Hypofractionated Radiotherapy-Related Lymphopenia Is Associated With Worse Survival in Unresectable Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The aim of this study was to evaluate the incidence of radiotherapy (RT)-related lymphopenia, its predictors, and association with survival in unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT). METHODS: Retrospective analysis of 96 patients with unresectable ICC who underwent HF-RT (median 58.05 Gy in 15 fractions) between 2009 and 2022 was performed. Absolute lymphocyte count (ALC) nadir within 12 weeks of RT was analyzed. Primary variable of interest was severe lymphopenia, defined as Grade 3+ (ALC <0.5 k/µL) per CTCAE v5.0. Primary outcome of interest was overall survival (OS) from RT. RESULTS: Median follow-up was 16 months. Fifty-two percent of patients had chemotherapy pre-RT, 23% during RT, and 40% post-RT. Pre-RT, median ALC was 1.1 k/µL and 5% had severe lymphopenia. Post-RT, 68% developed RT-related severe lymphopenia. Patients who developed severe lymphopenia had a significantly lower pre-RT ALC (median 1.1 vs. 1.5 k/µL, P=0.01) and larger target tumor volume (median 125 vs. 62 cm3, P=0.02). In our multivariable Cox model, severe lymphopenia was associated with a 1.7-fold increased risk of death (P=0.04); 1-year OS rates were 63% vs 77% (P=0.03). Receipt of photon versus proton-based RT (OR=3.50, P=0.02), higher mean liver dose (OR=1.19, P<0.01), and longer RT duration (OR=1.49, P=0.02) predicted severe lymphopenia. CONCLUSIONS: HF-RT-related lymphopenia is an independent prognostic factor for survival in patients with unresectable ICC. Patients with lower baseline ALC and larger tumor volume may be at increased risk, and use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia.

Beauty is in the nose of the beholder: Fragrance modulates attractiveness, confidence and femininity ratings and neural responses to faces of self and others.

Previous research investigated cross-modal influence of olfactory stimuli on perception and evaluation of faces. However, little is known about the neural dynamics underpinning this multisensory perception, and no research examined perception for images of oneself, and others, in presence of fragrances. This study investigated the neural mechanisms of olfactory-visual processing using electroencephalography (EEG) and subjective evaluations of self- and other-images. 22 female participants evaluated images of female actors and themselves while being exposed to the fragrance of a commercially available body wash or clean air delivered via olfactometer. Participants rated faces for attractiveness, femininity, confidence and glamorousness on visual analogue scales. EEG data was recorded and event-related potentials (ERPs) associated with onset of face stimuli were analysed to consider effects of fragrance presence on face processing, and interactions between fragrance and self-other image-type. Subjective ratings of confidence, attractiveness and femininity were increased for both image-types in pleasant fragrance relative to clean air condition. ERP components covering early-to-late stages of face processing were modulated by the presence of fragrance. Findings also revealed a cross-modal fragrance-face interaction, with pleasant fragrance particularly affecting ERPs to self-images in mid-latency ERP components. Results showed that the pleasant fragrance of the commercially available body wash impacted how participants perceived faces of self and others. Self- and other-image faces were subjectively rated as more attractive, confident and feminine in the presence of the pleasant fragrance compared to an un-fragranced control. The pleasant fragrance also modulated underlying electrophysiological activity. For the first time, an effect of pleasant fragrance on face perception was observed in the N1 component, suggesting impact within 100 ms. Pleasant fragrance also demonstrated greater impact on subsequent neural processing for self, relative to other-faces. The findings have implications for understanding multisensory integration during evaluations of oneself and others.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Proton versus photon radiotherapy for hepatocellular carcinoma: Current data and technical considerations.

Radiation is an accepted standard of care for unresectable hepatocellular carcinoma (HCC), and while photon radiation is the current standard, the use of proton beam radiotherapy (PBT) is an active area of investigation given its ability to better spare uninvolved liver. Patients with HCC typically have background liver disease and many patients die of their underlying liver function in the absence of tumor progression. Early photon-based series showed promising rates of local control however the risk of non-classic radiation induced liver disease (RILD) remains relatively high and may be associated with poorer outcomes. There is a theoretical advantage to PBT in its ability to spare uninvolved liver parenchyma and potentially allow for further dose escalation. There are technical considerations for image guidance, respiratory motion management, and conformality to both PBT and photon radiotherapy that are critical to optimizing each modality. Whether the use of PBT affects clinical outcomes is the subject of the ongoing NRG Oncology GI003 trial, that randomizes patients with HCC to protons or photons. This article reviews the technical differences and literature on individual outcomes for PBT and photon radiation as well as the available comparative data.

