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Objectives: Core binding factor (CBF) leukemias represent an important prognostic group in acute myeloid leukemia (AML). The t(8;21)(q22;q22)/RUNX1 -RUNX1T1 is one of the most frequent abnormalities in childhood AML (7–16%) and is related to a good prognosis. However, on rare occasions, an additional chromosome may be involved in this translocation, which may result in a poor clinical outcome for the patient. In this sense, the prognostic value of the RUNX1 -RUNX1T1 fusion has been widely discussed in the literature. Approximately 3–4% of AML cases with t(8;21)/RUNX1 -RUNX1T1 occur in the context of complex rearrangements, with only a few cases reported in children (0.05–1.1%). Our aim in this work is to demonstrate the clinical and molecular data from four AML pediatric patients with variant three-way translocations t(8;V;21), characterizing in detail the extra chromosomes and fusion products. Material and methods: In our cohort of 146 children diagnosed with AML, we observed 22 with complex karyotypes (>3 abnormalities). To date, we detected the t(8;21) in 5/22 cases, among which 4 patients presented the involvement of a third chromosome in t(8;21), characterizing variant three-way translocations t(8;V;21). To characterize the patient's karyotypes, G-banding, FISH, and high-resolution molecular cytogenetics experiments (PCP, WCP, M-FISH, and MCB) were performed on bone marrow and/or peripheral blood cells under standard protocols. Discussion: Regarding the mechanism of this type of translocation, Downing et al. (1993) and Tanaka et al. (2012) reported that there are at least two stages for the formation of such complex variants. The region 21(q22) (harboring the RUNX1 gene) translocates to the long arm of chromosome 8, while region 8q22 (harboring the RUNX1T1 gene) translocates to a third chromosome. Interestingly, in our 4 cases, t(8;V;21) demonstrated the same biological behavior in the rearrangement as the other cases reported in the literature. Although, unlike the cases previously reported in the literature, the karyotypes characterized in our study were cryptic, reaffirming the importance of an accurate diagnosis of RUNX1 -RUNX1T1 fusion products. Conclusion: With our approach by molecular cytogenetic techniques, we were able to precisely define the breakpoints of the three-way translocations, which will be of importance for future studies, investigating putative genes with impact on the genesis of pediatric CBF leukemias.

Objectives: Intrachromosomal amplification of chromosome 21 (iAMP21) occurs in 2% of B-cell acute lymphoblastic leukemia (ALL) and is considered to confer a poor prognosis. Alterations related to chromosome 21, such as the constitutional r(21)c and rob(15;21)c, have been associated with a high hazard ratio for iAMP21-ALL. Here we describe the case of an adolescent with iAMP21-B-ALL presenting a non-Robertsonian somatic t(15;21)(q25.3;q22.1) with NTRK3 gene rearrangement, chromothripsis, and breakage-fusion-bridge of chromosome 21, besides a somatic homozygous deletion of the SH2B3 gene. Material and methods: A 12-year-old girl was admitted to the Lagoa Federal Hospital, Rio de Janeiro, Brazil, with a 2-month history of fever, weight loss, arthritis, bone pain, and hepatomegaly. The bone marrow aspirate was hypercellular, with blasts cell suggestive of ALL phenotype. The Flow cytometry analysis confirmed a diagnosis compatible with pre-B-ALL phenotype. Due to the cytogenetics findings, the patient was treated under the high-risk ALL-BFM-2009 v.13 protocol. She achieved remission three months after the initial diagnosis. Currently, she is out of treatment and has been followed up on an outpatient basis. G-banding and FISH experiments were performed on bone marrow cells under standard protocols. Array-comparative genomic hybridization (aCGH) was performed according to standard procedures. Transcriptional expression of genes involved in the aberrations as revealed by aCGH analysis was determined by RT-qPCR. The copy number of SH2B3 was quantified by RT-qPCR in constitutive (epithelial) cells collected from mouth swabs. Results: Phytohemagglutinin-stimulated lymphocyte culture during follow-up, showed a normal karyotype 46,XX, eliminating the hypothesis of t(15;21) as a germline mutation. FISH analysis in bone marrow cells detected iAMP21, with aCGH analysis revealing further genomic imbalances. The RT-qPCR analysis detected elevated expression levels of the RUNX1 (68-fold) and reduced expression of the CDK6 (0.057-fold). Studies with constitutive cells collected from mouth swabs showed that SH2B3 biallelic deletion was a somatic alteration occurring during clonal evolution. Discussion: iAMP21 has been associated with type I and type II mutations as secondary aberrations. Besides, Harrison and co-workers have been describing a relation between chromosome 21 constitutional abnormalities and iAMP21 leukemogenesis. Thus, along with the standard clinical profile, a precise molecular characterization may help in iAMP21-ALL differential diagnosis. In our work, high-resolution cytogenetics combined with molecular approaches helped us characterize a non-Robertsonian somatic t(15;21)(q25.3;q22.1), with rearrangement of the putative leukemic gene NTRK3, ruling out the involvement of r(21)c and rob(15;21)c, both in constitutive and tumor cells. Conclusion: The identification of novel secondary genetic changes was valuable to discuss sporadic iAMP21 leukemogenic mechanisms. For the first time, we show a non-Robertsonian translocation t(15;21)(q25.3;q22.1) with NTRK3 rearrangement in an adolescent with iAMP21-ALL with a favorable prognosis.

