Impact of unitary synaptic inhibition on spike timing in ventral tegmental area dopamine neurons.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents (uIPSCs) produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus (RMTg) and ventral pallidum (VP) afferents. We next determined the phase resetting curve (PRC), the reversal potential for GABAA receptor-mediated IPSCs, and the average inter-spike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the inter-spike interval (ISI), or phase. Simulations were performed to predict the pause duration resulting from synchronous arrival of multiple uIPSGs, and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns like those observed in vivo.Significance Statement This study dissects the input-output relationship of VTA dopamine neurons receiving inputs from single presynaptic inhibitory neurons. We measured unitary IPSCs from two major inhibitory inputs (the RMTg and VP) and simulated their impact on dopamine neuron firing based on new experimental data including the phase resetting curve (PRC) and the reversal potential of the GABAA receptor-mediated currents. The results predict the impact of single and multiple unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and suggest that asynchronous, low-frequency inhibition can summate in a supralinear manner to powerfully slow or halt a dopamine neuron's firing.

A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy.

Real-time monitoring of dynamic biological processes in the body is critical to understanding disease progression and treatment response. This data, for instance, can help address the lower than 50% response rates to cancer immunotherapy. However, current clinical imaging modalities lack the molecular contrast, resolution, and chronic usability for rapid and accurate response assessments. Here, we present a fully wireless image sensor featuring a 2.5$\times$5 mm$^2$ CMOS integrated circuit for multicolor fluorescence imaging deep in tissue. The sensor operates wirelessly via ultrasound (US) at 5 cm depth in oil, harvesting energy with 221 mW/cm$^{2}$ incident US power density (31% of FDA limits) and backscattering data at 13 kbps with a bit error rate <$10^{-6}$. In-situ fluorescence excitation is provided by micro-laser diodes controlled with a programmable on-chip driver. An optical frontend combining a multi-bandpass interference filter and a fiber optic plate provides >6 OD excitation blocking and enables three-color imaging for detecting multiple cell types. A 36$\times$40-pixel array captures images with <125 $\mu$m resolution. We demonstrate wireless, dual-color fluorescence imaging of both effector and suppressor immune cells in ex vivo mouse tumor samples with and without immunotherapy. These results show promise for providing rapid insight into therapeutic response and resistance, guiding personalized medicine.

Preliminary assessment of blood mercury contamination in four African crocodile species.

Heavy metal contamination in the environment is an increasingly pervasive threat to the long-term persistence of wildlife. As high trophic level consumers, crocodylians are at substantial risk from bioaccumulation of mercury (Hg). Despite that they are generally well-studied and the focal species of many conservation efforts around the world, little is known about Hg contamination levels in most crocodylians. Here we preliminarily evaluate blood Hg contamination in four African species - Central African slender-snouted crocodile (Mecistops leptorhynchus), African dwarf crocodile (Osteolaemus tetraspis), West African crocodile (Crocodylus suchus), and Nile crocodile (Crocodylus niloticus) - from a diversity of sites and habitats across 5 different countries representing varying degrees of environmental pollution. All of our sampled crocodiles were Hg contaminated and, worryingly, these African crocodiles generally showed the highest levels of Hg contamination of any crocodylian species examined to date. Of most concern was that Hg concentrations were not only highest in M. leptorhynchus, the most threatened amongst our study species, but also in individuals sampled in what are believed to be some of the most remote and pristine natural areas left in Africa - Gabon's national parks. Our results underscore the need to better understand the impact of longstanding petroleum, mining, forestry, and agricultural industries on the entire aquatic food chain throughout much of Africa, including on the threatened species in these habitats and the human populations that depend on them for their subsistence and livelihoods.

Incorporating social determinants of health into transmission modeling of COVID-19 vaccine in the US: a scoping review.

During COVID-19 in the US, social determinants of health (SDH) have driven health disparities. However, the use of SDH in COVID-19 vaccine modeling is unclear. This review aimed to summarize the current landscape of incorporating SDH into COVID-19 vaccine transmission modeling in the US. Medline and Embase were searched up to October 2022. We included studies that used transmission modeling to assess the effects of COVID-19 vaccine strategies in the US. Studies' characteristics, factors incorporated into models, and approaches to incorporate these factors were extracted. Ninety-two studies were included. Of these, 11 studies incorporated SDH factors (alone or combined with demographic factors). Various sets of SDH factors were integrated, with occupation being the most common (8 studies), followed by geographical location (5 studies). The results show that few studies incorporate SDHs into their models, highlighting the need for research on SDH impact and approaches to incorporating SDH into modeling. Funding: This research was funded by the Centers for Disease Control and Prevention (CDC).