Scent detection dogs as a novel method for oestrus detection in an endangered species, the Tasmanian devil (Sarcophilus harrisii).

Captive breeding is a critical tool for conservation of endangered species. Identifying the correct time to pair males and females can be a major challenge for captive breeding programmes, with current methods often being invasive or slow. Detection dogs may provide a non-invasive way to determine female receptivity, but this has not been explored in captive wildlife. This exploratory study investigated the use of detection dogs as a novel method of oestrus detection in the endangered Tasmanian devil (Sarcophilus harrisii). Faecal samples were collected from 11 captive female devils during the breeding seasons of 2020 and 2021. Three dogs with prior detection experience were trained and subsequently assessed (n = 188 searches per dog), on their ability to discriminate between oestrus and non-oestrus devil faecal samples, in a one sample set-up. When assessed on training samples, dogs were able to correctly discriminate oestrus from non-oestrus with a mean sensitivity of 69.1% and mean specificity of 65.7%. When assessed on novel samples, their sensitivity to oestrus dropped (mean sensitivity of 48.6%). However, they were still able to correctly identify non-oestrus samples (mean specificity of 68.1%). This study is the first to explore detection dogs' ability to identify oestrus in a captive breeding programme for endangered wildlife, providing a promising tool for non-invasive monitoring of reproductive status in wildlife.

Feasibility, Safety, and Efficacy of Aggressive Multimodal Management of Elderly Patients with Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: We aimed to evaluate the safety and efficacy of NAT followed by surgical resection in patients with PDAC aged ≥75 years. SUMMARY BACKGROUND DATA: Whether administration of neoadjuvant therapy (NAT) followed by surgical resection in elderly patients with pancreatic ductal adenocarcinoma (PDAC) is safe and effective is unknown. METHODS: The present study is a three-part comparison of older (≥ 75 years) versus younger (< 75 years) patients in different settings throughout the continuum of PDAC care. The first analysis was a comparison of older versus younger consecutive patients with non-metastatic PDAC who were initiated on FOLFIRINOX. The second was a comparison of older vs. younger patients who underwent NAT followed by surgical resection, and the third and final analysis was a comparison of older patients who underwent either NAT followed by surgical resection vs. upfront surgical resection. Postoperative complications, overall survival (OS), and time to recurrence (TTR), were compared. Propensity-score matching (PSM) analysis was performed to adjust for potential confounders. RESULTS: In the first analysis, a lower proportion of older patients (n=40) were able to complete the intended neoadjuvant FOLFIRINOX (8) cycles compared to younger patients (n=214) (65.0% vs. 81.4%, P=0.021). However, older patients were just as likely to undergo surgical exploration as younger patients (77.5% vs 78.5%, P=0.89) as well as surgical resection (57.5% vs 55.6%, P=0.70). In the second analysis, PSM was conducted to compare older (n=54) vs. younger patients (n=54) who underwent NAT followed by surgical resection. There were no significant differences in postoperative complications between the matched groups. While there was a significant difference in overall survival (OS) between older and younger patients (median OS: 16.43 months vs. 30.83 months, P=0.002), importantly, there was no significant difference in time to recurrence (TTR, median: 7.65 months vs. 11.83 months, P=0.215). In the third analysis, older patients who underwent NAT followed by surgical resection (n=48) were compared with similar older patients who underwent upfront surgical resection (n=48). After PSM, there was a significant difference in OS (median OS: 15.78 months vs. 11.51 months, P=0.037) as well as TTR (median TTR: 8.81 months vs. 7.10 months, P=0.046) representing an association with improved outcomes that favored the neoadjuvant approach among older patients alone. CONCLUSIONS: This comprehensive three-part study showed that administration of NAT followed by surgical resection appears to be safe and effective among patients ≥ 75 years of age. An aggressive approach should be offered to older adults undergoing multimodal treatment of PDAC.

Decoding biological age from face photographs using deep learning.