Objectives: KMT2A gene aberrations are more frequent in infants less than one year (yr) of age, accounting for about 70% of acute lymphoblastic leukemia (ALL) patients, and about 30% are diagnosed with acute myeloid leukemia (AML). The most common abnormality found in these patients is the translocation t(11;19)(q23;p13.3), corresponding to 22% of KMT2A rearranged (KMT2A-r) positive cases. Related literature data shows that infants

The treatment of human diseases using gene-editing technology has been envisioned for several decades with the realisation that so many were associated with mutations in DNA. The Human Genome Project opened new doors for identifying the genetic bases for human suffering. Research on gene editing has been active since the 1970s, but the technology has seen substantial growth and application just within the past decade. Simply stated, CRISPR technology has become a phenomenon in both biomedical and therapeutics research. Concurrently, cell therapies and pluripotent stem cell research have also been refined and now interfaced with CRISPR technology to enhance and maximise their potential in modelling as well as treatment of human diseases. In this review, we discuss the novel and revolutionary modality of gene editing, as this marks a new era in research and medicine. We also discuss gene-modifying technologies leading to CRISPR, as they are still being used for a wide variety of genomic applications. The modes and challenges for delivery of gene editing components are also discussed. Lastly, we review examples of human diseases that are not only amenable to gene editing techniques, but also show true promise of cure in the early 21st century of genetic correction and gene repair.

Transesophageal echocardiography (TEE) was performed in 114 patients with rheumatic mitral valvular disease and its results were compared with those of transthoracic echocardiography (TTE). Of 114 patients, LA thrombus was detected in 32 patients by TEE whereas TTE could detect LA thrombus in only 4 of them. Out of 32 cases, thrombus was located in left atrial appendage (LAA) in 20 (62%). TTE could detect LAA thrombus in only one patient. The procedure of TEE was well tolerated and there was no complication. We conclude that TEE is superior to TTE in detection of LA cavity and LA appendage thrombus. Hence, TEE should be a routine procedure to detect LA thrombus in patients with rheumatic mitral valvular disease prior to any surgical intervention. [ABSTRACT FROM AUTHOR]

ALT-C, an ECD motif (glutamic acid, cysteine, aspartic acid) disintegrin from Bothrops alternatus snake venom, induces α2β1 integrin-mediated signaling and neutrophil chemotaxis. In vitro, in human umbilical vein endothelial cells (HUVEC), ALT-C induces cell proliferation, thus showing an interesting potential for tissue regeneration studies. This work aimed to evaluate the influence of ALT-C in myoblast viability and differentiation. Myoblasts were obtained from hind limb muscles of 3 to 4-day old Wistar rats. The cells were incubated with ALT-C at different concentrations and incubation periods were followed by total RNA isolation. cDNA synthesis and real time polymerase chain reaction (PCR) were performed with primers of myoD as well as of both (slow and fast) myosin heavy chain isoforms (MHC). ECD-disintegrin increased myoblast viability in a dose-dependent way, mostly with 50 to 100 nM concentrations, and such effect was more prevalent after 48 hours. No changes in gene expression of both MHC isoforms were observed in ALT-C-treated cells. MyoD expression was not detected, which suggests that myoblasts were in mature stages. Protease activity and cytokine array tested in a medium of 50 nM ALT-C-treated cells after 48 hours were not different from controls. In conclusion, it was shown that myoblats are sensitive to ALT-C indicating an integrin-mediated intracellular signaling that increases cell viability.

Brown tumours may occur secondary to hyperparathyroidism in patients with chronic renal failure (CRF). Diagnosing a spinal brown tumour causing cord compression requires a high index of suspicion. We report a 65-year-old woman, who had been on haemodialysis for CRF for over 10 years, who presented with leg weakness and back pain over the thoracolumbar junction. She had a brown tumour at T8 causing subacute spinal cord compression. Ambulation was regained after surgical decompression and stabilisation. Adherence to the National Kidney Foundation guidelines in the management of patients with CRF may prevent renal osteodystrophy. Treatment of spinal brown tumour depends on the severity of the neurological deficit. Remineralisaton is expected after correction of the parathyroid level, thus negating the need for total excision of the parathyroid glands.

