Geographic Inequities in Access to Phase 3 Clinical Trials for Inflammatory Bowel Disease in the United States.

Randomized controlled trials (RCTs) are an important mode of access to treatments for patients with inflammatory bowel diseases (IBDs) (eg, Crohn's disease [CD], ulcerative colitis [UC]), and a critical step in the regulatory process toward the approval of new therapies. Prior studies examining disparities in RCT participation for patients with IBD have importantly focused on racial and age-related disparities.1,2 Lack of geographic access to trials may be an important barrier to participation and a source of inequity. The aim of our study was to geographically map access to phase 3 clinical trials in IBD within the United States, and identify the impact of rural residence and socioeconomic status on access to trials.

First-year medical students' perceptions of a self-regulated learning-informed intervention: an exploratory study.

BACKGROUND: Students with developed self-regulated learning (SRL) skills demonstrate an ability to set individualized educational goals, select optimal learning strategies for reaching these goals, and reflect on overall progress. The primary aims of this study were to investigate first-year medical students' perceived utility of a self-regulated learning-informed intervention and to assess the impact of its implementation on students' intended use of SRL throughout medical school. METHODS: A two-part educational intervention focused on SRL skill development was carried out at Harvard Medical School during the start of the 2021 academic year. For the first component of the intervention, 169 first-year medical students engaged in an interactive class session structured around SRL concept videos, a brief lecture, small group discussions and individual reflection. Students completed pre- and post-intervention surveys which inquired about learners' current and anticipated application of SRL skills. During the second component of the intervention, 15 first-year medical students participated in a set of one-on-one academic SRL coaching sessions. All coaching participants completed follow-up semi-structured interviews. RESULTS: A statistically significant increase was observed between students' use of skills in all domains of self-regulated learning prior to the intervention and their anticipated use of these skills following the intervention. Prior to the intervention, 60.1% (n = 92) of students reported utilizing evidence-based learning strategies, compared to 92.8% (n = 142) of students (p < 0.001) who anticipated applying this SRL skills at the completion of the classroom session. Six core themes emerged from qualitative analysis of the post-intervention survey including learning plan development, accountability and progress tracking, goals for growth, engagement through active learning, routine reflection, and adapting to the curriculum. CONCLUSIONS: Both classroom-based learning sessions and one-on-one academic coaching programs are feasible approaches for encouraging the use of self-regulated learning techniques in the preclinical setting.

Mosquitoes Eating Mosquitoes: How Toxorhynchites amboinensis, Psorophora ciliata, and Sabethes cyaneus (Diptera: Culicidae) Capture Prey.

High-speed microcinematography was used to elucidate the details of prey capture by the larvae of three predatory mosquito species. The obligate predators Toxorhynchites amboinensis and Psorophora ciliata exhibited a high degree of convergence as both utilize three essential elements: 1) abdominally-generated hemostatic pressure to propel the head towards the prey; 2) lateral palatal brushes (LPB) opening and fanning into anterior-directed basket-like arrangements; 3) simultaneously with the LPB-basket formation, the wide opening of sharp-toothed mandibles. Thus, LPBs and mandibles are used for prey capture by both species. The facultative predator Sabethes cyaneus utilizes a vastly different prey-capture mechanism that involves ventro-lateral body arching and scooping of prey with axially pointed siphons into the grasp of open maxillae bearing elongate apical teeth. Prey consumption, which is typically incomplete in this species, then involves the action of teeth on the mandibles which cut into the held prey. Although prey consumption is incomplete, simple experiments show that Sa. cyaneus do gain nutritionally from consuming mosquito larvae and that they do discriminate heterospecific from conspecific larvae and actively approach heterospecific mosquito prey. These findings indicate that independent evolutionary pathways have produced diverse predatory behaviors and morphologies in aquatic environments where the immature stages of mosquitoes co-occur.

Effects of Intraoperative Fluid Management on Postoperative Outcomes: A Hospital Registry Study.

OBJECTIVE: Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients. BACKGROUND: Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery. METHODS: This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors. RESULTS: A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6-7 mL/kg/hr or 1 L of fluid for a 3-hour case. CONCLUSIONS: Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay.

Customizing longitudinal electric field profiles using spatial dispersion in dielectric wire arrays.

