Baseline demographics and disease characteristics of patients with episodic or chronic cluster headache: data from two phase 3 randomized clinical trials in Europe and North America.

Objective: Two phase 3 galcanezumab trials were conducted in Europe and North America to analyze the reduction of weekly cluster headache (CH) attack frequency in populations with episodic and chronic CH. The current study aims to illustrate prospectively recorded baseline clinical data from these trials and to identify possible predictors of response.

Methods: Patients (aged 18-65 years) met The International Classification of Headache Disorders 3rd edition-beta criteria for CH.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

Context: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy.

Objective: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety.

Methods: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo).

Reproductive genetics laboratory may impact euploid blastocyst and live birth rates: a comparison of 4 national laboratories' PGT-A results from vitrified donor oocytes.

Objective: To evaluate potential variation in the euploid blastocyst rate and live birth rate (LBR) per single frozen euploid blastocyst transfer, among 4 unique United States reproductive genetics laboratories. Analyses were limited to blastocysts derived from vitrified donor oocytes, to minimize variation in oocyte quality.

Design: Retrospective cohort study from 2016 to 2020.

Challenges and complexities in designing cluster headache prevention clinical trials: A narrative review.

Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies.

Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995.

Tolerability and safety of galcanezumab in patients with chronic cluster headache with up to 15 months of galcanezumab treatment.

Objective: The objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment.

Background: Chronic CH is a highly debilitating disease with a substantial and unmet medical need.

Methods: Patients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52-week open-label extension and 16-week posttreatment follow-up (washout).

Impact of Galcanezumab on Total Pain Burden: A Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study in Patients with Episodic Cluster Headache.

Purpose: In a phase 3 study, galcanezumab significantly reduced the frequency of episodic cluster headache attacks across weeks 1-3 (primary endpoint) compared with placebo. However, multiple pain dimensions may contribute to the total burden of episodic cluster headache pain. This post hoc analysis assessed the impact of galcanezumab on the total pain burden of episodic cluster headache using a composite measure.

Treatment Outcomes in Patients Treated With Galcanezumab vs Placebo: Post Hoc Analyses From a Phase 3 Randomized Study in Patients With Episodic Cluster Headache.

Background: Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking.

Methods: This was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria.

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

Objective: To report efficacy and safety of galcanezumab in adults with chronic cluster headache.

Background: Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity.

Methods: This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period.

Immunological Role of the Maternal Uterine Microbiome in Pregnancy: Pregnancies Pathologies and Alterated Microbiota.

Understanding what happens at the time of embryo implantation has been the subject of significant research. Investigators from many differing fields including maternal fetal medicine, microbiology, genetics, reproductive endocrinology and immunology have all been studying the moment the embryo interacts with the maternal endometrium. A perfect relationship between the uterus and the embryo, mediated by a tightly controlled interaction between the embryo and the endometrium, is required for successful implantation.

Trial of Galcanezumab in Prevention of Episodic Cluster Headache.

Background: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache.

Methods: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month.

The Association between Solo versus Group Obstetrical Practice Model and Delivery Outcomes.

Objective: To determine if women under the care of obstetricians in solo practice have different delivery outcomes from women in a group practice.

Study Design: This is a retrospective cohort of live, term, singleton, vertex (LTSV) deliveries at one hospital from 2011 to 2015. We compared outcomes between women whose obstetrician was in solo practice with women in a group practice model.

Association Between Senior Obstetrician Supervision of Resident Deliveries and Mode of Delivery.

Objective: In December 2012, the Mount Sinai Hospital implemented a program to have senior obstetricians (more than 20 years of experience) supervise residents on labor and delivery during the daytime. The objective of this study was to estimate the association of resident supervision by senior obstetricians with mode of delivery.

Methods: This was a retrospective cohort study of all resident deliveries at Mount Sinai from July 2011 to June 2015.

Cloud Based Surveys to Assess Patient Perceptions of Health Care: 1000 Respondents in 3 days for US $300.

Background: There are many challenges in conducting surveys of study participants, including cost, time, and ability to obtain quality and reproducible work. Cloudsourcing (an arrangement where a cloud provider is paid to carry out services that could be provided in-house) has the potential to provide vastly larger, less expensive, and more generalizable survey pools.

Objective: The objective of this study is to evaluate, using Amazon's Mechanical Turk (MTurk), a cloud-based workforce to assess patients' perspectives of health care.

A national survey on public perceptions of miscarriage.

Objective: To assess attitudes and perceptions of U.S. survey respondents regarding prevalence, causes, and emotional effects of miscarriage.

The high cost of spasticity in multiple sclerosis to individuals and society.

Background: Spasticity is an extremely common, distressing and disabling symptom of multiple sclerosis. Limited data suggest the associated health care costs correlate with increasing severity and place a high economic burden on individuals, health care systems and society.

Objective: The aim of this study was to quantify the impact of multiple sclerosis spasticity on health care resources and the associated costs at different levels of severity in people with multiple sclerosis in the United Kingdom.

1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity.

Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position.

Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives.

Substitution at the 7-position of the chromen-4-one pharmacophore of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.

Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K.

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers.

DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain.

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC(50)=8 nM).

Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors.

Replacement of the core heterocycle of a defined series of chromen-4-one DNA-PK inhibitors by the isomeric chromen-2-one (coumarin) and isochromen-1-one (isocoumarin) scaffolds was investigated. Structure-activity relationships for DNA-PK inhibition were broadly consistent, albeit with a reduction of potency compared with the parent chromenone.

Negative and positive regulation of HIF-1: a complex network.

Hypoxia inducible factor-1 (HIF-1) is as a key transcriptional mediator of the hypoxic response in eukaryotic cells, regulating the expression of a myriad of genes involved in oxygen transport, glucose uptake and glycolysis and angiogenesis. Deregulation of HIF-1 activity occurs in many human cancers, usually at the level of the HIF-1alpha subunit. HIF-1 is regulated by a variety of mechanisms including transcription, translation post-translational modification, protein-protein interaction and degradation.