Background: There remain persistent racial and ethnic disparities in the receipt of post-mastectomy breast reconstruction for breast cancer. Yet, patient-reported outcomes and advocacy efforts around living flat overwhelmingly have focused on white women. We sought to characterize the lived experiences among women of color living flat after mastectomy for breast cancer., Patients and Methods: Our community-partnered study included a sociodemographic and health questionnaire followed by semistructured interviews. Using an interview guide designed in an interdisciplinary manner, we explored themes related to culture and community after mastectomy. Women ≥ 18 years old who underwent mastectomy without reconstruction for breast cancer were included. Interviews were performed by formally trained community-based research fellows and conducted virtually over video conferencing, recorded, and transcribed. Data were analyzed on NVivo using an integrated (inductive and deductive) team-based approach., Results: The final cohort included 20 women, 60% identified as Black, 20% as Asian, 10% as multiracial, 5% as Latina, and 5% as white. Key concepts included: (a) cancer stigma, (b) privacy around breasts, (c) finding support through shared experiences, (d) sacrifice of breast for life/health, (e) spirituality, (f) patients' familial roles and relationship to breast, and (g) societal expectations. Women described the intersection of cancer stigma and privacy around breasts influencing knowledge of family history and support during cancer treatment., Conclusion: Among women of color, breast cancer stigma and spirituality are key contributors to quality of life after mastectomy without breast reconstruction, domains not routinely included in contemporary patient-reported outcome measures. Representation of diverse experiences is critical to achieving equity., (© 2024. Society of Surgical Oncology.)

Background: Axillary staging in early-stage breast cancer can impact adjuvant treatment options but also has associated morbidity. The incidence of pathologic nodal positivity (pN+) in patients with microinvasive or T1a disease is poorly characterized and the value of sentinel node biopsy remains controversial., Methods: Women with cN0 and pathologic microinvasive or T1a cancer who underwent upfront surgery were identified from the National Cancer Database. Pathologic nodal stage at the time of surgery was the primary outcome. Multivariable logistic modeling was used to assess predictors of pN+., Results: Overall, 141,840 women were included; 139,206 had pathologic node-negative (pN0) disease and 2634 had pN+ disease. Rates of pN+ disease differed by receptor status, with the highest rates in hormone receptor-negative/human epidermal growth factor receptor 2-positive (HR-/HER2+) disease compared with triple-negative breast cancer (TNBC), HR-positive/HER2-negative (HR+/HER2-), and triple positive breast cancer. Rates of pN+ were also higher with lobular histology compared with ductal histology. Multivariable analysis demonstrated that compared with White women, Black women had higher odds of pN+ disease, and compared with women <50 years of age, women >70 years of age had higher odds of pN+ disease. Compared with women with HR+/HER2- disease, women with TNBC, triple-positive breast cancer, and HR-/HER2+ all had lower odds, and women with invasive lobular disease had higher odds compared with women with invasive ductal disease. Women with significant comorbidities also had higher odds of node positivity., Conclusion: Over 90% of patients with clinically node-negative, microinvasive and T1a breast cancer remain pathologically node-negative following axillary staging. However, higher rates of nodal disease were found among Black patients, older patients, and patients with lobular cancer and significant comorbidities., (© 2024. Society of Surgical Oncology.)

As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1 -/- mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate., (© 2024. The Author(s).)

