Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy.

BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study.

BACKGROUND: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. METHODS: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. FINDINGS: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. INTERPRETATION: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. FUNDING: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome.

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.

Zika virus co-opts microRNA networks to persist in placental niches detected by spatial transcriptomics.

BACKGROUND: Zika virus congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta without causing overt cellular or tissue damage is fundamental to deciphering mechanisms of maternal-fetal vertical transmission. OBJECTIVE: Placenta-specific microRNAs are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that the Zika virus functionally disrupts placental microRNAs, enabling viral persistence and fetal pathogenesis. STUDY DESIGN: To test this hypothesis, we used orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation to identify any significant alterations in the functional loading of microRNAs and their targets onto the RNA-induced silencing complex. Trophoblasts from same-donors were split and infected with a contemporary first-passage Zika virus strain HN16 (multiplicity of infection=1 plaque forming unit per cell) or mock infected. To functionally cross-validate microRNA-messenger RNA interactions, we compared our Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation results with an independent analysis of published bulk RNA-sequencing data from human placental disk specimens (n=3 subjects; Zika virus positive in first, second, or third trimester, CD45- cells sorted by flow cytometry) and compared it with uninfected controls (n=2 subjects). To investigate the importance of these microRNA and RNA interference networks in Zika virus pathogenesis, we used a gnotobiotic mouse model uniquely susceptible to the Zika virus. We evaluated if small-molecule enhancement of microRNA and RNA interference pathways with enoxacin influenced Zika virus pathogenesis (n=20 dams total yielding 187 fetal specimens). Lastly, placentae (n=14 total) from this mouse model were analyzed with Visium spatial transcriptomics (9743 spatial transcriptomes) to identify potential Zika virus-associated alterations in immune microenvironments. RESULTS: We found that Zika virus infection of primary human trophoblast cells led to an unexpected disruption of placental microRNA regulation networks. When compared with uninfected controls, Zika virus-infected placentae had significantly altered SLC12A8, SDK1, and VLDLR RNA-induced silencing complex loading and transcript levels (-22; adjusted P value <.05; Wald-test with false discovery rate correction q<0.05). In silico microRNA target analyses revealed that 26 of 119 transcripts (22%) in the transforming growth factor-ß signaling pathway were targeted by microRNAs that were found to be dysregulated following Zika virus infection in trophoblasts. In gnotobiotic mice, relative to mock controls, Zika virus-associated fetal pathogenesis included fetal growth restriction (P=.036) and viral persistence in placental tissue (P=.011). Moreover, spatial transcriptomics of murine placentae revealed that Zika virus-specific placental niches were defined by significant up-regulation of complement cascade components and coordinated changes in transforming growth factor-ß gene expression. Finally, treatment of Zika virus-infected mice with enoxacin abolished placental Zika virus persistence, rescued the associated fetal growth restriction, and the Zika virus-associated transcriptional changes in placental immune microenvironments were no longer observed. CONCLUSION: These results collectively suggest that (1) Zika virus infection and persistence is associated with functionally perturbed microRNA and RNA interference pathways specifically related to immune regulation in placental microenvironments and (2) enhancement of placental microRNA and RNA interference pathways in mice rescued Zika virus-associated pathogenesis, specifically persistence of viral transcripts in placental microenvironments and fetal growth restriction.

Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024.

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

Paraxial and ray approximations of acoustic vortex beams.

A compact analytical solution obtained in the paraxial approximation is used to investigate focused and unfocused vortex beams radiated by a source with a Gaussian amplitude distribution. Comparisons with solutions of the Helmholtz equation are conducted to determine bounds on the parameter space in which the paraxial approximation is accurate. A linear relation is obtained for the dependence of the vortex ring radius on the topological charge, characterized by its orbital number, in the far field of an unfocused beam and in the focal plane of a focused beam. For a focused beam, it is shown that as the orbital number increases, the vortex ring not only increases in radius but also moves out of the focal plane in the direction of the source. For certain parameters, it is demonstrated that with increasing orbital number, the maximum amplitude in a focused beam becomes localized along a spheroidal surface enclosing a shadow zone in the prefocal region. This field structure is described analytically by ray theory developed in the present work, showing that the spheroidal surface in the prefocal region coincides with a simple expression for the coordinates of the caustic surface formed in a focused vortex beam.

Cleft lip Sidedness and the Association with Additional Congenital Malformations.

