Gray Bars Research Articles

Anticipation of sexually arousing visual event leads to overestimation of elapsed time.

Subjective estimates of duration are affected by emotional expectations about the future. For example, temporal intervals preceding a threatening event such as an electric shock are estimated as longer than intervals preceding a non-threatening event. However, it has not been unequivocally shown that such temporal overestimation occurs also when anticipating a similarly arousing but appealing event. In this study, we examined how anticipation of visual erotic material influenced perceived duration. Participants did a temporal bisection task, where they estimated durations of visual cues relative to previously learned short and long standard durations. The color of the to-be-timed visual cue signalled either a chance of seeing a preferred erotic picture at the end of the interval or certainty of seeing a neutral grey bar instead. The results showed that anticipating an appealing event increased the likelihood of estimating the cue duration as long as compared to the anticipation of a grey bar. Further analyses showed that this temporal overestimation effect was stronger for those who rated the anticipated erotic pictures as more sexually arousing. The results thus indicate that anticipation of appealing events has a similar dilating effect on perceived duration as does the anticipation of aversive events.

Correction to Biderman et al. (2023).

Reports an error in "The role of memory in counterfactual valuation" by Natalie Biderman, Samuel J. Gershman and Daphna Shohamy (Journal of Experimental Psychology: General, 2023[Jun], Vol 152[6], 1754-1767). In this article, several corrections have been made to two equations, the text, and Figure 3. First, there was an error in two equations of the policy gradient model depicted in the Model Description section. The correction did not alter the main conclusion of the model, but it did change slightly the comparison between experimental conditions of each model depicted in the Results section. The correct Equation 3 and correct Equation 4 are present in the erratum. Additionally, the last four sentences in the first paragraph of the A Policy Gradient Model Captures the Memory-Based Inverse Decision Bias have been revised. Finally, the model predictions shown in the gray bars of Figure 3 were slightly modified. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2023-72914-001.) Value-based decisions are often guided by past experience. If a choice led to a good outcome, we are more likely to repeat it. This basic idea is well-captured by reinforcement-learning models. However, open questions remain about how we assign value to options we did not choose and which we therefore never had the chance to learn about directly. One solution to this problem is proposed by policy gradient reinforcement-learning models; these do not require direct learning of value, instead optimizing choices according to a behavioral policy. For example, a logistic policy predicts that if a chosen option was rewarded, the unchosen option would be deemed less desirable. Here, we test the relevance of these models to human behavior and explore the role of memory in this phenomenon. We hypothesize that a policy may emerge from an associative memory trace formed during deliberation between choice options. In a preregistered study (n = 315) we show that people tend to invert the value of unchosen options relative to the outcome of chosen options, a phenomenon we term inverse decision bias. The inverse decision bias is correlated with memory for the association between choice options; moreover, it is reduced when memory formation is experimentally interfered with. Finally, we present a new memory-based policy gradient model that predicts both the inverse decision bias and its dependence on memory. Our findings point to a significant role of associative memory in valuation of unchosen options and introduce a new perspective on the interaction between decision-making, memory, and counterfactual reasoning. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

2168. Viral DNAemia and Herpesvirus Seropositivity are Associated with Mortality in Pediatric Patients with Severe Sepsis