We show how spatial dispersion can be used as a mechanism to customize the longitudinal profiles of electric fields inside modulated wire media, using a fast and remarkably accurate 1D inhomogeneous model. This customization gives fine control of the sub-wavelength behaviour of the field, as has been achieved recently for transverse fields in simpler slotted-slab media. Our scheme avoids any necessity to run a long series of computationally intensive 3D simulations of specific structures, in order to iteratively converge (or brute-force search) to an empirical 'best-performance' design according to an abstract figure-of-merit. Instead, if supplied with an 'ideal waveform' profile, we could now calculate how to construct it directly. Notably, and unlike most work on photonic crystal structures, our focus is specifically on the field profiles because of their potential utility, rather than other issues such as band-gap control, and/or transmission and reflection coefficients.

Differences in provider recommendations for Black/African American and White patients with irritable bowel syndrome.

BACKGROUND: Health disparities and barriers to equitable care for patients from racial and ethnic minority backgrounds are common. We sought to evaluate disparities in management recommendations among Black/African American (AA) patients seeking care for IBS. METHODS: We assembled a retrospective cohort of patients at two tertiary care centers who were self-identifying as Black/AA and attended a first gastroenterology consult for IBS. These patients were age- and sex-matched to White controls with IBS also attending an initial gastroenterology consult. Retrospective chart review determined patient demographics, income, comorbidities, as well as provider management recommendations including pharmacologic therapies and non-pharmacologic interventions. KEY RESULTS: Among 602 IBS patients ages 14-88 (M ± SD = 43.6 ± 18.6 years) with IBS, those who identified as Black/AA (n = 301) had a lower estimated mean income and were significantly more likely to have a number of specific chronic medical conditions. Black/AA patients were significantly less likely to have implemented dietary changes for symptoms prior to receiving a diagnosis of IBS from a gastroenterologist. Black/AA patients were also less likely to receive a referral to a dietician within 1 year following their diagnosis of IBS (p = 0.01). Black/AA patients were prescribed pharmacologic therapy more often for constipation (41.9% vs. 34.6%, p = 0.01). It was more common for White patients to present at the initial encounter having already initiated a neuromodulator (41.9% vs. 27.9%, p < 0.001). CONCLUSION & INFERENCES: Management recommendations for IBS appear to vary by race, specifically for dietary advice and referrals.

Age, Race, Ethnicity, and Sex of Participants in Clinical Trials Focused on Chronic Pain.

There is limited data on equitable inclusion in chronic pain trials. We aimed to 1) identify the frequency of reporting age, race, ethnicity, and sex in clinical trials targeting chronic pain, and 2) compare sociodemographic representation to the United States (US) population. We examined US-based intervention trials for chronic pain initiated between 2007 and 2021 and registered on ClinicalTrials.gov. We 1) assessed the frequency of reporting each demographic variable, 2) compared representation with US population estimates, and 3) explored change in reporting over time. Of 501 clinical trials, the frequency of reporting was as follows: 36.9% reported older adults, 54.3% reported race, 37.4% reported ethnicity, and 100% reported sex. Rates of race and ethnicity reporting increased, but older adult age reporting decreased over time (ps < .00001). Compared to 2020 US population estimates, there was an equitable representation of older adults, under-representation of individuals identifying as American Indian or Alaska Native (.8% vs .6%), Asian (5.6% vs 2.9%), Black or African American (12.6% vs 12.2%), with more than one race (2.9% vs 1.2%), and Hispanic/Latino (16.9% vs 14.1%). There was an over-representation of individuals identifying as Native Hawaiian or Pacific Islander (.2% vs .5%) or White (70.4% vs 72.9%), and of females (50.8% vs 68.4%). Some representation rates varied by chronic pain condition. Reporting of older adult age, race, and ethnicity was low in chronic pain trials in ClinicalTrials.gov, reinforcing the need for adhering to reporting guidelines. Representation varied across trials compared with US population data, particularly among those identifying as Hispanic/Latino and certain minority racial groups. PERSPECTIVE: Despite initiatives to increase the reporting of demographic information, doing so in clinical pain trials is far from ubiquitous. Moreover, efforts to improve diversity in these trials continue to be insufficient. Indeed, Black, Indigenous, and People of Color (BIPOC) remain under-represented in clinical pain trials.

Differences in Management and Outcomes of Older and Younger Adults with Acute Severe Ulcerative Colitis.