OBJECTIVE: To investigate the association between the sidedness of orofacial clefts and additional congenital malformations. DESIGN: Linkage of a national registry of cleft births to national administrative data of hospital admissions. SETTING: National Health Service, England. PARTICIPANTS: 2007 children born with cleft lip ± alveolus (CL ± A) and 2724 with cleft lip and palate (CLP) born between 2000 and 2012. MAIN OUTCOME MEASURE: The proportion of children with ICD-10 codes for additional congenital malformations by the sidedness (left, right or bilateral) of orofacial clefts. RESULTS: For CL ± A phenotypes, there was no evidence for a difference in the prevalence of additional anomalies between left (22%, reference), right (22%, aOR 1.02, 95% CI 0.80 to 1.28; P = .90) and bilateral clefts (23%, aOR 1.09, 95% CI 0.75 to 1.57; P = .66). For CLP phenotypes, there was evidence of a lower prevalence of additional malformations in left (23%, reference) compared to right (32%, aOR 1.54, 95% CI 1.25 to 1.91; P < .001) and bilateral clefts (33%, aOR 1.64, 95% CI 1.35 to 1.99; P < .001). CONCLUSIONS: The prevalence of additional congenital malformations was similar across sidedness subtypes with CL ± A phenotypes but was different for sidedness subtypes within CLP cases. These data support the hypothesis that CL ± A has a different underlying aetiology from CLP and that within the CLP phenotype, right sided CLP may lie closer in aetiology to bilateral CLP than it does to left sided CLP.

Trophic distribution of nutrient production in coral reef fisheries.

Coral reef fisheries supply nutritious catch to tropical coastal communities, where the quality of reef seafood is determined by both the rate of biomass production and nutritional value of reef fishes. Yet our understanding of reef fisheries typically uses targets of total reef fish biomass rather than individual growth (i.e. biomass production) and nutrient content (i.e. nutritional value of reef fish), limiting the ability of management to sustain the productivity of nutritious catches. Here, we use modelled growth coefficients and nutrient concentrations to develop a new metric of nutrient productivity of coral reef fishes. We then evaluate this metric with underwater visual surveys of reef fish assemblages from four tropical countries to examine nutrient productivity of reef fish food webs. Species' growth coefficients were associated with nutrients that vary with body size (calcium, iron, selenium and zinc), but not total nutrient density. When integrated with fish abundance data, we find that herbivorous species typically dominate standing biomass, biomass turnover and nutrient production on coral reefs. Such bottom-heavy trophic distributions of nutrients were consistent across gradients of fishing pressure and benthic composition. We conclude that management restrictions that promote sustainability of herbivores and other low trophic-level species can sustain biomass and nutrient production from reef fisheries that is critical to the food security of over 500 million people in the tropics.

Transcatheter closure of large postinfarct ventricular septal defect: Initial results of prototype Occlutech® device including the first-in-human.

BACKGROUND: Postinfarct ventricular septal rupture is a serious complication in delayed or failed reperfusion with a grim prognosis. The optimal timing and treatment option remain debatable in the absence of randomized controlled trials. Percutaneous device closure is a well-reported and less invasive treatment option but recent imaging studies indicate that majority of defects are too large to be adequately covered by the currently Conformite Europeenne and Food and Drug Administration approved occluder devices. METHODS: Six patients presented with large and complex postinfarct ventricular septal ruptures, considered unsuitable for the Amplatzer post-infarct ventricular septal defect Occluder, so were treated using the prototype Occlutech® 36 mm PI-VSD occluder, including the first-in-human use. RESULTS: The prototype device was successfully deployed in all patients with satisfactory immediate results and shunt reduction. Three patients (50%) in cardiogenic shock did not survive beyond discharge, of which two were complicated by device dislodgement or embolization. CONCLUSIONS: Percutaneous closure of large postinfarct ventricular septal ruptures is possible using newer device with a wider coverage. Further device refinement is necessary to improve treatment outcomes.

Characteristics of shunt failure in 38,095 adult shunt insertion surgeries: a systematic review and meta-analysis.

OBJECTIVE: The management of excess CSF in patients with hydrocephalus typically requires using a shunt to divert CSF. Unfortunately, there is a high rate of shunt failure despite improvements in device components and insertion techniques. Reoperation is frequently necessary, which contributes to patient harm and increased healthcare costs. While factors affecting shunt failure are well defined in the pediatric population, information regarding adults is lacking. The authors undertook a systematic review and meta-analysis to determine how shunt failure in the adult population is reported and investigated the etiologies of shunt failure. METHODS: This review is reported according to PRIMSA and utilized the MEDLINE, Embase, and Google Scholar databases. Abstracts were screened by two independent reviewers, and data were extracted in duplicate by two independent reviewers. Statistical analyses were performed using SPSS and Stata. RESULTS: The pooled rates of shunt failure were 10% (95% CI 5%-15%) in studies with a mean follow-up time of less than 1 year, 12% (95% CI 8%-14%) with a follow-up time between 1 and 2 years, and 32% in studies with a follow-up time of 2 years or greater (95% CI 19%-43%). The pooled rate of failure was 17% across all studies. The most common cause of shunt failure was obstruction at 3.0% (95% CI 2%-4%), accounting for 23.2% of shunt failures. Infection was the second most common at 2.8% (95% CI 2%-3%), accounting for 22.5% of shunt failures. The most common location of shunt failure was the distal catheter, with a failure rate of 4.0% (95% CI 3%-5%), accounting for 33.4% of shunt failures. The definition of shunt failure was heterogeneous and varied depending on institutional practices. The combination of symptoms with either CT or MRI was the most frequently reported method for assessing shunt failure. CONCLUSIONS: Important variation regarding how to define, investigate, and report shunt failure was identified. The overall shunt failure rate in adults is at least 32% after 2 years, which, while lower than that typically reported in the pediatric population, is significant. The most common causes of shunt failure in adults are infection and obstruction. The most common site of failure occurred at the distal catheter, highlighting the need to develop strategies to both report and mitigate distal shunt failure in adult shunt patients.