Abstract Background Sepsis is a leading cause of pediatric mortality. Little attention has been paid to latent and reactivated viral infection in critically ill children with sepsis. We report a large multi-center study of viral DNAemia and herpesvirus seropositivity in pediatric patients with severe sepsis. Methods We enrolled 401 pediatric patients from 9 Pediatric Intensive Care Units (PICUs). Patient samples were tested via qPCR for EBV, CMV, HSV, adenovirus, HHV6, BK and parvovirus B19 DNA. CMV, EBV, HSV and HHV6 IgG were also measured to classify patients as having no infection (IgG-negative without DNAemia), acute infection (IgG-negative with DNAemia), reactivated infection (IgG-positive with DNAemia), or latent infection without reactivation (IgG-positive without DNAemia). Results 55% of enrolled patients were male, 39% previously healthy, and 27% immunocompromised. 56% had documented infection(s) on enrollment (63% bacterial, 50% viral, and 2% fungal). 11% died in the PICU. Viral DNAemia was detected in 61% of immunocompromised patients and 46% of non-immunocompromised patients. DNAemia with 2 or more viruses on study, detected in 21% of patients, was independently associated with increased mortality in both immunocompromised (OR 5.5 [1.6, 22.6] p=0.023) and non-immunocompromised patients (OR 3.9 [1.4, 11.5] p=0.015). Viral detection was due to reactivated infection in 91% of patients with EBV DNAemia, 63% with CMV, and 100% with HSV and HHV-6, making acute infection rare. Viral seropositivity (HSV 33%, CMV 42%, EBV 61%, HHV6 98%) and latent infection (HSV 30%, CMV 35%, EBV 45%, HHV6 75%) were both common. Adjusted mortality was higher in patients seropositive for EBV (OR 9.1 [2.8, 172.8], p=0.002) compared to those seronegative for EBV. For HHV-6, mortality was higher in patients with viral reactivation compared to latent infection (18% vs. 7%, p=0.024). Mortality in patients with no detected viral infection (IgG-negative without DNAemia) was low (≤ 5% for each virus). Pediatric Sepsis Mortality and Viral DNAemia ICU mortality was significantly associated with the number of viruses detected during ICU stay in both non-immunocompromised patients (light grey bars) and immunocompromised patients (dark grey bars). In patients with 0 viruses detected, morality was less than 10% in both groups. If 1 virus was detected, mortality was 6% in non-immunocompromised patients and 14% in immunocompromised patients. In the 47 non-immunocompromised patients in which 2 or more viruses were detected, mortality was almost 25% and in the 31 immunocompromised patients mortality neared 40%. Among all patients, additional viral detection of 3, 4 or more viruses by PCR continued to increase risk of death, with mortality nearing 45% in patients who had 4 or more viruses detected during their ICU admission. Conclusion Viral DNAemia was common and associated with mortality in pediatric patients with severe sepsis. DNAemia with 2 or more viruses increased mortality risk, even in previously healthy patients. EBV seropositivity was strongly associated with PICU mortality, independent of concurrent viral DNAemia. Disclosures Andrew H. Walton, MS, RevImmune: Grant/Research Support|Thermo Fisher: Spouse employed by Thermo Fisher.

Knockout of microphthalmia-associated transcription factor (mitf) confers a red and yellow tilapia with few pigmented melanophores

As the most important genetic factor for melanophore differentiation and melanogenesis, mitf has been studied for over 30 years. The phenotypes of mitf mutants have also received continuous attention for nearly a century. Due to the third round of genome duplication, teleosts have two mitf genes. Mutation analysis demonstrates that mitfa plays an important role in zebrafish pigmentation. However, there have been no functional studies on body color regulation by mitfb or studies of mitfa;mitfb double mutants. In the present study, we mutated both mitf genes in tilapia using CRISPR/Cas9. Disruption of mitfa resulted in light yellow body color with weak gray vertical bars due to significantly reduced numbers of melanophores and increased sizes of xanthophores, while disruption of mitfb led to slight hypo-pigmentation. Double mutation of mitfa and mitfb resulted in dramatic hypo-pigmentation in trunk and fins due to loss of additional melanophores and increase in the number of iridophores compared to the single mutants, but had no influence on retinal pigment epithelium (RPE) pigmentation. The mitfa−/−;mitfb−/− mutants were yellow with black spots at early juvenile stage (60 dpf), yellow-reddish at late juvenile stage (120 dpf) and red and yellow (including iris) at adult stage (180 dpf), due to increased erythrophores and enlarged xanthophores. Our results demonstrated that both mitf genes are important for body color formation in tilapia, but mitfa plays a more important role than mitfb. Additionally, by comparing the phenotypes of the mitfa−/−;mitfb−/−, pmela−/−;pmelb−/− and hps4−/− mutants, we found that disruption of genes with different functions in different aspects of melanogenesis could lead to different body colors in tilapia. Mitf is the most important gene for melanophore differentiation and is probably also critical for differentiation of erythrophores, xanthophores and iridophores. To our knowledge, this is the first report showing that both mitf genes are involved in body color formation by loss of function study, and the first report showing that erythrophore numbers and xanthophore sizes were affected by mitf. Our research not only serves as a model for studying mitf function in tilapia and the closely related cichlids, but also provides new strategies for breeding red and yellow tilapia for aquaculture.