New-onset diabetes is a predictive risk factor for pancreatic lesions in high-risk individuals: An observational cohort study.

Background and Objectives: Pancreatic cancer (PC) is the third cause of cancer-related deaths. Early detection and interception of premalignant pancreatic lesions represent a promising strategy to improve outcomes. We evaluated risk factors of focal pancreatic lesions (FPLs) in asymptomatic individuals at hereditary high risk for PC. Methods: This is an observational single-institution cohort study conducted over a period of 5 years. Surveillance was performed through imaging studies (EUS or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and serum biomarkers. We collected demographic characteristics and used univariate and multivariate logistic regression models to evaluate associations between potential risk factors and odd ratios (ORs) for FPL development. Results: A total of 205 patients completed baseline screening. Patients were followed up to 53 months. We detected FPL in 37 patients (18%) at baseline; 2 patients had lesions progression during follow-up period, 1 of them to PC. Furthermore, 13 patients developed new FPLs during the follow-up period. Univariate and multivariate analyses revealed that new-onset diabetes (NOD) is strongly associated with the presence of FPL (OR, 10.94 [95% confidence interval, 3.01-51.79; P < 0.001]; OR, 9.98 [95% confidence interval, 2.15-46.33; P = 0.003]). Follow-up data analysis revealed that NOD is also predictive of lesions progression or development of new lesions during screening (26.7% vs. 2.6%; P = 0.005). Conclusions: In a PC high-risk cohort, NOD is significantly associated with presence of FPL at baseline and predictive of lesions progression or new lesions during surveillance.

Effect of surgical approach on early return to intended oncologic therapy after resection for pancreatic ductal adenocarcinoma.

BACKGROUND: Although robotic pancreatectomy may facilitate an earlier functional recovery, the impact of a robotic pancreatectomy program during its early experience on the timing of return to intended oncologic therapy (RIOT) after surgery is unknown. METHODS: In this retrospective cohort study, we used propensity score matching with a 1:2 ratio to compare patients who underwent robotic or open surgery (distal pancreatectomy or pancreatoduodenectomy) for pancreatic ductal adenocarcinoma (PDAC) during the first 3 years of our robotic pancreatectomy experience (January 2018-December 2021). Generalized estimating equations modeling was used to evaluate the effect of surgical approach on early RIOT, defined as adjuvant chemotherapy initiation within 8 weeks after surgery, and late RIOT, defined as initiation within 12 weeks after surgery. RESULTS: The matched cohort included 26 patients who underwent robotic pancreatectomy and 52 patients who underwent open pancreatectomy. Rates of receipt of adjuvant chemotherapy were 96.2% and 78.9%, respectively. Rate of early RIOT in the robotic group (73.1% was higher than that in the open group (44.2%; P = 0.018). In multivariable analysis, a robotic approach was associated with early RIOT (odds ratio, 3.54; 95% confidence interval 1.08-11.62; P = 0.038). Surgical approach did not impact late RIOT (odds ratio, 3.21; 95% confidence interval 0.71-14.38; P = 0.128). CONCLUSIONS: Compared with open pancreatectomy, robotic pancreatectomy did not delay RIOT. In fact, odds of early RIOT were increased, which supports the oncological safety of our robotic pancreatectomy program during its implementation.

