Vertical Transmission of SARS-CoV-2-Specific Antibodies and Cytokine Profiles in Pregnancy.

Despite intensive characterization of immune responses after COVID-19 infection and vaccination, research examining protective correlates of vertical transmission in pregnancy are limited. Herein, we profiled humoral and cellular characteristics in pregnant women infected or vaccinated at different trimesters and in their corresponding newborns. We noted a significant correlation between spike S1-specific IgG antibody and its RBD-ACE2 blocking activity (receptor-binding domain-human angiotensin-converting enzyme 2) in maternal and cord plasma (P < .001, R > 0.90). Blocking activity of spike S1-specific IgG was significantly higher in pregnant women infected during the third trimester than the first and second trimesters. Elevated levels of 28 cytokines/chemokines, mainly proinflammatory, were noted in maternal plasma with infection at delivery, while cord plasma with maternal infection 2 weeks before delivery exhibited the emergence of anti-inflammatory cytokines. Our data support vertical transmission of protective SARS-CoV-2-specific antibodies. This vertical antibody transmission and the presence of anti-inflammatory cytokines in cord blood may offset adverse outcomes of inflammation in exposed newborns.

Novel non-linear models for clinical trial analysis with longitudinal data: A tutorial using SAS for both frequentist and Bayesian methods.

Longitudinal data from clinical trials are commonly analyzed using mixed models for repeated measures (MMRM) when the time variable is categorical or linear mixed-effects models (ie, random effects model) when the time variable is continuous. In these models, statistical inference is typically based on the absolute difference in the adjusted mean change (for categorical time) or the rate of change (for continuous time). Previously, we proposed a novel approach: modeling the percentage reduction in disease progression associated with the treatment relative to the placebo decline using proportional models. This concept of proportionality provides an innovative and flexible method for simultaneously modeling different cohorts, multivariate endpoints, and jointly modeling continuous and survival endpoints. Through simulated data, we demonstrate the implementation of these models using SAS procedures in both frequentist and Bayesian approaches. Additionally, we introduce a novel method for implementing MMRM models (ie, analysis of response profile) using the nlmixed procedure.

Return to Driving Following Moderate-to-Severe Traumatic Brain Injury: A TBI Model System Longitudinal Investigation.

OBJECTIVE: To examine longitudinal patterns of return to driving (RTD), driving habits, and crash rates associated with moderate-to-severe traumatic brain injury (TBI). SETTING: Eight TBI Model System sites. PARTICIPANTS: Adults (N = 334) with TBI that required inpatient acute rehabilitation with follow-up of 197 and 218 at 1 and 2 years post-injury, respectively. Data collection at 2 years occurred almost exclusively during the pandemic, which may have affected results. DESIGN: Longitudinal and observational. MAIN MEASURES: Driving survey completed during rehabilitation and at phone follow-up 1 and 2 years after injury. RESULTS: The rate of RTD was 65% at 1-year follow-up and 70% at 2-year follow-up. RTD at both follow-up time points was positively associated with family income. The frequency of driving and distance driven were diminished compared to before injury. Limitation of challenging driving situations (heavy traffic, bad weather, and at night) was reported at higher rates post-injury than before injury. Crash rates were 14.9% in the year prior to injury (excluding crashes that resulted in TBI), 9.9% in the first year post-injury, and 6% during the second year. CONCLUSION: RTD is common after TBI, although driving may be limited in terms of frequency, distance driven, and avoiding challenging situations compared to before injury. Incidence of crashes is higher than population-based statistics; however, those who sustain TBI may be at higher risk even prior to injury. Future work is needed to better identify characteristics that influence the likelihood of crashes post-TBI.

Does phenology influence predation rate on Salmo trutta parr during lake migration?

