BACKGROUND: Maternal undernutrition is a direct risk factor for infant growth faltering.
OBJECTIVE: We evaluated the effect of postnatal Balanced Energy Protein (BEP) supplementation in lactating women and Azithromycin (AZ) in infants on infant growth outcomes.
METHODS: A randomized controlled superiority trial of lactating mother-newborn dyads was conducted in Karachi, Pakistan. Mothers intending to breastfeed their newborns with mid-upper arm circumference of less than 23 cm and live infants between 0-6 days of life were randomly assigned to one of three arms in a 1:1:1 ratio. Lactating mothers in the control arm received standard-of-care counseling on exclusive breastfeeding, nutrition, infant immunization and health promotion plus iron-folate supplementation until the infant was 6 months of age. In intervention arm 1, mothers additionally received two 75-gram sachets of BEP per day, while in intervention arm 2 along with the standard-of-care and BEP, the infant also received one dose of Azithromycin (at 20 mg per kilogram) at 42 days of life. The primary outcome was infant length velocity at 6 months. The total sample size was 957 (319 in each arm).
RESULTS: From August 1, 2018 to May 19, 2020, 319 lactating mother-newborn dyads were randomized in each arm, and the last follow-up was completed on November 20, 2020. The mean difference in length velocity (cm per month) between BEP alone and control was 0.01 (95% CI: -0.03, 0.06), BEP plus AZ and control was 0.08 (95% CI:0.03,0.13) and between BEP+AZ and BEP alone was 0.06 (95% CI: 0.01, 0.11). There were 1.46% (14/957) infant deaths in the trial, and 17.9% (171/957) non-fatal events (injectable treatment and/or hospitalizations) were recorded.
CONCLUSIONS: Postnatal maternal BEP supplementation and infant AZ administration could modestly improve infant growth outcomes at 6 months, suggesting potential benefits in simultaneously addressing maternal and infant undernutrition.
UNASSIGNED: This trial is registered on ClinicalTrials.gov NCT03564652 on June 21, 2018.

Telogen effluvium is characterized by excessive hair shedding usually following a stressful event. Ferritin has been used in clinical practice as a biomarker of nonanemic iron deficiency in cases of telogen effluvium. During the years of the COVID19 pandemic, telogen effluvium was reported as a part of post covid manifestations. As ferritin was also a biomarker for inflammation in cases with covid infection, this study was designed to evaluate the value of ferritin in cases with postcovid telogen effluvium one hundred patients recovering from covid 19 for 4-12 weeks were included in the study, detailed drug and laboratory history was obtained and serum ferritin level was measured. the mean serum level of ferritin among telogen effluvium patients was significantly lower than controls (68.52 ± 126 and 137 ± 137.597 ug/L respectively). Patients with telogen effluvium used significantly more azithromycin and ivermectin and significantly less vitamin C, D, lactoferrin and zinc than the controls Although serum ferritin is lower among telogen effluvium patients, it was still higher than the cutoff value for diagnosing nonanemic iron deficiency, we suggest that it will not be a good biomarkers in these cases. Our secondary outcomes showed that dietary supplements used during active infection such as vitamin C, D, lactoferrin and zinc might have a preventive value on postcovid hair loss, while azithromycin and ivermectin could have a negative long term effect on telogen effluvium.

OBJECTIVE: To characterize the prescribing trends and clinical outcomes related to azithromycin (AZI) among children hospitalized for critical asthma (CA).
METHODS: We performed a multicenter, retrospective cohort study using the Pediatric Health Information Systems registry of children 3 to 17 years of age hospitalized in a PICU for CA from January 2011 to December 2022. We excluded for alternative indications for AZI (eg, atypical pneumonia, B. pertussis infection, acute otitis media, acute sinusitis, pharyngitis/tonsillitis, and urethritis). The primary outcome was AZI prescribing rate by hospital and calendar year (trends assessed by Joinpoint regression). Cohorts with and without AZI exposure were further characterized by demographics, CA treatments, and inpatient outcomes using descriptive and comparative (ie, χ2 and Wilcoxon rank tests) statistics.
RESULTS: Of the 47 797 children studied, 9901 (20.7%) were prescribed AZI with a downward annual trend noted from 34.7% in 2011% to 12.4% in 2022 (-1.7% per year, R2 = 0.91). Median institutional AZI prescribing rate was 19.2% (interquartile range [IQR] 11.7%-28%; total range 5.6%-60%). Compared with children not prescribed AZI, those prescribed AZI were older (median 8.3 [IQR 5.7-11.6] vs 7.3 [4.9-10.8] years, P < .001) and experienced a more severe clinical trajectory with greater rates of bilevel positive airway pressure ventilation (19.7% vs 12.6%, P < .001), invasive ventilation (22.1% vs 13.5%, P < .001), extracorporeal life support (0.8% vs 0.1%, P < .001), and median length of stay (4 [IQR 3-6] vs 3 [IQR 2-4] days, P < .001).
CONCLUSIONS: Between 2011 and 2022, 20.7% of children hospitalized for CA were prescribed AZI notwithstanding the absence of trial-derived efficacy or safety data for this indication and population.

