Search

Abstract This study describes an automated data quality verification procedure supported by a database of power spectral densities (PSD) estimates for geophysical waveform data. The Royal Netherlands Meteorological Institute (KNMI) manages a 100‐TB archive of continuous geophysical data collected from accelerometers, geophones, broadband seismometers, and infrasonic arrays deployed across the continental and Caribbean Netherlands. This rapidly expanding network at a scale of over 700 instruments makes the manual evaluation of data quality impractical and must be supported by data policies and automated methods. A technique is presented to compress and store PSD estimates in a database with a storage footprint of less than 0.05% of the raw data archive. Every week, the instrument performance is validated by comparing statistical properties of its latest monthly probabilistic PSD distribution to strict quality metrics. The criteria include thresholds based on global noise models, datalogger quantization noise models, constraints imposed by ambient noise conditions, and confidence intervals based on PSD estimates calculated from validated archived data. When a threshold is crossed, the station operator is alerted of the suspected degraded instrument performance, severely limiting the required amount of manual labor and associated human errors. The automated PSD assessment technique is applicable to accelerometers, geophones, broadband seismometers, infrasonic stations, and is demonstrated to be extendable to hydrophones, gravimeters, tiltmeters, and Global Navigation Satellite System receivers. The approach is therefore suitable for other geophysical monitoring infrastructures, for example, observational networks dedicated to continuous volcano monitoring. It is shown that it possible to detect degraded instrument performance that may otherwise remain undetected.

Introduction: Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited., Methods: CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib., Results: In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%)., Conclusions: For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable., Competing Interests: Disclosure Dr. Besse reports receiving research funding (institution) from AstraZeneca, Pfizer, Eli Lilly, Onxeo, Bristol Myers Squibb, Inivata, AbbVie, Amgen, Blueprint Medicines, Celgene, GlaxoSmithKline, Sanofi, Takeda, Cristal Therapeutics, Daiichi Sankyo, Janssen, Ose Immunotherapeutics, BeiGene, Boehringer Ingelheim, Genentech/Roche, Tolero Pharmaceuticals, 4D Pharma, Aptitude Health, and Cergentis, outside of the current work. Dr. Goto reports serving in a consulting or advisory role for Takeda, Bayer US, Eli Lilly Japan, Amgen, Medpace Japan K.K., and Janssen; receiving honoraria from Guardant Health, Janssen, Daiichi Sankyo, Amgen, Eisai, AstraZeneca Japan, Chugai Pharmaceutical Co., Eli Lilly Japan, Boehringer Ingelheim, Takeda, Otsuka, Amoy Diagnostics, Bayer US, and Merck; and receiving research funding from Medical & Biological Laboratories, Kyowa Kirin, Kissei Pharmaceutical, Merck, Merus, Spectrum Pharmaceuticals, Shanghai HaiHe Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Takeda, Eisai, Eli Lilly Japan, Pfizer, Bristol Myers Squibb, Ignyta, Janssen, Loxo, Sysmex, Amgen, Thermo Fisher Scientific, Daiichi Sankyo, NEC Corporation, and Turning Point Therapeutics, outside of the current work. Dr. Lee reports serving in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, and Roche; receiving travel, accommodations, or expenses from Novartis; receiving honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck; and receiving research funding from Merck, outside of the current work. Dr. Marmarelis reports serving in a consulting or advisory role for AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ikena, Janssen, Novocure, Takeda, and Regeneron; holding stock in Janssen; and receiving research funding (institution) from AstraZeneca, Eli Lilly, Janssen, Takeda, and Genentech, outside of the current work. Dr. Ohe reports serving in a consulting or advisory role for AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly Japan, Ono Pharmaceutical, Novartis, Kyorin, Takeda, Celltrion, and Amgen; receiving honoraria from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, Boehringer Ingelheim, Bayer, Pfizer, Merck Sharp & Dohme, Taiho Pharmaceutical, Kyorin, Kyowa Kirin, Takeda, Celltrion, Amgen, Novartis, and Nippon Kayaku; and receiving research funding (institution) from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, Kyorin, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Ignyta, Janssen, Loxo, and Kissei Pharmaceutical, outside of the current work. Dr. Kim reports receiving research funding (institution) from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GlaxoSmithKline, Hanmi, inno.N, Janssen, Merck, Merus, Mirati Therapeutics, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan; and receiving medical writing assistance from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chong Keun Dang, Daiichi Sankyo, GlaxoSmithKline, Pfizer, Merck Sharp & Dohme, Merck, Novartis, Roche, Takeda, and Yuhan, outside of the current work. Dr. Cousin reports receiving honoraria from AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Roche, and AbbVie, outside of the current work. Dr. Ichihara reports receiving research funding from Janssen, Bristol Myers Squibb, Takeda, Pfizer, and Ono Pharmaceutical; receiving honoraria from AstraZeneca, Janssen, Eli Lilly Japan K.K., Bristol Myers Squibb, Takeda, Novartis, Chugai Pharmaceutical Co., Pfizer, Ono Pharmaceutical Co., and Boehringer Ingelheim; and receiving equipment, materials, drugs, medical writing, gifts, or other services from Astellas Pharma, Janssen, and Eli Lilly Japan K.K., outside of the current work. Dr. Paz-Ares reports receiving grants or contracts from Merck Sharp & Dohme, AstraZeneca, Pfizer, and Bristol Myers Squibb; receiving consulting fees from Eli Lilly, Merck Sharp & Dohme, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati Therapeutics, GlaxoSmithKline, Janssen, and Takeda; receiving honoraria from AstraZeneca, Janssen, Merck, and Mirati Therapeutics; participating on a data safety monitoring board or advisory board for Altum Sequencing and Genomica; and serving in a leadership or fiduciary role for Alkermes, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, IO Biotech, Janssen-Cilag, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro, outside of the current work. Dr. Ono reports receiving research funding (institution) from AstraZeneca K.K., Chugai Pharmaceutical Co., and Janssen Pharmaceutical K.K.; and receiving honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ono Pharmaceutical, and Indica Labs, outside of the current work. Dr. Sanborn reports serving in a consulting or advisory role for Amgen, AstraZeneca, BeiGene, GE HealthCare, Gilead, G1 Therapeutics, GlaxoSmithKline, EMD Serono, Daiichi Sankyo, Eli Lilly Oncology, Janssen Oncology, Macrogenics, Sanofi/Aventis, and Regeneron; receiving honoraria from Targeted Oncology, Illumina, and OncLive; and receiving research funding from AstraZeneca (self), Bristol Myers Squibb (institution), and Merck (self), outside of the current work. Dr. Watanabe reports receiving grants or contracts from Janssen Oncology, Ono Pharmaceutical, Pfizer, and Dizal Pharma, outside of the current work. Dr. Jose de Miguel reports receiving research funding from Merck Sharp & Dohme, PharmaMar, Roche, Novartis, AbbVie, Array BioPharma, Eisai, Faron, and Sanofi; and serving on a speakers bureau for Merck Sharp & Dohme, Janssen, and Roche, outside of the current work. Dr. Helissey reports receiving honoraria from Janssen, Astellas Pharma, Sanofi, AstraZeneca, Bayer, Ipsen, and Roche; and receiving travel, accommodations, or expenses from Janssen, outside of the current work. Dr. Shu reports serving as a consulting or advisory role for AstraZeneca, Genentech/Roche, Janssen, Mirati Therapeutics, Arcus Biosciences, Gilead, and Takeda; and receiving research funding (institution) from AstraZeneca, Genentech/Roche, and Janssen, outside of the current work. Dr. Spira reports serving in a leadership role at NEXT Oncology Virginia; holding stock in Eli Lilly; receiving honoraria from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Bayer; serving in a consulting or advisory role for Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Array BioPharma, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, and Blueprint Medicines; and receiving research funding from LAM Therapeutics, Regeneron, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Bio, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, and Revolution Medicines, outside of the current work. Dr. Tomasini reports receiving honoraria from Takeda, Bristol Myers Squibb, Roche, Janssen, Amgen, and AstraZeneca; and receiving travel, accommodations, or expenses from Takeda, Bristol