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Abstract Background/objectives Epileptiform activity (EA), including seizures and periodic patterns, worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized control trials (RCTs) assessing anti‐seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, and complex physiology of acute brain injury, RCTs are lacking or hindered by design constraints. We used a pharmacological model‐guided simulator to design and determine the feasibility of RCTs evaluating EA treatment. Methods In a single‐center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic‐pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework, we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. Results Sample sizes ranged from 500 for levetiracetam 7 mg/kg versus placebo, to >4000 for levetiracetam 15 versus 7 mg/kg to achieve 80% power (5% type I error). For propofol 1 mg/kg/h versus placebo, 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. Conclusions Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo‐control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and propose use of this simulation‐based RCT paradigm to assess the feasibility of future trials of anti‐seizure treatment in acute brain injury.

Abstract Aims The aim of this study is to evaluate and compare the impact of the bicaval technique versus the biatrial technique (by Lower and Shumway) in paediatric heart transplant patients. Only a few studies investigate this matter regarding the long‐term outcome after paediatric heart transplantation. We compared the two surgical methods regarding survival, the necessity of pacemaker implantation. Methods and results All 134 patients (aged

Abstract Background Apparently healthy dogs of various breeds eating nontraditional, high‐pulse diets can have larger left ventricular diameter, lower systolic function, and more ventricular premature complexes (VPCs) compared with dogs eating traditional, low‐pulse diets. It is unknown whether Irish Wolfhounds eating high‐pulse diets have similar cardiac abnormalities. Hypothesis/Objectives To compare electrocardiographic and echocardiographic findings between Irish Wolfhounds eating high‐ or low‐pulse diets. Animals Ninety‐seven Irish Wolfhounds. Methods Retrospective study of Irish Wolfhounds that had echocardiography performed at dog shows between October 2018 and May 2021. Demographic information, echocardiographic measurements, cardiac rhythm (1‐minute lead II rhythm strip), and main diet were recorded retrospectively. Diets were classified as high‐pulse or low‐pulse based on the presence and location of pulses (peas, lentils, chickpeas, or dry beans) on the ingredient list. Results Thirty‐five of 97 Irish Wolfhounds (36%) were eating high‐pulse diets and 62 of 97 (64%) were eating low‐pulse diets. There were no significant differences between diet groups in echocardiographic measurements. A significantly higher percentage of dogs in the high‐pulse diet group (6/35 [17%]) had VPCs compared with those in the low‐pulse diet group (1/62 [2%]; effect size = 0.15 [95% confidence interval: 0.004‐0.31]; P = .005). Conclusions and Clinical Importance In this retrospective study of apparently healthy Irish Wolfhounds, high‐pulse diets were associated with a higher prevalence of VPCs which could represent early cardiac abnormalities.

Abstract Boron to calcium (B/Ca) records in benthic foraminifera, used for reconstructing the carbonate ion saturation state (ΔCO3) of the deep ocean, suggest that carbon sequestration in the Southern Pacific contributed to lowering atmospheric CO2 during the last glacial interval. However, the spatial and temporal extent of this storage is debated due to limited ΔCO3 records. To increase available ΔCO3 records, we explored using strontium and sulfur to calcium (Sr/Ca, S/Ca) in Planulina wuellerstorfi as additional proxies for ΔCO3 based on comparison with paired B/Ca down‐core records from Pacific Sites U1486 (1,332 m depth) and U1487 (874 m depth) cored during the International Ocean Discovery Program Expedition 363. The Sr/Ca and S/Ca records from P. wuellerstorfi closely covary with the B/Ca‐derived ΔCO3 records. Temperature, reconstructed using Uvigerina peregrina magnesium to calcium (Mg/Ca), has no discernible effect on Sr/Ca, whereas S/Ca also varies with Mg/Ca in both U. peregrina and P. wuellerstorfi, suggesting an additional temperature effect. Mg/Ca records from P. wuellerstorfi are affected by both temperature and ΔCO3. We assess calibrations of Sr/Ca to ΔCO3 for the Atlantic, Pacific, and Indian Oceans and recommend using the down‐core rather than core‐top calibrations as they yield consistent sensitivity, though with offsets, in all ocean basins. Reconstructing Pacific ΔCO3 records from sites U1486, U1487, and DSDP 593, we demonstrate the benefit of using Sr/Ca as an additional ΔCO3 proxy to assess the contribution of the Southern Pacific to the increase of atmospheric CO2 at glacial terminations.

