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VRC01-class broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV-1, but they have not yet been elicited by vaccination. They are extensively somatically mutated and sometimes accumulate CDRL1 deletions. Such indels may allow VRC01-class antibodies to accommodate the glycans expressed on a conserved N276 N-linked glycosylation site in loop D of the gp120 subunit. These glycans constitute a major obstacle in the development of VRC01-class antibodies, as unmutated antibody forms are unable to accommodate them. Although immunizations of knock-in mice expressing human VRC01-class B-cell receptors (BCRs) with specifically designed Env-derived immunogens lead to the accumulation of somatic mutations in VRC01-class BCRs, CDRL1 deletions are rarely observed, and the elicited antibodies display narrow neutralizing activities. The lack of broad neutralizing potential could be due to the absence of deletions, the lack of appropriate somatic mutations, or both. To address this point, we modified our previously determined prime-boost immunization with a germline-targeting immunogen nanoparticle (426c.Mod.Core), followed by a heterologous core nanoparticle (HxB2.WT.Core), by adding a final boost with a cocktail of various stabilized soluble Env trimers. We isolated VRC01-like antibodies with extensive somatic mutations and, in one case, a seven-amino acid CDRL1 deletion. We generated chimeric antibodies that combine the vaccine-elicited somatic mutations with CDRL1 deletions present in human mature VRC01 bnAbs. We observed that CDRL1 indels did not improve the neutralizing antibody activities. Our study indicates that CDRL1 length by itself is not sufficient for the broadly neutralizing phenotype of this class of antibodies., Importance: HIV-1 broadly neutralizing antibodies will be a key component of an effective HIV-1 vaccine, as they prevent viral acquisition. Over the past decade, numerous broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV. Despite an in-depth knowledge of their structures, epitopes, ontogenies, and, in a few rare cases, their maturation pathways during infection, bnAbs have, so far, not been elicited by vaccination. This necessitates the identification of key obstacles that prevent their elicitation by immunization and overcoming them. Here we examined whether CDRL1 shortening is a prerequisite for the broadly neutralizing potential of VRC01-class bnAbs, which bind within the CD4 receptor binding site of Env. Our findings indicate that CDRL1 shortening by itself is important but not sufficient for the acquisition of neutralization breadth, and suggest that particular combinations of amino acid mutations, not elicited so far by vaccination, are most likely required for the development of such a feature., Competing Interests: The authors declare no conflict of interest.

Background: New drugs to target different pathways in pulmonary hypertension has resulted in increased combination therapy, but details of this use in infants are not well described. In this large multicenter database study, we describe the pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants., Methods: We identified inborn infants discharged home from a Pediatrix neonatal ICU from 1997 to 2020 exposed to inhaled nitric oxide, sildenafil, epoprostenol, or bosentan for greater than two consecutive days. We compared clinical variables and drug utilisation between infants receiving simultaneous combination and monotherapy. We reported each combination's frequency, timing, and duration and graphically represented drug use over time., Results: Of the 7681 infants that met inclusion criteria, 664 (9%) received combination therapy. These infants had a lower median gestational age and birth weight, were more likely to have cardiac and pulmonary anomalies, receive cardiorespiratory support, and had higher in-hospital mortality than those receiving monotherapy. Inhaled nitric oxide and sildenafil were most frequently used, and utilisation of combination and monotherapy for all drugs increased over time. Inhaled nitric oxide and epoprostenol were used in infants with a higher gestational age, earlier postnatal age, and shorter duration than sildenafil and bosentan. Dual therapy with inhaled nitric oxide and sildenafil was the most common combination therapy., Conclusion: Our study revealed an increased use of combination pulmonary vasodilator therapy, favouring inhaled nitric oxide and sildenafil, yet with considerable practice variation. Further research is needed to determine the optimal combination, sequence, dosing, and disease-specific indications for combination therapy.