Introduction and Importance: Stroke, a global health concern, often results from embolic events of cardiac origin. Coxsackie B virus (CBV) myocarditis, a common cause of viral heart infections, can lead to cardiac thrombi formation, subsequently causing devastating complications such as embolic stroke. The authors present a rare case of a 26-year-old male who experienced an embolic stroke following CBV myocarditis and cardiomyopathy., Case Presentation: The patient exhibited left-sided weakness, facial droop, and respiratory distress. Laboratory findings indicated leukocytosis, hyponatremia, and elevated troponin I. Imaging revealed an acute right basal ganglia infarct and multifocal pulmonary embolism. The diagnosis involved positive CBV serology, severely reduced left ventricular function, and a large apical thrombus., Discussion: Cardioembolic strokes, often attributable to atrial fibrillation, can also result from intracardiac thrombosis associated with myocarditis. CBV, implicated in up to 40% of acute myocarditis cases, binds to cardiac myocytes, triggering inflammation and potential thrombus formation. Myocarditis-induced hypercoagulability increases the risk of thromboembolic events, complicating the clinical course., Conclusion: CBV myocarditis poses a risk of heart failure, cardiomyopathy, and thromboembolic complications such as embolic stroke. Vigilant monitoring for complications and prompt management is crucial, as primary disease treatment remains primarily supportive. This case highlights the need for increased awareness and further studies to understand the intricate relationship between viral myocarditis and embolic strokes., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The optimal approach to implementing telemedicine hypertension management in the United States is unknown., Methods: We examined telemedicine hypertension management versus the effect of usual clinic-based care on blood pressure (BP) and patient/clinician-related heterogeneity in a systematic review/meta-analysis. We searched United States-based randomized trials from Medline, Embase, CENTRAL, CINAHL, PsycINFO, Compendex, Web of Science Core Collection, Scopus, and 2 trial registries. We used trial-level differences in BP and its control rate at ≥6 months using random-effects models. We examined heterogeneity in univariable metaregression and in prespecified subgroups (clinicians leading pharmacotherapy [physician/nonphysician], self-management support [pharmacist/nurse], White versus non-White patient predominant trials [>50% patients/trial], diabetes predominant trials [≥25% patients/trial], and White patient predominant but not diabetes predominant trials versus both non-White and diabetes patient predominant trials]., Results: Thirteen, 11, and 7 trials were eligible for systolic and diastolic BP difference and BP control, respectively. Differences in systolic and diastolic BP and BP control rate were -7.3 mm Hg (95% CI, -9.4 to -5.2), -2.7 mm Hg (-4.0 to -1.5), and 10.1% (0.4%-19.9%), respectively, favoring telemedicine. Greater BP reduction occurred in trials where nonphysicians led pharmacotherapy, pharmacists provided self-management support, White patient predominant trials, and White patient predominant but not diabetes predominant trials, with no difference by diabetes predominant trials., Conclusions: Telemedicine hypertension management is more effective than clinic-based care in the United States, particularly when nonphysicians lead pharmacotherapy and pharmacists provide self-management support. Non-White patient predominant trials achieved less BP reduction. Equity-conscious, locally informed adaptation of telemedicine interventions is needed before wider implementation., Competing Interests: Disclosures None.

Background: The impact of ongoing efforts to decrease opioid use on patients with cancer remains undefined. Our objective was to determine trends in new and additional opioid use in patients with and without cancer., Methods: This retrospective cohort study used data from Surveillance, Epidemiology, and End Results program-Medicare for opioid-naive patients with solid tumor malignancies diagnosed from 2012 through 2017 and a random sample of patients without cancer. We identified 238 470 eligible patients with cancer and further focused on 4 clinical strata: patients without cancer, patients with metastatic cancer, patients with nonmetastatic cancer treated with surgery alone ("surgery alone"), and patients with nonmetastatic cancer treated with surgery plus chemotherapy or radiation therapy ("surgery+"). We identified new, early additional, and long-term additional opioid use and calculated the change in predicted probability of these outcomes from 2012 to 2017., Results: New opioid use was higher in patients with cancer (46.4%) than in those without (6.9%) (P < .001). From 2012 to 2017, the predicted probability of new opioid use was more stable in the cancer strata (relative declines: 0.1% surgery alone; 2.4% surgery+; 8.8% metastatic cancer), than in the noncancer stratum (20.0%) (P < .001 for each cancer to noncancer comparison). Early additional use declined among surgery patients (‒14.9% and ‒17.5% for surgery alone and surgery+, respectively) but was stable among patients with metastatic disease (‒2.8%, P = .50)., Conclusions: Opioid prescribing declined over time at a slower rate in patients with cancer than in patients without cancer. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Health disparities (HD) impact care delivery and health outcomes in individuals with vestibular disorders (IVD)., Objective: The purpose of this study is to identify whether health disparities (HD) exist in Vestibular Rehabilitation (VR) between individuals identifying as Caucasians or racial or ethnic minorities (REM)., Methods: This study was a retrospective chart review of IVD who attended outpatient VR between 1/2014 and 9/2020. Data recorded included age, gender, race/ethnicity, vestibular diagnosis, VR interventions, and pre-post outcome measures such as Dizziness Handicap Inventory (DHI), and Activities-Specific Balance Confidence Scale (ABC), Gait speed (GS), and Functional Gait Assessment (FGA). Chi-squared tests, one-tailed, and two-tailed t-tests (α= 0.05) were utilized to compare Caucasian and REM groups., Results: Three hundred and forty-three charts (N = 343) met inclusion/exclusion criteria. REM demonstrated higher median DHI scores (46 vs. 38, p = 0.008) and lower ABC scores (53.10% vs. 66.30%, p < 0.001) at VR evaluation compared to Caucasians. There were no statistically significant differences in DHI, ABC, FGA, and GS scores between Caucasians and REM at discharge., Conclusions: VR was able to equalize HD in DHI and ABC which initially existed between REM and Caucasians. VR therapists should work with public health and policy researchers to improve access to VR.