Abstract Dams have negatively affected freshwater biodiversity throughout the world. These negative effects tend to be exacerbated for aquatic taxa with migratory life histories, and for taxa whose habitat is fundamentally altered by the formation of large reservoirs. Sauger (Sander candadensis; Percidae), large‐bodied migratory fishes native to North America, have seen population declines over much of the species' range, and dams are often implicated for their role in blocking access to spawning habitat and otherwise negatively affecting river habitat. Furthermore, hybridization appears to be more frequent between sauger and walleye in the reservoirs formed by large dams. In this study, we examine the role of dams in altering sauger population connectivity and facilitating hybridization with introduced walleye in Wyoming's Wind River and Bighorn River systems. We collected genomic data from individuals sampled over a large spatial scale and replicated sampling throughout the spawning season, with the intent to capture potential variation in hybridization prevalence or genomic divergence between sauger with different life histories. The timing of sampling was not related to hybridization prevalence or population divergence, suggesting limited genetic differences between sauger spawning in different time and places. Overall, there was limited hybridization detected, however, hybridization was most prevalent in Boysen Reservoir (a large impounded section of the Wind River). Dams in the lower Wind River and upper Bighorn River were associated with population divergence between sauger upstream and downstream of the dams, and demographic models suggest that this divergence has occurred in concordance with the construction of the dam. Sauger upstream of the dams exhibited substantially lower estimates of genetic diversity, which implies that disrupted connectivity between Wind River and Bighorn River sauger populations may already be causing negative demographic effects. This research points towards the importance of considering the evolutionary consequences of dams on fish populations in addition to the threats they pose to population persistence.

Abstract Background Mouse double minute‐2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. Methods This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high‐risk myelodysplastic syndromes. Results Seventy‐four patients (monotherapy, n = 57; milademetan‐AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14–21 days of 28‐day cycles as monotherapy and on Days 5–14 in combination with AZA. Dose‐limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment‐emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre‐existing below standard detection frequency by droplet digital polymerase chain reaction. Interpretation Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

Abstract Introduction Kazakhstan has one of the fastest‐growing HIV epidemics in the world, with increasing rates among adolescents and young adults (AYA). Innovative strategies are needed to increase HIV testing uptake and decrease HIV stigma among AYA. Citizen science, defined as the active engagement of the general public in scientific research tasks, promotes and facilitates community engagement throughout the research process. This citizen science study used crowdsourcing to engage AYA in Kazakhstan to develop a digital intervention to reduce HIV stigma and promote HIV self‐testing. Our objectives in this paper are to describe the approach used, its feasibility and acceptability, and AYA motivations for and lessons learned collaborating on the study. Methods From October 2021 to July 2022, in collaboration with a Community Collaborative Research Board and a Youth Advisory Board, we developed an open call requesting multimedia submissions to reduce HIV testing stigma. Eligible submissions were separated by age group (13−19 or 20−29 years) and judged by a panel composed of AYA (n = 23), healthcare professionals (n = 12), and representatives from the local government and non‐governmental organizations (n = 17). Each entry was reviewed by at least four judges and ranked on a 5‐point scale. The top 20 open call contestants were asked to submit self‐recordings sharing their motivation for and experience participating in the contest and lessons learned. Descriptive statistics were calculated for quantitative data. Qualitative data were coded using open coding. Results We received 96 submissions from 77 youth across Kazakhstan. Roughly, three‐quarters (n = 75/96) of entries met judging eligibility criteria. Of the eligible entries, over half (n = 39/75) scored 3.5 or higher on a 5‐point scale (70.0%). The most frequent types of entries were video (n = 36/96, 37.5%), image (n = 28/96, 29.2%) and text (n = 24/96, 25.0%). AYA's primary motivations for collaborating on the study included a desire to improve society and help youth. The main challenges included creating content to address complex information using simple language, finding reliable information online and technological limitations. Conclusions Crowdsourcing was feasible and highly acceptable among AYA in Kazakhstan. Citizen science approaches hold great promise for addressing the increasingly complex health and social challenges facing communities today.