Paths to Healthier Eating: Perceptions and Interventions for Success

Paths to Healthier Eating: Perceptions and Interventions for Success

Stimulation of medial amygdala GABA neurons with kinetically different channelrhodopsins yields opposite behavioral outcomes.

The medial amygdala (MeA) receives pheromone information about conspecifics and has crucial functions in social behaviors. A previous study showed that activation of GABA neurons in the postero-dorsal MeA (MeApd) with channelrhodopsin-2H134R (ChR2) stimulates inter-male aggression. When performing these experiments using the faster channelrhodopsinH134R,E123T (ChETA), we find the opposite behavioral outcome. A systematic comparison between the two channelrhodopsin variants reveals that optogenetic activation of MeApd GABA neurons with ChETA suppresses aggression, whereas activation under ChR2 increases aggression. Although the mechanism for this paradoxical difference is not understood, we observe that activation of MeApd GABA neurons with ChR2 causes larger plateau depolarizations, smaller action potentials, and larger local inhibition than with ChETA. Thus, the channelrhodopsin variant used for invivo optogenetic experiments can radically influence the behavioral outcome. Future work should continue to study the role of specific sub-populations of MeApd GABA neurons in aggression control.

PM 7/53 (2) Liriomyza spp.

PM 7/53 (2) <i>Liriomyza</i> spp.

Corrigendum

Fish and FisheriesVolume 23, Issue 3 p. 768-769 CORRIGENDUMFree Access Corrigendum This article corrects the following: Integrating seabird dietary and groundfish stock assessment data: Can puffins predict pollock spawning stock biomass in the North Pacific? William J. Sydeman, Sarah Ann Thompson, John F. Piatt, Stephani G. Zador, Martin W. Dorn, Volume 23Issue 1Fish and Fisheries pages: 213-226 First Published online: September 13, 2021 First published: 11 April 2022 https://doi.org/10.1111/faf.12652AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the article ‘Integrating seabird dietary and groundfish stock assessment data: Can puffins predict pollock spawning stock biomass in the North Pacific?’ by W. J. Sydeman et al. (2022), Figure 4 was published incorrectly. FIGURE 4Open in figure viewerPowerPoint Spearman rank cross-correlations between SSB and age-0 abundance or growth from all WGoA sites or Aiktak Island alone. (a) WGoA SSB vs. age-0 abundance, (b) WGoA SSB and growth, (c) EBS SSB and age-0 abundance, and (d) EBS SSB and growth. Spearman ρ is shown on the y-axis, and lags/leads of up to 3 years are shown on the x-axis. Negative lags indicate age-0 abundance or growth leading SSB, while positive values indicate SSB leading age-0 abundance or growth. WGoA correlations are hatched bars, while Aiktak correlations are grey bars. Significance (p-value) of the correlations is shown by asterisks: *≤.1, **≤.01 and ***≤.001. Regressions of key selected key relationships are shown in Table 2, with corresponding scatter plots of relationships in Figure 5 The correct figure is reproduced here. The authors apologize for the error. REFERENCE Sydeman, W. J., Thompson, S. A., Piatt, J. F., Zador, S. G., & Dorn, M. W. (2022). Integrating seabird dietary and groundfish stock assessment data: Can puffins predict pollock spawning stock biomass in the North Pacific? Fish and Fisheries, 23, 213– 226. https://doi.org/10.1111/faf.12611 Volume23, Issue3May 2022Pages 768-769 FiguresReferencesRelatedInformation

Liver Transplantation After Organ Donation Due to Hydrogen Sulfide Intoxication: Report of the First Case.