Because humans age at different rates, a person's physical appearance may yield insights into their biological age and physiological health more reliably than their chronological age. In medicine, however, appearance is incorporated into medical judgments in a subjective and non-standardized fashion. In this study, we developed and validated FaceAge, a deep learning system to estimate biological age from easily obtainable and low-cost face photographs. FaceAge was trained on data from 58,851 healthy individuals, and clinical utility was evaluated on data from 6,196 patients with cancer diagnoses from two institutions in the United States and The Netherlands. To assess the prognostic relevance of FaceAge estimation, we performed Kaplan Meier survival analysis. To test a relevant clinical application of FaceAge, we assessed the performance of FaceAge in end-of-life patients with metastatic cancer who received palliative treatment by incorporating FaceAge into clinical prediction models. We found that, on average, cancer patients look older than their chronological age, and looking older is correlated with worse overall survival. FaceAge demonstrated significant independent prognostic performance in a range of cancer types and stages. We found that FaceAge can improve physicians' survival predictions in incurable patients receiving palliative treatments, highlighting the clinical utility of the algorithm to support end-of-life decision-making. FaceAge was also significantly associated with molecular mechanisms of senescence through gene analysis, while age was not. These findings may extend to diseases beyond cancer, motivating using deep learning algorithms to translate a patient's visual appearance into objective, quantitative, and clinically useful measures.

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis.

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

Economic value in the Brain: A meta-analysis of willingness-to-pay using the Becker-DeGroot-Marschak auction.

Forming and comparing subjective values (SVs) of choice options is a critical stage of decision-making. Previous studies have highlighted a complex network of brain regions involved in this process by utilising a diverse range of tasks and stimuli, varying in economic, hedonic and sensory qualities. However, the heterogeneity of tasks and sensory modalities may systematically confound the set of regions mediating the SVs of goods. To identify and delineate the core brain valuation system involved in processing SV, we utilised the Becker-DeGroot-Marschak (BDM) auction, an incentivised demand-revealing mechanism which quantifies SV through the economic metric of willingness-to-pay (WTP). A coordinate-based activation likelihood estimation meta-analysis analysed twenty-four fMRI studies employing a BDM task (731 participants; 190 foci). Using an additional contrast analysis, we also investigated whether this encoding of SV would be invariant to the concurrency of auction task and fMRI recordings. A fail-safe number analysis was conducted to explore potential publication bias. WTP positively correlated with fMRI-BOLD activations in the left ventromedial prefrontal cortex with a sub-cluster extending into anterior cingulate cortex, bilateral ventral striatum, right dorsolateral prefrontal cortex, right inferior frontal gyrus, and right anterior insula. Contrast analysis identified preferential engagement of the mentalizing-related structures in response to concurrent scanning. Together, our findings offer succinct empirical support for the core structures participating in the formation of SV, separate from the hedonic aspects of reward and evaluated in terms of WTP using BDM, and show the selective involvement of inhibition-related brain structures during active valuation.

Nurses' Medication Administration Workarounds when Using Electronic Systems: An Analysis of Safety Incident Reports.

Electronic medication management systems (EMMS) have been implemented in most acute care settings in Australia to reduce medication error rates. One of the key challenges related to the introduction of EMMS in hospitals is the uptake of informal "workarounds" by clinicians, including nurses. In this study, we aimed to examine one workaround in depth, nurses not documenting medication administration in the EMMS at the time of administration. We conducted a review of incident reports to identify the factors that contribute to this workaround occurring and the consequences or potential consequences of this workaround on patients. We identified a range of contributing factors, with factors relating to the user (e.g. nurses being time poor) occurring most frequently in incident reports. The most frequently seen consequence of this workaround was the patient receiving an additional dose. This research revealed that strategies to reduce the uptake of this workaround should consider user and organisational factors rather than just EMMS design alone.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX , defining molecular alterations in IDH -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX knockout glioma models in the presence and absence of the IDH1 R 132 H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo . However, the presence of IDH1 R 132 H dampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1 R132H inhibition. IDH1 R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

Epinephrine autoinjectors: individualizing device and dosage to optimize anaphylaxis management in the community setting.

