Optimized Aesthetic Outcomes When Treating Glabellar Lines with Botulinum Toxin Type A: GLO 3 + 2: A Precise Technique Based on Anatomy.

Good patient outcomes after treatment of the glabellar complex with botulinum toxin type A entail elimination of glabellar lines and maintenance of a natural eyebrow position. A precise injection technique that accurately targets the muscles that influence eyebrow position is required to reduce the risk of adverse aesthetic outcomes or unmasking an underlying eyelid ptosis. Here, we describe the glabellar lines optimization (GLO 3 + 2) injection anatomy technique, a precise five-point injection pattern that is based on current understanding of facial functional anatomy and which aims to minimize the risk of affecting nontargeted muscles. Injection sites above the brow or that do not target the precise location of the muscles in the glabellar complex are likely to inadvertently expose the frontalis to botulinum toxin type A and result in undesirable aesthetic outcomes. Because the frontalis is a strong determinant of aesthetic outcomes, it is important to consider the overall effects of the interactions between the eyebrow depressors and the opposing forces of the frontalis on brow outcomes in both the resting brow position and during dynamic brow movement.

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-ß (MENß) are two long noncoding RNAs upregulated in multiple cancers, marking these RNAs as therapeutic targets. While traditional small-molecule and antisense-based approaches are effective, we report a locked nucleic acid (LNA)-based approach that targets the MALAT1 and MENß triple helices, structures comprised of a U-rich internal stem-loop and an A-rich tract. Two LNA oligonucleotides resembling the A-rich tract (i.e., A9GCA4) were examined: an LNA (L15) and a phosphorothioate LNA (PS-L15). L15 binds tighter than PS-L15 to the MALAT1 and MENß stem loops, although both L15 and PS-L15 enable RNA•LNA-RNA triple-helix formation. Based on UV thermal denaturation assays, both LNAs selectively stabilize the Hoogsteen interface by 5-13 °C more than the Watson-Crick interface. Furthermore, we show that L15 and PS-L15 displace the A-rich tract from the MALAT1 and MENß stem loop and methyltransferase-like protein 16 (METTL16) from the METTL16-MALAT1 triple-helix complex. Human colorectal carcinoma (HCT116) cells transfected with LNAs have 2-fold less MALAT1 and MENß. This LNA-based approach represents a potential therapeutic strategy for the dual targeting of MALAT1 and MENß.

Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

PURPOSE: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. MATERIALS AND METHODS: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. RESULTS: Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. CONCLUSIONS: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. SIGNIFICANCE: We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS: TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. CONCLUSIONS: This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.

Effectiveness and Safety of Resilient Hyaluronic Acid (RHA) Dermal Fillers for the Correction of Moderate-to-Severe Nasolabial Folds in People of Color: Post Hoc Subgroup Analyses of US Pivotal Clinical Data.

BACKGROUND: People of color (POC) are often underrepresented in clinical studies evaluating the safety and effectiveness of aesthetic products, including hyaluronic acid (HA) fillers, for which there is to date limited clinical data in POC. OBJECTIVES: The aim of this study was to assess the safety and effectiveness of a new line of dynamic resilient HA fillers (RHA; Revance, Nashville, TN) for treating moderate-to-severe nasolabial folds (NLFs) in POC vs non-POC. METHODS: Post hoc subgroup analyses compared the efficacy and safety of POC vs non-POC subjects treated with RHA2, RHA3, or RHA4 for correction of moderate-to-severe NLFs in the pooled per-protocol population (N = 217) in 2 clinical trials. Evaluated population cohorts were classified by Fitzpatrick skin type (FST) (high FST [IV-VI] vs low FST [I-III]) and by subject-reported race (non-White vs White) relative to baseline at 6, 9, 12, and 15 months. RESULTS: POC consistently showed greater improvement in wrinkle severity and higher responder rates compared with non-POC, which reached statistical significance at several measured time points. Global Aesthetic Improvement Scale scores and subject satisfaction ratings were similar for POC and non-POC and remained high throughout the course of the study. Treatment-related adverse event rates were generally lower for high FSTs vs low FSTs, with no reported cases of keloidal scarring. CONCLUSION: The RHA line of dynamic fillers is well tolerated and effective for the correction of moderate-to-severe NLFs in POC and can be confidently used in this important and growing patient population.See the abstract translated into Hindi, Portuguese, Korean, German, Italian, Arabic, Chinese, and Taiwanese online here: https://doi.org/10.1093/asj/sjad251.