The discrepancy of patients on the waiting list and the availability of organs suitable for transplantation continues to represent a relevant problem in transplantation medicine. Regarding liver transplantation, the increasing use of organs from donors with so-called extended criteria meanwhile has become daily practice in many countries.1 Consequently, every potential donor reported is carefully evaluated for suitability for organ donation. When a liver from a young brain-dead donor after hydrogen sulfide (H2S) intoxication was offered for a high-urgency listed patient, research of the literature did not provide any help for decision making in organ allocation. Herewith, we want to share our experience following the successful use of this donor liver for transplantation. A 60-y-old female patient with acute liver failure caused by an autoimmune hepatitis was transferred to our center and eventually listed for high-urgency liver transplantation following biopsy-proven diagnosis and rapid worsening of the clinical condition despite thorough intensive medical treatment (see Figure 1). Within 5 h after approval of high-urgency status, we were offered a liver from a 19-y-old female brain-dead donor following H2S intoxication in suicidal intent. Apart from depression, the donor was in excellent general condition before intoxication and had no other known illnesses. Despite recently promoted organ protective effects in experimental studies,2 inhalation of H2S in higher concentrations is highly toxic and eventually led to cardiac arrest in this patient.3 Following a short period of resuscitation, the donor was admitted to an intensive care unit and eventually diagnosed brain dead. Within 24 h, severe lung edema and subsequently respiratory failure developed as signs of multiorgan failure. Regarding the liver, apart from an initial peak of transaminases (peak AST and ALT levels of 357 and 438 U/L, respectively), the laboratory findings were all unremarkable. Because of the severe condition of our recipient with severe hepatic encephalopathy, we thus accepted the organ after intense interdisciplinary discussion despite the lack of any data on successful use of organs for transplant under these conditions. Upon arrival of the organ at our center, histological work-up of the liver by frozen section was performed despite excellent macroscopic appearance, which did not reveal any signs of acute liver injury or chronic alterations‚ such as steatosis or fibrosis (see Figure 2). Subsequent liver transplantation was completely uneventful. The patient’s clinical condition improved rapidly, with discharge at day 15 after transplantation (see Figure 1). During follow-up of 6 mo, no irregularities were observed, with excellent graft function and medical condition of the recipient at last visit. In conclusion, to our knowledge‚ this is the first report of a liver transplant from a brain-dead donor after hydrogen sulfide intoxication. Based on this single-case experience, potential donors after hydrogen sulfide intoxication should be carefully evaluated and considered for organ donation. Particularly evaluation of potential grafts applying normothermic machine perfusion might represent another valuable option in case of less urgent conditions of the recipients.4FIGURE 1.: Course of laboratory parameters (AST, ALT [both U/L], bilirubin [µmol/L], and INR) of the recipient before and after LTx, with time points of liver biopsy, PE and steroid therapy‚ and day of transplantation indicated by gray bars. ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; LTx, liver transplantation; PE, plasmapheresis.FIGURE 2.: Histopathology of liver wedge biopsy: hematoxylin and eosin staining shows no steatosis, fibrosis, or cirrhosis ([A] ×40 magnification and [B] ×100 magnification), and Elastica van Gieson staining highlights absence of fibrosis within the liver parenchyma ([C] ×40 magnification and [D] ×100 magnification).

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

Elements of exogenous attentional cueing preserved during optokinetic motion of the visual scene.

