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Respiratory syncytial virus (RSV) is a major cause of respiratory illness and hospitalization in older adults during fall and winter in the United States. The 2023-2024 RSV season was the first during which RSV vaccination was recommended for U.S. adults aged ≥60 years, using shared clinical decision-making. On June 26, 2024, the Advisory Committee on Immunization Practices voted to update this recommendation as follows: a single dose of any Food and Drug Administration-approved RSV vaccine (Arexvy [GSK]; Abrysvo [Pfizer]; or mResvia [Moderna]) is now recommended for all adults aged ≥75 years and for adults aged 60-74 years who are at increased risk for severe RSV disease. Adults who have previously received RSV vaccine should not receive another dose. This report summarizes the evidence considered for these updated recommendations, including postlicensure data on vaccine effectiveness and safety, and provides clinical guidance for the use of RSV vaccines in adults aged ≥60 years. These updated recommendations are intended to maximize RSV vaccination coverage among persons most likely to benefit, by clarifying who is at highest risk and by reducing implementation barriers associated with the previous shared clinical decision-making recommendation. Continued postlicensure monitoring will guide future recommendations.

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BACKGROUND: Despite the burden of pyelonephritis after kidney transplantation, there is no consensus on initial empirical antibiotic management. METHODS: We surveyed clinicians throughout the world on their practice and opinions about the initial empirical therapy of post-transplant pyelonephritis, using clinical vignettes. A panel of experts from 19 countries on six continents designed this survey, and invited 2145 clinicians to participate. RESULTS: A total of 721 clinicians completed the survey (response rate: 34%). In the hypothetical case of a kidney transplant recipient admitted with pyelonephritis but not requiring intensive care, most respondents reported initiating either a 3rd-generation cephalosporin (37%) or piperacillin-tazobactam (21%) monotherapy. Several patient-level factors dictated the selection of broader-spectrum antibiotics, including having a recent urine culture showing growth of a resistant organism (85% for extended-spectrum ß-lactamase-producing organisms, 90% for carbapenemase-producing organisms, and 94% for Pseudomonas aeruginosa). Respondents attributed high importance to the appropriateness of empirical therapy, which 87% judged important to prevent mortality. Significant practice and opinion variations were observed between and within countries. CONCLUSION: High-quality studies are needed to guide the empirical management of post-transplant pyelonephritis. In particular, whether prior urine culture results should systematically be reviewed and considered remains to be determined. Studies are also needed to clarify the relationship between the appropriateness of initial empirical therapy and outcomes of post-transplant pyelonephritis.

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Histone proteins affect gene expression through multiple mechanisms, including through exchange with histone variants. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. Most notably, widely expressed variants of H2B remain elusive. We applied recently developed antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters, and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Further, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a mechanism linking histone variants to chromatin accessibility, transcriptional regulation, neuronal function, and memory. This work further identifies a widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.

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The elongation of Caenorhabditis elegans embryos allows examination of mechanical interactions between adjacent tissues. Muscle contractions during late elongation induce the remodeling of epidermal circumferential actin filaments through mechanotransduction. Force inputs from the muscles deform circumferential epidermal actin filament, which causes them to be severed, eventually reformed, and shortened. This squeezing force drives embryonic elongation. We investigated the possible role of the nonmuscle myosins NMY-1 and NMY-2 in this process using nmy-1 and nmy-2 thermosensitive alleles. Our findings show these myosins act redundantly in late elongation, since double nmy-2(ts); nmy-1(ts) mutants immediately stop elongation when raised to 25°C. Their inactivation does not reduce muscle activity, as measured from epidermis deformation, suggesting that they are directly involved in the multistep process of epidermal remodeling. Furthermore, NMY-1 and NMY-2 inactivation is reversible when embryos are kept at the nonpermissive temperature for a few hours. However, after longer exposure to 25°C double mutant embryos fail to resume elongation, presumably because NMY-1 was seen to form protein aggregates. We propose that the two C. elegans nonmuscle myosin II act during actin remodeling either to bring severed ends or hold them.

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Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. We assessed the effects of intranasal OT injected once at different doses (0.15, 0.3, and 0.6 IU) and time points (5, 15, and 30 min) following administration, or chronically, on ASD-related behaviours (social interaction and preference, stereotypies, anxiety, nociception) in Oprm1+/+ and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like symptoms, and measured gene expression in the reward/social circuit. Acute intranasal OT at 0.3 IU improved social behaviour in Oprm1-/- mice 5 min after administration, with limited effects on non-social behaviours. Chronic (8-17 days) OT maintained rescuing effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context. Under these conditions, the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. We detected no sex difference in OT effects. Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment in ASD.

