Honeycomb: a template for reproducible psychophysiological tasks for clinic, laboratory, and home use

Objective: To improve the ability of psychiatry researchers to build, deploy, maintain, reproduce, and share their own psychophysiological tasks. Psychophysiological tasks are a useful tool for studying human behavior driven by mental processes such as cognitive control, reward evaluation, and learning. Neural mechanisms during behavioral tasks are often studied via simultaneous electrophysiological recordings. Popular online platforms such as Amazon Mechanical Turk (MTurk) and Prolific enable deployment of tasks to numerous participants simultaneously. However, there is currently no task-creation framework available for flexibly deploying tasks both online and during simultaneous electrophysiology. Methods: We developed a task creation template, termed Honeycomb, that standardizes best practices for building jsPsych-based tasks. Honeycomb offers continuous deployment configurations for seamless transition between use in research settings and at home. Further, we have curated a public library, termed BeeHive, of ready-to-use tasks. Results: We demonstrate the benefits of using Honeycomb tasks with a participant in an ongoing study of deep brain stimulation for obsessive compulsive disorder, who completed repeated tasks both in the clinic and at home. Conclusion: Honeycomb enables researchers to deploy tasks online, in clinic, and at home in more ecologically valid environments and during concurrent electrophysiology.

Depression in Female Adolescents with Heavy Menstrual Bleeding.

OBJECTIVE: To assess the degree to which heavy menstrual bleeding is associated with depression, independent of hormonal contraception. STUDY DESIGN: We performed a retrospective cohort study of 1168 female adolescents 9-18 years old presenting to general pediatricians for heavy menstrual bleeding or well visits. Depression was the primary outcome and defined as a diagnosis in the health record. Univariable and multivariable regression models were fit to the data to identify factors associated with depression diagnosis. RESULTS: In total, 581 adolescents with heavy menstrual bleeding and 587 without heavy menstrual bleeding were included. Depression diagnoses occurred with greater frequency in youth with heavy menstrual bleeding compared with those without heavy menstrual bleeding (50.9% vs 24.2% P < .001; risk ratio 1.67, 95% CI 1.39-2.01) but did not significantly differ between those taking vs not taking hormonal contraception (risk ratio 0.99; 95% CI 0.84-1.17). Most patients with depression and heavy menstrual bleeding developed depression following or concurrent with heavy menstrual bleeding (261/296, 88%). Of these, 199 of 261 (76%) were treated with hormonal contraception, but the majority (168/199; 84%) were diagnosed with depression before initiation. CONCLUSIONS: Heavy menstrual bleeding is associated with depression diagnosis in female adolescents. The use of hormonal contraception was not associated with depression diagnosis in multivariable analysis, covarying heavy menstrual bleeding, age, body mass index, anxiety, sexual activity, and substance use. As hormonal contraception is often used to treat heavy menstrual bleeding, heavy menstrual bleeding may be partially driving previous reports of increased depression risk in those taking hormonal contraception.

Honeycomb: a template for reproducible psychophysiological tasks for clinic, laboratory, and home use.

OBJECTIVE: To improve the ability of psychiatry researchers to build, deploy, maintain, reproduce, and share their own psychophysiological tasks. Psychophysiological tasks are a useful tool for studying human behavior driven by mental processes such as cognitive control, reward evaluation, and learning. Neural mechanisms during behavioral tasks are often studied via simultaneous electrophysiological recordings. Popular online platforms such as Amazon Mechanical Turk (MTurk) and Prolific enable deployment of tasks to numerous participants simultaneously. However, there is currently no task-creation framework available for flexibly deploying tasks both online and during simultaneous electrophysiology. METHODS: We developed a task creation template, termed Honeycomb, that standardizes best practices for building jsPsych-based tasks. Honeycomb offers continuous deployment configurations for seamless transition between use in research settings and at home. Further, we have curated a public library, termed BeeHive, of ready-to-use tasks. RESULTS: We demonstrate the benefits of using Honeycomb tasks with a participant in an ongoing study of deep brain stimulation for obsessive compulsive disorder, who completed repeated tasks both in the clinic and at home. CONCLUSION: Honeycomb enables researchers to deploy tasks online, in clinic, and at home in more ecologically valid environments and during concurrent electrophysiology.

Is abnormal gallbladder ejection fraction hokum? Retrospective chart review of gallbladder ejection fraction and subsequent postoperative symptom relief, surgical pathology, and current literature review.