Acoustic tags fitted with predation sensors, which trigger following ingestion by piscivorous predators, were used to compare direct predation rates during downstream migration (out-migration) of potamodromous (freshwater) brown trout (Salmo trutta L.) parr from their natal river into a large freshwater lake system during spring and autumn. Thirty-eight spring migrants were tagged across two study years (2021 and 2022) of which 13 individuals (34%) were predated. By contrast 40 autumn migrants were tagged (2020 and 2021) of which three individuals (7.5%) experienced predation. The overall predation loss rate for spring migrants was 0.342% day-1 and was 0.075% day-1 for autumn migrants. Most predation events during spring (77%) occurred within the lower river before tagged fish entered the lake, whilst no predation events were recorded within the river in the autumn. Predation events were significantly linked to tagging season (spring or autumn), with the probability of tags remaining untriggered (as a proxy for survival) being higher 93% (95% confidence interval [CI] [87%, 100%]) in autumn than in spring 66% (95% CI [53%, 83%]). The spring migration periods showed significantly lower river discharge (0.321 m3 /s mean daily discharge, April 1 to May 31) to those measured during autumn (1.056 m3 /s mean daily discharge, October 1 to November 30) (Mann-Whitney U-test, U = 1149, p < 0.001). Lower flows, clearer water, and longer sojourn in the river may have contributed to greater predation losses in the spring relative to the autumn.

Migration patterns and navigation cues of Atlantic salmon post-smolts migrating from 12 rivers through the coastal zones around the Irish Sea.

The freshwater phase of the first seaward migration of juvenile Atlantic salmon (Salmo salar) is relatively well understood when compared with our understanding of the marine phase of their migration. In 2021, 1008 wild and 60 ranched Atlantic salmon smolts were tagged with acoustic transmitters in 12 rivers in England, Scotland, Northern Ireland and Ireland. Large marine receiver arrays were deployed in the Irish Sea at two locations: at the transition of the Irish Sea into the North Atlantic between Ireland and Scotland, and between southern Scotland and Northern Ireland, to examine the early phase of the marine migration of Atlantic salmon smolts. After leaving their natal rivers' post-smolt migration through the Irish Sea was rapid with minimum speeds ranging from 14.03 to 38.56 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal river, to 9.69-39.94 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal estuary. Population minimum migration success through the study area was strongly correlated with the distance of travel, populations further away from the point of entry to the open North Atlantic exhibited lower migration success. Post-smolts from different populations experienced different water temperatures on entering the North Atlantic. This was largely driven by the timing of their migration and may have significant consequences for feeding and ultimately survivorship. The influence of water currents on post-smolt movement was investigated using data from previously constructed numerical hydrodynamic models. Modeled water current data in the northern Irish Sea showed that post-smolts had a strong preference for migrating when the current direction was at around 283° (west-north-west) but did not migrate when exposed to strong currents in other directions. This is the most favorable direction for onward passage from the Irish Sea to the continental shelf edge current, a known accumulation point for migrating post-smolts. These results strongly indicate that post-smolts migrating through the coastal marine environment are: (1) not simply migrating by current following (2) engage in active directional swimming (3) have an intrinsic sense of their migration direction and (4) can use cues other than water current direction to orientate during this part of their migration.

Determinants of riverine migration success by Atlantic salmon (Salmo salar) smolts from rivers across the UK and Ireland.

There is some evidence that the river migration success of Atlantic salmon smolts, on their first migration to sea, varies both spatially and temporally. However, we have only a poor understanding of what may be driving this variation. In this study, we used acoustic telemetry to quantify the spatial and temporal variations in river migration success in Atlantic salmon smolts on their first migration to sea. In total 4120 Atlantic salmon smolts migrating through 22 rivers in Scotland, England, Ireland, and Northern Ireland over multiple years were included in the study. Individuals were defined as successful migrants if detected leaving the river to enter marine waters. The results show significant temporal (up to 4 years) and spatial (river) variations in migration success, with overall between-river migration success varying from 3.4% to 97.0% and between years from 3.4% and 61.0%. Temporal variation in migration success was river specific, with some rivers being more temporally stable (exhibiting little variation between years) than others. Across all rivers and years, individual migration success was predicted positively by body condition and negatively by tag burden. The rate of migration success for a population (migration success standardized to a common river distance [proportion km-1]) was predicted by a number of environmental factors. The proportion of river catchment that comprised wetland and woodland positively predicted migration success, whereas the proportion of grassland and peatland in a catchment negatively predicted the rate of migration success. Although the mechanisms through which these effects may be operating were not directly examined in this study, we discuss some potential routes through which they may occur.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity.

This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

National Norms for Hospitalizations Due to Ambulatory Care Sensitive Conditions among Adults in the US.

