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J Scott Andrews,1 David Kudrow,2 Mallikarjuna Rettiganti,1 Tina Oakes,1 Jennifer N Bardos,1 Richard Wenzel,1 Dulanji K Kuruppu,1 Charly Gaul,3 James M Martinez1 1Eli Lilly and Company, Indianapolis, IN, USA; 2California Medical Clinic for Headache, Santa Monica, CA, USA; 3Headache Center, Frankfurt, GermanyCorrespondence: Mallikarjuna RettigantiEli Lilly and Company, Lilly Corporate Center, 893 Delaware St., Indianapolis, IN, 46285, USATel +1 3176519378Email rettiganti_mallikarjuna@lilly.comPurpose: 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.Patients and Methods: Patients with episodic cluster headache were randomized 1:1 to galcanezumab 300 mg or placebo once monthly for 8 weeks. Mean weekly total pain burden was calculated (daily cluster headache attack frequency × average duration × average pain severity summed over 7 days) using data collected in an electronic patient-reported outcomes diary. Change from baseline in weekly total pain burden across weeks 1– 3 was compared between galcanezumab and placebo. To explore construct validity, mean weekly total pain burden scores were stratified by Patient Global Impression of Improvement (PGI-I) responses at the week 4 clinic visit.Results: The reduction from baseline in mean weekly total pain burden was significantly greater with galcanezumab (N=49) than with placebo (N=57): the least squares mean difference was − 11.18 severity-weighted hours (p=0.035). Median weekly total pain burden decreased as PGI-I ratings improved, from 33.6 to 5.0 severity-weighted hours for patients who felt “very much worse” and “very much better,” respectively.Conclusion: Galcanezumab significantly reduced mean weekly total pain burden compared with placebo in patients with episodic cluster headache. The composite pain measure demonstrated construct validity. Total pain burden may provide a holistic measure of the pain of episodic cluster headache.Clinical Trials: ClinicalTrials.gov, NCT02397473.Keywords: composite pain, frequency, severity, duration, CGRP

Introduction DNA double-strand breaks (DSBs) are the most cytotoxic lesions induced by ionising radiation (IR) and anticancer drugs, such as topoisomerase II poisons (eg, doxorubicin). The major DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR), in which DNA-Dependent Protein Kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) are key components. DNA-PK in particular is up-regulated in hepatocellular carcinoma, (GEO profiles) possibly contributing to resistance to cytotoxic therapies. Aim To assess DNA-PK and ATM as therapeutic targets for chemo- and radio-sensitisation in hepatoma. Method Basal protein levels and activities were determined by Western blot analysis in hepatoma cell lines. DNA-PK and ATM activity following doxorubicin stimulation was measured using antibodies specific to phosphorylated Ser-2056 DNA-PKcs and phosphorylated Ser-1981 ATM. DSB repair was measured by immunofluorescence detection of γ-H2AX foci. Cell survival was determined by clonogenic assay. Results We demonstrated high basal levels of DNA-PK in three hepatoma cell lines (Huh7, Hep3B and HepG2), with DNA-PK activation induced by 0.25 μM doxorubicin. Despite similar DNA-PK activation, we observed differential sensitivity to doxorubicin (7%, 49% and 75% survival at 10 nM doxorubicin in Huh7, Hep3B and HepG2, respectively). HepG2 cells with the greatest resistance to doxorubicin displayed a 10-fold activation of ATM relative to the other cell lines. The DNA-PK inhibitor NU7441, increased doxorubicin and ionising radiation (IR) induced cytotoxicity in all cell lines (1.3 up to fourfold), correlating with a reduction in DSB repair measured by γ-H2AX foci. Importantly, in doxorubicin resistant HepG2 cells, while incubation with NU7441 or the ATM inhibitor (KU55933) alone, had minimal effects on cell survival (91% and 86%, respectively), their combination in the absence of a cytotoxic agent markedly inhibited cell survival (21%; p<0.001, ANOVA). The addition of 10 nM doxorubicin reduced survival to less than 5% of colonies. Conclusion These findings support the clinical application of DNA-PK and ATM inhibitors as chemo- and radio-sensitisors in hepatoma patients. Furthermore, these data suggest that hepatoma cell survival is dependent on up-regulation of DSB repair, effected by either DNA-PK or ATM, and that inhibition of both induces synthetic lethality—preventing DSB repair by both NHEJ and HR. The therapeutic implication is that in combination, these agents could be used to specifically induce cancer cell death, with minimal toxicity to surrounding liver tissues. [ABSTRACT FROM PUBLISHER]

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., Setting: Donor Egg Bank Database., Patient(s): Patients undergoing in vitro fertilization with donor oocytes. We excluded patients with uterine factor, male factor, or surgically extracted sperm. Only healthy women <34 years old were accepted as oocyte donors., Intervention(s): Next generation sequencing platforms for chromosomal analysis MAIN OUTCOME MEASURE(S): Euploid blastocyst rate and LBR per euploid transfer. Secondary outcomes included the rate of aneuploidy, mosaic calls, biochemical pregnancy loss, and miscarriage rate., Result(s): A total of 2,633 embryos were included. Four laboratories had >200 embryos tested. Euploid blastocyst rate was significantly higher in laboratory A (73.6%) vs. B (63.3%), C (60.9%), and D (52.3%). Mosaic rate was significantly lower for Laboratories B (2.8%) and C (5.5%) vs. Laboratories A (9.9%) and D (11.5). The LBR was significantly higher in laboratory A (58.73%) vs. laboratory D (47.3%). There were no significant differences in the implantation or miscarriage rate among laboratories., Conclusion(s): In this large study, controlling for oocyte quality, some preimplantation genetic testing for aneuploidy (PGT-A) laboratories report a significantly higher euploid blastocyst rate with concurrent higher LBR. This type of comparison is important as it provides insight into the role of the PGT-A process in outcomes. Further research is needed to evaluate the differences in laboratory techniques and bioinformatic algorithms accounting for variable outcomes across PGT-A laboratories., (Copyright © 2022 American Society for Reproductive Medicine. All rights reserved.)

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). This is a secondary analysis and long-term follow-up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings., Results: A total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab-treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment-emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open-label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo-controlled treatment period in laboratory values, vital signs, or ECGs., Conclusions: Galcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment., (© 2021 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

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. In this post hoc analysis, we evaluated the median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed., Results: The median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ≥50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ≥75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3])., Conclusions: Faster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo., (© 2020 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC, on behalf of American Headache Society.)

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. Any factors affecting this communication, such as altered microbiome may lead to poor reproductive outcomes. Current theories suggest that altered microbiota may trigger an inflammatory response in the endometrium that affects the success of embryo implantation, as inflammatory mediators are tightly regulated during the adhesion of the blastocyst to the epithelial endometrial wall. In this review, we will highlight the various microbiome found during the periconceptual period, the microbiomes interaction with immunological responses surrounding the time of implantation, its effect on implantation, placentation and ultimately maternal and neonatal outcomes., (Copyright © 2020 Bardos, Fiorentino, Longman and Paidas.)

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., Results: There were 18,214 LTSV deliveries by private obstetricians. Solo obstetricians were more likely to deliver at night (41.0 vs. 37.5%, p  = 0.002) and less likely to induce labor (22.6 vs. 30.6%, p  < 0.001). Solo obstetricians had a significantly higher rate of cesarean delivery (35.7 vs. 27.2%, adjusted odds ratio, aOR: 1.53, 95% confidence interval, CI [1.32, 1.78]), but also had a significantly lower rate of shoulder dystocia (0.4 vs. 1.4, aOR: 0.42, 95% CI [0.19, 0.89]), third or fourth degree lacerations (1.6 vs. 2.4%, aOR: 0.56, 95% CI [0.35, 0.914]), and neonatal intensive care unit admission rates (3.2 vs. 6.2%, aOR: 0.57, 95% CI [0.42, 0.77])., Conclusion: In a large, tertiary care hospital, solo obstetricians have similar neonatal outcomes as group obstetricians. Their higher cesarean delivery rate is balanced by fewer shoulder dystocias and third/fourth degree lacerations, indicating a more conservative approach to labor management. Patient outcomes should not be a reason to discourage a solo practice model., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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. We included all patients with live, term, singleton, vertex fetuses. We compared delivery outcomes between patients delivered before December 2012 and patients delivered December 2012 and later using logistic regression analysis to control for age, body mass index, parity, induction, and prior cesarean delivery. During the study period there were no other specific departmental initiatives to increase forceps deliveries aside from having six obstetricians with significant experience in operative deliveries supervise and teach residents on labor and delivery., Results: There were 5,201 live, term, singleton, vertex deliveries under the care of residents, 1,919 (36.9%) before December 2012 and 3,282 (63.1%) December 2012 or later. The rate of forceps deliveries significantly increased from 0.6% to 2.6% (adjusted odds ratio [OR] 8.44, 95% confidence interval [CI] 3.1-23.1), and the rate of cesarean deliveries significantly decreased from 27.3% to 24.5% (adjusted OR 0.68, 95% CI 0.55-0.83). There were no statistically significant differences in the rates of third- or fourth-degree lacerations or 5-minute Apgar scores less than 7. Among nulliparous women, the forceps rate increased from 1.0% to 3.4% (adjusted OR 4.87, 95% CI 1.74-13.63) and the cesarean delivery rate decreased from 25.6% to 22.7% (adjusted OR 0.69, 95% CI 0.53-0.89). The increase in forceps deliveries and the decrease in cesarean deliveries were seen only in daytime hours (7 AM to 7 PM), that is, the shift that was covered by senior obstetricians., Conclusion: Having senior obstetricians supervise resident deliveries is significantly associated with an increased rate of forceps deliveries and a decreased rate of cesarean deliveries.

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., Methods: A national online survey posted to Amazon's MTurk consisted of 33 multiple choice and open-ended questions. Continuous attributes were compared using t tests., Results: We obtained 1084 responses for a total cost of US $298.10 in less than 3 days with 300 responses in under 6 hours. Of those, 44.74% (485/1084) were male and 54.80% (594/1084) female, representing 49 out of 50 states and aged 18 to 69 years., Conclusions: Amazon's MTurk is a potentially useful survey method for attaining information regarding public opinions and/or knowledge with the distinct advantage of cost, speed, and a wide and relatively good representation of the general population, in a confidential setting for respondents., Competing Interests: Conflicts of Interest: None declared.

Objective: To assess attitudes and perceptions of U.S. survey respondents regarding prevalence, causes, and emotional effects of miscarriage., Methods: We used a questionnaire consisting of 33 questions administered in January of 2013 to men and women aged 18-69 years across the United States., Results: Participants from 49 states completed the questionnaire: 45% male and 55% female (N=1,084). Fifteen percent reported they or their partner experienced at least one miscarriage. Fifty-five percent of respondents believed that miscarriage occurred in 5% or less of all pregnancies. Commonly believed causes of miscarriage included a stressful event (76%), lifting a heavy object (64%), previous use of an intrauterine device (28%), or oral contraceptives (22%). Of those who had a miscarriage, 37% felt they had lost a child, 47% felt guilty, 41% reported feeling that they had done something wrong, 41% felt alone, and 28% felt ashamed. Nineteen percent fewer people felt they had done something wrong when a cause for the miscarriage was found. Seventy-eight percent of all participants reported wanting to know the cause of their miscarriage, even if no intervention could have prevented it from occurring. Disclosures of miscarriages by public figures assuaged feelings of isolation for 28% of respondents. Level of education and gender had a significant effect on perceptions and understanding of miscarriage., Conclusion: Respondents to our survey erroneously believed that miscarriage is a rare complication of pregnancy, with the majority believing that it occurred in 5% or less of all pregnancies. There were also widespread misconceptions about causes of miscarriage. Those who had experienced a miscarriage frequently felt guilty, isolated, and alone. Identifying a potential cause of the miscarriage may have an effect on patients' psychological and emotional responses., Level of Evidence: II.

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. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.

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.

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. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor for at least 4 hours at nontoxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof-of-principle in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.

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)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Expression of the adenomatous polyposis coli (APC) gene derived exon BS (e.g., brain-specific exon) has been analyzed by RT-PCR. Four novel APC mRNA isoforms derived from alternative splicing of exons 1A, BS and 1 were identified, which were ubiquitously expressed. One novel cDNA was characterized by cloning and DNA sequence analysis, which combined the exon 1A (identical with exon 0.3) 3' end with nucleotide position +101 of intron 1A and continued throughout exon BS. A second cDNA isoform was isolated, which joined the 3' end of exon 1A with nucleotide position +118 of exon BS. Both novel isoforms were found to be expressed together with a third novel APC exon connection, which was specified by exon BS/2 joining. This interesting exon junction resulted in novel deduced amino terminal open reading frames, which are completely in-frame with sequences located further downstream. Systematic exon connection analyses revealed that APC transcripts with exon BS/2 junctions were predominantly detected with a fixed exon composition. RT-PCR analyses did not identify facultative skipping of exons 9, 10A and 14 in this type of mRNA, in contrast to exon 1-containing APC transcripts analyzed from the same cDNA pool under identical conditions. Hence, exon 1 skipping of exon BS-positive mRNA molecules might preferentially encode unique APC polypeptide chains, which are characterized by an alternative amino terminus and extended heptad repeat structures due to combined incorporation of exons 9 and 10A.

1,2-Dihydro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-2-oxo-5-methylpyrazine 4-oxide was synthesized by condensation of the silylated pyrazine base with the blocked chloro sugar, followed by removal of the protecting groups. The compound inhibited the growth of leukemia L1210 cells in vitro by 50% at 2 x 10-7 M. At 400 mg/kg/day x 6 it increased the life-span of leukemia L1210 bearing mice by approximately 55%, without apparent toxicity to the host.

This is a report about 21 children, aged 10 till 15 years, who were admitted between 1977--1980 in a children's hospital because of attempted suicide. Exploration of the psychosocial situation and psychological tests brought many common factors of the suicidal development; a nonfunctioning relationship among the members of the family was the basal cause of a disturbed development of personality. This was responsible for failure in school, what was the cause for further problems in the family. There were many signs and symptoms of a presuicidal situation in each case, but in no one this was recognized by family or school.