Patient and Caregiver Perception of Adenoidectomies: A Non-Real-World Social Media Analysis.

Objective: To survey the social media outlets Twitter and Instagram for public posts related to adenoidectomy surgery. This study aims to investigate the attitudes and perceptions of patients and caregivers on social media, through thematic content-analysis of social media posts regarding adenoidectomy. Study Design: Non-real world qualitative study. Setting: Twitter and Instagram social media platforms. Methods: Public posts uploaded between February, 2021 and February, 2023 using the hashtags "#adenoidectomy," and "#adenoidectomyrecovery" were searched. Posts were excluded if they were unrelated to adenoidectomy or were in a non-English language. Relevant posts were stratified demographically as patient or caregiver and pre- or postoperative, and categorized into relevant themes for analysis. Outcomes were measured as the total number of posts. Results: A total of 394 relevant posts were analyzed. A significance threshold of P < 0.05 was used. Patients posted significantly more posts regarding procedure pain (P = 0.002) and concern for appearance (P = 0.048) compared to caregivers. Caregivers posted significantly (P < 0.001) more posts regarding condition awareness and were significantly (P < 0.001) more likely to spread positivity in their posts compared to patients themselves. Posts made by female caregivers were more likely to reference fear, while those made by male caregivers were more likely to provide education (P = 0.002). Conclusion: Patients may worry about appearance and mental health while caregivers are more likely to spread information and positivity. Male and female caregivers may also use social media differently. A better understanding of patient and caregiver concerns may optimize physician interaction and involvement.

Effect of Interbody Composition on the Development of Pseudarthrosis Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort study. PURPOSE: To determine if polyetheretherketone (PEEK) or titanium alloy cages increase the rate of pseudarthrosis development or revision surgery rate compared with structural allograft following anterior cervical discectomy and fusion (ACDF) and identify if the cage type results in differences in patient-reported outcome measures (PROMs) versus structural allograft. OVERVIEW OF LITERATURE: PEEK and titanium alloy cages have become popular options for ACDF intervertebral spacers. However, while data is beginning to emerge on how cage types affect arthrodesis rates, the effect of their composition on PROMs is less clear. METHODS: All patients aged >18 years who underwent primary one- to four-level ACDF at a single institution were retrospectively identified. Propensity matching was performed to compare patients' PEEK or titanium alloy cages with structural allograft. Multivariate logistic regression analysis was performed to measure the effect of interbody spacer composition on the likelihood of pseudarthrosis development. RESULTS: Of the 502 patients who received structural allograft and had 1-year postoperative dynamic radiographs, 96 patients were propensity matched to 32 patients who received a PEEK cage, and 162 patients were propensity matched to 54 patients who received a titanium alloy cage. Multivariate logistic regression analysis identified that PEEK cage implants (odds ratio [OR], 3.34; p =0.007) predicted pseudarthrosis development compared with structural allograft implantation. Titanium alloy cage (OR, 1.64; p =0.156) implantation was not predictive of pseudarthrosis. One-year postoperative PROMs were not significantly different between patients who received PEEK or titanium alloy cages and those who received structural allograft (all p >0.05). CONCLUSIONS: Compared with structural allograft, receiving a PEEK cage increased the risk of pseudarthrosis development following ACDF, whereas receiving a titanium alloy cage had no significant effect on pseudarthrosis development. One-year postoperative patient-reported outcomes were similar between patients who received structural allograft, PEEK, and titanium alloy interbody spacers.

Effect of Drain Duration and Output on Perioperative Outcomes and Readmissions after Lumbar Spine Surgery.

STUDY DESIGN: Single-center retrospective cohort. PURPOSE: To compare surgical outcomes of patients based on lumbar drain variables relating to output and duration. OVERVIEW OF LITERATURE: The use of drains following lumbar spine surgery, specifically with respect to hospital readmission, postoperative hematoma, postoperative anemia, and surgical site infections, has been controversial. METHODS: Patients aged ≥18 years who underwent lumbar fusion with a postoperative drain between 2017 and 2020 were included and grouped based on hospital readmission status, last 8-hour drain output (<40 mL cutoff), or drain duration (2 days cutoff). Total output of all drains, total output of the primary drain, drain duration in days, drain output per day, last 8-hour output, penultimate 8-hour output, and last 8-hour delta (last 8-hour output subtracted by penultimate 8-hour output) were collected. Continuous and categorical data were compared between groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis were performed to determine whether drain variables can predict hospital readmission, postoperative blood transfusions, and postoperative anemia. Alpha was 0.05. RESULTS: Our cohort consisted of 1,166 patients with 111 (9.5%) hospital readmissions. Results of regression analysis did not identify any of the drain variables as independent predictors of hospital readmission, postoperative blood transfusion, or postoperative anemia. ROC analysis demonstrated the drain variables to be poor predictors of hospital readmission, with the highest area under curve of 0.524 (drain duration), corresponding to a sensitivity of 61.3% and specificity of 49.9%. CONCLUSIONS: Drain output or duration did not affect readmission rates following lumbar spine surgery.