How to define CSF overdrainage: a systematic literature review.

PURPOSE: Overdrainage (OD) is one of the most frequent complications related to drainage of the cerebrospinal fluid (CSF). It is mostly associated with valve-bearing shunt systems but should probably be considered as a risk factor in any type of CSF diversion procedure. There is extreme variation in the reported incidence of OD due to the lack of consensus on defining criteria and an unclear perception of the pathophysiology. Hence, OD is probably underreported and underestimated. The objective of this paper was to establish a definition of OD, based on a systematic review of the literature. METHODS: A systematic search was conducted in MEDLNE and EMBASE. Studies providing a definition or a description of diagnostic findings related to OD in ventriculoperitoneal shunt treated hydrocephalus were included. Non-English titles, abstracts and manuscripts were excluded. Extracted descriptions were graded into five groups (class I-V studies) based on how precise the terminology used to describe OD was. Class I studies were included for further analysis and characteristics of OD were extracted. The quality of included descriptions was assessed by a clinical expert panel. RESULTS: A total of 1309 studies were screened, 190 were graded into groups, and 22, which provided specific definitions or descriptions of OD, were graded as class I studies. We extracted 32 different characteristics consistent with OD (e.g., clinical symptoms, radiological signs, and syndromes). CONCLUSION: There was an overall agreement that CSF overdrainage following implantation of a ventriculoperitoneal shunt in a mixed pediatric and adult population is characterized as a persistent condition with clinically manifestations as postural dependent headache, nausea, and vomiting and/or radiological signs of slim ventricles and/or subdural collections.

Analytical solution for acoustic radiation force on a sphere near a planar boundary.

Acoustic radiation force on a sphere in an inviscid fluid near a planar boundary, which may be rigid or pressure release, is calculated using spherical wave functions to expand the total pressure field. The condition at the boundary is satisfied with the addition of a reflected wave and an image sphere. The total pressure field, which is exact in the linear approximation, is composed of the incident field, the reflected field, and the scattered fields due to the physical sphere and the image sphere. The expansion coefficients for the pressure field are used to evaluate the acoustic radiation force on the sphere using a known analytical expression obtained from integration of the radiation stress tensor. Calculations illustrate the influence of multiple scattering effects on the radiation force acting on the sphere. The model applies to compressible and elastic spheres and for any incident field structure. An approximation is introduced that extends the analytical model to other types of interfaces, including a fluid-fluid interface. The analytical model is validated by comparisons with an independent finite element model.

Nonlinear propagation of quasiplanar shear wave beams in soft elastic media with transverse isotropy.

Model equations are developed for shear wave propagation in a soft elastic material that include effects of nonlinearity, diffraction, and transverse isotropy. A theory for plane wave propagation by Cormack [J. Acoust. Soc. Am. 150, 2566 (2021)] is extended to include leading order effects of wavefront curvature by assuming that the motion is quasiplanar, which is consistent with other paraxial model equations in nonlinear acoustics. The material is modeled using a general expansion of the strain energy density to fourth order in strain that comprises thirteen terms defining the elastic moduli. Equations of motion for the transverse displacement components are obtained using Hamilton's principle. The coupled equations of motion describe diffraction, anisotropy of the wave speeds, quadratic and cubic plane wave nonlinearity, and quadratic nonlinearity associated with wavefront curvature. Two illustrative special cases are investigated. Spatially varying shear vertical wave motion in the fiber direction excites a quadratic nonlinear interaction unique to transversely isotropic soft solids that results in axial second harmonic motion with longitudinal polarization. Shear horizontal wave motion in the fiber plane reveals effects of anisotropy on third harmonic generation, such as beam steering and dependence of harmonic generation efficiency on the propagation and fiber directions.

Longitudinal motion of focused shear wave beams in soft elastic media.