Background: Anaphylaxis is the most severe manifestation of a systemic allergic reaction, and, in the community setting, the immediate administration of an epinephrine autoinjector (EAI) can be life-saving. Physicians are tasked with selecting the most appropriate EAI for each individual and counseling patients and/or their caregivers to maximize the likelihood of successful deployment of the EAI. Objective: To offer an evidence-based expert clinical perspective on how physicians might best tailor EAI selection to their patients with anaphylaxis. Methods: A group of eight adult and pediatric allergists with expertise in anaphylaxis management reviewed and assessed the published data and guidelines on anaphylaxis management and EAI device selection. Results: Personalized EAI selection is influenced by intrinsic individual factors, extrinsic factors such as the properties of the individual EAI (e.g., dose, needle length, overall design) as well as cost and coverage. The number and the variety of EAIs available have expanded in most jurisdictions in recent years, which provide a greater diversity of options to meet the characteristics and needs of patients with anaphylaxis. Conclusion: There currently are no EAIs with customizable dose and needle length. Although precise personalization of each patient's EAI remains an optimistic future aspiration, careful consideration of all variables when prescribing EAIs can support optimal management of anaphylaxis.

Optimal Neoadjuvant Strategies for Locally Advanced Rectal Cancer by Risk Assessment and Tumor Location.

Neoadjuvant therapy is standard of care for locally advanced rectal cancer (LARC). Advancements in multimodality therapy options and sequencing of radiation therapy (RT), surgery, and chemotherapy make decision-making challenging. Traditional treatment of patients with LARC involves neoadjuvant chemoradiation followed by total mesorectal excision and consideration of adjuvant chemotherapy. Advancement in RT has led to trials offering both short-course and long-course RT with good long-term clinical outcomes. Intensification of therapy in high-risk patients has led to studies of total neoadjuvant therapy with chemotherapy and chemoradiation, now standard management for most LARC. De-escalation of therapy in patients with favorable prognosis has led to several considerations, including non-total mesorectal excision management or neoadjuvant chemotherapy only. Several considerations of patient and disease factors can help inform the optimal chemotherapy regimens in different sequencing of neoadjuvant strategies. Finally, novel biomarkers, such as microsatellite instability, has led to utilization of novel therapies, including neoadjuvant immunotherapy, with substantial response. This review attempts to frame the rapidly growing data in LARC in context of disease and patient risk factors, to inform optimal, personalized treatment of patients with LARC.

Clinical validation of deep learning algorithms for radiotherapy targeting of non-small-cell lung cancer: an observational study.

BACKGROUND: Artificial intelligence (AI) and deep learning have shown great potential in streamlining clinical tasks. However, most studies remain confined to in silico validation in small internal cohorts, without external validation or data on real-world clinical utility. We developed a strategy for the clinical validation of deep learning models for segmenting primary non-small-cell lung cancer (NSCLC) tumours and involved lymph nodes in CT images, which is a time-intensive step in radiation treatment planning, with large variability among experts. METHODS: In this observational study, CT images and segmentations were collected from eight internal and external sources from the USA, the Netherlands, Canada, and China, with patients from the Maastro and Harvard-RT1 datasets used for model discovery (segmented by a single expert). Validation consisted of interobserver and intraobserver benchmarking, primary validation, functional validation, and end-user testing on the following datasets: multi-delineation, Harvard-RT1, Harvard-RT2, RTOG-0617, NSCLC-radiogenomics, Lung-PET-CT-Dx, RIDER, and thorax phantom. Primary validation consisted of stepwise testing on increasingly external datasets using measures of overlap including volumetric dice (VD) and surface dice (SD). Functional validation explored dosimetric effect, model failure modes, test-retest stability, and accuracy. End-user testing with eight experts assessed automated segmentations in a simulated clinical setting. FINDINGS: We included 2208 patients imaged between 2001 and 2015, with 787 patients used for model discovery and 1421 for model validation, including 28 patients for end-user testing. Models showed an improvement over the interobserver benchmark (multi-delineation dataset; VD 0·91 [IQR 0·83-0·92], p=0·0062; SD 0·86 [0·71-0·91], p=0·0005), and were within the intraobserver benchmark. For primary validation, AI performance on internal Harvard-RT1 data (segmented by the same expert who segmented the discovery data) was VD 0·83 (IQR 0·76-0·88) and SD 0·79 (0·68-0·88), within the interobserver benchmark. Performance on internal Harvard-RT2 data segmented by other experts was VD 0·70 (0·56-0·80) and SD 0·50 (0·34-0·71). Performance on RTOG-0617 clinical trial data was VD 0·71 (0·60-0·81) and SD 0·47 (0·35-0·59), with similar results on diagnostic radiology datasets NSCLC-radiogenomics and Lung-PET-CT-Dx. Despite these geometric overlap results, models yielded target volumes with equivalent radiation dose coverage to those of experts. We also found non-significant differences between de novo expert and AI-assisted segmentations. AI assistance led to a 65% reduction in segmentation time (5·4 min; p<0·0001) and a 32% reduction in interobserver variability (SD; p=0·013). INTERPRETATION: We present a clinical validation strategy for AI models. We found that in silico geometric segmentation metrics might not correlate with clinical utility of the models. Experts' segmentation style and preference might affect model performance. FUNDING: US National Institutes of Health and EU European Research Council.