Abstract Introduction There is a research gap in how mental health and cognition are associated with antiretroviral treatment (ART) adherence among people living with HIV (PLWH) in Kazakhstan. Methods We randomly selected and enrolled 230 PLWH from the Almaty City AIDS Center registry (June−November 2019) into a cross‐sectional study. We examined associations between self‐reported ART adherence for the last 1 and 2 weeks; the Adherence Self‐Efficacy Scale (ASES) and symptoms of depression (Patient Health Questionnaire‐9 [PHQ‐9]), anxiety (Generalized Anxiety Disorder tool [GAD‐7]), post‐traumatic stress disorder (PTSD Checklist [PTSD]); cognitive function (PROMIS v2.0 Adult Cognitive Function 8a short form) and forgetfulness (Forgetfulness Assessment Inventory). We used cut points of ≥5 for at least mild and ≥10 for at least moderate symptom severity for PHQ‐9 and GAD‐7 and of ≥44 for PTSD. Logistic and linear regression analyses were used. Results Participants’ median age was 40.0 (IQR: 34−47) with 40.9% (n = 94) of females in the sample. Those who missed at least one pill for the last 2 weeks had higher odds of reporting at least mild depression (aOR = 3.34, 95% CI: 1.22–9.11, p

Abstract Background Primary cutaneous B‐cell lymphoma (PCBCL) is a group of B‐cell lymphomas of the skin containing primary cutaneous follicle centre lymphoma (PCFCL) and marginal zone B‐cell lymphoma/lymphoproliferative disorder (PCMZL), which are indolent, and diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), which is aggressive. Objectives To evaluate treatment outcomes between PCBCL subtypes after treatment with rituximab and to compare the efficacy of intralesional against systemic rituximab in indolent subtypes. Methods A search for patients diagnosed with PCBCL and treated with rituximab (systemic or intralesional) across all Mayo Clinic sites was performed, yielding 39 patients. Results Eight patients had PCFCL (six treated intralesionally and two systemically), 11 had PCMZL (four intralesional, eight systemic with one dual‐treated) and 20 had PCDLBCL‐LT (all systemic). The average age at diagnosis was 62.1 years (SD = 15.1), with average follow‐up of 1852.6 days (SD = 1473.2). 69.2% of all patients treated with any form of rituximab experienced a complete response (100% PCFCL, 81.8% PCMZL and 50% PCDLBCL‐LT). When comparing all three subtypes, a significant difference was seen in overall treatment response (p = 0.022), and progressive disease rates (p = 0.015), but not in retreatment with rituximab (p = 0.440), time to retreatment (p = 0.757), recurrence (p = 0.907) or survival (p = 0.093). In the indolent subtypes, no difference in overall treatment response (p = 1.000), progressive disease rates (p = 1.000), recurrence (p = 0.650), rituximab retreatment (p = 0.650) or time to retreatment (p = 0.724) was observed. Conclusions This study suggests that rituximab, as systemic therapy and intralesional therapy, is effective in the management of PCBCL, and that intralesional therapy should be considered before more aggressive therapy in indolent disease.

Abstract Reconstruction of the marine inorganic carbon system relies on proxy signal carriers, such as element/calcium (El/Ca) ratios in foraminiferal shells. Concentrations of boron, lithium, strontium, and sulfur have been shown to vary with carbonate system parameters, but when comparing individual proxy reconstructions based on these elements, they are rarely in complete agreement. This is likely caused by the simultaneous effects of multiple environmental factors on element incorporation. Culture experiments with benthic foraminifera have revealed that the shell's S/Ca reflects the carbon chemistry and can potentially be used as a proxy for seawater [CO32−]. Aiming to investigate the application potential of sulfur incorporation for carbonate speciation reconstruction, we present S/Ca ratios in five planktonic foraminiferal species, namely Globigerina bulloides, Globigerinoides ruber albus, Globigerinoides ruber ruber, Trilobatus sacculifer, and Neogloboquadrina incompta from core‐top sediments in regions with contrasting [CO32−], [HCO3−], temperature, and salinity. Analyses of B/Ca and Mg/Ca ratios are included here since these elements have been shown to depend to a certain degree on carbon system parameters (e.g., calcite saturation state and pH, respectively) as well. Moreover, foraminiferal Mg/Ca values covary with S/Ca values and thereby might compromise its proxy application. In contrast to previously published results, this new data set shows a positive correlation between the incorporation of sulfur in the foraminifer's shell and seawater [CO32−]. As the incorporation of sulfur and magnesium are positively correlated, S/Mg values of the same foraminifera may be used to improve inorganic carbon system reconstructions.