Background: Zavegepant nasal spray is a novel CGRP receptor antagonist that has been developed for the acute treatment of migraine - a prevalent disease leading to disability and economic burden. The meta-analysis aims to quantify the efficacy of Zavegepant compared to standard care or placebo in achieving pain freedom, freedom from most bothersome symptoms (MBS), sustained pain freedom, and pain relapse at 2 to 48 hours., Methods: Databases and registers were systematically searched to identify relevant clinical trials. Two independent reviewers used a standardized data extraction form to collect relevant data on primary and secondary outcomes. Statistical analysis was performed in RevMan 5.4 software. The efficacy of Zavegepant was compared to placebo using odds ratios (OR) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic, chi-square test, Z value, and P value. Cochrane ROB-2 and ROBINS-I tools were used to assess the biases (osf.io/b32ne)., Results: Of 36 identified studies, 3 were included in this meta-analysis. Zavegepant was more effective in achieving pain freedom (OR: 1.6, P < .00001), and freedom from MBS at 2 hours (OR = 1.4, P < .00001). The intervention group demonstrated a higher likelihood of sustained pain freedom between 2 and 48 hours (OR = 1.74, P < .00001). Although there was a trend towards reduced pain relapse between 2 and 48 hours in the intervention group, the difference was insignificant (OR = 0.67, P = .11)., Conclusion: This meta-analysis confirms the effectiveness of Zavegepant nasal spray in treating acute migraine, with significant improvements in pain and symptom relief. Further research is needed to determine the effect on pain relapse and overall safety., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

As SARS-CoV-2 variants of concern (VoCs) that evade immunity continue to emerge, next-generation adaptable COVID-19 vaccines which protect the respiratory tract and provide broader, more effective, and durable protection are urgently needed. Here, we have developed one such approach, a highly efficacious, intranasally delivered, trivalent measles-mumps-SARS-CoV-2 spike (S) protein (MMS) vaccine candidate that induces robust systemic and mucosal immunity with broad protection. This vaccine candidate is based on three components of the MMR vaccine, a measles virus Edmonston and the two mumps virus strains [Jeryl Lynn 1 (JL1) and JL2] that are known to provide safe, effective, and long-lasting protective immunity. The six proline-stabilized prefusion S protein (preS-6P) genes for ancestral SARS-CoV-2 WA1 and two important SARS-CoV-2 VoCs (Delta and Omicron BA.1) were each inserted into one of these three viruses which were then combined into a trivalent "MMS" candidate vaccine. Intranasal immunization of MMS in IFNAR1 -/- mice induced a strong SARS-CoV-2-specific serum IgG response, cross-variant neutralizing antibodies, mucosal IgA, and systemic and tissue-resident T cells. Immunization of golden Syrian hamsters with MMS vaccine induced similarly high levels of antibodies that efficiently neutralized SARS-CoV-2 VoCs and provided broad and complete protection against challenge with any of these VoCs. This MMS vaccine is an efficacious, broadly protective next-generation COVID-19 vaccine candidate, which is readily adaptable to new variants, built on a platform with a 50-y safety record that also protects against measles and mumps.

Introduction Hepatic encephalopathy (HE) is a common complication of cirrhosis and a common reason for hospital admission. We aimed to determine whether expert consultation from gastroenterology (GI) leads to better clinical outcomes for inpatients with HE. Methods A retrospective review was performed of all adult patients (age ≥ 18) admitted with HE to a tertiary care hospital between January 2013 and April 2018. Patients who received a GI consult were compared to patients who did not receive a GI consult (No consult group). The primary outcome was hospital length of stay (LOS); secondary outcomes were rates of 30-day hospital readmission and 90-day mortality. Multivariate analysis was conducted to adjust for known confounders.  Results Four hundred and twenty-five patients (814 encounters) were included in the study; of these, 236 patients had received a GI consultation for HE. Patients in the GI consult group were younger (mean age 55 vs 58 years, p= 0.02) and had higher Model For End-Stage Liver Disease-sodium (MELD-Na) score (mean MELD-Na 23.5 vs 17.5, p<0.01) compared to patients who did not receive GI consultation. The precipitants of HE were significantly different between the groups: there was more spontaneous bacterial peritonitis (SBP) and GI bleeding (GIB) in the GI consult group and more lactulose non-adherence in the no consult group. There was no difference in the etiology of liver disease between the two groups. Median LOS for the GI consult group was six days vs three days in the no consult group (p<0.01); the incidence rate ratio was 1.79 (95%CI 1.59-2.02, p<0.01) on multivariate analysis. There was no difference in 30-day readmission or 90-day mortality between the two groups.  Conclusion GI consultation for patients with HE admitted to a hospital medicine service may be associated with longer LOS. In selected patients admitted with HE, GI consultation may not be necessary to achieve good clinical outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Dutta et al.)