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Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

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Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice and cynomolgus macaques from severe disease. The mechanisms of NTD non-neutralizing antibody-mediated protection are unknown. Here we show that Fc effector functions mediate NTD non-neutralizing antibody (non-nAb) protection against SARS-CoV-2 MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious viral titers in the lung as potently as neutralizing antibody (nAb) infusion, disease markers including gross lung discoloration were similar in nAb and non-nAb groups. Fc functional knockout substitutions abolished non-nAb protection and increased viral titers in the nAb group. Fc enhancement increased non-nAb protection relative to WT, supporting a positive association between Fc functionality and degree of protection from SARS-CoV-2 infection. For therapeutic administration of antibodies, non-nAb effector functions contributed to virus suppression and lessening of lung discoloration, but the presence of neutralization was required for optimal protection from disease. This study demonstrates that non-nAbs can utilize Fc-mediated mechanisms to lower viral load and prevent lung damage due to coronavirus infection.

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Polymer-stabilised liquid crystals (PSLCs) have recently been used to maintain the focal conic domains (FCDs) typical of the smectic A phase in the nematic phase for smart window applications. The newly discovered twist-bend nematic phase of bent-shaped dimers also exhibits FCDs due to its pseudo-layered structure. The variety of topological defects in the NTB phase is arguably even greater than in the smectic A phase, but the NTB phase is often metastable and usually crystallises at room temperature, which hinders its use in electro-optical applications. Here we show how different textures (FCDs, rope-like texture, double helices) of the NTB phase can be polymerised and then maintained in the nematic phase, at room temperature. This allows us to combine in PSLCs the optical properties of these defects, the thermal stability of the nematic phase and its reversible response to an electric field. We also show that the polymerised FCDs of the NTB phase could be used in smart glass applications and that the polymerised rope-like texture could be of interest for optical modulators and beam steering. In addition, the polymerisation of double helices could help to better understand their formation and structure in the NTB phase. More fundamentally, our work shows that despite the lack of density modulation, the textures of the NTB phase, thanks to its periodic character, can be exploited in the same way as those of the smectic A phase.

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BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.

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BACKGROUND: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. OBJECTIVE: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. PATIENTS AND METHODS: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. RESULTS: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3-134.2, and 74.8-126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. CONCLUSIONS: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).

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This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

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Generative probabilistic models emerge as a new paradigm in data-driven, evolution-informed design of biomolecular sequences. This paper introduces a novel approach, called Edge Activation Direct Coupling Analysis (eaDCA), tailored to the characteristics of RNA sequences, with a strong emphasis on simplicity, efficiency, and interpretability. eaDCA explicitly constructs sparse coevolutionary models for RNA families, achieving performance levels comparable to more complex methods while utilizing a significantly lower number of parameters. Our approach demonstrates efficiency in generating artificial RNA sequences that closely resemble their natural counterparts in both statistical analyses and SHAPE-MaP experiments, and in predicting the effect of mutations. Notably, eaDCA provides a unique feature: estimating the number of potential functional sequences within a given RNA family. For example, in the case of cyclic di-AMP riboswitches (RF00379), our analysis suggests the existence of approximately 1039 functional nucleotide sequences. While huge compared to the known <4000 natural sequences, this number represents only a tiny fraction of the vast pool of nearly 1082 possible nucleotide sequences of the same length (136 nucleotides). These results underscore the promise of sparse and interpretable generative models, such as eaDCA, in enhancing our understanding of the expansive RNA sequence space.

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In 2023, the Food and Drug Administration approved 2 recombinant subunit respiratory syncytial virus (RSV) vaccines based on prefusion RSV F glycoproteins for the prevention of RSV-associated lower respiratory tract disease. These vaccines were subsequently recommended for individuals ≥60 years of age using shared clinical decision-making by the Center for Disease Control and Prevention's Advisory Committee on Immunization Practices. The development, deployment, and uptake of respiratory virus vaccines are of particular importance for solid organ recipients who are at higher risk of infectious complications and poor clinical outcomes, including from RSV-associated lower respiratory tract disease, compared to patients without immunocompromise. This review aims to summarize what is currently known about the burden of RSV disease in solid organ transplantation, to describe the currently available tools to mitigate the risk, and to highlight considerations regarding the implementation of these vaccines before and after transplantation. We also explore areas of unmet need for organ transplant recipients including questions of RSV vaccine effectiveness and safety, inequities in disease and vaccine access based on race and socioeconomic status, and expansion of coverage to immunocompromised individuals below the age of 60 years.

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Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.

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