Abstract Though survival outcomes among adolescents and young adults (AYAs) with lymphoma have improved over the last three decades, socially vulnerable populations including non‐White, low‐income, and publicly insured groups continue to trail behind on survival curves. These disparities, while likely the result of both biological and non‐biological factors, can be largely attributed to inequities in care over the full cancer continuum. Nationally representative studies have demonstrated that from diagnosis through therapy and into long‐term survivorship, socially vulnerable AYAs with lymphoma face barriers to care that impact their short and long‐term survival. Thus, improving outcomes for all AYAs with lymphoma requires dedicated study to understand, and then address the unique challenges faced by non‐White and low‐income lymphoma populations within this age group.

Abstract Background Previous studies in dogs with degenerative mitral valve disease (DMVD) have identified altered myocardial energy metabolism and oxidation, which might contribute to cardiac hypertrophy. Diets rich in medium chain fatty acids and antioxidants are a potential means of treatment. A previous clinical study found significantly smaller left atrial diameter (LAD) and left atrium‐to‐aorta diameter ratio (LA : Ao) in dogs with subclinical DMVD fed a specially formulated diet vs control diet for 6 months. Hypothesis/Objectives A specially formulated diet will slow or arrest left heart enlargement in dogs with subclinical DMVD over 365 days. Animals One hundred twenty‐seven dogs with unmedicated subclinical DMVD; 101 dogs in the per protocol cohort. Methods Randomized double‐blinded controlled multicenter clinical trial. Results The study's primary composite outcome measure was the sum of percentage change in LAD and left ventricular internal dimension at end‐diastole (LVIDd) at day 365. In the per protocol cohort, the outcome measure increased by 8.0% (95% confidence interval [CI], 2.9%‐13.1%) in dogs receiving the test diet vs 8.8% (95% CI, 5.1%‐12.5%) in dogs receiving control diet (P = .79). Neither component of the primary outcome measure was significantly different between groups (LAD, P = .65; LVIDd, P = .92). No difference was found in mitral valve E wave velocity (P = .36) or the proportion of dogs withdrawn from the study because of worsening DMVD and heart enlargement (P = .41). Conclusions and Clinical Importance Feeding a specially formulated diet for 365 days was not associated with a significantly different rate of change of left heart size in dogs with subclinical DMVD as compared to control.

Abstract SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L‐serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8‐year‐old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant‐negative N‐glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L‐serine.

Abstract Changes in Southern Ocean biological pump efficiency are frequently invoked as a source of glacial/interglacial CO2 variability. It was recently suggested that Southern Ocean biological pump weakening also contributed to Holocene CO2 increase. Here we test the causes and downstream effects of biological pump inefficiency during the Holocene. We first provide evidence that a southward shift of the South Westerly Winds, was likely the cause of increasing upwelling in the Southern Ocean leading to local biological pump weakening as reflected in fossil‐bound δ15N. We then introduce a series of ultra‐high resolution (6 m/ky) productivity records from the Chilean Margin to determine the fate of Southern Ocean nutrients. A compilation of records from Pacific sites supports export and complete consumption of preformed Southern Ocean nutrients, which might have reduced the contributions of Southern Ocean marine source to the Holocene increase in atmospheric CO2.

Abstract Practice‐based research networks (PBRNs) support the translation and evaluation of evidence‐based practices and interventions on a large scale and have primarily been used in primary care settings. Few pharmacy PBRNs exist. Our objective is to describe the composition and characteristics of the Rural Research Alliance of Community Pharmacies (RURAL‐CP), which is the first PBRN exclusively for rural community pharmacies. For each enrolled pharmacy, a pharmacist liaison completed a survey that assessed the pharmacy's operational characteristics, including business operations, human resource management, division of clinical responsibilities, technology and enhanced services, organizational context, and research priorities. Additionally, up to five other pharmacy staff members completed a brief survey on organizational context. Descriptive statistics were calculated. As of May 2023, there were 126 pharmacies across seven southeastern states that were enrolled in RURAL‐CP. Most pharmacies (91%) were independent pharmacies and operated 6 days per week (82%). On average, pharmacies employed 10 staff members and most trained student pharmacists. Pharmacies offered valuable services in their community, including immunizations, naloxone dispensing, and medication delivery. Blood glucose testing was the most common point‐of‐care (POC) test offered, and most pharmacies were interested in expanding POC offerings, particularly A1c testing and cholesterol screening. RURAL‐CP pharmacies have, on average, relatively strong organizational contexts and readiness for change. Pharmacists' top research priorities were expansion of clinical services, reimbursement, patient adherence, and addressing diabetes and hypertension. Although not generalizable to all rural pharmacies, results indicate that rural pharmacies deliver many important services in their communities and are interested in increasing services provided.

