Publications

Acute myeloid leukemia (AML) is one of the leading leukemic malignancies in adults. The heterogeneity of the disease makes the diagnosis and treatment extremely difficult. With the advent of next-generation sequencing (NGS) technologies, exploration at the molecular level for the identification of biomarkers and drug targets has been the focus for the researchers to come up with novel therapies for better prognosis and survival outcomes of AML patients. However, the huge amount of data from NGS platforms requires a comprehensive AML platform to streamline literature mining efforts and save time. To facilitate this, we developed AMLdb, an interactive multi-omics platform that allows users to query, visualize, retrieve, and analyse AML related multi-omics data. AMLdb contains 86 datasets for gene expression profiles, 15 datasets for methylation profiles, CRISPR-Cas9 knockout screens of 26 AML cell lines, sensitivity of 26 AML cell lines to 288 drugs, mutations in 41 unique genes in 23 AML cell lines, and information on 41 experimentally validated biomarkers. In this study, we have reported five genes, i.e. CBFB, ENO1, IMPDH2, SEPHS2, and MYH9 identified via our analysis using AMLdb. ENO1 is uniquely identified gene which requires further investigation as a novel potential target while other reported genes have been previously confirmed as targets through experimental studies. Top of form we believe that these findings utilizing AMLdb can make it an invaluable resource to accelerate the development of effective therapies for AML and assisting the research community in advancing their understanding of AML pathogenesis. AMLdb is freely available at https://project.iith.ac.in/cgntlab/amldb.

BACKGROUND: Practicing neuroendoscopic skills like hand-eye coordination is mandatory before embarking on actual surgeries. Synthetic models are able alternatives for cadavers and animals. Presently available models in the literature are either very costly or lack a feedback mechanism, which makes training difficult.

OBJECTIVE: We aimed to make a basic low-cost neuroendoscopic hand-eye coordination model with a feedback mechanism.

METHODS AND MATERIALS: An electronic circuit in series was designed inside a clay utensil to test inadvertent contact of the working instrument with implanted steel pins, which on completion lighted a light-emitting diode (LED) and raised an alarm. Two exercises-moving-a-rubber exercise and passing copper rings of multiple sizes were made and tested by 15 neurosurgeons.

RESULTS: The moving-a-rubber exercise was completed by 6/15 (40%) neurosurgeons in the first attempt, 6/15 (40%) in the second, and 3/15 (20%) in the third attempt. For the 1.5 cm copper ring passing exercise, 12/15 (80%) successfully performed in the first attempt; for 1 cm copper ring, 6/15 (40%) performed in the first; and for the 0.5 cm copper ring, 1/15 (6.6%) performed in the first attempt. The time to finish all the exercises significantly decreased in the third successful attempt compared to the first.

CONCLUSION: The model gave excellent feedback to the trainee and examiner for basic neuroendoscopic hand-eye coordination skills.

Outer and middle ear pathologies are known to disproportionately affect low-income countries but data is limited. We aim to quantify the prevalence rate of patients presenting with middle/outer ear pathologies at ABC Hearing Clinic and Training Centre in Lilongwe, Malawi. Audiological consultations (adult and paediatric) from 2018-2020 were reviewed for outer and middle ear pathologies. Secondary outcomes included patient type (private vs. community) compared to otoscopy findings, tympanometry findings, need for follow up, and follow up compliance. Out of 1576 patients reviewed, the proportion of abnormal cases' was 98.2%, with 41.4% being unilateral and 57.4% bilateral. Eighty-three percent presented with outer/middle ear pathologies. 68% of those presented with a pathology often associated with some degree of conductive hearing loss (occluding wax, perforation, discharge, Type B/Type C tympanogram). Average age was 29 + 0.527 years; 41.6% private and 58.2% community patients. Cerumen impaction was most common finding (51%). Higher rates of otoscopic abnormalities and type B tympanograms were noted in community vs. private patient ( 40% vs.  30%;  70% vs.  30%). Adherence to follow up was higher for community vs. private patients (29% vs. 17%);  70% reported subjective improvement upon follow up. The majority required multiple interventions on follow up. Secondary follow up was recommended in 64.8%. A significant disease burden of outer and middle ear pathologies was identified. Further research is required to understand the disease burden and promote health policy.