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implementing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to conduct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields-cardiovascular, cancer, and diabetes-and to further underscore the potential risks associated with the emergence of antimicrobial resistance (AMR) when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By comprehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

BACKGROUND: In November 2019, the world faced a pandemic called SARS-CoV-2, which became a major threat to humans and continues to be. To overcome this, many plants were explored to find a cure.
METHODS: Therefore, this research was planned to screen out the active constituents from Artemisia annua that can work against the viral main protease Mpro as this non-structural protein is responsible for the cleavage of replicating enzymes of the virus. Twenty-five biocompounds belonging to different classes namely alpha-pinene, beta-pinene, carvone, myrtenol, quinic acid, caffeic acid, quercetin, rutin, apigenin, chrysoplenetin, arteannunin b, artemisinin, scopoletin, scoparone, artemisinic acid, deoxyartemisnin, artemetin, casticin, sitogluside, beta-sitosterol, dihydroartemisinin, scopolin, artemether, artemotil, artesunate were selected. Virtual screening of these ligands was carried out against drug target Mpro by CB dock.
RESULTS: Quercetin, rutin, casticin, chrysoplenetin, apigenin, artemetin, artesunate, sopolin and sito-gluside were found as hit compounds. Further, ADMET screening was conducted which represented Chrysoplenetin as a lead compound. Azithromycin was used as a standard drug. The interactions were studied by PyMol and visualized in LigPlot. Furthermore, the RMSD graph shows fluctuations at various points at the start of simulation in Top1 (Azithromycin) complex system due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points resulting in increased RMSD with a time frame of 50 ns. But this change remains stable after the extension of simulation time intervals till 100 ns. On other side, the Top2 complex system remains highly stable throughout the time scale. No such structural dynamics were observed bu the ligand attached to the active site residues binds strongly.
CONCLUSIONS: This study facilitates researchers to develop and discover more effective and specific therapeutic agents against SARS-CoV-2 and other viral infections. Finally, chrysoplenetin was identified as a more potent drug candidate to act against the viral main protease, which in the future can be helpful.

OBJECTIVE: The prevalence of respiratory infectious diseases has changed in the post-COVID-19 epidemic era, and mycoplasma pneumoniae (MP) infection in children has attracted wide attention.
METHODS: Children hospitalized for pneumonia in Wuhan, China, in 2023 were enrolled. Respiratory secretions were obtained for the targeted next-generation sequencing (tNGS) including mutation of MP. Pulmonary inflammation was divided into bronchopneumonia and pulmonary consolidation/atelectasis according to lung computed tomography imaging.
RESULTS: Of the 667 pediatric pneumonia, 478 were MP positive (72%). The positive rate of MP detected by tNGS increased from April, and MP had become the primary pathogen of pneumonia in children in 2023. The 23S rRNA mutations were all A2063G, accounting for 85% of detected MP. The clinical symptoms of the mutant and wild-type strains were similar, with half of them experiencing atelectasis and lung consolidation. Early bronchoscopic lavage combined with azithromycin in pediatric pulmonary consolidation was an effective therapy strategy, which could be an alternative selection to MP pneumonia treatment.
CONCLUSIONS: A2063G mutant strain MP was the primary pathogen of mycoplasma pneumoniae in children recently, which was often complicated by extra-pulmonary symptoms and complications.

BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting.
RESULTS: The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability.
CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored.
BACKGROUND: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Asymptomatic long-term carriers of Shigatoxin producing Escherichia coli (STEC) are regarded as potential source of STEC-transmission. The prevention of outbreaks via onward spread of STEC is a public health priority. Accordingly, health authorities are imposing far-reaching restrictions on asymptomatic STEC carriers in many countries. Various STEC strains may cause severe hemorrhagic colitis complicated by life-threatening hemolytic uremic syndrome (HUS), while many endemic strains have never been associated with HUS. Even though antibiotics are generally discouraged in acute diarrheal STEC infection, decolonization with short-course azithromycin appears effective and safe in long-term shedders of various pathogenic strains. However, most endemic STEC-strains have a low pathogenicity and would most likely neither warrant antibiotic decolonization therapy nor justify social exclusion policies. A risk-adapted individualized strategy might strongly attenuate the socio-economic burden and has recently been proposed by national health authorities in some European countries. This, however, mandates clarification of strain-specific pathogenicity, of the risk of human-to-human infection as well as scientific evidence of social restrictions. Moreover, placebo-controlled prospective interventions on efficacy and safety of, e.g., azithromycin for decolonization in asymptomatic long-term STEC-carriers are reasonable. In the present community case study, we report new observations in long-term shedding of various STEC strains and review the current evidence in favor of risk-adjusted concepts.

OBJECTIVE: To evaluate the effectiveness of a flapless surgical approach in the treatment of peri-implantitis and to explore the factors influencing its outcome.
METHODS: The present retrospective study evaluated patients with at least one implant diagnosed with peri-implantitis and treated with a flapless surgical access, with or without systemic antimicrobials, curettage and, when needed, prostheses modification. Clinical and radiographic parameters were assessed at baseline and at 3 months and at least 12 months. The primary outcome was disease resolution (≤1 bleeding sites, probing depth [PD] ≤5 mm, no bone loss >0.5 mm). Multilevel regression analyses were used to identify predictors influencing the probability of attaining disease resolution.
RESULTS: One hundred and seventeen patients with 338 implants were included. Disease resolution was attained in 54.4% of the 338 implants receiving flapless surgical access. At the end of the follow-up period, 111 patients (94.9%) with 295 implants (87.3%) did not require any further treatment, with 81.4% of these implants presenting PD ≤ 5 mm. History of periodontitis and PD at baseline were identified as negative predictors, while compliance with supportive peri-implant care, a machined surface and the adjunctive use of systemic azithromycin or metronidazole were identified as positive predictive factors for disease resolution.
CONCLUSIONS: A flapless surgical approach led to disease resolution in 54.4% of the implants with peri-implantitis. Several risk/protective predictors for disease resolution were identified.

BACKGROUND: Regular quality-assured whole-genome sequencing linked to antimicrobial resistance (AMR) and patient metadata is imperative to elucidate the shifting gonorrhoea epidemiology, both nationally and internationally. We aimed to examine the gonococcal population in the European Economic Area (EEA) in 2020, elucidate emerging and disappearing gonococcal lineages associated with AMR and patient metadata, compare with 2013 and 2018 whole-genome sequencing data, and explain changes in gonococcal AMR and gonorrhoea epidemiology.
METHODS: In this retrospective genomic surveillance study, we analysed consecutive gonococcal isolates that were collected in EEA countries through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) in 2020, and made comparisons with Euro-GASP data from 2013 and 2018. All isolates had linked AMR data (based on minimum inhibitory concentration determination) and patient metadata. We performed whole-genome sequencing and molecular typing and AMR determinants were derived from quality-checked whole-genome sequencing data. Links between genomic lineages, AMR, and patient metadata were examined.
RESULTS: 1932 gonococcal isolates collected in 2020 in 21 EEA countries were included. The majority (81·2%, 147 of 181 isolates) of azithromycin resistance (present in 9·4%, 181 of 1932) was explained by the continued expansion of the Neisseria gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) clonal complexes (CCs) 63, 168, and 213 (with mtrD/mtrR promoter mosaic 2) and the novel NG-STAR CC1031 (semi-mosaic mtrD variant 13), associated with men who have sex with men and anorectal or oropharyngeal infections. The declining cefixime resistance (0·5%, nine of 1932) and negligible ceftriaxone resistance (0·1%, one of 1932) was largely because of the progressive disappearance of NG-STAR CC90 (with mosaic penA allele), which was predominant in 2013. No known resistance determinants for novel antimicrobials (zoliflodacin, gepotidacin, and lefamulin) were found.
CONCLUSIONS: Azithromycin-resistant clones, mainly with mtrD mosaic or semi-mosaic variants, appear to be stabilising at a relatively high level in the EEA. This mostly low-level azithromycin resistance might threaten the recommended ceftriaxone-azithromycin therapy, but the negligible ceftriaxone resistance is encouraging. The decreased genomic population diversity and increased clonality could be explained in part by the COVID-19 pandemic resulting in lower importation of novel strains into Europe.
BACKGROUND: European Centre for Disease Prevention and Control and Örebro University Hospital.