Abstract INTRODUCTION Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function GRN mutations. METHODS A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function GRN mutation (FTD‐GRN). RESULTS Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐GRN to levels that approximated those seen in healthy volunteers. DISCUSSION Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐GRN. Highlights GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD). Latozinemab is being developed as a PGRN‐elevating therapy. Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial. Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐GRN participants.

Abstract Aim To identify the contextual factors influencing parents' assessments of the family‐centredness of care received during a paediatric emergency department visit. Design A qualitative cross‐sectional case study. Methods We interviewed parents who were at their child's bedside during an emergency department encounter. We independently coded the first 3 transcripts and met to discuss the coding structure and to refine existing codes, add new codes and develop tentative categories. We repeated this process for every 3–5 transcripts until thematic saturation was reached. Results We conducted 16 interviews and identified 2 themes: (1) Not all parents expected physicians to provide family‐centred care in the emergency department and (2) feeling overwhelmed and powerless influenced parents' perceptions of family‐centred care. Poor family‐centred care worsened parents' sense of powerlessness and reinforced parents' low expectations from physicians. Similarly, low expectations and powerlessness exacerbated poor family‐centred care. Interventions are needed to break this cycle and improve family‐centredness of care.

Abstract Despite small direct changes to radiative forcing, solar sunspot cycles are observed in climate records because of climate system amplification that primarily affects wind and precipitation belts. We present a proxy record resolving the dominant sub‐millennial periodicities across the entire Holocene in the Southern Westerly Winds (SWW), whose migrations are linked to ocean‐atmosphere heat and carbon exchange. We use X‐ray fluorescence core scanning to examine a rapidly accumulating sediment record (6 m/kyr) recovered from the Chilean margin, yielding unprecedented

Abstract Objective To determine the efficacy of a surgical training model for fluorescence‐guided cancer surgery and validate its utility to detect any residual tumors after tumor resection using electrocautery. Methods We developed surgical training models containing indocyanine green (ICG) for near‐infrared (NIR) fluorescence imaging using a root vegetable organic material (konjac). After the fluorescence assessment for the models, the surgical simulation for fluorescence‐guided cancer surgery using electrocautery was performed. ICG‐containing tumors were divided into two surgical groups: “Enucleation” (removal of the entire visible tumor) and “Complete resection” (removal of the tumor with an appropriate 5‐mm surgical margin). Results All 12 ICG‐containing tumors were clearly visible from the normal view but not from the flipped view. The tumor resection time was significantly longer in the “Complete resection” group than in the “Enucleation” group (p

Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1–12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.

Abstract Background An ASCO taskforce comprised of representatives of oncology clinicians, the American Cancer Society National Lung Cancer Roundtable (NLCRT), LUNGevity, the GO2 Foundation for Lung Cancer, and the ROS1ders sought to: characterize U.S. oncologists’ biomarker ordering and treatment practices for advanced non‐small‐cell lung cancer (NSCLC); ascertain barriers to biomarker testing; and understand the impact of delays on treatment decisions. Methods We deployed a survey to 2374 ASCO members, targeting U.S. thoracic and general oncologists. Results We analyzed 170 eligible responses. For non‐squamous NSCLC, 97% of respondents reported ordering tests for EGFR, ALK, ROS1, and BRAF. Testing for MET, RET, and NTRK was reported to be higher among academic versus community providers and higher among thoracic oncologists than generalists. Most respondents considered 1 (46%) or 2 weeks (52%) an acceptable turnaround time, yet 37% usually waited three or more weeks to receive results. Respondents who waited ≥3 weeks were more likely to defer treatment until results were reviewed (63%). Community and generalist respondents who waited ≥3 weeks were more likely to initiate non‐targeted treatment while awaiting results. Respondents