Conversion of an outpatient pharmacy to a mail-order pharmacy within a health system.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The establishment of a new outpatient pharmacy provided a strategic opportunity to repurpose and convert an existing outpatient pharmacy into a closed-door mail-order pharmacy within a health system. This article describes the steps taken to successfully make this change and evaluates the impact. SUMMARY: The mail-order pharmacy conversion project was divided into 3 phases: phase 1 (before conversion) from July through August 2022, phase 2 (conversion) from October through November 2022, and phase 3 (after conversion) from December 2022 through February 2023. Phase 1 included standardizing workflows with standard operating procedure (SOP) development, improving automation, determining staffing ratios, gathering baseline staff engagement data, and identifying primary and secondary outcomes of interest. Phase 2 encompassed SOP implementation and training of mail-order team members. Phase 3 involved evaluating available pharmacy floorspace, marketing mail-order services, and the second distribution of the staff engagement survey. The measured outcomes of this project were total prescription volumes, increase in total revenue, and staff engagement. Data collection was completed in phase 3. CONCLUSION: The existing outpatient pharmacy was successfully converted to a closed-door pharmacy, and the associated prescription volume increased. Developing a strategic action plan to establish SOPs, calculate staffing performance metrics, and identify opportunities for growth and engaging frontline team members were essential to the success of this project.

Observations of diapycnal upwelling within a sloping submarine canyon.

Small-scale turbulent mixing drives the upwelling of deep water masses in the abyssal ocean as part of the global overturning circulation1. However, the processes leading to mixing and the pathways through which this upwelling occurs remain insufficiently understood. Recent observational and theoretical work2-5 has suggested that deep-water upwelling may occur along the ocean's sloping seafloor; however, evidence has, so far, been indirect. Here we show vigorous near-bottom upwelling across isopycnals at a rate of the order of 100 metres per day, coupled with adiabatic exchange of near-boundary and interior fluid. These observations were made using a dye released close to the seafloor within a sloping submarine canyon, and they provide direct evidence of strong, bottom-focused diapycnal upwelling in the deep ocean. This supports previous suggestions that mixing at topographic features, such as canyons, leads to globally significant upwelling3,6-8. The upwelling rates observed were approximately 10,000 times higher than the global average value required for approximately 30 × 106 m3 s-1 of net upwelling globally9.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Differences in Volatile Organic Compounds Between Concussed and Non-concussed Division I Athletes.

Introduction Diagnosing a concussion is challenging because of complex and variable symptoms. Establishing a viable biomarker of injury may rely on physiologic measurements rather than symptomology. Volatile organic compounds (VOCs) such as breath acetone have been identified as potential physiological markers that can capture changes in the utilization of energy substrates post-concussion. Here, we aimed to explore whether differences in VOCs exist between concussed and non-concussed athletes at the initial and later stages of injury recovery. Methods Six (N=6) non-concussed athletes were enrolled as control participants prior to the competitive season. Control participants' breath acetone, heart rate, and anthropometric measures were obtained at rest and throughout a single exercise challenge by breathalyzer. Six (N=6) athletes diagnosed with concussion during the competitive season had breath acetone measured daily until cleared to return to activity or approximately four weeks following enrollment where they participated in an exit exercise challenge having breath acetone, heart rate, and anthropometric measures obtained. Comparisons were made between at-rest measures of concussed and non-concussed participants at multiple time points during the recovery period. Paired t-test comparisons with individuals serving as their own control were used to determine individual differences in recovery. Visual graphs were used to demonstrate differences in obtained measures amongst individuals and between groups during the exercise challenges. Results Results demonstrated statistically significant differences in breath acetone between concussed and control participants when the highest day measured during the first week of concussion was compared to the control participant's resting values (P=0.017). Additionally, when the concussed participants served as their own control and their highest measured day of the first week post-concussion was compared to values when cleared to return to activity or at 26 days post-concussion, there was a significant difference in breath acetone (P=0.028). Comparing breath acetone during exercise between non-concussed and cleared concussed participants or four weeks post-injury, demonstrated no significant differences throughout the challenge or at rest prior. Visual graph comparisons in a single participant before and after concussion suggest differences may appear following exercise during the recovery period. Discussion These results suggest VOCs, particularly breath acetone, have the potential to serve as diagnostic markers of concussion. However, longitudinal research within larger cohorts and with equipment able to expel VOCs other than acetone from measures are needed to make informed recommendations.

Intra-neighborhood associations between residential greenness and blood pressure.