Epstein-Barr virus (EBV) is associated with infectious mononucleosis, cancer, and multiple sclerosis. A vaccine that prevents infection and/or EBV-associated morbidity is an unmet need. The viral gH/gL glycoprotein complex is essential for infectivity, making it an attractive vaccine target. Here, we evaluate the immunogenicity of a gH/gL nanoparticle vaccine adjuvanted with the Sigma Adjuvant System (SAS) or a saponin/monophosphoryl lipid A nanoparticle (SMNP) in rhesus macaques. Formulation with SMNP elicits higher titers of neutralizing antibodies and more vaccine-specific CD4 + T cells. All but one animal in the SMNP group were infected after oral challenge with the EBV ortholog rhesus lymphocryptovirus (rhLCV). Their immune plasma had a 10- to 100-fold lower reactivity against rhLCV gH/gL compared to EBV gH/gL. Anti-EBV neutralizing monoclonal antibodies showed reduced binding to rhLCV gH/gL, demonstrating that EBV gH/gL neutralizing epitopes are poorly conserved on rhLCV gH/gL. Prevention of rhLCV infection despite antigenic disparity supports clinical development of gH/gL nanoparticle vaccines against EBV., Competing Interests: Declaration of interests A.T.M. holds a patent (US11116835B2) on the AMMO1 monoclonal antibody. D.J.I. is an inventor on a patent related to SMNP adjuvant (US11,547,672)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Antimicrobial growth promoters (AGPs) are commonly used in broiler production. There is a huge societal concern around their use and their contribution to the proliferation of antimicrobial resistance (AMR) in food-producing animals and dissemination to humans or the environment. However, there is a paucity of comprehensive experimental data on their impact on poultry production and the AMR resistome. Here, we investigated the effect of five antimicrobial growth promoters (virginiamycin, chlortetracycline, bacitracin methyl disalicylate, lincomycin, and tylosin) used in the commercial broiler production in the Indian subcontinent and in the different parts of the world for three consecutive production cycles on performance variables and also the impact on gut bacteria, bacteriophage, and resistome profile using culture-independent approaches. There was no significant effect of AGPs on the cumulative growth or feed efficiency parameters at the end of the production cycles and cumulative mortality rates were also similar across groups. Many antibiotic resistance genes (ARGs) were ubiquitous in the chicken gut irrespective of AGP supplementation. In total, 62 ARGs from 15 antimicrobial classes were detected. Supplementation of AGPs influenced the selection of several classes of ARGs; however, this was not correlated necessarily with genes relevant to the AGP drug class; some AGPs favored the selection of ARGs related to antimicrobials not structurally related to the AGP. AGPs did not impact the gut bacterial community structure, including alpha or beta diversity significantly, with only 16-20 operational taxonomic units (OTUs) of bacteria being altered significantly. However, several AGPs significantly reduced the population density of some of the potential pathogenic genera of bacteria, such as Escherichia coli . Chlortetracycline increased the abundance of Escherichia phage, whereas other AGPs did not influence the abundance of bacteriophage significantly. Considering the evidence that AGPs used in poultry production can select for resistance to more than one class of antimicrobial resistance, and the fact that their effect on performance is not significant, their use needs to be reduced and there is a need to monitor the spread of ARGs in broiler chicken farms., Competing Interests: 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., (Copyright © 2022 Paul, Rama Rao, Hegde, Williams, Chatterjee, Raju, Reddy, Kumar, Phani Kumar, Mallick and Gargi.)

Staphylococcus aureus is a major etiological agent of clinical and subclinical bovine mastitis. Owing to the mostly backyard dairy practices, we hypothesized that genetic diversity among mastitis-associated S. aureus from India would be high, and investigated 166 isolates obtained mostly from the Southern State of Karnataka, but also from a few other states. The results revealed (a) 8 to 13 fragments in pulsed-field gel electrophoresis (PFGE), forming 31 distinct patterns, and (b) 34 spa types, of which three (t17680, t18314, and t18320) were newly identified. Multi-locus sequencing typing (MLST) identified 39 sequence types (STs), with ST2454 (34.4%) and ST2459 (24%) being the most commonly represented, which clustered to clonal complexes (CC) CC9 and CC97, respectively; 12 STs were newly identified. Thirty-four (20.5%) of the 166 isolates displayed oxacillin resistance. On the other hand, whereas none were mecC + , 44 (26.5%) isolates were mecA + , with a predominance of SCCmecIVb (26/32 isolates, others being untypeable); 24 isolates (14.46%) were oxacillin-susceptible methicillin-resistant S. aureus (OS-MRSA; mecA + but OS). Integrated analysis revealed that CC9-ST2454- and CC97-ST2459-SCCmecIVb were the predominant MRSA, although the distribution of CC9 and CC97 was similar between methicillin-resistant and -susceptible isolates. By PCR, 56.25%, 28.75% and 47.5% of the 166 isolates were positive for hlg, tsst and pvl genes, respectively. Our results, for the first time describe the application of a combination of various molecular methods to bovine mastitis-associated S. aureus isolates from India, corroborate the worldwide distribution of CC97 and CC9, and suggest pathogenic potential of the isolates., (© 2021. The Author(s).)

Dental caries is the single most common chronic childhood disease. In early childhood caries, there is early carious involvement and gross destruction of the maxillary anterior teeth. This leads to difficulty in speech, decreased masticatory efficiency, development of abnormal tongue habits and subsequent malocclusion and psychological problems if esthetics are compromised. The restoration of severely decayed primary incisors is often a difficult procedure that presents a special challenge to pediatric dentists. This case report documents the restoration of severely mutilated lateral incisors in a patient with early childhood caries.