Navigating through our environment raises challenges for perception by generating salient background visual motion and eliciting prominent eye movements to stabilise the retinal image. It remains unclear if exogenous spatial attentional orienting is possible during background motion and the eye movements it causes and whether this compromises the underlying neural processing. To test this, we combined exogenous orienting, visual scene motion, and electroencephalography (EEG). A total of 26 participants viewed a background of moving black and grey bars (optokinetic stimulation). We tested for effects of non-spatially predictive peripheral cueing on visual motion discrimination of a target dot, presented either at the same (valid) or opposite (invalid) location as the preceding cue. Valid cueing decreased reaction times not only when participants kept their gaze fixed on a central point (fixation blocks) but also even when there was no fixation point, so that participants performed intensive, repetitive tracking eye movements (eye movement blocks). Overall, manual response reaction times were slower during eye movements. Cueing also produced reliable effects on neural activity on either block, including within the first 120 ms of neural processing of the target. The key pattern with larger event-related potential (ERP) amplitudes on invalid versus valid trials showed that the neural substrate of exogenous cueing was highly similar during eye movements or fixation. Exogenous peripheral cueing and its neural correlates are robust against distraction from the moving visual scene, important for perceptual cognition during navigation.

355. A Novel Likelihood-Based Model to Estimate SARS-CoV-2 Viral Titer from Next-Generation Sequencing Data

BackgroundThe quantitative level of pathogens present in a host is a major driver of infectious disease (ID) state and outcome. However, the majority of ID diagnostics are qualitative. Next-generation sequencing (NGS) is an emerging ID diagnostics and research tool to provide insights, including tracking transmission, evolution, and identifying novel strains.MethodsWe built a novel likelihood-based computational method to leverage pathogen-specific genome-wide NGS data to detect SARS-CoV-2, profile genetic variants, and furthermore quantify levels of these pathogens. We used de-identified clinical specimens tested for SARS-CoV-2 using RT-PCR, SARS-CoV-2 NGS Assay (hybrid capture, Twist Bioscience), or ARTIC (amplicon-based) platform, and COVID-DX software. A training (n=87) and validation (n=22) set was selected to establish the strength of our quantification model. We fit non-uniform probabilistic error profiles to a deterministic sigmoidal equation that more realistically represents observed data and used likelihood maximized over several different read depths to improve accuracy over a wide range of values of viral load. Given the proportion of the genome covered at varying depths for a single sample as input data, our model estimated the Ct of that sample as the value that produces the maximum likelihood of generating the observed genome coverage data.ResultsThe model fit on 87 SARS-CoV-2 NGS Assay training samples produced a good fit to the 22 validation samples, with a coefficient of correlation (r2) of ~0.8. The accuracy of the model was high (mean absolute % error of ~10%, meaning our model is able to predict the Ct value of each sample within a margin of ±10% on average). Because of the nature of the commonly used ARTIC protocol, we found that all quantitative signals in this data were lost during PCR amplification and the model is not applicable for quantification of samples captured this way. The ability to model quantification is a major advantage of the SARS-CoV-2 NGS assay protocol.The likelihood-based model to estimate SARS-CoV-2 viral titer LeftObserved genome coverage (y-axis) plotted against Ct value (x-axis). The best-fitting logistic curve is demonstrated with a red line with shaded areas above and below representing the fitted error profile. RIGHT: Model-estimated Ct values (y-axis) compared to laboratory Ct values (x-axis) with grey bars representing estimated confidence intervals. The 1:1 diagonal is shown as a dotted line.ConclusionTo our knowledge, this is the first model to incorporate sequence data mapped across the genome of a pathogen to quantify the level of that pathogen in a clinical specimen. This has implications in ID diagnostics, research, and metagenomics.Disclosures Heather L. Wells, MPH, Biotia, Inc. (Consultant) Joseph Barrows, MS, Biotia (Employee) Mara Couto-Rodriguez, MS, Biotia (Employee) Xavier O. Jirau Serrano, B.S., Biotia (Employee) Marilyne Debieu, PhD, Biotia (Employee) Karen Wessel, PhD, Labor Zotz/Klimas (Employee) Christopher Mason, PhD, Biotia (Board Member, Advisor or Review Panel member, Shareholder) Dorottya Nagy-Szakal, MD PhD, Biotia Inc (Employee, Shareholder) Niamh B. O’Hara, PhD, Biotia (Board Member, Employee, Shareholder)