INTRODUCTION: Previous investigations have reported that individuals living in greener neighborhoods have better cardiovascular health. It is unclear whether the effects reported at large geographic scales persist when examined at an intra-neighborhood level. The effects of greenness have not been thoroughly examined using high-resolution metrics of greenness exposure, and how they vary with spatial scales of assessment or participant characteristics. METHODS: We conducted a cross-sectional assessment of associations between blood pressure and multiple high-resolution measures of residential area greenness in spatially concentrated HEAL Study cohort of the Green Heart Project. We employed generalized linear models, accounting for individual-level covariates, to examine associations between different high-resolution measures of greenness and blood pressure among 667 participants in a 4 sq. mile contiguous neighborhood area in Louisville, KY. RESULTS: In adjusted models, we observed significant inverse associations between residential greenness, measured by leaf area index (LAI), and systolic blood pressure (SBP) within 150-250 m and 500 m of homes, but not for Normalized Difference Vegetation Index (NDVI) or grass cover. Weaker associations were also found with diastolic blood pressure (DBP). Significant positive associations were observed between LAI and SBP among participants who reported being female, White, without obesity, non-exercisers, non-smokers, younger age, of lower income, and who had high nearby roadway traffic. We found few significant associations between grass cover and SBP, but an inverse association in those with obesity, but positive associations for those without obesity. CONCLUSIONS: We found that leaf surface area of trees around participants home is strongly associated with lower blood pressure, with little association with grass cover. These effects varied with participant characteristics and spatial scales. More research is needed to test causative links between greenspace types and cardiovascular health and to develop population-, typology-, and place-based evidence to inform greening interventions.

Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in haematopoietic stem and progenitor cells.

Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis-the non-pathogenic hyper-production of red blood cells-that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34+ human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a ß-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.

An Amygdalar-Vagal-Glandular Circuit Controls the Intestinal Microbiome.

Psychological states can regulate intestinal mucosal immunity by altering the gut microbiome. However, the link between the brain and microbiome composition remains elusive. We show that Brunner's glands in the duodenal submucosa couple brain activity to intestinal bacterial homeostasis. Brunner's glands mediated the enrichment of gut probiotic species in response to stimulation of abdominal vagal fibers. Cell-specific ablation of the glands triggered transmissible dysbiosis associated with an immunodeficiency syndrome that led to mortality upon gut infection with pathogens. The syndrome could be largely prevented by oral or intra-intestinal administration of probiotics. In the forebrain, we identified a vagally-mediated, polysynaptic circuit connecting the glands of Brunner to the central nucleus of the amygdala. Intra-vital imaging revealed that excitation of central amygdala neurons activated Brunner's glands and promoted the growth of probiotic populations. Our findings unveil a vagal-glandular neuroimmune circuitry that may be targeted for the modulation of the gut microbiome. The glands of Brunner may be the critical cells that regulate the levels of Lactobacilli species in the intestine.

Neurodevelopment in preschool children exposed and unexposed to Zika virus in utero in Nicaragua: a prospective cohort study.

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Recent and anticipated novel drug approvals (Q2 2024 through Q1 2025).

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. SUMMARY: Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic L-amino acid decarboxylase deficiency. CONCLUSION: The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Does theta synchronicity of sensory information enhance associative memory? Replicating the theta-induced memory effect.

The binding of information from different sensory or neural sources is critical for associative memory. Previous research in animals suggested that the timing of theta oscillations in the hippocampus is critical for long-term potentiation, which underlies associative and episodic memory. Studies with human participants showed correlations between theta oscillations in medial temporal lobe and episodic memory. Clouter et al. directly investigated this link by modulating the intensity of the luminance and the sound of the video clips so that they 'flickered' at certain frequencies and with varying synchronicity between the visual and auditory streams. Across several experiments, better memory was found for stimuli that flickered synchronously at theta frequency compared with no-flicker, asynchronous theta, or synchronous alpha and delta frequencies. This effect - which they called the theta-induced memory effect - is consistent with the importance of theta synchronicity for long-term potentiation. In addition, electroencephalography data showed entrainment of cortical regions to the visual and auditory flicker, and that synchronicity was achieved in neuronal oscillations (with a fixed delay between visual and auditory streams). The theoretical importance, large effect size, and potential application to enhance real-world memory mean that a replication of theta-induced memory effect would be highly valuable. The present study aimed to replicate the key differences among synchronous theta, asynchronous theta, synchronous delta, and no-flicker conditions, but within a single experiment. The results do not show evidence of improved memory for theta synchronicity in any of the comparisons. We suggest a reinterpretation of theta-induced memory effect to accommodate this non-replication.