Feeding Issues in Infants Referred for Frenotomy.

INTRODUCTION: The diagnosis of ankyloglossia has increased significantly around the world over the last decade. Frenotomy is indicated in infants with ankyloglossia to improve breastfeeding, although there is little scientific evidence of its efficacy. The purpose of this study is to evaluate whether infants being referred for frenotomy had feeding issues prior to the procedure. METHODS: A retrospective chart review was undertaken for all infants under one year of age referred with ankyloglossia to a pediatric otolaryngology practice or a pediatric hospital between 2018 and 2020. Data included age at referral, gender, comorbidities, feeding issues, whether ankyloglossia was diagnosed, and whether frenotomy was done. Frequencies and non-parametric comparisons were calculated. RESULTS: Of the 646 consultations made for tongue tie, a diagnosis of ankyloglossia was made in 94.7% (N=612) of the patients based on clinical judgment. The most common feeding complaints were poor latch (57.1%, N=369) and painful latch (50.3%, N=325). Eighty one (12.5%) patients did not have a reported feeding difficulty. Most patients had an anterior tongue tie (85.8%, N=554), with some showing signs of restricted tongue movement (30.1%, N=184). Ankyloglossia was 4.03 times more likely to be diagnosed (p<.001) and frenotomy was 1.76 times more likely to be performed (p<.001) in the hospital setting compared to the clinic setting.  Conclusion: Children under the age of one referred to otolaryngology for ankyloglossia were often diagnosed concordantly, although some lacked feeding issues that would indicate frenotomy. There are still knowledge gaps about infantile ankyloglossia in referring medical personnel.

Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001.

As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).

The Alignment of Real-World Evidence and Digital Health: Realising the Opportunity.

In the new era of healthcare digitalization, there is a golden opportunity in the overlap between digital health and Real-World Evidence (RWE). In this commentary, we define RWE and digital health and investigate their intersection. We describe the stages in the RWE value chain critical to the evidence generation process, how these stages change with new digital technologies and the opportunities and challenges that arise from how these stages evolve-including their application for stakeholders such as patients, physicians and regulators. We also discuss the current published guidelines and frameworks regarding digital health. We categorise these publications in terms of their clarity as "Extensive", "Intermediate" or "Basic" and according to whether they encompass all levels of digital health or are more focussed in their guidance. Finally, we provide recommendations to increase synergy between RWE and digital health.

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

Outcomes of Dog Bite Avulsion Injury Reconstruction With Urinary Bladder Matrix.

Dog bite avulsion injuries of the head and neck are difficult to manage in pediatric patients. This study assesses the outcomes of using porcine urinary bladder extracellular matrix (UBM) for reconstruction of these complete avulsion injuries. Five male pediatric patients underwent reconstruction using UBM. Two (40%) patients underwent reconstruction of the nose; the other 3 patients underwent reconstruction of the forehead, forehead/glabella, and auricle. The average size of the avulsion defect was 7.0 ± 2.4 cm2. No patient developed wound dehiscence, graft loss, or wound infection. Four (80%) patients received pulsed dye laser treatment to improve wound cosmesis. Use of UBM is a safe and effective reconstructive option after dog bite avulsion injuries of the head and neck. Given the advantages of convenient availability and avoidance of donor site morbidity, UBM can be considered for reconstruction of posttraumatic avulsion injuries or Mohs defects.

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Strengthening pharma's contract with society: the value of trusted partnerships between pharma and healthcare facilitated by real-world data.

This White Paper is authored by 11 industry real-world evidence (RWE) experts, with support from IQVIA, as part of the 'RWE Leadership Forum': a group of industry leaders who come together as noncompetitive partners to understand and respond to internal or external RWD/E challenges and opportunities with a single expert voice. Herein we aim to clarify the rules of engagement between pharma and healthcare in order to establish trust-based partnerships, which will unlock unique value for society, including the medical community and the ultimate beneficiary, the patient.

Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.

Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.

The ubiquity of asymptomatic respiratory viral infections in the tonsils and adenoids of children and their impact on airway obstruction.

BACKGROUND: Airway obstruction due to enlargement of tonsils and adenoids is a common pediatric problem resulting in sleep disordered breathing. The cause for the relatively abnormal growth of tonsils and adenoids is poorly understood. METHODS: Non-acutely ill children undergoing tonsillectomy and adenoidectomy (T&A) for various reasons were enrolled prospectively in a study to determine the frequency of asymptomatic respiratory viral infections in each lymphoid tissue and to relate the number and types of virus to the degree of airway obstruction. Molecular techniques were used to detect 9 respiratory viruses while Brodsky scores and measurements of percentages airway obstruction were used to estimate the degree of airway compromise due to the tonsil and adenoid, respectively. RESULTS: Viruses were detected in 70.9% of tonsils and 94.7% of adenoids, p < 0.001. Adenovirus was the most common virus detected at 71.1%. Adenoids had an average of 2.4 viruses compared to 0.92 for tonsils, p < 0.001. Higher Brodsky scores were only associated with EBV in tonsils, p = 0.03, while greater percentages of airway obstruction in the adenoids were associated with adenovirus, EBV, corona virus, parainfluenza virus and rhinovirus, p ≤ 0.005. CONCLUSIONS: Asymptomatic viral infections are common and directly related to the degree of airway obstruction significantly more often in adenoids than tonsils.