Island Mammal Extinctions are Determined by Interactive Effects of Life History, Island Biogeography, Mesopredator Suppression

Island Mammal Extinctions are Determined by Interactive Effects of Life History, Island Biogeography, Mesopredator Suppression

S1120 When Your Lab Didn’t Read the Guidelines: The Ability of Physicians in a Teaching Hospital Clinic to Identify Abnormal Alanine Aminotransferase (ALT) Values

Introduction: ACG guidelines define normal ALT as 29 to 33 for males and 19 to 25 for females. An elevated ALT, even if borderline, warrants consideration as to the cause, and monitoring for worsening. However, different laboratories use different reference values for normal, and many report ALTs greater than 25 or 33 as normal. Our hospital’s lab reports ALT 6-55 as normal. In this study, we aimed to assess physicians’ identification of abnormal ALT values, particularly in instances when the lab did not identify it as abnormal (by bolding). Methods: We reviewed the charts of 4965 patients seen in Internal Medicine (IM) and GI clinics to identify patients with elevated ALTs. Only the first instance of elevated ALT was included for each patient. We excluded patient who had a history of liver disease. We identified the patients who had ALTs that were abnormal but not marked as such by the laboratory. For each patient, we reviewed the clinic notes to find any comment or plan for work-up. Results: Results are summarized in the chart and table. 1018 patients with elevated ALT and no history of liver disease were identified and included. Elevated ALT was identified by the physician in 29.1% of patients. Of elevated ALT values that were less than 55, only 31/491 were identified. Of these 31 patients, 11 were not seen again and 5 had no additional testing. One patient underwent liver biopsy. The rest had an ultrasound and serologic testing. After work-up, two patients were presumed to have alcoholic liver disease, 5 NAFLD, one was diagnosed with choledocholithiasis, and 3 were diagnosed with DILI. Furthermore, there was a significant difference in the identification of abnormal ALTs between 50-55 (not bolded) and ALTs between 56-64 (bolded): ALT of 50-55 was identified as abnormal in 16.4% of visits, while ALT of 56-64 in 39.7% (P-value .005). Of note, GI physicians were significantly more likely to identify elevated ALT values than IM physicians (see table). Conclusion: Physicians were more likely to identify an abnormal ALT if it was bolded. In both clinics, non-bolded ALTs were largely ignored. Amongst the patients whose non-bolded elevated ALT were identified, most received additional testing and were found or presumed to have modifiable etiologies. This study demonstrates the need for physicians to better familiarize themselves with normal ranges of liver tests, and consider the need for further evaluation or monitoring when an ALT value is abnormal even if their laboratory does not identify it as such.Table 1Figure 1.: Identification of Elevated ALT as Abnormal. Blue bar shows GI clinic; Orange bar shows IM clinic; Gray bar shows Total

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

End-of-Treatment CT and Serial FDG-PET Imaging to Assess Residual Disease in Primary Mediastinal B-Cell Lymphoma