Age-stratified comparison of active surveillance versus radiofrequency ablation for papillary thyroid microcarcinoma using decision analysis.

BACKGROUND: Papillary thyroid microcarcinomas may be treated with radiofrequency ablation, active surveillance, or surgery. The objective of this study was to use mathematical modeling to compare treatment alternatives for papillary thyroid microcarcinomas among those who decline surgery. We hypothesized that radiofrequency ablation would outperform active surveillance in avoiding progression and surgery but that the effect size would be small for older patients. METHODS: We engaged stakeholders to identify meaningful long-term endpoints for papillary thyroid microcarcinoma treatment-(1) cancer progression/surgery, (2) need for thyroid replacement therapy, and (3) permanent treatment complication. A Markov decision analysis model was created to compare the probability of these endpoints after radiofrequency ablation or active surveillance for papillary thyroid microcarcinomas and overall cost. Transition probabilities were extracted from published literature. Model outcomes were estimated to have a 10-year time horizon. RESULTS: The primary outcome yielded a number needed to treat of 18.1 for the avoidance of progression and 27.4 for the avoidance of lifelong thyroid replacement therapy for radiofrequency ablation compared to active surveillance. However, as patient age increased, the number needed to treat to avoid progression increased from 5.2 (age 20-29) to 39.1 (age 60+). The number needed to treat to avoid lifelong thyroid replacement therapy increased with age from 7.8 (age 20-29) to 59.3 (age 60+). The average 10-year cost/treatment for active surveillance and radiofrequency ablation were $6,400 and $11,700, respectively, translating to a cost per progression-avoided of $106,500. CONCLUSION: As an alternative to active surveillance, radiofrequency ablation may have a greater therapeutic impact in younger patients. However, routine implementation may be cost-prohibitive for most patients with papillary thyroid microcarcinomas.

Ghost authors revealed: The structure and function of human N6 -methyladenosine RNA methyltransferases.

Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N6 -methyladenosine (m6 A) is the most abundant modification in eukaryotic messenger RNA (mRNA) and has also been detected in non-coding RNAs, including long non-coding RNA, ribosomal RNA, and small nuclear RNA. In general, m6 A marks can alter RNA secondary structure and initiate unique RNA-protein interactions that can alter splicing, mRNA turnover, and translation, just to name a few. Although m6 A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m6 A marks have been established only recently. Thus far, there are four confirmed human methyltransferases that catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the N6 position of adenosine, producing m6 A: methyltransferase-like protein (METTL) 3/METTL14 complex, METTL16, METTL5, and zinc-finger CCHC-domain-containing protein 4. Though the methyltransferases have unique RNA targets, all human m6 A RNA methyltransferases contain a Rossmann fold with a conserved SAM-binding pocket, suggesting that they utilize a similar catalytic mechanism for methyl transfer. For each of the human m6 A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m6 A marks in human viruses and parasites, assigning m6 A marks in the transcriptome to specific methyltransferases, small molecules targeting m6 A methyltransferases, and the enzymes responsible for hypermodified m6 A marks and their biological functions in humans. Understanding m6 A methyltransferases is a critical steppingstone toward establishing the m6 A epitranscriptome and more broadly the RNome. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Bridging the Gap: Sustained Treatment Effect of Glabellar Lines With Twice-A-Year Treatment With DaxibotulinumtoxinA.

BACKGROUND: To achieve natural-looking outcomes when treating dynamic lines with botulinum toxin (BoNT), retreatment must be timed such that the patient maintains a relatively constant aesthetic outcome. Although first-generation BoNT products require retreatment with 3- to 4-month frequency to avoid discontinuous correction, the average patient returns for treatment every 6 months, when these toxins have generally fully worn off. OBJECTIVE: To discuss the number of days a typical patient treated with daxibotulinumtoxinA for injection (DAXI) or legacy BoNT products will spend undertreated or uncorrected in a given calendar year. MATERIALS AND METHODS: Median time for maintaining glabellar lines in the "none" or "mild" severity range was compared for approved doses of onabotulinumtoxinA (ONA; 120 days) and DAXI (168 days). RESULTS: The average patient treated with 40U of DAXI every 6 months can expect to be uncorrected (with "moderate" or "severe" glabellar lines) for 14.5 days between visits compared with 61.5 days for 20U of ONA. CONCLUSION: An extended duration BoNT product can be expected to create greater consistency in aesthetic outcome and minimize the discontinuous correction commonly seen with first-generation BoNT products for patients treated twice a year, without requiring a change in patient behavior regarding visit frequency.