BACKGROUND: Ambulatory care sensitive conditions (ACSCs) are acute or chronic health issues that lead to potentially preventable hospitalizations when not treated in the outpatient primary care setting. OBJECTIVE: To describe national hospitalization rates due to ACSCs among adult inpatients in the US. DESIGN: A retrospective cross-sectional analysis of the 2018 US National Inpatient Sample (NIS) dataset from the Healthcare Cost and Utilization Project at the Agency of Healthcare Research and Quality was completed in the year 2022. PARTICIPANTS: Participants were adult inpatients from community hospitals in 48 states of the US and District of Columbia. MAIN MEASURES: ACSC admission rates were calculated using ICD-10 codes and the Purdy ACSC definition. The admission rates were weighted to the US inpatient population and stratified by age, sex, and race. KEY RESULTS: ACSC hospitalization rates varied considerably across age and average number of hospitalizations varied across sex and race. ACSC hospitalization rates increased with age, male sex, and Native American and Black race. The most common ACSCs were pneumonia, diabetes, and congestive heart failure. CONCLUSIONS: Previous studies have emphasized the importance of preventable hospitalizations, however, the national rates for ACSC hospitalizations across all ages in the US have not been reported. The national rates presented will facilitate comparisons to identify hospitals and health care systems with higher-than-expected rates of ACSC admissions that may suggest a need for improved primary care services.

Brain and Systemic Inflammation in De Novo Parkinson's Disease.

OBJECTIVE: To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD). BACKGROUND: Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression. METHODS: We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18 F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented. RESULTS: Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased 18 F-DPA-714 signal in PD subjects. 18 F-DPA-714 signal correlated with several cognitive measures and some chemokines. CONCLUSIONS: 18 F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3.

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.

Crash Risk Following Return to Driving After Moderate-to-Severe TBI: A TBI Model Systems Study.

OBJECTIVE: To examine motor vehicle crash frequency and risk factors following moderate-to-severe traumatic brain injury (TBI). SETTING: Eight TBI Model Systems sites. Participants: Adults ( N = 438) with TBI who required inpatient acute rehabilitation. DESIGN: Cross-sectional, observational design. MAIN MEASURES: Driving survey completed at phone follow-up 1 to 30 years after injury. RESULTS: TBI participants reported 1.5 to 2.5 times the frequency of crashes noted in the general population depending on the time frame queried, even when accounting for unreported crashes. Most reported having no crashes; for those who experienced a crash, half of them reported a single incident. Based on logistic regression, age at survey, years since injury, and perception of driving skills were significantly associated with crashes. CONCLUSION: Compared with national statistics, crash risk is higher following TBI based on self-report. Older age and less time since resuming driving were associated with lower crash risk. When driving was resumed was not associated with crash risk. These results do not justify restricting people from driving after TBI, given that the most who resumed driving did not report experiencing any crashes. However, there is a need to identify and address factors that increase crash risk after TBI.

Barriers to driving and psychosocial outcomes after traumatic brain injury.

OBJECTIVE: Examine considerations and perceived barriers to return to driving, and their association with psychosocial outcomes among adults with traumatic brain injury (TBI) who were not driving. METHODS: 174 adults with moderate-to-severe TBI enrolled in the TBI Model System participated in this cross-sectional study. All participants were drivers prior to their TBI. Outcome measures included the Barriers to Driving Questionnaire, Disability Rating Scale, Patient Health Questionnaire-9, General Anxiety Disorder-7, and Satisfaction With Life Scale. Descriptive analyses examined considerations and barriers to driving, including differences associated with demographic characteristics. Moderation analyses investigated the extent to which disability moderated the relationship between barriers and psychosocial outcomes. RESULTS: Social barriers were the most strongly endorsed domain, whereas physical barriers were endorsed least. The profile of endorsements differed for men and women, and for Black and White participants, on both theoretical considerations in returning to drive and experiences of barriers in doing so. Disability level moderated the relationship between barriers to driving and depression and life satisfaction, but not anxiety. CONCLUSION: The experience of barriers to driving is differentially associated with psychosocial outcomes among nondriving adults with TBI. Adults with low disability appear to be at risk for distress, even compared to other nondrivers.

Programmed acoustic tags reveal novel information on late-phase marine life in Atlantic salmon, Salmo salar.

This pilot study used programmed acoustic tags implanted into Salmo salar smolts, in conjunction with an extensive offshore marine receiver array, to investigate late-stage migratory behaviour and survival of returning adult salmon. A total of 100 smolts were tagged in 2020, and a number of individuals were successfully detected as returning adults in 2021. After detection efficiency was accounted for, 5-9 adults were estimated to have returned to the offshore array c. 45 km from the river mouth. A total of three fish were subsequently detected in the river. Losses of between 40% and 66% were evident during the final stages of ocean migration, and one tagged fish provided direct evidence of a predation event.

Post-Processing Automatic Transcriptions with Machine Learning for Verbal Fluency Scoring.

Objective: To compare verbal fluency scores derived from manual transcriptions to those obtained using automatic speech recognition enhanced with machine learning classifiers. Methods: Using Amazon Web Services, we automatically transcribed verbal fluency recordings from 1400 individuals who performed both animal and letter F verbal fluency tasks. We manually adjusted timings and contents of the automatic transcriptions to obtain "gold standard" transcriptions. To make automatic scoring possible, we trained machine learning classifiers to discern between valid and invalid utterances. We then calculated and compared verbal fluency scores from the manual and automatic transcriptions. Results: For both animal and letter fluency tasks, we achieved good separation of valid versus invalid utterances. Verbal fluency scores calculated based on automatic transcriptions showed high correlation with those calculated after manual correction. Conclusion: Many techniques for scoring verbal fluency word lists require accurate transcriptions with word timings. We show that machine learning methods can be applied to improve off-the-shelf ASR for this purpose. These automatically derived scores may be satisfactory for some applications. Low correlations among some of the scores indicate the need for improvement in automatic speech recognition before a fully automatic approach can be reliably implemented.

Distinct Homologous and Variant-Specific Memory B-Cell and Antibody Response Over Time After Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccination.

The durability of protective humoral immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection is largely dependent on the generation and persistence of antigen-specific isotype-switched memory B cells (MBCs) and long-lived plasma cells that reside in the bone marrow and secrete high-affinity neutralizing antibodies. The reactivity of vaccine-induced MBCs to emerging clinically significant SARS-CoV-2 variants of concern (VoCs) is largely unknown. In a longitudinal cohort study (up to 6 months following coronavirus disease 2019 messenger RNA vaccination), we measured MBCs in concert with other functional antibody measures. We found statistically significant differences between the frequencies of MBCs responding to homologous and VoC (Beta, Gamma, and Delta) receptor-binding domains after vaccination that persisted over time. In concert with a waning antibody response, the reduced MBC response to VoCs could translate to a weaker subsequent recall immune response and increased susceptibility to the emerging SARS-CoV-2 variant strains after vaccination.

The Influence of Sex, Body Mass Index, and Age on Cellular and Humoral Immune Responses Against Measles After a Third Dose of Measles-Mumps-Rubella Vaccine.

BACKGROUND: A third dose of measles-mumps-rubella vaccine (MMR3) is recommended in mumps outbreak scenarios, but the immune response and the need for widespread use of MMR3 remain uncertain. Herein, we characterized measles-specific immune responses to MMR3 in a cohort of 232 healthy subjects. METHODS: Serum and peripheral blood mononuclear cells (PBMCs) were sampled at day 0 and day 28 after MMR3. Measles-specific binding and neutralizing antibodies were quantified in sera by enzyme-linked immunosorbent assay and a microneutralization assay, respectively. PBMCs were stimulated with inactivated measles virus, and the release of cytokines/chemokines was assessed by a multiplex assay. Demographic variables of subjects were examined for potential correlations with immune outcomes. RESULTS: Of the study participants, 95.69% and 100% were seropositive at day 0 and day 28, respectively. Antibody avidity significantly increased from 38.08% at day 0 to 42.8% at day 28 (P = .00026). Neutralizing antibodies were significantly enhanced, from 928.7 at day 0 to 1289.64 mIU/mL at day 28 (P = .0001). Meanwhile, cytokine/chemokine responses remained largely unchanged. Body mass index was significantly correlated with the levels of inflammatory cytokines/chemokines. CONCLUSIONS: Measles-specific humoral immune responses, but not cellular responses, were enhanced after MMR3 receipt, extending current understanding of immune responses to MMR3 and supporting MMR3 administration to seronegative or high-risk individuals.

A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide, ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours.

BACKGROUND: We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. METHODS: We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours. RESULTS: Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease. CONCLUSIONS: Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.