The purpose of this report is to investigate the clinical importance of increased or decreased gallbladder ejection fraction (GBEF) and ultrasound findings for biliary dyskinesia by evaluating postsurgical symptom relief and surgical pathology. Single institution electronic medical record review was prepared for patients who underwent hepatobiliary iminodiacetic acid (HIDA) scan with GBEF and cholecystectomy between January 2013 and March 2020. Relevant data included patient demographics, ultrasound results, surgical pathology, HIDA with GBEF results, and postoperative symptom relief at the time of follow-up. Student's t-test was also utilized for additional statistical analysis. A total of 67 patients underwent cholecystectomy within a 1-month period of time after HIDA with GBEF. Of these patients, 97% had findings consistent with chronic cholecystitis and 3% of the patients demonstrated both acute and chronic cholecystitis surgical pathology. Fifty-seven percent of the patients demonstrated a GBEF <38%, 30% had a GBEF >80%, and 13% had a GBEF 38%-80% with a postoperative symptom resolution around 82%, 77%, and 100%, respectively. GBEF alone may not be determinative regarding gallbladder pathology or postoperative symptom relief in patients that present with typical symptoms. Regarding dyskinetic gallbladders, elevated and decreased GBEF groups were not significantly different in terms of surgical pathology or symptom relief. These patients may benefit from being treated as a single group rather than as separate entities. Elevated and decreased GBEF groups demonstrated mostly normal ultrasound results that raised concern for the utility of ultrasound as a rule out test for gallbladder inflammation.

Clinical predictors of I-131 therapy failure in differentiated thyroid cancer by machine learning: A single-center experience.

Well-differentiated thyroid carcinoma is predominantly a slow-growing malignancy, amendable to treatment, and has an excellent prognosis following thyroidectomy and radioiodine (RAI) therapy. However, patients who fail the initial RAI treatment attempt may require repeated RAI or other treatments and with this, comes an associated impact on patient quality of life. Therefore, the anticipation of patients in whom there is a higher risk of RAI failure may help in patient risk stratification and subsequent management. We conducted a retrospective review to determine the factors associated with initial RAI therapy failure in well-differentiated thyroid cancer patients. Using scikit-learn from Python, we implemented a machine-learning algorithm to determine the clinical patient factors associated with a higher likelihood of treatment resistance. We found that clinical factors such as tumor focality (P = 0.026) and lymph node invasion at surgical resection (P = 0.0135) were significantly associated with initial treatment failure following RAI. Elevated serum thyroglobulin (Tg) and Tg antibody levels following surgery but before RAI were also associated with treatment resistance (P < 0.0001 and P = 0.011 respectively). Less expected factors such as decreased time from surgery to RAI were also associated with treatment failure, however not to a statistically significant degree (P > 0.064). Clinical outcomes following RAI can be stratified by identifying factors that are associated with initial treatment failure. These findings can help restratify patients for RAI treatment and change patient management in certain cases. Such stratification will ultimately help to optimize successful treatment outcomes and improve patient quality of life.

Relapsed Wilms' Tumor Presenting as Metastasis to the Zygoma.

Wilms' tumor accounts for the majority of renal tumors in children. Rarely, Wilms' tumor may metastasize to the bone. We present a case of a 15-month-old female who presented with severe abdominal distension and signs of cachexia. Abdominal ultrasonography and radiography of the abdomen both demonstrated a large abdominal mass. Follow-up computed tomography of the abdomen revealed a heterogeneous intra-abdominal mass arising from the left kidney which was surrounded by a thin rim of renal parenchyma. Biopsy of the mass revealed findings consistent with Wilms' tumor. The patient was 14 months status-post nephrectomy and chemoradiation but returned to the clinic with left facial swelling. Magnetic resonance imaging of the face demonstrated a multilobulated, heterogeneously enhancing solitary mass lesion in the left temple centered in the left zygoma with signs of bone breakdown. Despite its rarity, metastatic Wilms' tumor to bone should be considered in a child presenting with a new focal mass overlying bony-structures.

Double and single mixed-lineage leukemia-rearranged subclones in pediatric acute myeloid leukemia: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a disease with a significant amount of cytogenetic heterogeneity including mixed-lineage leukemia (MLL) gene rearrangements. Pediatric AML commonly has genetic rearrangements which involve chromosome 11q23 in 15-20% of cases, and these genetic abnormalities have been associated with a poorer prognosis (Grimwade et al. in Blood 92:2322-2333, 1998; Raimondi et al. in Blood 94:3707-3716, 1999; Lie et al. in Br J Haematol 122: 217-225). MLL rearrangements in AML have been shown to have multiple different fusion partners (Meyer et al. in Leukemia 23:1490-1499). Heterogeneity of these cytogenetic abnormalities makes it difficult to determine how to approach patients from a treatment standpoint. This difficulty is further complicated when patients have more than a single MLL rearrangement. CASE PRESENTATION: A 10-year-old Caucasian girl presented with easy bruising and was found to have acute myeloid leukemia. Her cytogenetics showed two different MLL rearrangements, t(9;11)(p22;q23) and t(11;19)(q23;p13.3). At initial presentation she had no other cytogenetic findings. She responded well to initial therapy and achieved remission following the first induction cycle and completed four rounds of chemotherapy. She subsequently had a relapse of her AML, and her cytogenetics were consistent with a single MLL rearrangement, t(9;11)(p22;q23), in addition to monosomy 7. She was treated with reduction therapy and a haplo-identical bone marrow transplant but ultimately succumbed to her disease. CONCLUSION: MLL rearrangements are common in AML, but clinical significance continues to be elusive, and there is conflicting data on the prognostic significance. In the setting of multiple MLL rearrangements, there is concern for reduced survival, although treatment modifications are not currently done in this setting. This report details a case with multiple MLL rearrangements that initially responded to therapy but ultimately had disease progression with a selection of a leukemic clone containing a single MLL rearrangement.