Adult Cardiac Surgery-Associated Acute Kidney Injury: Joint Consensus Report.

OBJECTIVES: Acute kidney injury (AKI) is increasingly recognized as a source of poor patient outcomes after cardiac surgery. The purpose of the present report is to provide perioperative teams with expert recommendations specific to cardiac surgery-associated AKI (CSA-AKI). METHODS: This report and consensus recommendations were developed during a joint, in-person, multidisciplinary conference with the Perioperative Quality Initiative and the Enhanced Recovery After Surgery Cardiac Society. Multinational practitioners with diverse expertise in all aspects of cardiac surgical perioperative care, including clinical backgrounds in anesthesiology, surgery and nursing, met from October 20 to 22, 2021, in Sacramento, California, and used a modified Delphi process and a comprehensive review of evidence to formulate recommendations. The quality of evidence and strength of each recommendation were established using the Grading of Recommendations Assessment, Development, and Evaluation methodology. A majority vote endorsed recommendations. RESULTS: Based on available evidence and group consensus, a total of 13 recommendations were formulated (4 for the preoperative phase, 4 for the intraoperative phase, and 5 for the postoperative phase), and are reported here. CONCLUSIONS: Because there are no reliable or effective treatment options for CSA-AKI, evidence-based practices that highlight prevention and early detection are paramount. Cardiac surgery-associated AKI incidence may be mitigated and postsurgical outcomes improved by focusing additional attention on presurgical kidney health status; implementing a specific cardiopulmonary bypass bundle; using strategies to maintain intravascular euvolemia; leveraging advanced tools such as the electronic medical record, point-of-care ultrasound, and biomarker testing; and using patient-specific, goal-directed therapy to prioritize oxygen delivery and end-organ perfusion over static physiologic metrics.

The landscape of BRCA1 and BRCA2 large rearrangements in an international cohort of over 20 000 ovarian tumors identified using next-generation sequencing.

BACKGROUND: Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly-ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. METHODS: Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. RESULTS: Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. CONCLUSIONS: Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

B cell-dependent subtypes and treatment-based immune correlates to survival in stage 3 and 4 lung adenocarcinomas.

Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments.

Screening and Testing for Hepatitis B Virus Infection: CDC Recommendations - United States, 2023.

Chronic hepatitis B virus (HBV) infection can lead to substantial morbidity and mortality. Although treatment is not considered curative, antiviral treatment, monitoring, and liver cancer surveillance can reduce morbidity and mortality. Effective vaccines to prevent hepatitis B are available. This report updates and expands CDC's previously published Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection (MMWR Recomm Rep 2008;57[No. RR-8]) regarding screening for HBV infection in the United States. New recommendations include hepatitis B screening using three laboratory tests at least once during a lifetime for adults aged ≥18 years. The report also expands risk-based testing recommendations to include the following populations, activities, exposures, or conditions associated with increased risk for HBV infection: persons incarcerated or formerly incarcerated in a jail, prison, or other detention setting; persons with a history of sexually transmitted infections or multiple sex partners; and persons with a history of hepatitis C virus infection. In addition, to provide increased access to testing, anyone who requests HBV testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks.

Regionalization of Head and Neck Oncology Tumor Boards: Perspectives of Collaborating Physicians.

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion. Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021. Setting: The University of Maryland Medical Center and regional practices in the state of Maryland. Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type. Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%). Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients.

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial.

PURPOSE: The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non-BRCA1 or BRCA2 homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS: Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non-BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non-BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS: The non-BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non-BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non-BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes (BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non-BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION: Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

Efficacy and Safety of DaxibotulinumtoxinA for Injection in the Treatment of Glabellar Lines by Age and Race: Subgroup Analysis of the SAKURA Clinical Trials.

