We examined antibody and memory B cell responses longitudinally for ∼9–10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 ...and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%–50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit the added protection afforded by repeat short interval boosting. These data provide insight into the quantity and quality of mRNA-vaccine-induced immunity over time through 3 or more antigen exposures.
Display omitted
•Neutralizing antibody titers stabilize ∼6 months after primary vaccination•Memory B cells are stable for >9 months postvaccination and >50% cross-bind Omicron•Omicron-reactive memory B cells are reactivated by a 3rd dose of wild-type vaccine•Low preboost antibody levels correlate with a greater fold increase after boosting
Immunization with 2 doses of mRNA vaccine encoding the ancestral SARS-CoV-2 spike protein induces a population of durable memory B cells with broad reactivity to viral variants including Omicron. Boosting with a 3rd dose of ancestral vaccine increases variant-neutralizing antibody levels, highlighting the significance of vaccine-induced B cell memory.
Abstract
We show the improvement to cosmological constraints from galaxy cluster surveys with the addition of cosmic microwave background (CMB)-cluster lensing data. We explore the cosmological ...implications of adding mass information from the 3.1
σ
detection of gravitational lensing of the CMB by galaxy clusters to the Sunyaev–Zel’dovich (SZ) selected galaxy cluster sample from the 2500 deg
2
SPT-SZ survey and targeted optical and X-ray follow-up data. In the ΛCDM model, the combination of the cluster sample with the Planck power spectrum measurements prefers
σ
8
Ω
m
/
0.3
0.5
=
0.831
±
0.020
. Adding the cluster data reduces the uncertainty on this quantity by a factor of 1.4, which is unchanged whether the 3.1
σ
CMB-cluster lensing measurement is included or not. We then forecast the impact of CMB-cluster lensing measurements with future cluster catalogs. Adding CMB-cluster lensing measurements to the SZ cluster catalog of the ongoing SPT-3G survey is expected to improve the expected constraint on the dark energy equation of state
w
by a factor of 1.3 to
σ
(
w
) = 0.19. We find the largest improvements from CMB-cluster lensing measurements to be for
σ
8
, where adding CMB-cluster lensing data to the cluster number counts reduces the expected uncertainty on
σ
8
by respective factors of 2.4 and 3.6 for SPT-3G and CMB-S4.
This study aimed to explore the successes and barriers to the implementation of Public Health England (PHE) infection prevention and control guidance in English maternity units during the COVID-19 ...pandemic.
Qualitative semi-structured interviews with obstetricians, midwives and neonatologists who worked in a maternity unit in England, UK, between March 2020 and July 2021. A thematic analysis was performed.
Successes to the implementation of PHE guidance were related to existing infrastructure, training satisfaction, and organisational culture where subthemes considered the importance of a multidisciplinary approach, COVID-19 dedicated roles and hospital-wide communication. Barriers to implementation related to the applicability of the guidance with subthemes highlighting contradictions between updates, specialties and hospitals, undesirable timings and frequency of guidance updates, reductions in staff compliance and delayed implementation. Finally, the layout of some units made it difficult to implement various aspects of the guidance (e.g., social distancing), and many detailed issues related to information technology compatibility, a lack of availability and accessibility to appropriate personal protective equipment (PPE), and variations in testing arrangements between units.
This research provides information on the experiences of healthcare professionals working on maternity units during the COVID-19 pandemic. Findings illustrate the importance of effective hospital-wide communication and the need for consistent, easily understood guidance. These results will be used to inform the content of an expert panel consensus meeting.
Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of ...matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.
Variations in pregnancy rates (PR) between IVF programs are due to multiple factors, including embryo quality. Standardized embryo grading systems have been developed to improve communication between ...embryologists and clinicians. However, these grading systems have not been validated. We sought to quantify both interobserver and intraobserver variability using a standardized day 3 embryo grading system (Veeck scale).
Prospective, sample-randomized, controlled, blinded study.
University hospital.
Twenty-six practicing embryologists.
Observation and grading of 35 video clips of day 3 embryos.
Interobserver and intraobserver variability. Embryologists were also assessed by education level, years of experience, size of IVF program, and type of grading system used. Kappa scores and intraclass correlation coefficients were calculated.
Practicing embryologists differed from control (Lucinda Veeck) by as much as two grades, despite using the same grading system (Kappa = 0.24, interclass correlation coefficient = 0.98). There was also variability in grading the same embryo (Kappa = 0.69, interclass correlation coefficient = 0.88). Programs with higher cycle numbers per year had lower variability.