Kinesin-mediated transport along microtubules is critical for axon development and health. Mutations in the kinesin Kif21a, or the microtubule subunit β-tubulin, inhibit axon growth and/or maintenance resulting in the eye-movement disorder congenital fibrosis of the extraocular muscles (CFEOM). While most examined CFEOM-causing β-tubulin mutations inhibit kinesin-microtubule interactions, Kif21a mutations activate the motor protein. These contrasting observations have led to opposed models of inhibited or hyperactive Kif21a in CFEOM. We show that, contrary to other CFEOM-causing β-tubulin mutations, R380C enhances kinesin activity. Expression of β-tubulin-R380C increases kinesin-mediated peroxisome transport in S2 cells. The binding frequency, percent motile engagements, run length and plus-end dwell time of Kif21a are also elevated on β-tubulin-R380C compared with wildtype microtubules in vitro. This conserved effect persists across tubulins from multiple species and kinesins from different families. The enhanced activity is independent of tail-mediated kinesin autoinhibition and thus utilizes a mechanism distinct from CFEOM-causing Kif21a mutations. Using molecular dynamics, we visualize how β-tubulin-R380C allosterically alters critical structural elements within the kinesin motor domain, suggesting a basis for the enhanced motility. These findings resolve the disparate models and confirm that inhibited or increased kinesin activity can both contribute to CFEOM. They also demonstrate the microtubule's role in regulating kinesins and highlight the importance of balanced transport for cellular and organismal health.

BACKGROUND: No reliable or standardized system exists for measuring the size of deceased donor livers to determine whether they will fit appropriately into intended recipients.

METHODS: This retrospective, single-center study evaluated the efficacy of Tampa General Hospital's size-matching protocol for consecutive, deceased donor liver transplantations between October 2021 and November 2022. Our protocol uses cross-sectional imaging at the time of organ offer to compare the donor's right hepatic lobe size with the recipient's right hepatic fossa. Outcomes were analyzed, including large-for-size syndrome, small-for-size syndrome, early allograft dysfunction, primary nonfunction, graft survival, and patient survival.

RESULTS: We included 171 patients in the study. The donor liver physically fit in all the patients except one whose pretransplant imaging was outdated. One patient (0.6%) had large-for-size syndrome, none had small-for-size syndrome, 15 (10%) had early allograft dysfunction, and none had primary nonfunction. There were 11 (7%) patient deaths and 11 (7%) graft failures.

CONCLUSION: Our measurement system is fast and effective. It reliably predicts whether the donor liver will fit in the intended recipient and is associated with low rates of early allograft dysfunction.

BACKGROUND AND AIM: The quality of clinical practice guidelines (CPGs) for the management of antithrombotic agents in patients undergoing gastrointestinal (GI) endoscopy has not been systematically appraised. The goal of this study was to evaluate the methodological quality of CPGs for the management of antithrombotic agents in periendoscopic period published within last 6 years.

METHODS: A systematic search of PubMed and Embase databases was performed to identify eligible CPGs published between January 1, 2016, and April 14, 2022, addressing the management of antithrombotic agents in the periendoscopic period. The quality of the CPG was independently assessed by six reviewers using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Domain scores were considered of sufficient quality when > 60% and of good quality when > 80%.

RESULTS: The search yielded 343 citations, of which seven CPGs published by the gastroenterology associations in Asia (n = 3), Europe (n = 2), and North America (n = 2) were included for the critical appraisal. The overall median score for the AGREE II domains was 93% (interquartile range [IQR] 11%) for scope and purpose, 79% (IQR 61%) for stakeholder involvement, 79% (IQR 36%) for rigor of development, 100% (IQR 14%) for clarity of presentation, 32% (IQR 36%) for applicability, 93% (IQR 29%) for editorial independence, and 86% (IQR 29%) for overall assessment.

CONCLUSIONS: The findings show that the overall methodological quality of the CPGs for the management of antithrombotic agents in the periendoscopic period varies across the domains. There is significant scope for improvement in the methodological rigor and applicability of CPGs.

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.

OBJECTIVE: Parental vaccine hesitancy is a significant contributor to low adolescent HPV vaccination. Shared HPV vaccination decision-making among adolescents and parents is an important determinant of vaccination uptake. We performed a scoping review to identify studies that used parent-adolescent dyads in HPV vaccination research.

METHODS: We searched peer-reviewed articles in PubMed, Embase, and PsychInfo from 2012 to 2023. Randomized or observational studies with parent-adolescent dyads related to HPV vaccination were eligible for inclusion. Articles were coded for the main themes related to use of parent-adolescent dyads in HPV vaccination research.

RESULTS: Fifteen articles met the inclusion criteria and were categorized into two main themes: qualitative decision-making and quantitative vaccination intentions. Dyad members reported substantially different roles, barriers, and facilitators of HPV vaccine decisions and intentions. Dyad members disagreed on who made the final decision. Provider recommendation style and content were important to parental confidence in the vaccine decision.

CONCLUSION: The recent evidence for parent-adolescent HPV vaccination dyad research is sparse but indicates that factors that account for dyad vaccination decisions and intentions often differ between dyad members.

PRACTICE IMPLICATIONS: Studies in this review support ongoing research with parent-adolescent dyads to target HPV vaccine interventions at individual dyad members to increase HPV vaccination.