BACKGROUND: DaxibotulinumtoxinA for Injection (DAXI) is a novel botulinum toxin type A formulation approved for the treatment of glabellar lines. The efficacy, safety, and extended duration of response of DAXI 40 U for glabellar lines were demonstrated in 2 Phase 3, randomized, double-blind studies (SAKURA 1 and 2) and a Phase 3 open-label trial (SAKURA 3). OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of the first DAXI 40 U treatment received in SAKURA 1, 2, or 3 across age and race subgroups. METHODS: Adults with moderate-to-severe glabellar lines (Investigator Global Assessment-Frown Wrinkle Severity [IGA-FWS] and Patient FWS [PFWS] scales) were evaluated for glabellar line severity for ≤36 weeks after the first DAXI treatment. Efficacy and safety were analyzed by age (18-45, >45-55, and >55 years) and race (Asian, Black and African American, and White). RESULTS: Overall, 2785 patients were included in the efficacy analysis. The proportion of patients achieving none or mild glabellar line severity at maximum frown (IGA-FWS) after DAXI treatment was high in all age and race subgroups (>96% at Week 4). Glabellar line severity of none or mild by composite IGA-FWS and PFWS rating was maintained for a median of 24.0 weeks in all age subgroups, and for 27.0, 25.3, and 24.0 weeks in the Asian, Black and African American, and White subgroups, respectively. Treatment-emergent adverse events were similar across all subgroups. CONCLUSIONS: Consistent with the overall study population, DAXI 40 U demonstrated a high response rate and duration of effect of ≥24 weeks across all age and race subgroups.

Impact of DaxibotulinumtoxinA for Injection on Brow Position and Frontalis Muscle Activity Following Treatment of Glabellar Lines.

BACKGROUND: Botulinum toxin type A (BoNTA) injections for the treatment of facial lines may lead to pleasant or undesirable changes in eyebrow height and position. OBJECTIVES: The aim of this study was to evaluate the impact of glabellar injection of DaxibotulinumtoxinA for Injection (DAXI), a novel BoNTA formulation, on eyebrow position and frontalis activity. METHODS: This study involved the post hoc analysis of adult patients from the Phase 2a forehead lines (FHL, N = 60) and open-label safety (OLS, N = 175) studies who received a single dose of DAXI 40 U to the glabella and for whom facial photographs were taken at rest and at maximum eyebrow elevation. Median vertical and horizontal displacement of the brows and median forehead strain (an objective quantitative assessment of frontalis activity) from baseline to 2 weeks after glabellar DAXI injection were measured. RESULTS: Two weeks after glabellar DAXI injection, vertical eyebrow movement (at rest) of the lateral brow was observed. In both studies, vertical movement was greatest in the lateral (0.6-0.9 mm) and mid (0.5-0.7 mm) brow regions; movement in the medial brow was negligible (0-0.23 mm). In both studies, a graded reduction in forehead strain was observed 2 weeks post glabellar DAXI injection, with the greatest reduction being in the lower segment (FHL, -73%; OLS, -82%). Treatment with DAXI showed improvements in FHL wrinkle severity. CONCLUSIONS: Glabellar injection of DAXI showed a positive reduction in dynamic frontalis activity that maintained or had a positive effect on eyebrow position. Vertical movement of the brow was suggestive of an improved eyebrow shape with a mild lateral arch.

Integrative Assessment for Optimizing Aesthetic Outcomes When Treating Glabellar Lines With Botulinum Toxin Type A: An Appreciation of the Role of the Frontalis.

Despite the perception that treatment of glabellar lines with botulinum toxin A is straightforward, the reality is that the glabellar region contains a number of interrelated muscles. To avoid adverse outcomes, practitioners need to appreciate how treatment of 1 facial muscle group influences the relative dominance of others. In particular, practitioners need to understand the independent role of the frontalis in eyebrow outcomes and the potential for negative outcomes if the lower frontalis is unintentionally weakened by botulinum toxin A treatment. In addition, practitioners must recognize how inter-individual variation in the depth, shape, and muscle fiber orientation among the upper facial muscles can affect outcomes. For optimal results, treatment of the glabellar complex requires a systematic and individualized approach based on anatomical principles of opposing muscle actions rather than a one-size-fits-all approach. This review provides the anatomical justification for the importance of an integrated assessment of the upper facial muscles and eyebrow position prior to glabellar treatment. In addition, a systematic and broad evaluation system is provided that can be employed by practitioners to more comprehensively assess the glabellar region in order to optimize outcomes and avoid negatively impacting resting brow position and dynamic brow movement.

Impact of Glabellar Injection Technique With DaxibotulinumtoxinA for Injection on Brow Position.