Serotonin Reuptake Inhibitor Increases Pseudarthrosis Rates in Anterior Cervical Discectomy and Fusions.

STUDY DESIGN: Retrospective cohort. PURPOSE: To determine (1) the effects of serotonin reuptake inhibitors in pseudarthrosis rates after anterior cervical decompression and fusion (ACDF) and (2) to identify patient-reported outcome measures in patients taking serotonin reuptake inhibitors. OVERVIEW OF LITERATURE: Recent literature suggests that selective serotonin reuptake inhibitors (SSRIs) may inhibit fracture healing via downregulation of osteoblast differentiation. Spinal fusion supplementation with osteoblast-rich substances enhances spinal fusion, thus SSRIs may be detrimental. METHODS: Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p - values of <0.05. RESULTS: Of the 523 patients who meet the inclusion criteria, 137 (26.2%) were prescribed an SSRI, SNRI, or TCA. Patients with these prescriptions were more likely to have pseudarthrosis (p =0.008) but not a revision surgery due to pseudarthrosis (p =0.219). Additionally, these patients had worse 1-year postoperative mental component summary (MCS)-12 (p =0.015) and Neck Disability Index (NDI) (p =0.006). The multivariate logistic regression analysis identified SSRI/SNRI/TCA use (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.11-2.99; p =0.018) and construct length (OR, 1.91; 95% CI, 1.50-2.44; p <0.001) as pseudarthrosis predictors. A SSRI/SNRI/TCA prescription was a revision surgery predictor due to adjacent segment disease on univariate analysis (OR, 2.51; p =0.035) but not on multivariate logistic regression analysis (OR, 2.24; p =0.10). CONCLUSIONS: Patients taking serotonin reuptake-inhibiting antidepressants are at increased risk of worse postoperative outcome scores, including NDI and MCS-12, likely due to their underlying depression. This may contribute to their greater likelihood of having adjacent segment surgery. Additionally, preoperative use of serotonin reuptake inhibitors in patients undergoing an ACDF is a predictor of radiographic pseudarthrosis but not pseudarthrosis revision.

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

Dental management of a patient with systemic mastocytosis.

Mastocytosis is a term encompassing a group of clinical disorders characterised by clonal proliferation of abnormal mast cells (MCs) in organ systems of the body. Mastocytosis can be systemic (with or without skin involvement) or cutaneous, and can affect organs including bone marrow, liver, spleen, lymph nodes and mucosal surfaces. Patients with systemic mastocytosis (SM) are susceptible to triggers that could cause activation of abnormal MCs, resulting in multiorgan dysfunction and life-threatening anaphylactic reactions. Mastocytosis has a number of ramifications for the dental management of a patient with the condition. Patients are at increased risk of complications due to a number of risk factors for MC activation present within the dental context, including stress, certain prescribed drugs, oral hygiene products and dental materials. This report presents the oral management of an adult with SM, discussing the implications of the condition within the context of the limited existing literature on the subject.

Endocrine therapy use and cardiovascular risk in postmenopausal breast cancer survivors.