Background: Primary mediastinal B-cell lymphoma (PMBCL) is biologically related to classic nodular-sclerosis Hodgkin lymphoma. R-CHOP alone appears to be inadequate for many pts with retrospective studies indicating a benefit for consolidation XRT or use of intensive therapy regimens. End-of-therapy (EOT) FDG-PET is used to assess residual disease, but cannot accurately distinguish lymphoma from inflammation. We previously showed DA-EPOCH-R is effective in PMBCL, obviating the need for XRT in most pts, and showed that a positive EOT FDG-PET was typically not associated with treatment failure (Dunleavy et al. NEJM. 2013;368(15):1408-1416). We assessed the role of serial FDG-PET imaging to more accurately distinguish active disease from inflammation following DA-EPOCH-R for PMBCL.Methods: Ninety-three untreated PMBCL pts received DA-EPOCH-R without XRT. EOT FDG-PET was performed in 83 (89%) pts within 1 week of completing treatment and retrospectively scored per Deauville criteria in a blinded manner. Twenty-five (44%) of 57 pts with a negative (Deauville 1-3) EOT scan underwent follow-up FDG-PET imaging, mostly due to Deauville 3, which is no longer considered to indicate a positive FDG-PET scan. Twenty-three (88%) of 26 pts with a positive (Deauville 4-5) EOT scan underwent serial FDG-PET imaging approximately every 6 weeks. Three Deauville 4 pts (all non-progressors) did not have follow-up scans per protocol. If progressive SUV changes were noted on follow-up PET and/or size increase on concurrent CT, biopsy was attempted to confirm disease prior to implementing salvage therapy.Results: Characteristics were similar between the 83 pts with and 10 pts without evaluable EOT FDG-PET scans, aside from greater bulky tumor >/= 10 cm in the former group (63% vs. 20%, P = 0.014) (Table 1). All 93 pts were evaluable for response by CT with an ORR of 99% (88% CR, 11% PR). All 89 pts with complete tumor measurements had a reduction in the bi-dimensional product of the largest mediastinal tumor mass by CT. There was no relationship between EOT tumor reduction and EOT FDG-PET Deauville score (Figure 1). Furthermore, there was no difference in tumor reduction between pts with (6) and without (83) treatment failure (red arrows); median reduction 92% (range, 65-99) vs. 93% (range, 62-100), respectively (Figure 1).EOT FDG-PET scan was negative (Deauville 1-3) in 57 (69%) and positive (Deauville 4-5) in 26 (31%) pts. Disease progression occurred among 1/57 (2%) Deauville 1-3 pts, 1/18 (6%) Deauville 4 pts and 4/8 (50%) Deauville 5 pts. Two pts (both Deauville 5) died of progressive disease and 2 pts (Deauville 2 and 4, respectively) died without disease.In the 83 pts with EOT FDG-PET scans, 113 follow-up scans in 48 pts were performed (median, 1; range, 0-6). Pts with a negative EOT FDG-PET scan underwent a median of 0 (range, 0-4) scans compared to a median of 2 (range, 0-6) scans in pts with a positive EOT scan. Among pts who did not relapse/progress, the SUVmax remained relatively stable over time in the 21 pts with positive (Figure 2, upper) and 56 pts with negative EOT FDG-PET scans (data not shown). Five of 6 pts with treatment failure had a progressive increase in SUVmax on serial imaging (Figure 2, lower). Four of these pts (#2, 3, 5, and 6) had normalization of SUVmax following intervention (indicated by gray diagonal bars) with 1 pt (#1) having continued progression despite multiple salvage therapies. One patient (#4) with an elevated SUVmax at EOT had normalization of uptake following XRT.Conclusions: The degree of EOT tumor reduction by CT scan was unrelated to FDG-PET Deauville score or risk of disease recurrence. Negative EOT FDG-PET scans are highly predictive of cure following DA-EPOCH-R and further FDG-PET scanning should not be performed. Positive EOT FDG-PET scans were only indicative of residual disease in a minority of pts and should not be used alone to identify pts with residual disease. However, serial scans can identify pts with residual disease who require treatment. In conclusion, serial imaging should be performed in pts with positive EOT FDG-PET scans to accurately identify pts with disease. [Display omitted] DisclosuresAdvani:Merck: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding; Nanostring: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Juno Therapeutics: Consultancy; Sutro: Consultancy; Infinity: Research Funding; FortySeven: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Cell Medica: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Kura: Research Funding; Gilead: Consultancy; Genentech: Research Funding; Spectrum: Consultancy; Millennium: Research Funding. Miljkovic:Pfizer Oncology: Research Funding.

Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells.

SummaryB cell responses are critical for antiviral immunity. However, a comprehensive picture of antigen-specific B cell differentiation, clonal proliferation, and dynamics in different organs after infection is lacking. Here, by combining single-cell RNA and B cell receptor (BCR) sequencing of antigen-specific cells in lymph nodes, spleen, and lungs after influenza infection in mice, we identify several germinal center (GC) B cell subpopulations and organ-specific differences that persist over the course of the response. We discover transcriptional differences between memory cells in lungs and lymphoid organs and organ-restricted clonal expansion. Remarkably, we find significant clonal overlap between GC-derived memory and plasma cells. By combining BCR-mutational analyses with monoclonal antibody (mAb) expression and affinity measurements, we find that memory B cells are highly diverse and can be selected from both low- and high-affinity precursors. By linking antigen recognition with transcriptional programming, clonal proliferation, and differentiation, these finding provide important advances in our understanding of antiviral immunity.

COVID–19の第1波への対応に係るJAAM全国調査(JAAM Nationwide Survey on the response to the first wave of COVID–19 in Japan)

ABSTRACT Aim: To clarify how the medical institutions overcame the first wave of coronavirus disease 2019 (COVID–19) in Japan and to discuss its impact on the medical labor force. Methods: We analyzed questionnaire data from the end of May 2020 from 180 hospitals (102,578 beds) certified by the Japanese Association for Acute Medicine. Results: Acute (emergency) medicine physicians treated severe COVID–19 patients in more than half of hospitals. Emergency medical teams consisted of acute medicine physicians and other specialists. Frontline acute care physicians were concerned about their risk of infection in 80% of hospitals, and experienced stress due to a lack of personal protective equipment. Twenty–six of the 143 hospitals that had a mental health check/consultation system in place indicated that there was a doctor who experienced mental health problems. Of the 37 hospitals without a system, only one hospital was aware of the presence of a doctor complaining of mental health problems. Conclusion: Acute care physicians and physicians in other departments experienced high levels of stress as they fought to arrange COVID–19 treatment teams and inpatient COVID–19 wards for infected patients. Medical materials and equipment may be sufficient for a second or third wave; however, active support is needed for the physical and mental care of medical staff. Mental health problems may be missed in facilities without mental check and consultation system.

108. Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy

BackgroundHIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well-defined in people on ART.MethodsWe separately quantified intact and defective proviruses (using an intact proviral DNA assay), residual plasma viremia, and markers of inflammation and activation in people on long-term ART. Longitudinal measurements were done at three timepoints: timepoint 1 was a median of 7.1 years on ART; timepoint 2 was a median of 3.7 years later; timepoint 3 was a median of 5.5 years after timepoint 1 and a median 12 years after starting ART (Figure 1).Figure 1: Study timepoints ResultsAmong 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life 7.1 years; 95% confidence interval [CI], 3.9, 18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6, 75). When we evaluated the change in proviral DNA per year, intact proviral DNA declined significantly more (p< 0.001) than defective proviral DNA (the latter did not change) (Figure 2). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART timepoint to about 5% at the last timepoint (Figure 3). At timepoint 1, intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation.Figure 2: Percent change in HIV-1 proviral DNA per year Figure 3: Total HIV-1 proviruses (grey bars) and the percentage of intact proviruses (red lines, displaying median, Q1, Q3) by timepoint. ConclusionCells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.Disclosures Rajesh Gandhi, MD, Merck (Advisor or Review Panel member) Gregory Laird, PhD, Accelevir Diagnostics (Shareholder, Other Financial or Material Support, Employee) Albine Martin, PhD, Accelevir Diagnostics (Shareholder, Other Financial or Material Support, Employee) Bernard Macatangay, MD, Gilead (Grant/Research Support) Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV Healthcare (Consultant, Research Grant or Support) Janet Siliciano, PhD, Gilead (Advisor or Review Panel member)US Military HIV Research Program (Advisor or Review Panel member) John Mellors, MD, Abound Bio (Shareholder)Accelevir Diagnostics (Consultant)Co-Crystal Pharmaceuticals (Shareholder)Gilead (Consultant, Grant/Research Support)Merck (Consultant)