Abstract The scope of the present review is to synthesize existing literature data on fluid biomarkers for Parkinson's disease (PD) and atypical parkinsonian syndromes (APS). Parkinsonian syndromes encompass a body of heterogeneous neurodegenerative diseases marked by characteristic movement dysfunction, among which PD is the most prevalent form. In addition to the stereotypical presentation of PD, patients may also manifest atypical symptoms that raise the suspicion of APS, such as PD with dementia, progressive supranuclear palsy, multiple system atrophy, dementia with Lewy body, and corticobasal degeneration. Clinical diagnosis of PD and APS depends heavily on patients’ presenting symptoms without reliable objective tests or imaging studies. Fluid biomarkers are powerful tools that facilitate diagnosing and monitoring various parkinsonian syndromes. Therefore, establishing parkinsonian biomarkers is a necessary step in the scope of basic science research and clinical practice. This review will discuss some of the past decade's most promising cerebrospinal fluid and other fluid biomarkers. We highlighted the shortcomings of alpha‐synuclein (α‐syn), Aβ42, and tau as differences in the expression of these proteins are moderate at best. Protein misfolding cyclic amplification and real‐time quaking‐induced conversion are novel techniques with remarkable discriminatory capacity for PD and APS. Autoantibodies have also introduced a marker for possible early diagnosis and staging for PD. Neurofilament light chain and microRNAs are promising fluid biomarkers that may be more suitable as biomarkers compared to α‐syn, Aβ42, and tau. At its current stage, fluid‐based biomarkers have improved significantly in diagnosing PD from healthy controls and differentiating between PD and APS, but insufficient for clinical usage due to a lack of validation and limitation in discriminatory power.

Background Intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) for large‐vessel occlusion (LVO) stroke is increasingly controversial. Recent trials suggest MT without IVT is reasonable for patients presenting directly to MT‐capable “hub” centers. However, bypassing IVT has not been evaluated for patients presenting to IVT‐capable “spoke” hospitals that require hub transfer for MT. A perceived lack of efficacy of IVT to result in LVO early recanalization (ER) is often cited to support bypassing IVT, but data for IVT in patients who require interhospital transfer are limited. Here, we examined LVO ER rates after spoke‐administered IVT in our hub‐and‐spoke stroke network. Methods Patients presenting to 25 spokes before hub transfer for MT consideration from 2018 to 2020 were retrospectively identified from a prospectively maintained database. Inclusion criteria were pretransfer computed tomography angiography–defined LVO, Alberta Stroke Program Early Computed Tomography Score ≥6, and posttransfer repeat vessel imaging. Results Of 167 patients, median age was 69, and 51% were women. Seventy‐six received spoke IVT, and 91 did not. Alteplase was the only IVT used in this study. Comorbidities and National Institutes of Health Stroke Scale were similar between groups. ER frequency was increased 7.2‐fold in patients who received spoke IVT (12/76 [15.8%] versus 2/91 [2.2%]; P

Abstract Objective Fistula remains a common complication of upper aerodigestive tract reconstruction. Optimal timing of oral feeding is unknown and the impact of early feeding on swallow function and fistula rates remains controversial. The purpose of this study is to better understand the effects of “early feeding” on fistula rate and swallow in patients with free flap reconstruction of upper aerodigestive tract defects. Methods Retrospective cohort study. One hundred and four patients undergoing free flap reconstruction of mucosalized head and neck defects. Two groups, early feeding (oral intake on or before postoperative day 5) and late‐feeding (oral intake after postoperative day 5). Primary outcome was incidence of salivary fistula. Secondary outcomes included Functional Oral Intake Scale scores. Results Fistula rate was 16.5% in late‐feeding group and 0% in early‐feeding group (P = .035). Patients who were fed early had an association with progression to a full oral diet by 30 days (P = .027). Discussion This cohort analysis suggests that in properly selected patients with free flap reconstruction for mucosal defects, early feeding may not increase risk of salivary fistula and may improve swallow functional outcomes earlier. Level of Evidence: 3