Importance: Improvements in cancer outcomes have led to a need to better understand long-term oncologic and nononcologic outcomes and quantify cancer-specific vs noncancer-specific mortality risks among long-term survivors., Objective: To assess absolute and relative cancer-specific vs noncancer-specific mortality rates among long-term survivors of cancer, as well as associated risk factors., Design, Setting, and Participants: This cohort study included 627 702 patients in the Surveillance, Epidemiology, and End Results cancer registry with breast, prostate, or colorectal cancer who received a diagnosis between January 1, 2003, and December 31, 2014, who received definitive treatment for localized disease and who were alive 5 years after their initial diagnosis (ie, long-term survivors of cancer). Statistical analysis was conducted from November 2022 to January 2023., Main Outcomes and Measures: Survival time ratios (TRs) were calculated using accelerated failure time models, and the primary outcome of interest examined was death from index cancer vs alternative (nonindex cancer) mortality across breast, prostate, colon, and rectal cancer cohorts. Secondary outcomes included subgroup mortality in cancer-specific risk groups, categorized based on prognostic factors, and proportion of deaths due to cancer-specific vs noncancer-specific causes. Independent variables included age, sex, race and ethnicity, income, residence, stage, grade, estrogen receptor status, progesterone receptor status, prostate-specific antigen level, and Gleason score. Follow-up ended in 2019., Results: The study included 627 702 patients (mean [SD] age, 61.1 [12.3] years; 434 848 women [69.3%]): 364 230 with breast cancer, 118 839 with prostate cancer, and 144 633 with colorectal cancer who survived 5 years or more from an initial diagnosis of early-stage cancer. Factors associated with shorter median cancer-specific survival included stage III disease for breast cancer (TR, 0.54; 95% CI, 0.53-0.55) and colorectal cancer (colon: TR, 0.60; 95% CI, 0.58-0.62; rectal: TR, 0.71; 95% CI, 0.69-0.74), as well as a Gleason score of 8 or higher for prostate cancer (TR, 0.61; 95% CI, 0.58-0.63). For all cancer cohorts, patients at low risk had at least a 3-fold higher noncancer-specific mortality compared with cancer-specific mortality at 10 years of diagnosis. Patients at high risk had a higher cumulative incidence of cancer-specific mortality than noncancer-specific mortality in all cancer cohorts except prostate., Conclusions and Relevance: This study is the first to date to examine competing oncologic and nononcologic risks focusing on long-term adult survivors of cancer. Knowledge of the relative risks facing long-term survivors may help provide pragmatic guidance to patients and clinicians regarding the importance of ongoing primary and oncologic-focused care.

