Genetic and epigenetic differentiation in response to genomic selection for avian lay date.

Anthropogenic climate change has led to globally increasing temperatures at an unprecedented pace and, to persist, wild species have to adapt to their changing world. We, however, often fail to derive reliable predictions of species' adaptive potential. Genomic selection represents a powerful tool to investigate the adaptive potential of a species, but constitutes a 'blind process' with regard to the underlying genomic architecture of the relevant phenotypes. Here, we used great tit (Parus major) females from a genomic selection experiment for avian lay date to zoom into this blind process. We aimed to identify the genetic variants that responded to genomic selection and epigenetic variants that accompanied this response and, this way, might reflect heritable genetic variation at the epigenetic level. We applied whole genome bisulfite sequencing to blood samples of individual great tit females from the third generation of bidirectional genomic selection lines for early and late lay date. Genomic selection resulted in differences at both the genetic and epigenetic level. Genetic variants that showed signatures of selection were located within genes mostly linked to brain development and functioning, including LOC107203824 (SOX3-like). SOX3 is a transcription factor that is required for normal hypothalamo-pituitary axis development and functioning, an essential part of the reproductive axis. As for epigenetic differentiation, the early selection line showed hypomethylation relative to the late selection line. Sites with differential DNA methylation were located in genes important for various biological processes, including gonadal functioning (e.g., MSTN and PIK3CB). Overall, genomic selection for avian lay date provided insights into where within the genome the heritable genetic variation for lay date, on which selection can operate, resides and indicates that some of this variation might be reflected by epigenetic variants.

Revisiting Perdeck's massive avian migration experiments debunks alternative social interpretations.

Whether avian migrants can adapt to their changing world depends on the relative importance of genetic and environmental variation for the timing and direction of migration. In the classic series of field experiments on avian migration, A. C. Perdeck discovered that translocated juveniles failed to reach goal areas, whereas translocated adults performed 'true-goal navigation'. His translocations of > 14 000 common starlings (Sturnus vulgaris) suggested that genetic mechanisms guide juveniles into a population-specific direction, i.e. 'vector navigation'. However, alternative explanations involving social learning after release in juveniles could not be excluded. By adding historical data from translocation sites, data that was unavailable in Perdeck's days, and by integrated analyses including the original data, we could not explain juvenile migrations from possible social information upon release. Despite their highly social behaviour, our findings are consistent with the idea that juvenile starlings follow inherited information and independently reach their winter quarters. Similar to more solitarily migrating songbirds, starlings would require genetic change to adjust the migration route in response to global change.

para-Aminoazobenzenes - Bipolar Redox-Active Molecules.

Azobenzenes (ABs) are versatile compounds featured in numerous applications for energy storage systems, such as solar thermal storages or phase change materials. Additionally, the reversible one-electron reduction of these diazenes to the nitrogen-based anion radical has been used in battery applications. Although the oxidation of ABs is normally irreversible, 4,4'-diamino substitution allows a reversible 2e- oxidation, which is attributed to the formation of a stable bis-quinoidal structure. Herein, we present a system that shows a bipolar redox behaviour. In this way, ABs can serve not only as anolytes, but also as catholytes. The resulting redox potentials can be tailored by suitable amine- and ring-substitution. For the first time, the solid-state structure of the oxidized form could be characterized by X-ray diffraction.

Unmasking a Silent Threat: Office-Based Diagnosis of an Ascending Aortic Dissection With Transthoracic Echocardiography.

Type A aortic dissection (TAAD) is a potentially life-threatening diagnosis that can present with elusive symptomatology. A high degree of clinical suspicion is necessary for prompt diagnosis and management. We describe a case of a transthoracic echo (TTE) in a non-suspicious clinic patient diagnosed with TAAD. A 66-year-old Caucasian male presented for a routine clinic visit with one episode of acute severe chest pain. An echocardiogram was ordered for further workup of hypertension and chest discomfort. The echocardiogram demonstrated an ejection fraction of 60% without significant valvular abnormalities. There was suspicion of aortic pathology, which required multiple attending to review the images. The final interpretation was TAAD with a thrombus present in the false lumen. The patient then presented to the Emergency Department. A computed tomographic angiography was performed, which subsequently confirmed the TAAD. The patient was admitted to the cardiovascular ICU and ultimately underwent a successful repair of the dissection. The patient had an unremarkable post-operative course and was ultimately discharged home. Our case demonstrated a diagnosis of TAAD by office-based TTE as the original imaging modality. While this was unconventional, a TAAD should remain on the differential diagnosis when being ordered for the patient's with uncontrolled hypertension with chest pain as a presenting symptom.