Abstract The iodine to calcium ratio in carbonate (I/Ca) has been widely used to indicate ocean oxygenation level in the past. Given the volatility of iodine, I/Ca has been measured in alkaline solutions in previous studies. However, this limits the application of I/Ca with other element/Ca (El/Ca) proxies at the same time and in the same foraminifera because other El/Ca data are preferably analyzed in acidic solutions. This study assesses the reliability of I/Ca measurements in acidic solutions measured with other El/Ca as well as the effects of different sample pre‐treatments on measured foraminiferal I/Ca. Our results show that when samples are measured within hours of prepaparation, the pH of the final solution has an insignificant effect on I/Ca measurements of a carbonate reference material JCp‐1 and a multi‐element standard solution, consistent with the slow kinetics of iodine volatilization. We find, however, that low pH possibly reduces the measured I/Ca in foraminiferal tests in some samples. Our experiments also suggest a resolvable effect of reductive cleaning, yielding lower foraminiferal I/Ca compared to without reductive cleaning. The HNO3 concentration used to dissolve foraminiferal shells has a negligible effect. Despite the different solution pHs and cleaning and dissolving methods, our core top planktic I/Ca data are able to differentiate well‐oxygenated from oxygen‐depleted waters in the upper ocean, and after correcting for cleaning effect, our data are generally consistent with the published studies that analyzed I/Ca without reductive cleaning and in basic solutions. This study shows that measurements of I/Ca within hours of sample dissolutions yield reliable planktic I/Ca data, while also allowing the acquisition of other El/Ca values for paleoceanographic studies.

Background For patients with large vessel occlusion (LVO) stroke, time to treatment with endovascular thrombectomy is crucial to prevent infarction and improve outcomes. We sought to evaluate the hub arrival‐to‐puncture times and outcomes for transferred patients accepted directly to the angio‐suite (LVO to operating room, LVO2OR) versus those accepted through the emergency department in a hub‐and‐spoke telestroke network. Methods Consecutive patients transferred for endovascular thrombectomy with spoke computed tomography angiography–confirmed LVO, spoke Alberta Stroke Program Early Computed Tomography score >6, and last known well–to–hub arrival

Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date.Unbiased global proteome analysis of patients' brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. Methods In this study, we conducted unbiased mass spectrometry‐based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11‐plex isobaric tandem mass tag (TMT)‐based multiplexing experiments. The identified proteins were subjected to statistical analysis, such as a permutation‐based statistical analysis in the significance analysis of microarray (SAM) method and bootstrap receiver operating characteristic curve (ROC)‐based statistical analysis. Subsequently, we conducted bioinformatics analyses using gene set enrichment analysis, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein‐protein interaction (PPI) analysis, and weighted gene co‐expression network analysis (WGCNA). Results We have identified 10,231 proteins with ∼1,000 differentially expressed proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non‐alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b‐c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent STRING PPI analysis and the WGCNA further supported that the mitochondrial proteins were the most highly enriched in PSP. Conclusion Our study showed that the mitochondrial respiratory electron transport chain complex was the key proteins that were dysregulated in GP of PSP, suggesting that the mitochondrial respiratory electron transport chain complex could potentially be involved in the pathogenesis of PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the mechanistic pathogenesis of PSP.

Abstract Sediment cores recently collected from the Chilean Margin during D/V JOIDES Resolution Expedition 379T (JR100) document variability in shipboard‐generated records of the green/blue (G/B) ratio. These changes show a strong coherence with benthic foraminiferal δ18O, Antarctic ice core records, and sediment lithology (e.g., higher diatom abundances in greener sediment intervals), suggesting a climate‐related control on the G/B. Here, we test the utility of G/B as a proxy for diatom productivity at Sites J1002 and J1007 by calibrating G/B to measured biogenic opal. Strong exponential correlations between measured opal% and the G/B were found at both sites. We use the empirical regressions to generate high‐resolution records of opal contents (opal%) on the Chilean Margin. Higher productivity tends to result in more reducing sedimentary conditions. Redox‐sensitive sedimentary U/Th generally co‐varies with the reconstructed opal% at both sites, supporting the association between sediment color, sedimentary U/Th, and productivity. Lastly, we calculated opal mass accumulation rate (MAR) at Site J1007 over the last ∼150,000 years. The G/B‐derived opal MAR record from Site J1007 largely tracks existing records derived from traditional wet‐alkaline digestion from the south and eastern equatorial Pacific (EEP) Ocean, with a common opal flux peak at ∼50 ka suggesting that increased diatom productivity in the EEP was likely driven by enhanced nutrient supply from the Southern Ocean rather than dust inputs as previously suggested. Collectively, our results identify the G/B ratio as a useful tool with the potential to generate reliable, high‐resolution paleoceanographic records that circumvent the traditionally laborious methodology.