BACKGROUND: Older adults with ulcerative colitis (UC) have greater morbidity than younger adults. The goal of this study was to investigate differences in the management and outcomes of older and younger patients hospitalized with severe UC. METHODS: We conducted a retrospective cohort study of patients hospitalized for acute severe ulcerative colitis requiring intravenous steroids. We compared outcomes of adults > 65 years with younger patients. Primary study outcomes included frequency and timing of medical and surgical rescue therapy during the hospitalization, postoperative complications, frailty, and mortality outcomes up to one year following the hospitalization. RESULTS: Our cohort included 63 older adults (≥65 years) and 137 younger adults (14-64 years). Despite similar disease severity at hospitalization, older adults were half as likely to receive medical rescue therapy (odds ratio 0.45, 95% CI 0.22 - 0.91). This difference was more striking among the frailest older adults. Older patients were similar likely to undergo surgery but were more likely to undergo urgent or emergent procedures (50%) compared to younger patients (13%) (p<0.004). The fraction of older adults at high-risk for frailty increased from 33% pre-hospitalization to 42% post-hospitalization. Nearly one-third (27.8%) of older adults died within one year of hospitalization with half the deaths among older adults being attributable to UC or complications of UC. CONCLUSIONS: In comparison to younger patients, older adults had lower frequency use of medical rescue therapy, higher rates of emergency surgery, and increased mortality within one year. Further research is needed to optimize care pathways in this population.

Unrecognized Functional Dyspepsia Among Those With Refractory Chronic Constipation: Analysis of a Tertiary Cohort.

BACKGROUND AND AIMS: Patients with functional constipation (FC) are frequently dissatisfied with current treatment options which may be related to persistent, unaddressed symptoms. We hypothesized that refractory FC may actually represent functional dyspepsia (FD) overlap. Among adults presenting with refractory FC, we sought to (1) identify the prevalence of concurrent FD and (2) identify the symptoms and presentations most frequently associated with concurrent FD and FC. METHODS: We assembled a retrospective cohort of 308 patients sequentially presenting to a tertiary neurogastroenterology clinic for evaluation of refractory FC, defined as having failed first-line therapy. Using Rome IV criteria, trained raters identified the presence and characteristics of concurrent FD in addition to demographics, presenting complaints, and psychological comorbidities. RESULTS: Among 308 patients presenting with refractory FC (average of 3.0 ± 2.3 constipation treatments tried unsuccessfully), 119 (38.6%) had concurrent FD. Aside from meeting FD criteria, the presence of concurrent FD was associated with patient complaints of esophageal symptoms (Odds ratio = 3.1; 95% confidence interval, 1.80-5.42) and bloating and distension (Odds ratio = 2.67; 95% confidence interval, 1.50-4.89). Patients with concurrent FD were more likely to have a history of an eating disorder (21.0% vs 12.7%) and were also more likely to present with current avoidant/restrictive food intake disorder-related symptoms (31.9% vs 21.7%). CONCLUSION: Almost 40% of adult patients referred for refractory FC met criteria for concurrent FD in a tertiary-level cohort. The presence of both FC and FD was associated with greater esophageal symptoms and bloating/distention. Determining presence of concurrent FD may represent an additional therapeutic opportunity in refractory patients who may attribute symptoms to FC alone.

A Prospective Observational Study on Short and Long-Term Outcomes of COVID-19 Patients with Acute Hypoxic Respiratory Failure Treated with High-Flow Nasal Cannula.

(1) The use of high-flow nasal cannula (HFNC) combined with frequent respiratory monitoring in patients with acute hypoxic respiratory failure due to COVID-19 has been shown to reduce intubation and mechanical ventilation. (2) This prospective, single-center, observational study included consecutive adult patients with COVID-19 pneumonia treated with a high-flow nasal cannula. Hemodynamic parameters, respiratory rate, inspiratory fraction of oxygen (FiO2), saturation of oxygen (SpO2), and the ratio of oxygen saturation to respiratory rate (ROX) were recorded prior to treatment initiation and every 2 h for 24 h. A 6-month follow-up questionnaire was also conducted. (3) Over the study period, 153 of 187 patients were eligible for HFNC. Of these patients, 80% required intubation and 37% of the intubated patients died in hospital. Male sex (OR = 4.65; 95% CI [1.28; 20.6], p = 0.03) and higher BMI (OR = 2.63; 95% CI [1.14; 6.76], p = 0.03) were associated with an increased risk for new limitations at 6-months after hospital discharge. (4) 20% of patients who received HFNC did not require intubation and were discharged alive from the hospital. Male sex and higher BMI were associated with poor long-term functional outcomes.

Sexual Dysfunction in Female Patients with Inflammatory Bowel Disease: An Overview.

Sexual dysfunction is common among females with inflammatory bowel disease and may result in issues involving intimacy, sexual activity, and satisfaction, as well both the formation and preservation of personal relationships. Risk factors for sexual dysfunction include select surgical interventions, medications, mental illnesses, and IBD-related intestinal and extraintestinal comorbidities. In addition, certain demographic factors such as age, disease type and activity may influence the severity of sexual dysfunction. Evaluation of sexual dysfunction may include the use of validated sexual functioning questionnaires, a brief mental health assessment, initial inquiry into vulvovaginal or perineal symptoms, and a gynecologic and GI-focused physical exam. An interdisciplinary care team involving IBD specialists, obstetrician-gynecologists, pelvic floor physical therapists, and primary care physicians may be best suited to provide optimal care and treatment recommendations for patients with sexual dysfunction. Options for management often include pelvic floor physical therapy, biofeedback, and mental health support. Further research is necessary to delineate the impact of IBD activity on sexual dysfunction, to determine if health outcome differences exist depending on surgical approaches utilized during J-pouch operations, and finally to evaluate the care and perceptions of patients with IBD who identify as sexual and gender minorities.

Feeding intolerance in critically ill patients with COVID-19.

BACKGROUND & AIMS: Early reports suggest significant difficulty with enteral feeding in critically ill COVID-19 patients. This study aimed to characterize the prevalence, clinical manifestations, and outcomes of feeding intolerance in critically ill patients with COVID-19. METHODS: We examined 323 adult patients with COVID-19 admitted to the intensive care units (ICUs) of Massachusetts General Hospital between March 11 and June 28, 2020 who received enteral nutrition. Systematic chart review determined prevalence, clinical characteristics, and hospital outcomes (ICU complications, length of stay, and mortality) of feeding intolerance. RESULTS: Feeding intolerance developed in 56% of the patients and most commonly manifested as large gastric residual volumes (83.9%), abdominal distension (67.2%), and vomiting (63.9%). Length of intubation (OR 1.05, 95% CI 1.03-1.08), ≥1 GI symptom on presentation (OR 0.76, 95% CI 0.59-0.97), and severe obesity (OR 0.29, 95% CI 0.13-0.66) were independently associated with development of feeding intolerance. Compared to feed-tolerant patients, patients with incident feeding intolerance were significantly more likely to suffer cardiac, renal, hepatic, and hematologic complications during their hospitalization. Feeding intolerance was similarly associated with poor outcomes including longer ICU stay (median [IQR] 21.5 [14-30] vs. 15 [9-22] days, P < 0.001), overall hospitalization time (median [IQR] 30.5 [19-42] vs. 24 [15-35], P < 0.001) and in-hospital mortality (33.9% vs. 16.1%, P < 0.001). Feeding intolerance was independently associated with an increased risk of death (HR 3.32; 95% CI 1.97-5.6). CONCLUSIONS: Feeding intolerance is a frequently encountered complication in critically ill COVID-19 patients in a large tertiary care experience and is associated with poor outcomes.

Tubulin posttranslational modifications modify the atypical spermatozoon centriole.

Sperm cells are transcriptionally and translationally silent. Therefore, they may use one of the remaining mechanisms to respond to stimuli in their environment, the post-translational modification of their proteins. Here we examined three post-translational modifications, acetylation, glutamylation, and glycylation of the protein tubulin in human and cattle sperm. Tubulin is the monomer that makes up microtubules, and microtubules constitute the core component of both the sperm centrioles and the axoneme. We found that the sperm of both species were labeled by antibodies against acetylated tubulin and glutamylated tubulin.

Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS-CoV-2 infection.

The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9P) on the extracellular plasma membrane surface. We hypothesized that the SARS-CoV-2-ARDS pathophenotype involves increased pulmonary endothelial N9P. Paraffin-embedded autopsy lung specimens were acquired from patients with SARS-CoV-2-​​​​​​ARDS (n = 13), ARDS from other causes (n = 10), and organ donor controls (n = 5). Immunofluorescence characterized the expression of N9P, fibrin, and transcription factor 12 (TCF12), a putative binding target of SARS-CoV-2 and known transcriptional regulator of NEDD9. We performed RNA-sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O2) for 24 h. Immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC-MS) profiled protein-protein interactions involving N9P relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19-fold, p = 0.001; false discovery rate = 0.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS-CoV-2-ARDS versus donor control lungs (p < 0.001). Compared to donor controls, pulmonary endothelial N9P-fibrin colocalization was increased in situ in non-SARS-CoV-2-ARDS and SARS-CoV-2-ARDS decedents (3.7 ± 1.2 vs. 10.3 ± 3.2 and 21.8 ± 4.0 arb. units, p < 0.001). However, total pulmonary endothelial N9P was increased significantly only in SARS-CoV-2-ARDS versus donor controls (15 ± 4.2 vs. 6.3 ± 0.9 arb. units, p < 0.001). In HPAEC plasma membrane isolates, IP-LC-MS identified a novel protein-protein interaction between NEDD9 and the ß3-subunit of the αvß3-integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS-CoV-2-ARDS is associated with increased pulmonary endothelial N9P expression and N9P-fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9P to the thrombotic pathophenotype of SARS-CoV-2-ARDS.

Homeostatic plasticity in the retina is associated with maintenance of night vision during retinal degenerative disease.

Neuronal plasticity of the inner retina has been observed in response to photoreceptor degeneration. Typically, this phenomenon has been considered maladaptive and may preclude vision restoration in the blind. However, several recent studies utilizing triggered photoreceptor ablation have shown adaptive responses in bipolar cells expected to support normal vision. Whether such homeostatic plasticity occurs during progressive photoreceptor degenerative disease to help maintain normal visual behavior is unknown. We addressed this issue in an established mouse model of Retinitis Pigmentosa caused by the P23H mutation in rhodopsin. We show robust modulation of the retinal transcriptomic network, reminiscent of the neurodevelopmental state, and potentiation of rod - rod bipolar cell signaling following rod photoreceptor degeneration. Additionally, we found highly sensitive night vision in P23H mice even when more than half of the rod photoreceptors were lost. These results suggest retinal adaptation leading to persistent visual function during photoreceptor degenerative disease.

Fluid Management in Patients with Acute Respiratory Distress Syndrome and Diabetes Mellitus: A propensity score matched analysis of the fluid and catheter treatment trial.

Diabetes mellitus results in an attenuated inflammatory response, reduces pulmonary microvascular permeability, and may decrease the risk of developing acute respiratory distress syndrome (ARDS). Studies have shown that patients with ARDS are better managed by a conservative as compared to liberal fluid management strategy. However, it is not known if the same fluid management principles hold true for patients with comorbid diabetes mellitus and ARDS.As diabetes mellitus results in reduced pulmonary microvascular permeability and an attenuated inflammatory response, we hypothesize that in the setting of ARDS, diabetic patients will be able to tolerate a positive fluid balance better than patients without diabetes.The Fluid and Catheter Treatment Trial (FACTT) randomized patients with ARDS to conservative versus liberal fluid management strategies. In a secondary analysis of this trial, we calculated the interaction of diabetic status and differing fluid strategies on outcomes. Propensity score subclassification matching was used to control for the differing baseline characteristics between patients with and without diabetes.Nine hundred fifty-six patients were analyzed. In a propensity score matched analysis, the difference in the effect of a conservative as compared to liberal fluid management strategy on ventilator free days was 2.23 days (95% CI: -0.97 to 5.43 days) in diabetic patients, and 2.37 days (95% CI: -0.21 to 4.95 days) in non-diabetic patients. The difference in the effect of a conservative as compared to liberal fluid management on 60 day mortality was 2% (95% CI: -11.8% to 15.8%) in diabetic patients, and -7.9% (95% CI: -21.7% to 5.9%) in non-diabetic patients.When comparing a conservative fluid management strategy to a liberal fluid management strategy, diabetic patients with ARDS did not have a statistically significant difference in outcomes than non-diabetic patients.

Susceptibility artifact correction for sub-millimeter fMRI using inverse phase encoding registration and T1 weighted regularization.

BACKGROUND: Functional magnetic resonance imaging (fMRI) enables non-invasive examination of both the structure and the function of the human brain. The prevalence of high spatial-resolution (sub-millimeter) fMRI has triggered new research on the intra-cortex, such as cortical columns and cortical layers. At present, echo-planar imaging (EPI) is used exclusively to acquire fMRI data; however, susceptibility artifacts are unavoidable. These distortions are especially severe in high spatial-resolution images and can lead to misrepresentation of brain function in fMRI experiments. NEW METHOD: This paper presents a new method for correcting susceptibility artifacts by combining a T1-weighted (T1w) image and inverse phase-encoding (PE) based registration. The latter uses two EPI images acquired using identical sequences but with inverse-PE directions. In the proposed method, the T1w image is used to regularize the registration, and to select the regularization parameters automatically. The motivation is that the T1w image is considered to reflect the anatomical structure of the brain. RESULTS: Our proposed method is evaluated on two sub-millimeter EPI-fMRI datasets, acquired using 3T and 7T scanners. Experiments show that the proposed method provides improved corrections that are well-aligned to the T1w image. COMPARISON WITH EXISTING METHODS: The proposed method provides more robust and sharper corrections and runs faster compared with two other state-of-the-art inverse-PE based correction methods, i.e. HySCO and TOPUP. CONCLUSIONS: The proposed correction method used the T1w image as a reference in the inverse-PE registration. Results show its promising performance. Our proposed method is timely, as sub-millimeter fMRI has become increasingly popular.

Vascular effects on the BOLD response and the retinotopic mapping of hV4.

Despite general acceptance that the retinotopic organisation of human V4 (hV4) takes the form of a single, uninterrupted ventral hemifield, measured retinotopic maps of this visual area are often incomplete. Here, we test hypotheses that artefact from draining veins close to hV4 cause inverted BOLD responses that may serve to obscure a portion of the lower visual quarterfield-including the lower vertical meridian-in some hemispheres. We further test whether correcting such responses can restore the 'missing' retinotopic coverage in hV4. Subjects (N = 10) viewed bowtie, ring, drifting bar and full field flash stimuli. Functional EPIs were acquired over approximately 1.5h and analysed to reveal retinotopic maps of early visual cortex, including hV4. Normalised mean maps (which show the average EPI signal amplitude) were constructed by voxel-wise averaging of the EPI time course and used to locate venous eclipses, which can be identified by a decrease in the EPI signal caused by deoxygenated blood. Inverted responses are shown to cluster in these regions and correcting these responses improves maps of hV4 in some hemispheres, including restoring a complete hemifield map in one. A leftwards bias was found whereby 6/10 left hemisphere hV4 maps were incomplete, while this was the case in only 1/10 right hemisphere maps. Incomplete hV4 maps did not correspond with venous artefact in every instance, with incomplete maps being present in the absence of a venous eclipse and complete maps coexisting with a proximate venous eclipse. We also show that mean maps of upper surfaces (near the boundary between cortical grey matter and CSF) provide highly detailed maps of veins on the cortical surface. Results suggest that venous eclipses and inverted voxels can explain some incomplete hV4 maps, but cannot explain the remainder nor the leftwards bias in hV4 coverage reported here.

Reporter Cell Assessment of TLR4-Induced NF-κB Responses to Cell-Free Hemoglobin and the Influence of Biliverdin.

Hemoglobin (Hb) released during red blood cell lysis can initiate TLR4-dependent signaling and trigger NF-κB activation in surrounding cells. Observations of chronic bleeding in various cancers leads us to hypothesize that Hb and Hb degradation products released from lysed RBC near cancer nests might modulate local TLR4-positive cells. We addressed the hypothesis in vitro by measuring Hb- and biliverdin (Bv)-induced NF-κB signaling in an engineered human TLR4 reporter cell model (HEK-BlueTM hTLR4). Therein, TLR4 stimulation was assessed by measuring NF-κB-dependent secreted alkaline phosphatase (SEAP). hTLR4 reporter cells incubated with 8 ηM lipopolysaccharide (LPS) or 20-40 µM fungal mannoprotein (FM) produced significant amounts of SEAP. hTLR4 reporter cells also produced SEAP in response to human, but not porcine or bovine, Hb. HEK-Blue Null2TM reporter cells lacking TLR4 did not respond to LPS, FM, or Hb. Bv was non-stimulatory in reporter cells. When Bv was added to Hb-stimulated reporter cells, SEAP production was reduced by 95%, but when Bv was applied during LPS and FM stimulation, SEAP production was reduced by 33% and 27%, respectively. In conclusion, Hb initiated NF-κB signaling that was dependent upon TLR4 expression and that Bv can act as a TLR4 antagonist. Moreover, this study suggests that hemorrhage and extravascular hemolysis could provide competitive Hb and Bv signaling to nearby cells expressing TLR4, and that this process could modulate NF-κB signaling in TLR4-positive cancer cells and cancer-infiltrating leukocytes.