OBJECTIVE: Examine the effect of tamoxifen and aromatase inhibitors (AIs) on the risk of 12 clinically relevant cardiovascular outcomes in postmenopausal female breast cancer survivors. METHODS: We carried out two prospective cohort studies among postmenopausal women with breast cancer in UK primary care and hospital data (2002-2016) and US Surveillance, Epidemiology and End Results-Medicare data (2008-2013). Using Cox adjusted proportional hazards models, we compared cardiovascular risks between AI and tamoxifen users; and in the USA, between users of both drug classes and women receiving no endocrine therapy. RESULTS: 10 005 (UK) and 22 027 (USA) women with postmenopausal breast cancer were included. In both countries, there were higher coronary artery disease risks in AI compared with tamoxifen users (UK age-standardised incidence rate: 10.17 vs 7.51 per 1000 person-years, HR: 1.29, 95% CI 0.94 to 1.76; US age-standardised incidence rate: 36.82 vs 26.02 per 1000 person-years, HR: 1.29, 95% C I1.06 to 1.55). However, comparisons with those receiving no endocrine therapy (US data) showed no higher risk for either drug class and a lower risk in tamoxifen users (age-standardised incidence rate tamoxifen vs unexposed: 26.02 vs 35.19 per 1000 person-years, HR: 0.74, 95% 0.60 to 0.92; age-standardised incidence rate AI vs unexposed: 36.82 vs 35.19, HR: 0.96, 95% CI 0.83 to 1.10). Similar patterns were seen for other cardiovascular outcomes (arrhythmia, heart failure and valvular heart disease). As expected, there was more venous thromboembolism in tamoxifen compared with both AI users and those unexposed. CONCLUSIONS: Higher risks of several cardiovascular outcomes among AI compared with tamoxifen users appeared to be driven by protective effects of tamoxifen, rather than cardiotoxic effects of AIs.

PCP and Wnt pathway components act in parallel during zebrafish mechanosensory hair cell orientation.

Planar cell polarity (PCP) plays crucial roles in developmental processes such as gastrulation, neural tube closure and hearing. Wnt pathway mutants are often classified as PCP mutants due to similarities between their phenotypes. Here, we show that in the zebrafish lateral line, disruptions of the PCP and Wnt pathways have differential effects on hair cell orientations. While mutations in the PCP genes vangl2 and scrib cause random orientations of hair cells, mutations in wnt11f1, gpc4 and fzd7a/b induce hair cells to adopt a concentric pattern. This concentric pattern is not caused by defects in PCP but is due to misaligned support cells. The molecular basis of the support cell defect is unknown but we demonstrate that the PCP and Wnt pathways work in parallel to establish proper hair cell orientation. Consequently, hair cell orientation defects are not solely explained by defects in PCP signaling, and some hair cell phenotypes warrant re-evaluation.

Spontaneous bleeding in a patient on enoxaparin with poor renal function.

Creatinine-based equations are used as standard ways to estimate glomerular filtration rate and kidney function. Unfortunately, serum creatinine varies based on factors such as age, gender, and muscle mass. Overestimation of renal function by creatinine-based equations can be dangerous for renally dosed medications, such as enoxaparin. We present a patient who developed spontaneous bleeding on enoxaparin where kidney function was significantly overestimated by creatinine-based equations. The use of cystatin C levels, which are creatinine independent, can provide a better prediction of renal function.

Author Correction: Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion.

In the initial published version of this article, there was an inadvertent omission from the Acknowledgements that this work was supported by Stowers Institute for Medical Research (SIMR-1004) and NIH National Cancer Institute grant to University of Kansas Cancer Center (P30 CA168524). This omission does not affect the description of the results or the conclusions of this work.

Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion.

Transplantation of hematopoietic stem cells (HSCs) from human umbilical cord blood (hUCB) holds great promise for treating a broad spectrum of hematological disorders including cancer. However, the limited number of HSCs in a single hUCB unit restricts its widespread use. Although extensive efforts have led to multiple methods for ex vivo expansion of human HSCs by targeting single molecules or pathways, it remains unknown whether it is possible to simultaneously manipulate the large number of targets essential for stem cell self-renewal. Recent studies indicate that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs critical for stem cell-fate determination by influencing their stability. Among several m6A readers, YTHDF2 is recognized as promoting targeted mRNA decay. However, the physiological functions of YTHDF2 in adult stem cells are unknown. Here we show that following the conditional knockout (KO) of mouse Ythdf2 the numbers of functional HSC were increased without skewing lineage differentiation or leading to hematopoietic malignancies. Furthermore, knockdown (KD) of human YTHDF2 led to more than a 10-fold increase in the ex vivo expansion of hUCB HSCs, a fivefold increase in colony-forming units (CFUs), and more than an eightfold increase in functional hUCB HSCs in the secondary serial of a limiting dilution transplantation assay. Mapping of m6A in RNAs from mouse hematopoietic stem and progenitor cells (HSPCs) as well as from hUCB HSCs revealed its enrichment in mRNAs encoding transcription factors critical for stem cell self-renewal. These m6A-marked mRNAs were recognized by Ythdf2 and underwent decay. In Ythdf2 KO HSPCs and YTHDF2 KD hUCB HSCs, these mRNAs were stabilized, facilitating HSC expansion. Knocking down one of YTHDF2's key targets, Tal1 mRNA, partially rescued the phenotype. Our study provides the first demonstration of the function of YTHDF2 in adult stem cell maintenance and identifies its important role in regulating HSC ex vivo expansion by regulating the stability of multiple mRNAs critical for HSC self-renewal, thus identifying potential for future clinical applications.

Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.

We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC50 = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC50 = 13 nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many other cell types, including PC3M (IC50 = 25 nM) and LnCaP-Vancouver prostate cells (IC50 = 66 nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement.

Cutaneous myeloid sarcoma associated with chronic myeloid leukemia.

Myeloid sarcoma is an extramedullary tumor of malignant myeloid cells often associated with acute myeloid leukemia, chronic myeloproliferative disorders and myelodysplastic syndromes. The skin is one of the most commonly affected sites. We report a rare case of cutaneous myeloid sarcoma associated with chronic myeloid leukemia.

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

Nasal Valve Reconstruction Using a Titanium Implant: An Outcomes Study.

Septoplasty alone is not always sufficient to correct nasal obstruction. Various techniques have been employed to repair nasal valve collapse and improve airflow. This article aimed to evaluate outcomes and quality of life following nasal valve reconstruction using a titanium implant in patients with nasal valve collapse. This is a single-center retrospective study that consisted of a telephone questionnaire of 37 quality-of-life measures and questions related to the surgical procedure and recovery process to evaluate postsurgical outcomes. Fifteen patients completed the survey. There was a significant improvement in nasal blockage/obstruction, breathing through the nose, sleeping, breathing through nose during exercise, the need to blow nose, sneezing, facial pain/pressure, fatigue, productivity, and restlessness/irritability after surgery. Overall, 100% of patients were satisfied with the results and would recommend this procedure. The most common postoperative complaints were pain (33%) and difficulty breathing (33%). Patients noticed no increase (20%) or a slight increase (73%) in the size of their nose. Sixty percent of patients cannot see the implant and 13% report the implant is barely noticeable. Nasal valve repair with a titanium implant was successful at improving symptoms of nasal obstruction and other quality-of-life issues. Satisfaction was high among all patients. The implants are palpable, thought to be visible by some patients, yet accepted by the majority of patients. This approach may be especially important in patients with prior nasal surgery but continue to experience refractory symptoms.

Proliferation-independent regulation of organ size by Fgf/Notch signaling.

Organ morphogenesis depends on the precise orchestration of cell migration, cell shape changes and cell adhesion. We demonstrate that Notch signaling is an integral part of the Wnt and Fgf signaling feedback loop coordinating cell migration and the self-organization of rosette-shaped sensory organs in the zebrafish lateral line system. We show that Notch signaling acts downstream of Fgf signaling to not only inhibit hair cell differentiation but also to induce and maintain stable epithelial rosettes. Ectopic Notch expression causes a significant increase in organ size independently of proliferation and the Hippo pathway. Transplantation and RNASeq analyses revealed that Notch signaling induces apical junctional complex genes that regulate cell adhesion and apical constriction. Our analysis also demonstrates that in the absence of patterning cues normally provided by a Wnt/Fgf signaling system, rosettes still self-organize in the presence of Notch signaling.

Use of negative pressure wound therapy on malignant wounds - a case report and review of literature.

The presence of malignancy is considered a contraindication to the use of negative pressure wound therapy (NPWT) because of concerns that it may promote tumourigenesis and expedite metastasis. This notion is extrapolated from studies evaluating NPWT in normal tissues. Despite the absence of direct evidence, the use of this technology in malignant wounds is widely considered a contraindication. We present the case of a patient with treatment-resistant metastatic colon cancer, who developed a chronic abdominal wound with positive margins. A staged reconstruction using NPWT was performed and wound closure allowed the patient to meet eligibility criteria and enrol in a clinical trial for treatment of his oncological disease. Skin closure remained intact until the patient expired 6 months after the wound closure. This case, as well as others in the literature, demonstrated that the use of NPWT should not be considered an absolute contraindication in malignancy. Individualised approaches taking into account the patient's clinical scenario, the available evidence, as well as the risks and benefits of this technology are recommended.