Myers Squibb, and AstraZeneca, outside of the current work. Dr. Yang reports serving in a consulting or advisory role for Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, and Incyte; receiving travel, accommodations, or expenses from Pfizer; receiving honoraria from Boehringer Ingelheim, Roche, Merck Sharp & Dohme, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Eli Lilly, and Pfizer; and receiving research funding (institution) from Boehringer Ingelheim, Merck Serono, Janssen, GlaxoSmithKline, Amgen, Takeda, Daiichi Sankyo, AstraZeneca, Novartis, and Merck Sharp & Dohme, outside of the current work. Dr. Felip reports serving in a consulting or advisory role for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda, and Peptomyc; receiving speakers bureau fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Roche, Takeda, and CME Outfitters; having other relationships with Grifols; and receiving research funding (institution) from Merck and Merck KGaA, outside of the current work. Dr. Griesinger reports serving in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, Takeda, and Regeneron; receiving honoraria from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, Takeda, Regeneron, and Sanofi; receiving speakers bureau fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Takeda; providing expert testimony for AbbVie, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Merck, Merck Sharp & Dohme, Novartis, Roche, Sanofi, and Takeda; and receiving grants or funding from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, Takeda, and Regeneron, outside of the current work. Dr. Waqar reports serving in a consulting or advisory role for AstraZeneca, Daiichi Sankyo, Gilead, Pfizer, Boehringer Ingelheim, and Janssen; receiving grants or funding from SWOG–Clinical Trials Partnership and American Society of Hematology (institution); receiving honoraria from American Society for Clinical Oncology for Editorial Board Role for ASCO-SEP; and receiving research funding (institution) from Nuvalent, AbbVie, Genentech, Immunomedics, Roche, Astellas Pharma, Daiichi Sankyo, Cullinan Pearl, Verastem, GlaxoSmithKline, Janssen, Elevation Oncology, Loxo Oncology, Takeda, Ribon Therapeutics, AstraZeneca, and Advenchen, outside of the current work. Dr. Calles reports serving in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Takeda, Eli Lilly, Roche, Sanofi, and Bayer, outside of the current work. Dr. Neal reports serving in a consulting or advisory role for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda, Eli Lilly, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Medicines, Regeneron, Natera, Sanofi, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, and Gilead; receiving honoraria from CME Matters and Clinical Care Options CME; and receiving research funding from Genentech/Roche, Exelixis, Takeda, Merck, Novartis, Boehringer Ingelheim, and Nektar Therapeutics, outside of the current work. Dr. Baik reports serving in a consulting or advisory role for Daiichi Sankyo, AstraZeneca, Pfizer, Janssen, Boehringer Ingelheim, Genentech, and Bristol Myers Squibb; and receiving research funding from Daiichi Sankyo, AbbVie, AstraZeneca, Pfizer, Eli Lilly, Turning Point Therapeutics, Janssen, Blueprint Medicines, Nuvalent, Black Diamond Therapeutics, Bristol Myers Squibb, Boehringer Ingelheim, and Ellipses, outside of the current work. Dr. Jänne reports serving in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi Oncology, Transcenta, Mirati Therapeutics, Nuvalent, Bayer, Allorion Therapeutics, Accutar Biotech, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines, and Dizal Pharma; receiving travel, accommodations, or expenses from AstraZeneca and Voronoi; receiving research funding from AstraZeneca, Eli Lilly, Revolution Medicines, Takeda, and Transcenta; and holding patents, royalties, or other intellectual property at Labcorp, outside of the current work. Dr. Shreeve, Dr. Curtin, Dr. Patel, Dr. Gormley, Dr. Lyu, Dr. Chen, Dr. Chu, Janine Mahoney, Dr. Trani, Dr. Bauml, Dr. Thayu, and Dr. Knoblauch report being employed by Janssen Research & Development (or were employed at the time of the study) and may be holding stock in Johnson & Johnson, outside of the current work. Dr. Cho reports serving in a consulting or advisory role for AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cyrus Therapeutics, Guardant Health, Janssen, J Ints Bio, Kanaph Therapeutics, Eli Lilly, Medpacto, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, Takeda, and Yuhan; serving in a leadership role for Interpark Bio and J Ints Bio; holding patents, royalties, or other intellectual property at Champions Oncology; having other relationships with DAAN Biotherapeutics; holding stock in Theravance, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, and Interpark Bio; and receiving research funding from Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, and Yuhan, outside of the current work. The remaining authors declare no conflict of interest., (Copyright © 2025 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: Self-criticism (SC) is a central transdiagnostic factor in several psychopathological conditions, influencing the development and maintenance of symptomatology. The importance of this construct has stimulated quantitative and qualitative research about it. The main purpose of this systematic review is to highlight which qualitative methods have been used most frequently and which are most suitable for studying SC., Method: We conducted a systematic search by searching the following databases to identify publications: PsycINFO, PsycARTICLES, MEDLINE, Scopus, Web of Science, PubMed, and ERIC (all years up to and including January 2024). We aggregated search terms into two concepts for all databases: "self-criticism" and "qualitative analysis"., Results: After removing duplicates, we screened a total of 852 records, resulting in the identification of 28 full-text articles that we assessed for eligibility. Upon closer examination, there was consensus that 16 of those studies met the inclusion criteria. Data extracted from the included studies revealed the lack of a shared approach regarding qualitative analysis of SC. Some studies employed a top-down coding approach, others used a bottom-up coding approach, and a few combined both methods. Consensual qualitative research and thematic analysis have been used most widely in the field. Furthermore, the data revealed no consensus among researchers on the conceptualization of SC. SC categories identified through qualitative analysis frequently do not align with existing theoretical models, and these categories are rarely re-examined in subsequent studies., Conclusions: There is a need to test existing theoretical models of SC through qualitative analysis and to develop new models that should be examined with qualitative and quantitative methods in different clinical populations to fully capture the complexity and multidimensionality of SC., Competing Interests: Competing interests: None., (© 2024 Giovanni Fioriti Editore s.r.l.)

Objective: Syncope is defined as a spontaneous and transient loss of consciousness and postural tone due to brief and reversible cerebral hypoperfusion. This review aimed to summarize the research findings regarding the psychological correlates associated with pediatric syncope. Moreover, the study aimed to deepen the understanding of the relationship between psychological disorders and the onset of syncopal episodes in childhood, focusing on clinical features and different clinical classifications., Method: A systematic review was carried out from inception to January 2023, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using the CINAHL Plus, APA PsycArticles, APA PsycInfo, MEDLINE, and Psychology and Behavioral Sciences Collection databases. The study search and selection were based on the Population Intervention Comparison Outcome Study Design (PICOS) strategy and the Quality Assessment was carried out using Critical Appraisal Skills Programme (CASP) scales. A combination of keywords related to a) syncope; b) psycho*; and c) child* (Subjects) was used. Studies concerning epilepsy-related syncope were excluded., Results: Overall, 912 records were identified. After excluding non-English, non-original, and duplicate studies, 579 records were selected for the title screening, 88 for the abstract screening, 37 full-text articles were assessed for eligibility and a total of 14 were included. The Risk of Bias in the included studies was assessed and 78,6% of the studies satisfied robustness quality criteria. The findings highlighted that children and adolescents with syncope showed a higher rate of psychopathology as compared to the healthy and clinical controls. Furthermore, patients reported social withdrawal and poor quality of life., Conclusions: The findings suggest that there is a robust relationship between psychopathology and syncope. Children and adolescents with syncope frequently report clinical symptoms related to emotional, relational, and psychosomatic dysregulation. Psychological assessment should be routinely included in the integrated care to identify potential targets for treatment and improve early differential diagnosis., Competing Interests: Competing interests: None., (© 2024 Giovanni Fioriti Editore s.r.l.)