Head and neck dog bites in children.

OBJECTIVES: 1) Demonstrate patterns of dog bite injury to the head and neck in children. 2) Identify treatment outcomes of dog bite injuries to the head and neck. STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Children aged 0 to 19 years, treated for head and neck dog bites at our tertiary care children's hospital (1999-2007), were included. Demographics, dog breed and ownership, seasonal incidence, wound location, characteristics, management, and complications were recorded. RESULTS: Eighty-four children, aged 10 months to 19 years (mean, 6.19 years) underwent primary repair of head and neck dog bite injuries. The cheek (34%) and lips (21%) were involved most commonly. Average wound length was 7.15 cm. Dog bite incidence peaked during summer months. Infection occurred in 10.7 percent. Pulsed dye laser was used to improve cosmesis. CONCLUSIONS: Children are vulnerable to head and neck dog bite injuries. Wound healing is excellent despite a contaminated wound. Infections occur infrequently. Pulsed dye laser improves cosmesis.

A new technique (the NOW test) for the detection of Streptococcus pneumoniae in the effusions of otitis media.

The presence of Streptococcus pneumoniae in chronic otitis media was determined with a new antigen detection kit, the NOW test. The NOW test was originally designed as a urinary antigen test but was adapted to middle-ear effusions for the present study. Middle-ear effusions from 52 children were studied. Streptococcus pneumoniae was cultured from 10 per cent of the effusions. The NOW test was positive in 23 per cent of the effusions, 80 per cent of culture positive and 17 per cent of culture negative effusions. The NOW test proved to be rapid, simple, reliable and relatively inexpensive for the detection of pneumococcal antigen in the middle-ear effusions. This test may prove valuable for the management of children with acute otitis media who undergo tympanocentesis.

Hemangiomas and vascular malformations: analysis of diagnostic accuracy.

OBJECTIVES: To evaluate the diagnostic accuracy and satisfaction of patient or family (or both) in the evaluation of hemangiomas and other vascular malformations. STUDY DESIGN: Prospective, relational database. METHODS: Ninety-eight patients participated in a prospective, Institutional Review Board-approved, relational database study in the Hemangioma and Vascular Birthmark Center at the Children's Hospital of Buffalo (Buffalo, NY) from July 1998 to April 2000. This included 68 patients with hemangiomas and 30 with vascular malformations. Data regarding presenting and final diagnosis and satisfaction of patient or family (or both) were obtained. RESULTS: Analysis of diagnostic accuracy revealed a concurrence between initial and final combined clinical and magnetic resonance imaging-based diagnosis in only 37% of cases. Analysis of patient and family satisfaction with the care received from previous consultants revealed only 26% "entirely" satisfied, 26% "somewhat" satisfied, and 37% "not at all" satisfied. On average, 2.5 (SD = 1.6; range, 1-9; median, 2) different physicians saw the patient before the patient or family (or both) was satisfied. CONCLUSIONS: Accurate diagnosis of hemangiomas and vascular malformations remains a challenge for physicians. Confusing terminology, lack of knowledge regarding lesion behavior, and poorly understood diagnostic criteria by physicians are some of the reasons for patient frustration. Education of primary care providers through improved communication helps to optimize a coordinated, interdisciplinary approach to patients and their families who present with vascular anomalies.

Examination of the kinetic mechanism of mitogen-activated protein kinase activated protein kinase-2.

The kinetic mechanism of mitogen-activated protein kinase activated protein kinase-2 (MAPKAPK2) was investigated using a peptide (LKRSLSEM) based on the phosphorylation site found in serum response factor (SRF). Initial velocity studies yielded a family of double-reciprocal lines that appear parallel and indicative of a ping-pong mechanism. The use of dead-end inhibition studies did not provide a definitive assignment of a reaction mechanism. However, product inhibition studies suggested that MAPKAPK2 follows an ordered bi-bi kinetic mechanism, where ATP must bind to the enzyme prior to the SRF-peptide and the phosphorylated product is released first, followed by ADP. In agreement with these latter results, surface plasmon resonance measurements demonstrate that the binding of the inhibitor peptide to MAPKAPK2 requires the presence of ATP. Furthermore, competitive inhibitors of ATP, adenosine 5'-(beta,gamma-imino)triphosphate (AMPPNP) and a staurosporine analog (K252a), can inhibit this ATP-dependent binding providing further evidence that the peptide substrate binds preferably to the E:ATP complex.