Bid outcome processing in Vickrey auctions: An ERP study.

Online retailers often sell products using a socially competitive second-price sealed-bid auction known as a Vickrey auction (VA), an incentivized demand-revealing mechanism used to elicit players' subjective values. The VA presents a situation of risky decision-making, which typically implements value processing and a loss aversion mechanism. Neural outcome processing of VA bids are not known; this study explores this for the first time using EEG. Twenty-eight healthy participants bid on household items against an anonymous, computerized opponent. Bid outcome event-related potentials were predicted to differentiate between three conditions: outbid (no-win), large margin win (bargain), and small margin win (snatch). Individual loss aversion values were evaluated in a separate behavioral experiment offering gains or losses of variable amounts but equal chances against an assured gain. Processing outcomes of VA bids were associated with a feedback-related negativity (FRN) potential with a spatial maximum at the vertex (251-271 ms), where bargain win trials resulted in greater FRN amplitudes than snatch win trials. Additionally, a P300 potential was sensitive to win versus no-win outcomes and to retail price. Individual loss aversion level did not correlate with the strength of FRN or P300. Results show that outcome processing in a VA is associated with FRN that differentiates between relatively advantageous and less advantageous gains, and a P300 that distinguishes between the more and less expensive auction items. Our findings pave the way to an objective exploration of economic decision-making and purchasing behavior involving a widely popular auction.

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: a preliminary report of COV006, a phase 2 single-blind, randomised, controlled trial.

BACKGROUND: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults. METHODS: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344). FINDINGS: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC50 [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination. INTERPRETATION: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial. FUNDING: AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research.

Reducing Readmission of Hospitalized Patients With Depressive Symptoms: A Randomized Trial.

PURPOSE: To determine if hospitalized patients with depressive symptoms will benefit from post-discharge depression treatment with care transition support. METHODS: This is a randomized controlled trial of hospitalized patients with patient health questionnaire-9 score of 10 or more. We delivered the Re-Engineered Discharge (RED) and randomized participants to groups receiving RED-only or RED for Depression (RED-D), a 12-week post-discharge telehealth intervention including cognitive behavioral therapy, self-management support, and patient navigation. Primary outcomes were hospital readmission and reutilization rates at 30 and 90 days post discharge. RESULTS: We randomized 709 participants (353 RED-D, 356 RED-only). At 90 days, 265 (75%) intervention participants had received at least 1 RED-D session (median 4). At 30 days, the intention-to-treat analysis showed no differences between RED-D vs RED-only in hospital readmission (9% vs 10%, incidence rate ratio [IRR] 0.92 [95% CI, 0.56-1.52]) or reutilization (27% vs 24%, IRR 1.14 [95% CI, 0.85-1.54]). The intention-to-treat analysis also showed no differences at 90 days in readmission (28% vs 21%, IRR 1.30 [95% CI, 0.95-1.78]) or reutilization (70% vs 57%, IRR 1.22 [95% CI, 1.01-1.49]). In the as-treated analysis, each additional RED-D session was associated with a decrease in 30- and 90-day readmissions. At 30 days, among 104 participants receiving 3 or more sessions, there were fewer readmissions (3% vs 10%, IRR 0.30 [95% CI, 0.07-0.84]) compared with the control group. At 90 days, among 109 participants receiving 6 or more sessions, there were fewer readmissions (11% vs 21%, IRR 0.52 [95% CI, 0.27-0.92]). Intention-to-treat analysis showed no differences between study groups on secondary outcomes. CONCLUSIONS: Care transition support and post-discharge depression treatment can reduce unplanned hospital use with sufficient uptake of the RED-D intervention.

Daily space-time activities, multiple environmental exposures, and anxiety symptoms: A cross-sectional mobile phone-based sensing study.