Background: Over 75% of menopausal women experience vasomotor symptoms (VMS), such as night sweats and hot flashes. Despite the prevalence of these symptoms, there is limited data on non-hormonal therapies to alleviate them., Methods: PubMed, Cochrane, Scopus, Ovid, Web of Science, and ClinicalTrials.Gov were searched for relevant studies. The search was performed using the following keywords, which were customized to suit the specific databases/registers: menopause, women, neurokinin 3, and/or Fezolinetant. The search was conducted until December 20, 2022. This systematic review was conducted in compliance with the PRISMA Statement 2020 guidelines., Results: A total of 326 records were found, with 10 studies (enrolling 1993 women) selected for inclusion. The women received 40-mg doses of NK1/3 receptor antagonists twice daily, with follow-ups at 1 to 3 weeks. Moderately strong evidence was found suggesting that NK1/3 receptor antagonists can help limit the frequency and severity of hot flashes in menopausal women., Conclusion: While the results should be interpreted with caution until further clinical trials validate the efficacy and safety of NK1/3 receptor antagonists among menopausal women, these findings suggest that they are promising targets for future pharmacological and clinical studies in addressing vasomotor symptoms., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Agenesis of the dorsal pancreas (ADP) is a clinically rare entity that occasionally presents with abdominal pain. It is also association with various disorders of glucose metabolism., Case Presentation: A 23-year-old male presented with continuous epigastric pain for 4 h and intermittent vomiting. He has a history of experiencing recurrent abdominal pain and diarrhoea for the past 5 years. Additionally, he has been diagnosed with type 1 diabetes mellitus for 15 years. Contrast-enhanced computed tomography of the abdomen showed the absence of body and tail of the pancreas., Discussion: ADP is caused by unknown factors, but may be linked to genetic mutations or changes in signalling pathways related to retinoic acid and hedgehog. Symptoms can be absent, but may include abdominal pain, pancreatitis, and hyperglycaemia due to beta-cell dysfunction and insulin deficiency. Imaging modalities, such as contrast tomography or magnetic resonance cholangiopancreatography, or endoscopic retrograde cholangiopancreatography, are crucial in the diagnosis of ADP., Conclusion: It is important to consider ADP as a differential diagnosis in patients with glucose metabolism disorders and associated symptoms such as abdominal pain, pancreatitis, or steatorrhea. It requires the combined use of imaging modalities such as ultrasound, contrast tomography, magnetic resonance cholangiopancreatography, or endoscopic retrograde cholangiopancreatography, as ultrasound alone may not provide a complete diagnosis., Competing Interests: None., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The COVID-19 pandemic has required significant modifications of hospital care. The objective of this study was to examine the operational approaches taken by US hospitals over time in response to the COVID-19 pandemic., Design, Setting and Participants: This was a prospective observational study of 17 geographically diverse US hospitals from February 2020 to February 2021., Outcomes and Analysis: We identified 42 potential pandemic-related strategies and obtained week-to-week data about their use. We calculated descriptive statistics for use of each strategy and plotted percent uptake and weeks used. We assessed the relationship between strategy use and hospital type, geographic region and phase of the pandemic using generalised estimating equations (GEEs), adjusting for weekly county case counts., Results: We found heterogeneity in strategy uptake over time, some of which was associated with geographic region and phase of pandemic. We identified a body of strategies that were both commonly used and sustained over time, for example, limiting staff in COVID-19 rooms and increasing telehealth capacity, as well as those that were rarely used and/or not sustained, for example, increasing hospital bed capacity., Conclusions: Hospital strategies during the COVID-19 pandemic varied in resource intensity, uptake and duration of use. Such information may be valuable to health systems during the ongoing pandemic and future ones., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Measles virus (MeV) has been an excellent vector platform for delivering vaccines against many pathogens because of its high safety and efficacy, and induction of long-lived immunity. Early in the COVID-19 pandemic, a recombinant MeV (rMeV) expressing the prefusion full-length spike protein stabilized by two prolines (TMV-083) was developed and tested in phase 1 and 1/2 clinical trials but was discontinued because of insufficient immunogenicity and a low seroconversion rate in adults. Here, we compared the immunogenicity of rMeV expressing a soluble prefusion spike (preS) protein stabilized by two prolines (rMeV-preS-2P) with a rMeV expressing a soluble preS protein stabilized by six prolines (rMeV-preS-6P). We found that rMeV-preS-6P expressed approximately five times more preS than rMeV-preS-2P in cell culture. Importantly, rMeV-preS-6P induced 30-60 and six times more serum immunoglobulin G and neutralizing antibody than rMeV-preS-2P, respectively, in IFNAR -/- mice. IFNAR -/- mice immunized with rMeV-preS-6P were completely protected from challenge with a mouse-adapted SARS-CoV-2, whereas those immunized with rMeV-preS-2P were partially protected. In addition, hamsters immunized with rMeV-preS-6P were completely protected from the challenge with a Delta variant of SARS-CoV-2. Our results demonstrate that rMeV-preS-6P is significantly more efficacious than rMeV-preS-2P, highlighting the value of using preS-6P as the antigen for developing vaccines against SARS-CoV-2., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

We aimed to study the virologic profile of immigrants from Africa with viral hepatitis-related hepatocellular carcinoma (HCC) who received care at our institution. We conducted a descriptive study among African-born patients with HCC who received care at University of Minnesota Medical Center from 2011 to 2018. We analyzed the prevalence, virologic profiles and treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections prior to HCC diagnosis. 74 African-born patients with HCC were eligible for analysis. 54 had HCV and 20 had HBV infection. 80% of HBV patients were treated but remained with inadequate viral suppression at the time of HCC diagnosis while only 39% of HCV patients were treated prior to HCC diagnosis. Lost to follow up was common in both groups. Our findings suggest that there is a significant gap in appropriate viral hepatitis care in an African immigrant population in Minnesota. Culturally-appropriate strategies are needed to bridge this gap., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Racial segregation is linked to poorer neighborhood quality and adverse health conditions among minorities, including worse cancer outcomes. We evaluated relationships between race, neighborhood social disadvantage, and cancer survival., Methods: We calculated overall and cancer-specific survival for 11,367 non-Hispanic Black (NHB) and 29,481 non-Hispanic White (NHW) individuals with breast, colorectal, lung, or prostate cancer using data from the Metropolitan Detroit Cancer Surveillance System. The area deprivation index (ADI) was used to measure social disadvantage at the census block group level, where higher ADI is associated with poorer neighborhood factors. Associations between ADI and survival were estimated using Cox proportional hazards mixed-effects models accounting for geographic grouping and adjusting for demographic and clinical factors., Results: Increasing ADI quintile was associated with increased overall mortality for all four cancer sites in multivariable-adjusted models. Stratified by race, these associations remained among breast (NHW: HR = 1.16, P < 0.0001; NHB: HR = 1.20, P < 0.0001), colorectal (NHW: HR = 1.11, P < 0.0001; NHB: HR = 1.09, P = 0.00378), prostate (NHW: HR = 1.18, P < 0.0001; NHB: HR = 1.18, P < 0.0001), and lung cancers (NHW: HR = 1.06, P < 0.0001; NHB: HR = 1.07, P = 0.00177). Cancer-specific mortality estimates were similar to overall mortality. Adjustment for ADI substantially attenuated the effects of race on mortality for breast [overall proportion attenuated (OPA) = 47%, P < 0.0001; cancer-specific proportion attenuated (CSPA) = 37%, P < 0.0001] prostate cancer (OPA = 51%, P < 0.0001; CSPA = 56%, P < 0.0001), and colorectal cancer (OPA = 69%, P = 0.032; CSPA = 36%, P = 0.018)., Conclusions: Area-level socioeconomic disadvantage is related to cancer mortality in a racially diverse population, impacting racial differences in cancer mortality., Impact: Understanding the role of neighborhood quality in cancer survivorship could improve community-based intervention practices., (©2023 American Association for Cancer Research.)