BACKGROUND: Precise injection technique is vital for avoiding suboptimal eyebrow position when treating glabellar lines with botulinum toxin type A. OBJECTIVES: The aim of this study was to evaluate the impact of glabellar injection technique on eyebrow position in patients treated with DaxibotulinumtoxinA for Injection (DAXI). METHODS: This retrospective post hoc analysis involved 60 adults who received a single treatment with DAXI 40 U to the glabella and had standardized facial photography. Median vertical and horizontal displacement of the brows (at rest) at baseline and 2 weeks after glabellar injection were measured. Brow position outcomes were evaluated by an oculoplastic surgeon and expert anatomist. Investigators were interviewed to ascertain individual injection techniques. RESULTS: Precise injection location and depth, and median resting brow position following treatment varied between investigators. Positive brow outcomes were achieved with deep DAXI injections into the medial corrugator, superficial lateral corrugator injections placed between the midpupil and lateral limbus, and deep midline procerus injections. Glabellar injection technique that more precisely targeted the corrugator muscles resulted in longer glabellar line treatment duration compared to a less targeted technique. Medial corrugator injections above the medial brow; lateral corrugator injections administered deeply or more medially, toward the medial third of the brow; and procerus injections superior to the inferomedial brow tended to be associated with suboptimal outcomes that were more apparent during dynamic expression. CONCLUSIONS: Aesthetically pleasing brow outcomes and greater duration of efficacy can be achieved with an injection pattern that precisely treats the anatomic location of the corrugator supercilii and procerus muscles, avoiding the frontalis.

Elucidating the Kinetic Mechanism of Human METTL16.

Methyltransferase-like protein 16 (METTL16) is one of four catalytically active, S-adenosylmethionine (SAM)-dependent m6A RNA methyltransferases in humans. Well-known methylation targets of METTL16 are U6 small nuclear RNA (U6 snRNA) and the MAT2A mRNA hairpins; however, METTL16 binds to other RNAs, including the 3' triple helix of the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Herein, we investigated the kinetic mechanism and biochemical properties of METTL16. METTL16 is a monomer in complex with either the MALAT1 triple helix or U6 snRNA and binds to these RNAs with respective dissociation constants of 31 nM and 18 nM, whereas binding to the methylated U6 snRNA product is 1.1 µM. The MALAT1 triple helix, on the other hand, is not methylated by METTL16 under in vitro conditions. Using the U6 snRNA to study methylation steps, preincubation and isotope partitioning assays indicated an ordered-sequential mechanism, whereby METTL16 binds U6 snRNA before SAM. The apparent dissociation constant for the METTL16·U6 snRNA·SAM ternary complex is 126 µM. Steady-state kinetic assays established a kcat of 0.07 min-1, and single-turnover assays established a kchem of 0.56 min-1. Furthermore, the methyltransferase domain of METTL16 methylated U6 snRNA with an apparent dissociation constant of 736 µM and a kchem of 0.42 min-1, suggesting that the missing vertebrate conserved regions weaken the ternary complex but do not induce any rate-limiting conformational rearrangements of the U6 snRNA. This study helps us to better understand the catalytic activity of METTL16 in the context of its biological functions.

Association Between Pressure Support During Extubation Readiness Testing and Time to First Extubation in Children With Congenital Heart Disease.

BACKGROUND: Extubation readiness testing (ERT) is often performed in children with congenital heart disease prior to liberation from mechanical ventilation. The ideal ERT method in this population is unknown. We recently changed our ERT method from variable (10, 8, or 6 cm H2O, depending on endotracheal tube size) to fixed (5 cm H2O) pressure support (PS). Our study assessed the association between this change and time to first extubation and need for re-intubation. METHODS: We studied 2 temporally distinct cohorts, one where ERT was conducted with variable PS and another using PS fixed at 5 cm H2O. Data were prospectively collected as part of a quality improvement project. The primary outcome was time to first extubation. Secondary outcomes were need for re-intubation and percentage of successful ERTs. We performed Poisson regression or logistic regression for the association between PS during ERT and time to first extubation or re-intubation, respectively. RESULTS: We included 320 subjects, 186 in the variable PS group and 152 in fixed PS group. In unadjusted analysis, median time to first extubation was longer in the fixed PS group compared to the variable PS group (4.1 [2.0-7.1] d vs 3.1 [1.1-5.9] d, P = .02), and there was no difference in re-intubation rate (11% vs 8%, P = .34). Subjects in the fixed PS group were significantly more likely to be mechanically ventilated after cardiac arrest, have a Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) category of 4 or 5, be extubated on day shift, receive enteral feeds at extubation, have higher respiratory support at extubation, and higher dead-space-to-tidal-volume ratio. After controlling for these variables in multivariable regression, we found no association between the choice of PS and time to first extubation or re-intubation. CONCLUSIONS: The use of a fixed PS of 5 cm H2O instead of variable PS during ERT was not associated with longer time to first extubation or extubation failure.