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia.

Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS's novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS's DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS's regulatory effects on the PI3K oncogenic signaling pathway.

Line Associated Thrombosis in Pediatric Patients With NF-κB Pathway Variants.

Our report explores the complex role that nuclear factor-kappa B (NF-κB) plays in thrombosis formation, inflammation, and immunity; while additionally demonstrating that patients with NF-κB pathway pathogenic variants appear to carry a substantial thrombotic risk, particularly when secondary thrombotic risk factors are present. We propose that prophylactic anticoagulation should be strongly considered in such patients during high-risk situations and provide additional hematologic management strategies for those with NF-κB pathway alterations. We hope our work also calls to attention the potential need for a broader assessment of venous thromboembolism risk in patients with immune dysregulation to better delineate which patient populations may benefit from anticoagulation prophylaxis.

High Number of Door Openings Increases the Bacterial Load of the Operating Room.

Background: Operating room (OR) traffic and door openings have emerged as potential modifiable risk factors for the development of surgical site infections. Methods: This study compared the microbial load of a Control OR without traffic versus a Simulated OR with the traffic in a typical orthopedic surgery case. Air particle counts and colony forming units (CFUs) were measured. A novel iOS app was developed to provide real-time door counts. Results: There were 1,862 particles >5.0 mcm in the Simulated OR compared with 56 in the Control OR. The CFUs from plates in the Simulated OR ranged from 4-22 (on brain heart infusion [BHI] agar), 2-266 (on mannitol salt agar [MSA]), and 1-19 (on Pseudomonas isolation agar [PIA]), while all plates in the Control OR grew 0-1 CFUs. Conclusions: High number of door openings leads to more airborne bacteria in the OR and viable bacterial on OR surfaces. The increased bacterial load throughout the OR was independent of distance from the door.

Incorporation of posttransplant cyclophosphamide as part of standard immunoprophylaxis for all allogeneic transplants: a retrospective, single institution study.

The addition of posttransplant cyclophosphamide (PTCy) to standard graft-versus-host disease (GVHD) prophylaxis following haploidentical blood stem transplants has resulted in relatively low rates of GVHD. As GVHD remains a major cause of morbidity and mortality in patients receiving transplants from matched donors, we began to use PTCy in all blood stem cell transplants in 2016 and compared our recent experience with PTCy after matched sibling and unrelated donor transplants (N = 49) to the earlier 2-year period (N = 41) when PTCy was not used. Endpoints included graft-versus-host, relapse-free-survival (GRFS), overall survival, non-relapse mortality, and percentage of patients disease-free and off immunosuppression (DFOI) at 1 year and at the last follow-up. The difference in GRFS between the standard and the PTCy cohort was not statistically significant. There was a statistically improved relapse-free and overall survival in the PTCY cohort that was due to a significant decrease in non-relapse mortality secondary to GVHD. There was also a borderline statistically improved DFOI at 1 year and at last follow-up in the PTCY group. These results suggest that PTCy after HLA-matched transplants provides at least comparable efficacy to other GVHD strategies and may allow more frequent discontinuation of immunosuppression.

A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (D-G6PD) is an X-linked recessive disorder resulted from deleterious variants in the housekeeping gene Glucose-6-phosphate 1-dehydrogenase (G6PD), causing impaired response to oxidizing agents. Screening for new variations of the gene helps with early diagnosis of D-G6PD resulting in a reduction of disease related complications and ultimately increased life expectancy of the patients. METHODS: One thousand five hundred sixty-five infants with pathological jaundice were screened for G6PD variants by Sanger sequencing all of the 13 exons, and the junctions of exons and introns of the G6PD gene. RESULTS: We detected G6PD variants in 439 (28.1%) of the 1565 infants with pathological jaundice. In total, 9 types of G6PD variants were identified in our cohort; and a novel G6PD missense variant c.1118 T > C, p.Phe373Ser in exon 9 of the G6PD gene was detected in three families. Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice, consistent with Class I G6PD deleterious variants. Analysis of the resulting protein's structure revealed this novel variant affects G6PD protein stability, which could be responsible for the pathogenesis of D-G6PD in these patients. CONCLUSIONS: High rates of G6PD variants were detected in infants with pathological jaundice, and a novel Class I G6PD deleterious variants was identified in our cohort. Our data reveal that variant analysis is helpful for the diagnosis of D-G6PD in patients, and also for the expansion of the spectrum of known G6PD variants used for carrier detection and prenatal diagnosis.

Discovery of an Atropisomeric PI3Kß Selective Inhibitor through Optimization of the Hinge Binding Motif.

A series of PI3Kß selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kß inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.