3,3',5-Triiodothyroacetic Acid Transporters.

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

Artificial light at night drives diel activity patterns of synanthropic pipistrelle bats and their prey.

The use of artificial light at night (ALAN) has increased drastically worldwide over the last decades. ALAN can have major effects on nocturnal communities, including insects and bats. Insects are attracted to street lights and few bat species take advantage of this by foraging on the attracted insects. ALAN potentially affects the temporal patterns of insect abundance and thereby bat foraging behaviour. In a natural dark environment, these patterns are usually bimodal, with an activity peak in the early evening and the morning. Little is known about how ALAN affects insect presence throughout the night, and whether the light spectrum plays a role. This is important, as these temporal changes may be a key driver of disturbances in bat-insect interactions. Here, we studied how white and red light affect insects' and bats' nightly activity patterns. The activity of insects and bats (Pipistrellus spp.) was recorded throughout the night at seven experimentally illuminated sites in a forest-edge ecosystem. ALAN disrupted activity patterns, with both insects and bats being more active throughout the night. ALAN facilitated all-night foraging in bats especially near white light, but these effects were attenuated near red light. The ability to forage throughout the night may be a key advantage causing synanthropic bats to dominate in illuminated environments, but this could also prove detrimental in the long term. As red light reduced disturbing effects of ALAN on insects and bats diel activity pattern, it opens the possibility of using spectral composition as a mitigation measure.

Computer vision digitization of smartphone images of anesthesia paper health records from low-middle income countries.

BACKGROUND: In low-middle income countries, healthcare providers primarily use paper health records for capturing data. Paper health records are utilized predominately due to the prohibitive cost of acquisition and maintenance of automated data capture devices and electronic medical records. Data recorded on paper health records is not easily accessible in a digital format to healthcare providers. The lack of real time accessible digital data limits healthcare providers, researchers, and quality improvement champions to leverage data to improve patient outcomes. In this project, we demonstrate the novel use of computer vision software to digitize handwritten intraoperative data elements from smartphone photographs of paper anesthesia charts from the University Teaching Hospital of Kigali. We specifically report our approach to digitize checkbox data, symbol-denoted systolic and diastolic blood pressure, and physiological data. METHODS: We implemented approaches for removing perspective distortions from smartphone photographs, removing shadows, and improving image readability through morphological operations. YOLOv8 models were used to deconstruct the anesthesia paper chart into specific data sections. Handwritten blood pressure symbols and physiological data were identified, and values were assigned using deep neural networks. Our work builds upon the contributions of previous research by improving upon their methods, updating the deep learning models to newer architectures, as well as consolidating them into a single piece of software. RESULTS: The model for extracting the sections of the anesthesia paper chart achieved an average box precision of 0.99, an average box recall of 0.99, and an mAP0.5-95 of 0.97. Our software digitizes checkbox data with greater than 99% accuracy and digitizes blood pressure data with a mean average error of 1.0 and 1.36 mmHg for systolic and diastolic blood pressure respectively. Overall accuracy for physiological data which includes oxygen saturation, inspired oxygen concentration and end tidal carbon dioxide concentration was 85.2%. CONCLUSIONS: We demonstrate that under normal photography conditions we can digitize checkbox, blood pressure and physiological data to within human accuracy when provided legible handwriting. Our contributions provide improved access to digital data to healthcare practitioners in low-middle income countries.

Comparative Performance of COVID-19 Test Methods in Healthcare Workers during the Omicron Wave.