There is substantial interobserver variability and moderate intraobserver variability among embryologists. Such variability could alter both the expected quality of embryos transferred, as well as the number transferred, both of which directly impact IVF program success.
A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor ...tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL-positive chronic myeloid leukemia.
We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated skin lesions that had been present for a long time.
In all four patients, a normal blood count was achieved within four weeks after treatment began. In the patient with skin disease, the lesions began to resolve shortly after treatment began. The t(5;12) translocation was undetectable by 12 weeks in three patients and by 36 weeks in the fourth patient. In the three patients with the ETV6-PDGFRB fusion gene, the transcript level decreased, and in one patient, it became undetectable by 36 weeks. All responses were durable at 9 to 12 months of follow-up.
Imatinib mesylate induces durable responses in patients with chronic myeloproliferative diseases associated with activation of PDGFRB.
Although understanding the diversity of HIV-1 reservoirs is key to achieving a cure, their study at the single-cell level in primary samples remains challenging. We combine flow cytometric ...multiplexed fluorescent in situ RNA hybridization for different viral genes with HIV-1 p24 protein detection, cell phenotyping, and downstream near-full-length single-cell vDNA sequencing. Stimulation-induced viral RNA-positive (vRNA+) cells from viremic and antiretroviral-therapy (ART)-suppressed individuals differ in their ability to produce p24. In participants on ART, latency-reversing agents (LRAs) induce a wide variety of viral gene transcription and translation patterns with LRA class-specific differences in reactivation potency. Reactivated proviruses, including in p24+ cells, are mostly defective. Although LRAs efficiently induce transcription in all memory cell subsets, we observe induction of translation mostly in effector memory cells, rather than in the long-lived central memory pool. We identify HIV-1 clones with diverse transcriptional and translational patterns between individual cells, and this finding suggests that cell-intrinsic factors influence reservoir persistence and heterogeneity.
Display omitted
•Expression of p24 protein in induced vRNA+ cells is rare during ART suppression•LRAs induce class-specific viral gene transcription and translation patterns•Induced transcriptionally active proviruses are mostly defective, even in p24+ cells•Identical HIV-1 clones can adopt diverse transcriptional and translational states
Sannier et al. describe diverse viral transcriptional and translational profiles of inducible HIV-1 reservoirs in antiretroviral-therapy (ART)-suppressed individuals, with class specificity of latency reversal agents. They reveal that reactivated proviruses are mostly defective, even in cells which express HIV-1 proteins, and that identical sequences can adopt diverse transcriptional patterns.
Management strategies are needed to optimise the number of piglets weaned from hyper-prolific sows. Nurse sow strategies involve transferring supernumerary new-born piglets onto a sow whose own ...piglets are either weaned or fostered onto another sow. Such 'nurse sows' have extended lactations spent in farrowing crates, which could have negative implications for their welfare. This study used 47 sows, 20 of which farrowed large litters and had their biggest piglets fostered onto nurse sows which were either 1 week (2STEP7, n=9) or 3 weeks into lactation (1STEP21, n=10). Sows from which piglets were removed (R) were either left with the remainder of the litter intact (I) (remain intact (RI) sows, n=10), or had their litters equalised (E) for birth weight using piglets of the same age from non-experimental sows (remain equalised (RE) sows, n=9). Piglets from 2STEP7 were fostered onto another nurse sow which was 3 weeks into lactation (2STEP21, n=9). Back-fat thickness was measured at entry to the farrowing house, at fostering (nurse sows only) and weaning. Sows were scored for ease of locomotion and skin and claw lesions at entry to the farrowing house and weaning. Salivary cortisol samples were collected and tear staining was scored at 0900 h weekly from entry until weaning. Saliva samples were also taken at fostering. Data were analysed using GLMs with appropriate random and repeated factors, or non-parametric tests were applied where appropriate. Back-fat thickness decreased between entry and weaning for all sows (F 1,42=26.59, P<0.001) and tended to differ between treatments (F 4,16=2.91; P=0.06). At weaning RI sows had lower limb lesion scores than 2STEP7 and RE sows (χ 2 4=10.8, P0.05) and all nurse sows had a higher salivary cortisol concentration at fostering, compared with the other days (F 10,426=3.47; P<0.05). Acute effects of fostering differed between nurse sow treatments (F 2,113=3.45, P0.05). In conclusion, no difference was detected between nurse sows and non-nurse sows in body condition or severity of lesions. Although some nurse sows experienced stress at fostering, no long-term effect of the nurse sow strategies was detected on stress levels compared with sows that raised their own litter.
PDF