Shear waves are employed in medical ultrasound imaging because they reveal variations in viscoelastic properties of soft tissue. Frequencies below 1 kHz are required due to the substantially higher attenuation and lower propagation speeds than for compressional waves. Shear waves exhibiting particle motion in the direction of propagation, referred to as longitudinal shear waves, can be generated with longitudinal motion of a circular disk on the surface of a soft elastic medium. This approach permits imaging of the longitudinal shear wave with a conventional ultrasound transducer that is coaxial with the source of the shear wave. Presented here is a mathematical model describing the complete wave field generated by displacement at the surface of an isotropic elastic half-space. Numerical simulations are shown for longitudinal, transverse, torsional, and radial source polarizations, with emphasis on focused longitudinal shear waves. Predictions are consistent with measurements of light beams revealing that the longitudinal electric field component produces a smaller focal spot than the transverse field component [Dorn, Quabis, and Leuchs, Phys. Rev. Lett. 91, 233901 (2003)]. Simulations are compared with preliminary measurements of a focused longitudinal shear wave beam generated in a soft tissue phantom by longitudinal motion of a spherically concave piston.

Effectiveness of complete primary vaccination against COVID-19 at primary care and community level during predominant Delta circulation in Europe: multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021.

IntroductionIn July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe.AimUsing a multicentre test-negative study, we measured COVID-19 vaccine effectiveness (VE) against symptomatic infection.MethodsIndividuals with COVID-19 or acute respiratory symptoms at primary care/community level in 10 European countries were tested for SARS-CoV-2. We measured complete primary course overall VE by vaccine brand and by time since vaccination.ResultsOverall VE was 74% (95% CI: 69-79), 76% (95% CI: 71-80), 63% (95% CI: 48-75) and 63% (95% CI: 16-83) among those aged 30-44, 45-59, 60-74 and ≥ 75 years, respectively. VE among those aged 30-59 years was 78% (95% CI: 75-81), 66% (95% CI: 58-73), 91% (95% CI: 87-94) and 52% (95% CI: 40-61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among people 60 years and older was 67% (95% CI: 52-77), 65% (95% CI: 48-76) and 83% (95% CI: 64-92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30-59 years was 87% (95% CI: 83-89) at 14-29 days and 65% (95% CI: 56-71%) at ≥ 90 days between vaccination and onset of symptoms.ConclusionsVE against symptomatic infection with the SARS-CoV-2 Delta variant varied among brands, ranging from 52% to 91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% at 90 days or more between vaccination and onset.

Nonlinear piezoelectric surface acoustic waves.

The theory for nonlinear surface acoustic waves in crystals developed using Hamiltonian mechanics [Hamilton, Il'inskii, and Zabolotskaya, J. Acoust. Soc. Am. 105, 639 (1999)] is modified to account for piezoelectric material properties. The derived spectral evolution equations permit analysis of nonlinear surface wave propagation along a cut surface of any orientation with respect to the crystallographic axes and for piezoelectric crystals with any symmetry. Numerical simulations of waveform distortion in the particle velocity and electric field components are presented for surface wave propagation in Y-cut lithium niobate along the X- and Z-crystallographic axes. The influence of piezoelectricity is illustrated by comparing the nonlinear evolution of waveforms along a surface bounded by a vacuum (free space) and an ideal conductor (short circuit). Contributions to the nonlinearity from elasticity, piezoelectricity, electrostriction, and dielectricity are quantified separately for the two boundary conditions.

Integrity and wound healing of rainbow trout intestinal epithelial cell sheets at hypo-, normo-, and hyper-thermic temperatures.

How temperature influences fish physiological systems, such as the intestinal barrier, is important for understanding and alleviating the impact of global warming on fish and aquaculture. Monolayers of the rainbow trout cell line, RTgutGC, with or without linear 500 µm wide gaps (wounds) were the in vitro models used to study the integrity and healing of intestinal epithelial sheets at different temperatures. Cultures at hypothermic (4 °C) or hyperthermic (≥ 26 °C) temperatures were compared to normothermic control cultures (18-22 °C). Monolayers remained intact for at least a week at temperatures from 4 to 28 °C, but had lost their integrity after 3 h at 32 °C as the cells pulled away from one another and from the plastic surface. F-actin appeared as prominent stress fibers in cells at 28 °C and as blobs in cells at 32 °C. At normothermia and at 26 °C, cells migrated as sheets into the gaps and closed (healed) the gaps within 5-6 days. By contrast, wounds took 14 days to heal at 4 °C. At 28 °C some cells migrated into the gap in the first few days but mainly as single cells rather than collectively and wounds never healed. When monolayers with wounds were challenged at 32 °C for 3 h and returned to 18-22 °C, cells lost their shape and actin organization and over the next 6 days detached and died. When monolayers were subjected to 26 °C for 24 h and challenged at 32 °C for 3 h prior to being placed at 18-22 °C, cell shape and actin cytoskeleton were maintained, and wounds were healed over 6 days. Thus, intestinal epithelial cells become thermostabilized for shape, cytoskeleton and migration by a prior heat exposure.