BACKGROUND: Few mobility-based studies have investigated the associations between multiple environmental exposures, including social exposures, and mental health. OBJECTIVE: To assess how exposure to green space, blue space, noise, air pollution, and crowdedness along people's daily mobility paths are associated with anxiety symptoms. METHODS: 358 participants were cross-sectionally tracked with Global Positioning System (GPS)-enabled mobile phones. Anxiety symptoms were measured at baseline using the Generalized Anxiety Disorder-7 (GAD-7) questionnaire. Green space, blue space, noise, and air pollution were assessed based on concentric buffers of 50 m and 100 m around each GPS point. Crowdedness was measured by the number of nearby Bluetooth-enabled devices detected along the mobility paths. Multiple linear regressions with full covariate adjustment were fitted to examine anxiety-environmental exposures associations. Random forest models were applied to explore possible nonlinear associations and exposure interactions. RESULTS: Regression results showed null linear associations between GAD-7 scores and environmental exposures. Random forest models indicated that GAD-7-environment associations varied nonlinearly with exposure levels. We found a negative association between green space and GAD-7 scores only for participants with moderate green space exposure. We observed a positive association between GAD-7 scores and noise levels above 60 dB and air pollution concentrations above 17.2 µg m-3. Crowdedness was positively associated with GAD-7 scores, but exposure-response functions flattened out with pronounced crowdedness of >7.5. Blue space tended to be positively associated with GAD-7 scores. Random forest models ranked environmental exposures as more important to explain GAD-7 scores than linear models. CONCLUSIONS: Our findings indicate possible nonlinear associations between mobility-based environmental exposures and anxiety symptoms. More studies are needed to obtain an in-depth understanding of underlying anxiety-environment mechanisms during daily life.

Modified oral food challenge protocol approach in the diagnosis of Food Protein-Induced Enterocolitis Syndrome.

BACKGROUND: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE mediated food allergy most commonly presenting in infants. The most common food triggers include soy, cow's milk and grains. Symptoms may include intractable vomiting, diarrhea, lethargy, pallor, abdominal distention, hypotension and/or shock. Oral food challenges (OFCs) given at food protein dose of 0.06-0.6 g/kg in 3 equivalent doses administered over a few hours are recommended in guidelines to confirm a diagnosis. CASE PRESENTATION: The patient is a 6-month-old girl with a history of severe FPIES symptoms to egg. In our clinic, we perform OFC with 1/100 serving dose on visit 1 and then increase the dose monthly. The patient takes the tolerated dose daily at home between visits. An OFC to baked egg at 1/100 of a serving was performed and was well-tolerated on her initial visit. The patient remained on the same dose upon returning home. Within 1-week, she developed FPIES symptoms including watery diarrhea and severe emesis requiring ondansetron. She required an Emergency Department visit for one of the reactions. CONCLUSIONS: Our patient had severe FPIES symptoms with a small amount of egg. We believe that administration of three large food challenge doses on one clinic visit, as guidelines currently suggest, does not allow adequate time for symptoms to appear. Our patient likely would have suffered a severe reaction. Also, this guidelines protocol does not allow for monitoring of more delayed or chronic FPIES. We propose a modified protocol to OFCs with cautious up-dosing to allow for safer OFCs and monitoring of chronic FPIES. We have implemented an OFC approach where only one food challenge dose (starting with 1/100 of final dose) is given at each visit. The up-titration of the dose is completed every 4-weeks with one dose only. When the serving sized dose is reached and tolerated, the food can be maintained in the diet.

To vax or not to vax: Predictors of anti-vax attitudes and COVID-19 vaccine hesitancy prior to widespread vaccine availability.

The novel coronavirus (COVID-19) is a highly contagious disease responsible for millions of deaths worldwide. Effective vaccines against COVID-19 are now available, however, an extreme form of vaccine hesitancy known as anti-vax attitudes challenge vaccine acceptance and distribution efforts. To understand these anti-vax attitudes and their associated psychological characteristics, we examined several predictors of vaccine hesitancy for COVID-19 and anti-vax attitudes generally. We surveyed 1004 adults (M = 47.0 years, SD = 17.1 years, range 18-98 years) in September-October 2020 across the United States (51% female, 49% male; 76.5% White, 23.5% non-White), prior to widespread availability of the COVID-19 vaccines. Attitudes toward vaccinations were influenced by a variety of factors, especially political attitudes. We should therefore anticipate and attempt to mitigate these challenges to achieving widespread vaccination to reduce the spread of COVID-19 and other communicable diseases.