Despite the essential role of innate immunity in defining the outcome of viral infections, the roles played by different components of the avian innate immune system are poorly delineated. Here, we investigated the potential implication of avian toll-like receptor (TLR) 3 (TLR3) and melanoma differentiation-associated (MDA) gene 5 (MDA5) receptors of double-stranded RNA (dsRNA) in induction of the interferon pathway and avian orthoavulavirus 1 (AOAV-1) replication in chicken-origin DF-1 fibroblast cells. TLR3 and MDA5 knockout (KO) DF-1 cells were generated using our avian-specific CRISPR/Cas9 system and stimulated with a synthetic dsRNA ligand polyinosinic:polycytidylic acid [poly(I:C)] or infected with AOAV-1 (previously known as Newcastle disease virus). Poly(I:C) treatment in cell culture media resulted in significant upregulation of interferon (IFN)α, IFNβ, and Mx1 gene expression in wild type (WT) DF-1 cells but not in TLR3-MDA5 double KO cells. Interestingly, poly(I:C) treatment induced rapid cell degeneration in WT and MDA5 KO cells, but not in TLR3 knockout or TRL3-MDA5 double knockout (DKO) cells, directly linking poly(I:C)-induced cell degeneration to TLR3-mediated host response. The double knockout cells supported significantly higher replication of AOAV-1 virus than did the WT cells. However, no correlation between the level of virus replication and type I IFN response was observed. Our study suggests that innate immune response is host- and pathogen specific, and further investigation is needed to understand the relevance of dsRNA receptor-mediated immune responses in viral replication and pathogenesis in avian species.

Introduction: Financial toxicity (FT) is a growing concern among cancer survivors that adversely affects the quality of life and survival. Individuals diagnosed with aggressive cancers are often at a greater risk of experiencing FT. The objectives of this study were to estimate FT among prostate cancer (PCa) survivors after 10-15 years of diagnosis, assess the relationship between PCa aggressiveness at diagnosis and FT, and examine whether current cancer treatment status mediates the relationship between PCa aggressiveness and FT., Methods: PCa patients enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP) were recontacted for long-term follow-up. The prevalence of FT in the PCaP cohort was estimated. FT was estimated using the COmprehensive Score for Financial Toxicity, a validated measure of FT. The direct effect of PCa aggressiveness and an indirect effect through current cancer treatment on FT was examined using causal mediation analysis., Results: More than one-third of PCa patients reported experiencing FT. PCa aggressiveness was significantly independently associated with high FT; high aggressive PCa at diagnosis had more than twice the risk of experiencing FT than those with low or intermediate aggressive PCa (adjusted odds ratio [aOR] = 2.13, 95% CI = 1.14-3.96). The proportion of the effect of PCa aggressiveness on FT, mediated by treatment status, was 10%, however, the adjusted odds ratio did not indicate significant evidence of mediation by treatment status (aOR = 1.05, 95% CI = 0.95-1.20)., Conclusions: Aggressive PCa was associated with high FT. Future studies should collect more information about the characteristics of men with high FT and identify additional risk factors of FT., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

Influenza A virus (IAV) and SARS-CoV-2 virus are both acute respiratory viruses currently circulating in the human population. This study aims to determine the impact of IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. Infection of human bronchial epithelial cells (HBEC), A549 cells, lung fibroblasts (HLF), monocyte derived macrophages (MDMs), cardiac fibroblasts (HCF) and hiPSC-derived cardiomyocytes with IAV enhanced the expression of ACE2, the SARS-CoV-2 receptor. Similarly, IAV infection increased levels of ACE2 in the lungs of mice and humans. Of interest, we detected heavily glycosylated form of ACE2 in hiPSC-CMs and poorly glycosylated ACE2 in other cell types. Also, prior IAV infection enhances SARS-CoV-2 spike protein binding and viral entry in all cell types. However, efficient SARS-CoV-2 replication was uniquely inhibited in cardiomyocytes. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Ang II, induction of eNOS and nitric oxide production, may provide a potential mechanism for the restricted SARS-CoV-2 replication in cardiomyocytes., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)