High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection.

The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mortality of such allogeneic transplants precludes widespread adoption of this HIV cure. Here, we show the application of CRISPR/Cas9 to achieve >90% CCR5 editing in human, mobilized hematopoietic stem progenitor cells (HSPC), resulting in a transplant that undergoes normal hematopoiesis, produces CCR5 null T cells, and renders xenograft mice refractory to HIV infection.

Clinical Outcomes of Transepithelial Photorefractive Keratectomy Performed with Smart Pulse Technology for the Correction of Moderate to High Myopia.

: To evaluate the safety and efficacy of the transepithelial photorefractive keratectomy (TransPRK) performed using smart pulse technology (SPT) in myopic eyes with refractive error ranging from -5.25 D to -9.75 D.

Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods.

The ability to alter genomes specifically by CRISPR-Cas gene editing has revolutionized biological research, biotechnology, and medicine. Broad therapeutic application of this technology, however, will require thorough preclinical assessment of off-target editing by homology-based prediction coupled with reliable methods for detecting off-target editing. Several off-target site nomination assays exist, but careful comparison is needed to ascertain their relative strengths and weaknesses.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.

Background: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours.

Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting.

To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients.

Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

Objective: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.

Methods: This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo.

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study.

Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations.

Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization.

Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted.

Association of self-reported recurrent mild hypoglycemia with incident cardiovascular disease and all-cause mortality in patients with type 2 diabetes: Prospective analysis of the Joint Asia Diabetes Evaluation Registry.

Severe hypoglycemia is an established risk marker for cardiovascular complications of diabetes, but whether mild hypoglycemia confers similar risks is unclear. We examined the association of self-reported recurrent mild hypoglycemic events with cardiovascular disease (CVD) and all-cause mortality in a prospective cohort of Chinese adults with type 2 diabetes.From June 2007 to May 2015, 19,019 patients in Hong Kong underwent comprehensive assessment of metabolic and complication status using the Joint Asia Diabetes Evaluation program.

Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial.

Context: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS.

Objective: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS.

Pharmacokinetics of a Novel Zolpidem Nasal Spray for Rapid Management of Insomnia: First Trial in Humans.

Study Objectives: The present single-dose, parallel-group, randomized, double-blind, placebo-controlled study is to evaluate the pharmacokinetics, tolerability and safety of zolpidem tartrate nasal spray (ZNS) as compared to placebo in healthy subjects.

Methods: Thirty-six healthy subjects participated in this study, with 19 male and 17 female subjects in 3 cohorts (12 subjects per cohort), who were randomly assigned to receive either an intranasal dose of ZNS 1.75 mg, 3.

Zolpidem Mucoadhesive Formulations for Intranasal Delivery: Characterization, In Vitro Permeability, Pharmacokinetics, and Nasal Ciliotoxicity in Rats.

Zolpidem is a non-benzodiazepine hypnotic for the treatment of insomnia characterized by difficulties with sleep initiation. Our study aimed at developing a zolpidem mucoadhesive formulation with minimal local toxicity, prolonged nasal residence time, and enhanced absorption after intranasal delivery. In vitro permeability studies using artificial membrane and Calu-3 cell culture model indicated efficient permeability of zolpidem.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

Importance: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.

Objective: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

Aim: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.

Methods: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually.

Outcomes and endpoints in cancer trials: bridging the divide.

Cancer is not one disease. Outcomes and endpoints in trials should incorporate the therapeutic modality and cancer type because these factors affect clinician and patient expectations. In this Review, we discuss how to: define the importance of endpoints; make endpoints understandable to patients; improve the use of patient-reported outcomes; advance endpoints to parallel changes in trial design and therapeutic interventions; and integrate these improvements into trials and practice.

Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.

Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention.

Objective: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention.

Methods: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks.

Long-term open-label safety study of rizatriptan acute treatment in pediatric migraineurs.

Objective: To evaluate the safety/tolerability of rizatriptan in the long-term acute treatment of migraine in pediatric patients.

Background: Acute migraine treatment options for children are limited. A recent single-attack trial demonstrated that rizatriptan is effective in eliminating migraine headache pain in this population.

Results of a 2-year retrospective cohort study of newly prescribed triptan users in European nationwide practice databases.

Objective: This study was conducted to characterize prescription refill patterns for triptans among European patients with new prescriptions of triptans.

Background: Persistency with prescriptions of triptan monotherapy for migraine headache among newly prescribed users in European primary-care practices has not been well described.

Methods: Using electronic medical databases in the UK (N = 3618), France (N = 2051) and Germany (N = 954), we conducted a retrospective cohort analysis to identify refill patterns over 2 years among migraineurs receiving new prescriptions of triptan monotherapy in 2006.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design.

Background: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents.

Methods: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol.

Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy.

Background: One of the newest methicillin-resistant Staphylococcus aureus (MRSA) antibiotics to receive FDA approval is ceftaroline fosamil, a member of a new subclass of cephalosporins with unique activity against MRSA. However, ceftaroline is currently only FDA approved for complicated skin/soft tissue infections and community-acquired pneumonia; there are currently no clinical data regarding its use in MRSA bacteraemia and endocarditis. We report a series of six patients in which ceftaroline was utilized as salvage monotherapy in persistent MRSA bacteraemia or endocarditis.

Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension.

Purpose: To compare the efficacy and safety of tafluprost, a preservative-free (PF) prostaglandin analogue, with PF timolol in patients with open-angle glaucoma or ocular hypertension.

Design: Randomized, double-masked, multicenter clinical trial.

Methods: After discontinuation and washout of existing ocular hypotensive treatment, patients who had intraocular pressure (IOP) ≥23 and ≤36 mm Hg in at least 1 eye at the 08:00 hour time point were randomized 1:1 to 12 weeks of treatment with either PF tafluprost 0.

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease.

Objective: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease.

Background: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated.

Methods: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine.