tbuckley/cabot-search huggingface dataset:
Antidepressants during pregnancy and autism in offspring: population based cohort study
Authors: Dheeraj Rai, Brian K Lee, Christina Dalman, Craig Newschaffer, Glyn Lewis, Cecilia Magnusson
Journal: BMJ (2017)

<b>Objectives</b>&nbsp;To study the association between maternal use of antidepressants during pregnancy and autism spectrum disorder (ASD) in offspring. <b>Design</b>&nbsp;Observational prospective cohort study with regression methods, propensity score matching, sibling controls, and negative control comparison. <b>Setting</b>&nbsp;Stockholm County, Sweden. <b>Participants</b>&nbsp;254 610 individuals aged 4-17, including 5378 with autism, living in Stockholm County in 2001-11 who were born to mothers who did not take antidepressants and did not have any psychiatric disorder, mothers who took antidepressants during pregnancy, or mothers with psychiatric disorders who did not take antidepressants during pregnancy. Maternal antidepressant use was recorded during first antenatal interview or determined from prescription records. <b>Main outcome measure</b>&nbsp;Offspring diagnosis of autism spectrum disorder, with and without intellectual disability. <b>Results</b>&nbsp;Of the 3342 children exposed to antidepressants during pregnancy, 4.1% (n=136) had a diagnosis of autism compared with a 2.9% prevalence (n=353) in 12 325 children not exposed to antidepressants whose mothers had a history of a psychiatric disorder (adjusted odds ratio 1.45, 95% confidence interval 1.13 to 1.85). Propensity score analysis led to similar results. The results of a sibling control analysis were in the same direction, although with wider confidence intervals. In a negative control comparison, there was no evidence of any increased risk of autism in children whose fathers were prescribed antidepressants during the mothers' pregnancy (1.13, 0.68 to 1.88). In all analyses, the risk increase concerned only autism without intellectual disability. <b>Conclusions</b>&nbsp;The association between antidepressant use during pregnancy and autism, particularly autism without intellectual disability, might not solely be a byproduct of confounding. Study of the potential underlying biological mechanisms could help the understanding of modifiable mechanisms in the aetiology of autism. Importantly, the absolute risk of autism was small, and, hypothetically, if no pregnant women took antidepressants, the number of cases that could potentially be prevented would be small.
Emergency Medical Services Response Times in Rural, Suburban, and Urban Areas
Authors: Howard K. Mell, Shannon N. Mumma, Brian Hiestand, Brendan G. Carr, Tara Holland, Jason Stopyra
Journal: JAMA Surgery (2017)

This study describes the interval between receipt of a 911 call and the arrival of the first emergency medical service unit on the scene of a reported emergency in the United States.
Image Gallery: Pink papules within a tattoo linked to <i>Mycobacterium chelonae</i> infection
Authors: C. Painsi, B. Lange-Asschenfeldt
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 46‐year‐old woman presented with pruritic, small pink papules localized within tattooed skin (a). The symptoms initially appeared 1 month after tattoo placement. Histological examination revealed lymphohistiocytic infiltrates and granulomatous inflammation (b), but stains for acid‐fast organisms were negative. Mycobacterium chelonae was isolated and confirmed by DNA sequencing. Infections with nontuberculous mycobacteria from tattooing are linked to contaminated inks.1 2 An empirical regimen of oral clarithromycin and moxifloxacin was initiated. After receiving species sensitivities this was modified to clarithromycin monotherapy, which resulted in complete clearance after 5 months. Our case serves as a reminder of tattoo‐associated risks in times of a growing vogue of body modifications.
Humanitarian leaders call for “redoubling” of aid for crisis engulfing Yemen
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

The heads of three of the world’s biggest humanitarian organisations have urged Yemeni authorities to take action to help millions of people affected by cholera and famine and for the international community “to redouble its support for the people of Yemen.”

“If we fail to do so, the catastrophe we have seen unfolding before our eyes will not only continue to claim lives but will scar future generations and the country for years to come,” wrote Anthony Lake, executive director of Unicef; David Beasley, executive director of the World Food Programme; and Tedros Adhanom Ghebreyesus, director general of the World Health Organization, in a statement after a joint visit to Yemen. …
PIK3CA mutational status and correlation with tumor glycolysis imaged with [18F]FDG PET/CT in early primary ER+ / HER2- breast cancer patients: A feasibility study.
Authors: Heinrich Florian Magometschnigg, Anita Brandstetter, Martin Filipits, Margaretha Rudas, Peter Christian Dubsky, Georgios Karanikas, Katja Pinker-Domenig
Journal: Journal of Clinical Oncology (2016)

e12050 Background: Mutations in the PIK3CA gene encoding are most common in ER+/HER2- breast cancers. PIK3CA mutational status, is a molecular trait with a relevant biologic downstream effect that can be quantitatively assessed using [18F]FDG PET/CT and thus might be used to translate imaging into indications such as prognostic and predictive assessments in ER+/HER2- breast cancers. In this study we test the relationship of PIK3CA mutational status and other tumor characteristics with aerobic glycolysis in primary ER+/HER2- breast cancers. Methods: In this IRB approved prospective study tissue samples of 70 early primary ER+/Her2- breast cancers without distant metastasis were assessed for PIK3CA mutational status. Pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9 and 20. Glucose-uptake of breast tumors was assessed quantitatively with [18F]FDG PET/CT using standardized uptake values (SUVmax). Results: PIK3CA mutations were detected in 32 patients (46%), a wild-type status in 38 patients. Mean SUVmax values were 5.54 (CI 4.21 – 6.87) and 4.64 (CI 3.71 – 5.58) (p = 0.257). A significant correlation of G1 tumors and PIK3CA mutations was found in IDC patients (p < 0.05). In 22 patients (31%) axillary lymph node metastases were found, which were associated with increased SUVmax levels (p < 0.01). SUVmax correlated positively with Ki67 (r = 0.53; p < 0.01) and tumor size (r = 0.25; p < 0.05). Stratified by PIK3CA status correlation of SUVmax and tumor size increased in the mutation subgroup (r = 0.53; p < 0.01). In subgroup analysis tumors with a PIK3CA-mutation and ≥ 2cm show a mean SUVmax of 8.08 vs 4.49 in wild-type tumors or tumors < 2cm (p < 0.001). SUVmax < 6.00 can depict a wild-type status in tumors ≥ 2cm (PPV 87%). Conclusions: Patients with early ER+/HER2- BC and PIK3CA mutations demonstrated higher [18F]FDG avidity compared to patients with wild-type tumors. Due to the small sample size significant differences could not be identified. Tumors ≥ 2cm with a SUVmax > 6 are frequently associated with a PIK3CA-mutational genotype. Thus, these patients may benefit from additional [18F]FDG PET/CT for guidance of prognostic and predictive assessments.
Oncogenic long noncoding RNA landscape in breast cancer
Authors: Shouping Xu, Dejia Kong, Qianlin Chen, Yanyan Ping, Da Pang
Journal: Molecular Cancer (2017)

Few long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified.Oncogenic lncRNAs associated with tumourigenesis and worse survival outcomes were examined and validated in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Then, the potential biological functions and expression regulation of these lncRNAs were studied via bioinformatics and genome data analysis. Moreover, progressive breast cancer subtype-specific lncRNAs were investigated via high-throughput sequencing in our cohort and TCGA validation. To elucidate the mechanisms of the regulation of these lncRNAs, genomic alterations from the TCGA, Broad, Sanger and BCCRC data, as well as epigenetic modifications from GEO data, were then applied and examined to meet this objective. Finally, cell proliferation assays, flow cytometry analyses and TUNEL assays were applied to validate the oncogenic roles of these lncRNAs in vitro.A cluster of oncogenic lncRNAs that was upregulated in breast cancer tissue and was associated with worse survival outcomes was identified. These oncogenic lncRNAs are involved in regulating immune system activation and the TGF-beta and Jak-STAT signalling pathways. Moreover, TINCR, LINC00511, and PPP1R26-AS1 were identified as subtype-specific lncRNAs associated with HER-2, triple-negative and luminal B subtypes of breast cancer, respectively. The up-regulation of these oncogenic lncRNAs is mainly caused by gene amplification in the genome in breast cancer and other solid tumours. Finally, the knockdown of TINCR, DSCAM-AS1 or HOTAIR inhibited breast cancer cell proliferation, increased apoptosis and inhibited cell cycle progression in vitro.These findings enhance the landscape of known oncogenic lncRNAs in breast cancer and provide insights into their roles. This understanding may potentially aid in the comprehensive management of breast cancer.
Phase I study of the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with docetaxel, cisplatin, and dacomitinib.
Authors: Zev A. Wainberg, Geoffrey Shapiro, Giuseppe Curigliano, Rebecca Sophie Kristeleit, Stephen Leong, Maria Alsina, Michele Milella, Carolyn D. Britten, Karen A. Gelmon, Anthony J. Olszanski, Ulka N. Vaishampayan, Jose A. Lopez-Martin, Kenneth Alan Kern, Kristen J. Pierce, Rachelle Perea, Brett Houk, Nuzhat Pathan, Albiruni R. Razak
Journal: Journal of Clinical Oncology (2016)

2566 Background: Inhibition of phosphatidylinositol-3-kinase (PI3K)-mediated signaling may overcome resistance to chemotherapy or human epidermal growth factor receptor (EGFR) inhibitors. Gedatolisib (G) is a dual inhibitor of PI3K/mammalian target of rapamycin (mTOR) in development for solid tumors. Methods: This is an ongoing study to determine the maximum tolerated dose (MTD) and safety of G in combination with: 1) docetaxel: Arm A, in castrate resistant prostate cancer, advanced breast cancer (BC), or non-small cell lung cancer (NSCLC) patients (pts); 2) cisplatin: Arm B, in urothelial transitional cell cancer (TCC), triple negative BC (TNBC), NSCLC or ovarian cancer pts; 3) the pan-EGFR TKI dacomitinib: Arm C, in refractory HER2+BC, HER2+esophagogastric cancer, head and neck cancer, or EGFR-mutated NSCLC pts. Pts received a G lead-in dose 7 days (A, B) or 14 days (C) prior to day 1, followed by weekly intravenous (IV) G plus: docetaxel or cisplatin (75 mg IV every 3 weeks); or oral dacomitinib (30–45 mg/d). Secondary objectives included pharmacokinetics (PK), clinical efficacy (partial or complete response [PR or CR]), and associated biomarkers. Results: 74 pts (median prior therapies: 2; range: 0–6) received 90–260 mg/week of G in: A, 21; B, 21; and C, 32. The top drug related adverse events: A: neutropenia, mucositis, alopecia; B: nausea, fatigue, vomiting; and C: mucositis, diarrhea, nausea, fatigue. Cycle 1 dose limiting toxicities (DLTs) were: A: grade 3 mucositis (n = 1); B: no DLT; C: grade 3 mucositis (n = 1), pneumonitis (n = 1), rash (n = 1), and grade 2 fatigue (n = 1). PK parameters for G were similar regardless of combination agent. Best overall response was A: 4/21 PRs; B: 8/21 PRs (5 TNBC, 2 NSCLC, 1 TCC), and C: 6/32, (1 CR, 5 PRs). In Arm B, 3 of the 8 PRs (2 NSCLC, 1 TCC) had prior platinum exposure. Next generation sequencing involving PI3K data from a subset of patients is under evaluation. Conclusions: G can be combined with docetaxel, cisplatin, or dacomitinib, with manageable toxicity profiles and preliminary antitumor activity, even when heavily pre-treated. Due to portfolio prioritization, dose escalation and expansion continues in Arm B, with closure of Arms A and C (MTD not reached). Clinical trial information: NCT01920061.
Erratum: Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: A 30-month pilot study (Hepatology (November 1991) 14 (838-847))
Authors: C. B. O'Brien, J. R. Senior, R. Arora-Mirchandani, A. K. Batta, G. Salen
Journal: Hepatology (1992)
In Treating Sepsis, Questions About Timing and Mandates
Authors: Jennifer Abbasi
Journal: JAMA (2017)

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Comparison of early versus late onset of cellular immunotherapy in glioblastoma multiforme WHO IV.
Authors: Jan Nesselhut, Dagmar Marx, Nicole Cillien, Raymond Y. Chang, Wulf-Peter Brockmann, Michael Martin, Thomas Nesselhut
Journal: Journal of Clinical Oncology (2017)

e13531 Background: Glioblastoma multiforme (GBM WHO grade IV glioma) is an aggressive disease with an unfavorable prognosis. The current first line treatment comprises radical operation and radiotherapy combined with temozolomide chemotherapy (Stupp protocol). After failure of first-line therapy there is currently no effective therapy. Here we report that dendritic cell therapy prolongs the survival for patients with newly diagnosed GBM V. Preliminary results show that adding checkpoint blockade with Nivolumab may cause a secondary therapy response. Methods: After isolating monocytes from peripheral blood of n = 11 patients with stage IV GBM, who underwent primary surgery and first-line radio-chemotherapy and from n = 34 patients, who failed first line therapy MoDC were generated using standard protocols. In 5 patients checkpoint blockade with Nivolumab was added after failure of DC therapy. Results: With a median overall survival of 41 months there is a clear improvement of the overall survival in patients, who received DC therapy after having finished the Stupp-protocol. The 3- year-survival rate after primary diagnosis is 46% (n = 5) and 1 patient is still alive after 81 months. In this patient a secondary therapy response of 16 months could be induced by adding low dose Nivolumab (1mg/kg body weight) after failure of DC therapy. The median survival after onset of DC therapy in patients who failed first line standard therapy is 10 months. The 3-year overall survival rate is 9% (n = 3). In 4 patients therapy with Nivolumab was combined causing only a limiting effect on the survival (4 to 10 months). Conclusions: Dendritic-cell based immune therapy started immediately after primary standard therapy has a clear impact on the overall survival of patients with newly diagnosed GBM IV. Whereas the therapeutic effect for patients after failure of first-line therapy is limited. Nivolumab may cause secondary therapy response in certain patients.
Abstract 10956: Early and Late Vascular Responses After Stent Implantation in Human Peripheral Artery Disease
Authors: Katsumi Inoue, Yohei Kobayashi, Takayuki Ishihara, Tatsuya Shiraki, Yusuke Tomoi, Seiichi Hiramori, Yoshimitsu Soga, Osamu Iida, Kenji Ando, Masaaki Uematsu, Masakiyo Nobuyoshi
Journal: Circulation (2015)

Background: Although stent implantation is now a first-line strategy for the treatment of peripheral artery disease (PAD), little is known about the pathological findings of arterial response following lower extremity stenting. Methods and Results: Histopathological studies were performed on 13 iliofemoral lesions (les) obtained by autopsy or surgical resection between 2.5 months (M) and 10 years (Y) after bare metal stent (BMS) implantation. In addition, paclitaxel-coating stents (Zilver PTX) (6 les; 10 M to 2.5 Y) implanted in superficial femoral arteries were also observed. Almost all arterial specimens were characterized by fibrocalcific intimal plaques as well as underlying Mönckeberg’s medial calcinosis. There were fibrin deposits around the struts, with smooth muscle cell (SMC) infiltration in varying degrees, at 2.5 M after BMS implantation; however, endothelial cell coverage remained poor in the surface area. Furthermore, stent malapposition is a frequent phenomenon, which is related to underlying medial and intimal calcification. Arteries from more than 1 Y after stenting exhibited thickened neointima consisting of significant proliferation of SMCs and abundant extracellular matrix on the intimal side of the stent struts. However, uncovered malapposed struts with fibrin deposition were still evident, predominantly at the calcified surface. In neointima of more than 8 Y after stenting, SMCs were spindle-shaped and ordered along the luminal surface, and intercellular space contained abundant collagen fibers. However, there was advanced luminal narrowing in 2 of the les, and the luminal surface of these segments was focally disrupted and covered by mural thrombi. Zilver PTX demonstrated notable uncovered struts, even more than 2 Y after stenting, and extensive in-stent thrombi were observed in all stented segments, including 2 les with occlusive thrombosis. Conclusions: These findings suggest that a longer duration of potent antiplatelet therapy may be more appropriate after BMS implantation for PAD, compared to coronary artery stenting. Furthermore, remarkable delayed healing with significant uncovered struts caused by paclitaxel exposure can result in late stent thrombosis after Zilver PTX implantation.
Association of gliomas and BRCA 1 germline mutation: A possible linkage.
Authors: Marc Frenay, Marie Amelie Met Domestici, Pascaline Berthet, Fanny Burel-Vandenbos, Philippe Vennin, Hagay Sobol, Christine Lebrun, Véronique Mari
Journal: Journal of Clinical Oncology (2012)

e12502 Background: Gliomas are known to occur in association with several well-defined hereditary tumor syndromes such as NF1 and NF2, tuberous sclerosis, Li Fraumeni syndrom and Turcot syndrome. In addition, familial clustering of glioma in absence of these tumor syndrome have also been described. Methods: We have already reported the case of a 35 years old man who was diagnosed with an oligodendroglioma. Familial history reported 3 ovarian cancers at the first degree. Genetic testing had shown the BRCA1 exonic deletion c.3819del GTAAA, p. 1241 ter. (Patient 1 ) We collected 2 more cases of patients diagnosed with glioma and carrying BRCA1 mutation, whom have been seen by other physicians in an other hospital. Results: The second patient is a 59-year-old woman diagnosed with a glioblastoma with important oligodendroglioma differenciation (Patient 2). She was 43 at the time of diagnosis. At the age of 54, she developed a bilateral breast cancer. Moreover, the pedigree revealed a familial history of 4 breast cancers at the first degree. Genetic testing had shown the BRCA1 exonic substitution c.181T&gt;G, p.Cys61Gly. The third patient is a 40-year -old woman diagnosed with an intra medullar pilocytic astrocytoma (Patient 3). This tumour is not usual which allows to keep in mind the genetic procedure. Beforehand, she had been diagnosed with a breast cancer at the age of 36. The pedigree revealed 6 breast cancers among the family and thus, BRCA analysis had been performed and showed the BRCA 1 exonic substitution c.3403 C&gt;T, p.Gln 1135 X. Consequently, the patient had a prophylactic ovarian surgery at the age of 37 and contralateral prophylactic mastectomy at the age of 40. Interestingly, P1 had a BRCA1 deletion whereas P2 and P3 had BRCA1 substitution. On the other hand, P1 and P3 had Exon 11 mutation that both resulted in a truncated protein. Whereas, P2 had an exon 5 missens mutation. Conclusions: No specific association has been reported between BRCA1 mutation and glial tumor occurrence. These cases point out a possible relationship between BRCA1 germline mutation and glioma occurrence such as the relevance of familial history screening in glioma patients. Further investigations are needed to identify a disease-causing locus by genetic linkage analysis.
Haploidentical Stem Cell Transplantation for Patients Relapsing after First Allogeneic Transplantation
Authors: Virginie Lavoipierre, Samia Harbi, Luca Castagna, Angela Granata, Sabine Fürst, Catherine Faucher, Faezeh Legrand, Stefania Bramanti, Christian Chabannon, Norbert Vey, Jérome Rey, Reda Bouabdallah, Jean Marc Schiano De Colella, Djamel Mokart, Pierre-Jean Weiller, Didier Blaise, Raynier Devillier
Journal: Blood (2016)
Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy
Authors: Joseph W. Frank, Travis I. Lovejoy, William C. Becker, Benjamin J. Morasco, Christopher J. Koenig, Lilian Hoffecker, Hannah R. Dischinger, Steven K. Dobscha, Erin E. Krebs
Journal: Annals of Internal Medicine (2017)

Background: Expert guidelines recommend reducing or discontinuing long-term opioid therapy (LTOT) when risks outweigh benefits, but evidence on the effect of dose reduction on patient outcomes has not been systematically reviewed. Purpose: To synthesize studies of the effectiveness of strategies to reduce or discontinue LTOT and patient outcomes after dose reduction among adults prescribed LTOT for chronic pain. Data Sources: MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library from inception through April 2017; reference lists; and expert contacts. Study Selection: Original research published in English that addressed dose reduction or discontinuation of LTOT for chronic pain. Data Extraction: Two independent reviewers extracted data and assessed study quality using the U.S. Preventive Services Task Force quality rating criteria. All authors assessed evidence quality using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Prespecified patient outcomes were pain severity, function, quality of life, opioid withdrawal symptoms, substance use, and adverse events. Data Synthesis: Sixty-seven studies (11 randomized trials and 56 observational studies) examining 8 intervention categories, including interdisciplinary pain programs, buprenorphine-assisted dose reduction, and behavioral interventions, were found. Study quality was good for 3 studies, fair for 13 studies, and poor for 51 studies. Many studies reported dose reduction, but rates of opioid discontinuation ranged widely across interventions and the overall quality of evidence was very low. Among 40 studies examining patient outcomes after dose reduction (very low overall quality of evidence), improvement was reported in pain severity (8 of 8 fair-quality studies), function (5 of 5 fair-quality studies), and quality of life (3 of 3 fair-quality studies). Limitation: Heterogeneous interventions and outcome measures; poor-quality studies with uncontrolled designs. Conclusion: Very low quality evidence suggests that several types of interventions may be effective to reduce or discontinue LTOT and that pain, function, and quality of life may improve with opioid dose reduction. Primary Funding Source: Veterans Health Administration. (PROSPERO: CRD42015020347)