The COVID-19 pandemic presents unique requirements for accessible, reliable testing, and many testing platforms and sampling techniques have been developed over the course of the pandemic. Not all test methods have been systematically compared to each other or a common gold standard, and the performance of tests developed in the early epidemic have not been consistently re-evaluated in the context of new variants. We conducted a repeated measures study with adult healthcare workers presenting for SARS-CoV-2 testing. Participants were tested using seven testing modalities. Test sensitivity was compared using any positive PCR test as the gold standard. A total of 325 individuals participated in the study. PCR tests were the most sensitive (saliva PCR 0.957 ± 0.048, nasopharyngeal PCR 0.877 ± 0.075, oropharyngeal PCR 0.849 ± 0.082). Standard nasal rapid antigen tests were less sensitive but roughly equivalent (BinaxNOW 0.613 ± 0.110, iHealth 0.627 ± 0.109). Oropharyngeal rapid antigen tests were the least sensitive (BinaxNOW 0.400 ± 0.111, iHealth brands 0.311 ± 0.105). PCR remains the most sensitive testing modality for the diagnosis of COVID-19 and saliva PCR is significantly more sensitive than oropharyngeal PCR and equivalent to nasopharyngeal PCR. Nasal AgRDTs are less sensitive than PCR but have benefits in convenience and accessibility. Saliva-based PCR testing is a viable alternative to traditional swab-based PCR testing for the diagnosis of COVID-19.

The great tit HapMap project: A continental-scale analysis of genomic variation in a songbird.

A major aim of evolutionary biology is to understand why patterns of genomic diversity vary within taxa and space. Large-scale genomic studies of widespread species are useful for studying how environment and demography shape patterns of genomic divergence. Here, we describe one of the most geographically comprehensive surveys of genomic variation in a wild vertebrate to date; the great tit (Parus major) HapMap project. We screened ca 500,000 SNP markers across 647 individuals from 29 populations, spanning ~30 degrees of latitude and 40 degrees of longitude - almost the entire geographical range of the European subspecies. Genome-wide variation was consistent with a recent colonisation across Europe from a South-East European refugium, with bottlenecks and reduced genetic diversity in island populations. Differentiation across the genome was highly heterogeneous, with clear 'islands of differentiation', even among populations with very low levels of genome-wide differentiation. Low local recombination rates were a strong predictor of high local genomic differentiation (FST), especially in island and peripheral mainland populations, suggesting that the interplay between genetic drift and recombination causes highly heterogeneous differentiation landscapes. We also detected genomic outlier regions that were confined to one or more peripheral great tit populations, probably as a result of recent directional selection at the species' range edges. Haplotype-based measures of selection were related to recombination rate, albeit less strongly, and highlighted population-specific sweeps that likely resulted from positive selection. Our study highlights how comprehensive screens of genomic variation in wild organisms can provide unique insights into spatio-temporal evolutionary dynamics.

Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.

Background: Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods: In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results: Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC50: 2.5 ± 1.5 µM) or thyroxine (T4) (IC50: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions: Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines in vivo.

Evaluating Humoral Immunity Elicited by XBB.1.5 Monovalent COVID-19 Vaccine.

Because novel SARS-CoV-2 variants continue to emerge, immunogenicity of XBB.1.5 monovalent vaccines against live clinical isolates needs to be evaluated. We report boosting of IgG (2.1×), IgA (1.5×), and total IgG/A/M (1.7×) targeting the spike receptor-binding domain and neutralizing titers against WA1 (2.2×), XBB.1.5 (7.4×), EG.5.1 (10.5×), and JN.1 (4.7×) variants.

Temperature has an overriding role compared to photoperiod in regulating the seasonal timing of winter moth egg hatching.

To accurately predict species' phenology under climate change, we need to gain a detailed mechanistic understanding of how different environmental cues interact to produce the seasonal timing response. In the winter moth (Operophtera brumata), seasonal timing of egg hatching is strongly affected by ambient temperature and has been under strong climate change-induced selection over the past 25 years. However, it is unclear whether photoperiod received at the egg stage also influences timing of egg hatching. Here, we investigated the relative contribution of photoperiod and temperature in regulating winter moth egg development using two split-brood experiments. We experimentally shifted the photoperiod eggs received by 2-4 weeks compared to the actual calendar date and measured the timing of egg hatching, both at a constant temperature and in combination with two naturally changing temperature treatments - mimicking a cold and a warm year. We found an eight-fold larger effect of temperature compared to photoperiod on egg development time. Moreover, the very small photoperiod effects we found were outweighed by both between- and within-clutch variation in egg development time. Thus, we conclude that photoperiod received at the egg stage does likely not play a substantial role in regulating the seasonal timing of egg hatching in the winter moth. These insights into the regulatory mechanism of seasonal timing could have important implications for predicting insect climate change adaptation, as we might expect different targets of selection depending on the relative contribution of different environmental cues.

Comparing the Effectiveness of the Blended Delivery Mode With the Face-to-Face Delivery Mode of Smoking Cessation Treatment: Noninferiority Randomized Controlled Trial.

BACKGROUND: Tobacco consumption is a leading cause of death and disease, killing >8 million people each year. Smoking cessation significantly reduces the risk of developing smoking-related diseases. Although combined treatment for addiction is promising, evidence of its effectiveness is still emerging. Currently, there is no published research comparing the effectiveness of blended smoking cessation treatments (BSCTs) with face-to-face (F2F) treatments, where web-based components replace 50% of the F2F components in blended treatment. OBJECTIVE: The primary objective of this 2-arm noninferiority randomized controlled trial was to determine whether a BSCT is noninferior to an F2F treatment with identical ingredients in achieving abstinence rates. METHODS: This study included 344 individuals who smoke (at least 1 cigarette per day) attending an outpatient smoking cessation clinic in the Netherlands. The participants received either a blended 50% F2F and 50% web-based BSCT or only F2F treatment with similar content and intensity. The primary outcome measure was cotinine-validated abstinence rates from all smoking products at 3 and 15 months after treatment initiation. Additional measures included carbon monoxide-validated point prevalence abstinence; self-reported point prevalence abstinence; and self-reported continuous abstinence rates at 3, 6, 9, and 15 months after treatment initiation. RESULTS: None of the 13 outcomes showed statistically confirmed noninferiority of the BSCT, whereas 4 outcomes showed significantly (P<.001) inferior abstinence rates of the BSCT: cotinine-validated point prevalence abstinence rate at 3 months (difference 12.7, 95% CI 6.2-19.4), self-reported point prevalence abstinence rate at 6 months (difference 19.3, 95% CI 11.5-27.0) and at 15 months (difference 11.7, 95% CI 5.8-17.9), and self-reported continuous abstinence rate at 6 months (difference 13.8, 95% CI 6.8-20.8). The remaining 9 outcomes, including the cotinine-validated point prevalence abstinence rate at 15 months, were inconclusive. CONCLUSIONS: In this high-intensity outpatient smoking cessation trial, the blended mode was predominantly less effective than the traditional F2F mode. The results contradict the widely assumed potential benefits of blended treatment and suggest that further research is needed to identify the critical factors in the design of blended interventions. TRIAL REGISTRATION: Netherlands Trial Register 27150; https://onderzoekmetmensen.nl/nl/trial/27150. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-doi.org/10.1186/s12889-016-3851-x.

Odours of caterpillar-infested trees increase testosterone concentrations in male great tits.

Trees release Herbivore-Induced Plant Volatiles (HIPVs) into the air in response to damage inflicted by insects. It is known that songbirds use those compounds to locate their prey, but more recently the idea emerged that songbirds could also use those odours as cues in their reproductive decisions, as early spring HIPVs may contain information about the seasonal timing and abundance of insects. We exposed pre-breeding great tits (Parus major) to the odours of caterpillar-infested trees under controlled conditions, and monitored reproduction (timing of egg laying, number of eggs, egg size) and two of its main hormonal drivers (testosterone and 17ß-estradiol in males and females, respectively). We found that females exposed to HIPVs did not advance their laying dates, nor laid larger clutches, or larger eggs compared to control females. 17ß-estradiol concentrations in females were also similar between experimental and control birds. However, males exposed to HIPVs had higher testosterone concentrations during the egg-laying period. Our study supports the hypothesis that insectivorous songbirds are able to detect minute amounts of plant odours. The sole manipulation of plant scents was not sufficient to lure females into a higher reproductive investment, but males increased their reproductive effort in response to a novel source of information for seasonal breeding birds.

Divergence in evolutionary potential of life history traits among wild populations is predicted by differences in climatic conditions.

Short-term adaptive evolution represents one of the primary mechanisms allowing species to persist in the face of global change. Predicting the adaptive response at the species level requires reliable estimates of the evolutionary potential of traits involved in adaptive responses, as well as understanding how evolutionary potential varies across a species' range. Theory suggests that spatial variation in the fitness landscape due to environmental variation will directly impact the evolutionary potential of traits. However, empirical evidence on the link between environmental variation and evolutionary potential across a species range in the wild is lacking. In this study, we estimate multivariate evolutionary potential (via the genetic variance-covariance matrix, or G-matrix) for six morphological and life history traits in 10 wild populations of great tits (Parus major) distributed across Europe. The G-matrix significantly varies in size, shape, and orientation across populations for both types of traits. For life history traits, the differences in G-matrix are larger when populations are more distant in their climatic niche. This suggests that local climates contribute to shaping the evolutionary potential of phenotypic traits that are strongly related to fitness. However, we found no difference in the overall evolutionary potential (i.e., G-matrix size) between populations closer to the core or the edge of the distribution area. This large-scale comparison of G-matrices across wild populations emphasizes that integrating variation in multivariate evolutionary potential is important to understand and predict species' adaptive responses to new selective pressures.

The genomics of adaptation to climate in European great tit (Parus major) populations.

The recognition that climate change is occurring at an unprecedented rate means that there is increased urgency in understanding how organisms can adapt to a changing environment. Wild great tit (Parus major) populations represent an attractive ecological model system to understand the genomics of climate adaptation. They are widely distributed across Eurasia and they have been documented to respond to climate change. We performed a Bayesian genome-environment analysis, by combining local climate data with single nucleotide polymorphisms genotype data from 20 European populations (broadly spanning the species' continental range). We found 36 genes putatively linked to adaptation to climate. Following an enrichment analysis of biological process Gene Ontology (GO) terms, we identified over-represented terms and pathways among the candidate genes. Because many different genes and GO terms are associated with climate variables, it seems likely that climate adaptation is polygenic and genetically complex. Our findings also suggest that geographical climate adaptation has been occurring since great tits left their Southern European refugia at the end of the last ice age. Finally, we show that substantial climate-associated genetic variation remains, which will be essential for adaptation to future changes.

Short-time exposure to light at night affects incubation patterns and correlates with subsequent body weight in great tits (Parus major).

Artificial light at night (ALAN) widely affects wildlife by blurring light-dark differences, including transitions such as sunrise and sunset, thereby affecting regulation of diel rhythms. As a result, activity onsets in many wild diurnal songbirds advance under ALAN. From chronobiological studies, it is known that the direction and strength of the response to light depends on when during the night exposure takes place. However, these experiments are mostly done under continuous light conditions, when animals have free-running rhythms. It remains unclear whether phase-dependence also holds in entrained, wild songbirds; i.e., does the effect of ALAN on activity patterns differ between exposure in the morning compared to the evening? This information is essential to assess the effects of mitigation measures by limiting ALAN to selected times of the night. We exposed incubating great tits (Parus major) inside the nest-box to 4 h of dim light, of which 1 h overlapped with dawn before sunrise or dusk after sunset. We found a small advancing effect of morning-light on activity onset and of evening-light on offset compared to dark controls but not vice versa. Breeding success and chick condition were unaffected by the light treatments. However, light-treated females had lower weights 9-18 days after the end of the treatment compared to the controls, independent of whether ALAN occurred in the morning or the evening, indicating possible costs of ALAN. Despite the weak behavioral response, ALAN might have affected the females' circadian clock or physiology resulting in lower body condition.

Contralateral second dose improves antibody responses to a 2-dose mRNA vaccination regimen.

BACKGROUNDVaccination is typically administered without regard to site of prior vaccination, but this factor may substantially affect downstream immune responses.METHODSWe assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second-dose boosters in the ipsilateral or contralateral arm relative to initial vaccination. We measured serum SARS-CoV-2 spike-specific Ig, receptor-binding domain-specific (RBD-specific) IgG, SARS-CoV-2 nucleocapsid-specific IgG, and neutralizing antibody titers against SARS-CoV-2.D614G (early strain) and SARS-CoV-2.B.1.1.529 (Omicron) at approximately 0.6, 8, and 14 months after boosting.RESULTSIn 947 individuals, contralateral boosting was associated with higher spike-specific serum Ig, and this effect increased over time, from a 1.1-fold to a 1.4-fold increase by 14 months (P < 0.001). A similar pattern was seen for RBD-specific IgG. Among 54 pairs matched for age, sex, and relevant time intervals, arm groups had similar antibody levels at study visit 2 (W2), but contralateral boosting resulted in significantly higher binding and neutralizing antibody titers at W3 and W4, with progressive increase over time, ranging from 1.3-fold (total Ig, P = 0.007) to 4.0-fold (pseudovirus neutralization to B.1.1.529, P < 0.001).CONCLUSIONSIn previously unexposed adults receiving an initial vaccine series with the BNT162b2 mRNA COVID-19 vaccine, contralateral boosting substantially increases antibody magnitude and breadth at times beyond 3 weeks after vaccination. This effect should be considered during arm selection in the context of multidose vaccine regimens.FUNDINGM.J. Murdock Charitable Trust, OHSU Foundation, NIH.

Effectiveness of a bivalent mRNA vaccine dose against symptomatic SARS-CoV-2 infection among U.S. Healthcare personnel, September 2022-May 2023.

BACKGROUND: Bivalent mRNA vaccines were recommended since September 2022. However, coverage with a recent vaccine dose has been limited, and there are few robust estimates of bivalent VE against symptomatic SARS-CoV-2 infection (COVID-19). We estimated VE of a bivalent mRNA vaccine dose against COVID-19 among eligible U.S. healthcare personnel who had previously received monovalent mRNA vaccine doses. METHODS: We conducted a case-control study in 22 U.S. states, and enrolled healthcare personnel with COVID-19 (case-participants) or without COVID-19 (control-participants) during September 2022-May 2023. Participants were considered eligible for a bivalent mRNA dose if they had received 2-4 monovalent (ancestral-strain) mRNA vaccine doses, and were ≥67 days after the most recent vaccine dose. We estimated VE of a bivalent mRNA dose using conditional logistic regression, accounting for matching by region and four-week calendar period. We adjusted estimates for age group, sex, race and ethnicity, educational level, underlying health conditions, community COVID-19 exposure, prior SARS-CoV-2 infection, and days since the last monovalent mRNA dose. RESULTS: Among 3,647 healthcare personnel, 1,528 were included as case-participants and 2,119 as control-participants. Participants received their last monovalent mRNA dose a median of 404 days previously; 1,234 (33.8%) also received a bivalent mRNA dose a median of 93 days previously. Overall, VE of a bivalent dose was 34.1% (95% CI, 22.6%-43.9%) against COVID-19 and was similar by product, days since last monovalent dose, number of prior doses, age group, and presence of underlying health conditions. However, VE declined from 54.8% (95% CI, 40.7%-65.6%) after 7-59 days to 21.6% (95% CI 5.6%-34.9%) after ≥60 days. CONCLUSIONS: Bivalent mRNA COVID-19 vaccines initially conferred approximately 55% protection against COVID-19 among U.S. healthcare personnel. However, protection waned after two months. These findings indicate moderate initial protection against symptomatic SARS-CoV-2 infection by remaining up-to-date with COVID-19 vaccines.

Term-BLAST-like alignment tool for concept recognition in noisy clinical texts.

MOTIVATION: Methods for concept recognition (CR) in clinical texts have largely been tested on abstracts or articles from the medical literature. However, texts from electronic health records (EHRs) frequently contain spelling errors, abbreviations, and other nonstandard ways of representing clinical concepts. RESULTS: Here, we present a method inspired by the BLAST algorithm for biosequence alignment that screens texts for potential matches on the basis of matching k-mer counts and scores candidates based on conformance to typical patterns of spelling errors derived from 2.9 million clinical notes. Our method, the Term-BLAST-like alignment tool (TBLAT) leverages a gold standard corpus for typographical errors to implement a sequence alignment-inspired method for efficient entity linkage. We present a comprehensive experimental comparison of TBLAT with five widely used tools. Experimental results show an increase of 10% in recall on scientific publications and 20% increase in recall on EHR records (when compared against the next best method), hence supporting a significant enhancement of the entity linking task. The method can be used stand-alone or as a complement to existing approaches. AVAILABILITY AND IMPLEMENTATION: Fenominal is a Java library that implements TBLAT for named CR of Human Phenotype Ontology terms and is available at https://github.com/monarch-initiative/fenominal under the GNU General Public License v3.0.