field visit. A pilot study was also conducted to check the feasibility of data collection. Data were collected by taking photographs of prescriptions after taking informed consent from each participant. Data such as patient's demographic details , diagnosis and medicines prescribed were entered in the data collection form. Data were entered in Microsoft Office Excel. Data were analysed separately for state govt. PHCs, central govt. PHCs and tertiary care teaching hospital. In the statistical analysis, frequencies, averages/means, and percentages were calculated. Statistical analysis was done by using Microsoft Office Excel 2010.A total of 900 prescriptions i.e. 630 from state govt. PHCs , 180 from central govt. PHCs and 90 from a tertiary care teaching hospital, were studied for antibiotic use. We found that 36.66 % of prescriptions  contained at least one antibiotic. Some prescriptions had more than one antibiotic. Thus, the total number of antibiotics prescribed were 299 in state govt. PHCs, 24 in central govt. PHCs and 10 in tertiary care teaching hospital. Various dose forms of antibiotics prescribed and percentage of different types of antibiotics prescribed in surveyed health facilities is given in Figure In our study, we found that antibiotics were prescribed more for males . In all three types of health facilities, antibiotics prescribing was highest for the age group 25-64 years. In all three types of health facilities, antibiotic use was reported more in the 2nd quarter . The baseline characteristics of patients who were prescribed antibiotics are given in Table Our result shows that in all three types of health facilities, antibiotics were more commonly prescribed from the access category followed by the watch category, while none of the antibiotics were prescribed from the reserve category Table .We found that URTIs (upper respiratory tract infections) was the most common indication for which antibiotic was prescribed in all surveyed health facilities. In state govt. PHCs, highest percentage of antibiotics 50.83%) were prescribed for URTIs such as common cold, pharyngitis and tonsillitis, followed by wound & injury (11.70%), and fever (9%). In central govt. PHCs, URTIs (25%), injury & wound (20.83%) and foot ulcer (12.3%) were top three indications for which antibiotics were prescribed. In the tertiary care teaching hospital, 70% antibiotics were prescribed for URTIs such as common cold, cough, pharyngitis followed by ear ache (10%), abdominal pain (10%) and fistula in ano (10%). Complete details of the top five indications for which antibiotics were prescribed in three types of health facilities are given in Figure % were prIn our study, antibiotic use was more in the 2nd quarter (July to October). Pondicherry has a tropical climate with no certain weather cycle. In Puducherry time, the period from July to September is mostly monsoon season. Light rain with cyclone formation continues till December. The monsoon season increases the risk of transmission of microbial diseases. A high incidence of bacterial and viral diseases, especially in rural areas in monsoon season, could be the reason for high antibiotic prescribing in the 2nd quarter (July to October) followed by the 3rd quarter (November to February). In our study, we found that antibiotic prescribing was more for male patients which could be because of several reasons such as males are more prone to be exposed to a polluted, contaminated environment, and communicate more with other people in day to day life which leads to increased risk of infections. In our study, we found that many male patients were prescribed antibiotics for cut injury and other accidental injuries which occurred at their job locations.To overcome the global problem of AMR, the WHO categorized antibiotics into three categories i.e. access, watch, and reserve, with the aim to increase treatment effectiveness, minimise drug resistance development, and preserve the effectiveness of "last resort" antibiotics . In our Antibiotics are available in different dosage forms and should be given according to the requirement of the patient. However, solid oral dosage forms such as capsules and tablets should be given preference, especially in adult patients because of advantages such as easy to swallow, high precision, lowest variability, more stability, accurate dosing, and easy transportation. In our study, most of the antibiotics  were prescribed as oral solid dosage form which is in agreement with the finding (94.8%) of a study conducted in Addis Ababa, Ethiopia . Our finIn our study, we found that amoxicillin was the most commonly prescribed antibiotic, followed by ciprofloxacin and cotrimoxazole. Our findings are in agreement with studies conducted in China  and NigeOur results indicate that a high percentage of antibiotics were prescribed for viral infections and fever. In the current study, we found that the most common indication for which antibiotic prescribed was URTIs , which is in agreement with the study conducted in Adis Ababa, Ethiopia where the most common diagnosis for antibiotic use was URTIs 24.5%) . The cur.5% . TheOur study has certain limitations. We conducted this study only in public health facilities. Thus, our results may not reflect the quantum of antibiotics use/misuse in private health facilities. The appropriateness of antibiotic use could not be confirmed by microbiological testing in patients who were prescribed antibiotics due to the lack of facilities at the PHC level. We report a high rate of antibiotic prescribing, especially at primary health centres. A high proportion of antibiotics were prescribed for conditions like URTIs such as common cold, pharyngitis, and tonsillitis which are viral in origin. Prescribing antibiotics for viral infections may increase the rate of AMR development as well as the cost of treatment for both patients and the government. Our study indicates that India’s NAP-AMR is not being implemented and followed in Puducherry. The Department of Medical Services, Puducherry should take initiatives to ensure the successful implantation of NAP-AMR in Puducherry. There is also a need to establish a separate committee to monitor and control the irrational use of antibiotics in Puducherry. Providing educational intervention for all drug stakeholders such as physicians, pharmacists, and policymakers could help to improve the rational use of antibiotics.