Background: Prenatal attachment refers to the affective investment that parents develop towards their unborn baby during pregnancy. Studies have identified depressive symptoms, affect dysregulation, and poor marital adjustment as potential risk factors for poor prenatal attachment. However, no research has concurrently examined these factors. This study aims to explore the simultaneous impact of depressive symptomatology, alexithymia, and couple functioning on prenatal attachment to develop a more comprehensive understanding of the factors shaping the emotional bond between expectant mothers and their fetuses., Methods: This cross-sectional study involved 344 women (mean age = 34.1, SD = 4.6) in their last trimester of pregnancy recruited from the National Health System. The participants completed the Edinburgh Postnatal Depression Scale, the Twenty-Item Toronto Alexithymia Scale, the Dyadic Adjustment Scale, and the Maternal Antenatal Attachment Scale., Results: Regression analyses indicated that perinatal depression and alexithymia negatively affected the Quality of Prenatal Attachment, while Dyadic Cohesion served as a protective factor., Conclusions: The results emphasize the need for early identification of perinatal depression and alexithymia, along with targeted interventions aimed at supporting Dyadic Cohesion during pregnancy. These efforts are crucial for fostering positive prenatal attachment and enhancing maternal mental health.

Background: The COVID-19 pandemic has exacerbated fears and anxieties, potentially influencing maternal perinatal mental health. This study addresses a gap in the literature on fear of COVID-19 in pregnant women, aiming to identify contributing factors., Method: Participants were 401 primiparous women with an average age of 34 years (SD = 4.56) who were recruited through the National Health System during birth support courses. They completed a series of self-reported instruments via an online survey, providing information on their levels of reflective functioning, dyadic consensus, perinatal maternal affectivity, and fear of COVID-19. Pearson's correlation and mediation analysis via a generalized linear model were implemented to analyze the collected data., Results: The relationship between dyadic consensus and fear of COVID-19 was significant and negative. Furthermore, a significant parallel mediation involving perinatal maternal affectivity and reflective functioning was found to the extent that, when these factors were inserted into the model, the direct association between dyadic consensus and fear of COVID-19 became non-significant (total mediation)., Conclusions: The results highlight the importance of dyadic adjustment in alleviating maternal COVID-19 fear, emphasizing interventions promoting couple functioning, mentalization, and addressing affective difficulties. Such approaches are vital for supporting expecting mothers during challenging times like the COVID-19 pandemic.

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL., Significance: Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7-Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Detection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. To accelerate DNV calling, we developed a graphics processing units-based workflow. We applied our workflow to whole-genome sequencing data from three parent-child sequenced cohorts including the Simons Simplex Collection (SSC), Simons Foundation Powering Autism Research (SPARK), and the 1000 Genomes Project (1000G) that were sequenced using DNA from blood, saliva, and lymphoblastoid cell lines (LCLs), respectively. The SSC and SPARK DNV callsets were within expectations for number of DNVs, percent at CpG sites, phasing to the paternal chromosome of origin, and average allele balance. However, the 1000G DNV callset was not within expectations and contained excessive DNVs that are likely cell line artifacts. Mutation signature analysis revealed 30% of 1000G DNV signatures matched B-cell lymphoma. Furthermore, we found variants in DNA repair genes and at Clinvar pathogenic or likely-pathogenic sites and significant excess of protein-coding DNVs in IGLL5; a gene known to be involved in B-cell lymphomas. Our study provides a new rapid DNV caller for the field and elucidates important implications of using sequencing data from LCLs for reference building and disease-related projects., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Objective: To investigate the association between prodromal symptoms of schizophrenia, autonomic activity, and personality functioning., Method: 10 adolescents underwent semi-structured interviews assessing prodromal symptoms of schizophrenia and personality functioning. Cardiac activity was recorded at baseline, during the clinical interviews, and at recovery to assess concurrent changes in autonomic functioning., Results: During the assessment of prodromal symptoms of schizophrenia, participants increased sympathetic activation compared to the recovery condition, and reduced vagal activation compared to the assessment of interpersonal functioning., Conclusions: The findings highlight the importance of integrating the autonomic assessment in clinical psychiatric and psychological practice., Competing Interests: Competing interests: None., (© 2021 Giovanni Fioriti Editore s.r.l.)

Purpose: Following automated variant calling, manual review of aligned read sequences is required to identify a high-quality list of somatic variants. Despite widespread use in analyzing sequence data, methods to standardize manual review have not been described, resulting in high inter- and intralab variability., Methods: This manual review standard operating procedure (SOP) consists of methods to annotate variants with four different calls and 19 tags. The calls indicate a reviewer's confidence in each variant and the tags indicate commonly observed sequencing patterns and artifacts that inform the manual review call. Four individuals were asked to classify variants prior to, and after, reading the SOP and accuracy was assessed by comparing reviewer calls with orthogonal validation sequencing., Results: After reading the SOP, average accuracy in somatic variant identification increased by 16.7% (p value = 0.0298) and average interreviewer agreement increased by 12.7% (p value < 0.001). Manual review conducted after reading the SOP did not significantly increase reviewer time., Conclusion: This SOP supports and enhances manual somatic variant detection by improving reviewer accuracy while reducing the interreviewer variability for variant calling and annotation.

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM&#95;033360.3:c.183A>C, NP&#95;203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference., Patients and Methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR., Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response., Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab., Clinicaltrials.gov Identifiers: NCT00513292, NCT00353483., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment., (© 2017 by The American Society of Hematology.)

Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1(-/-) mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer., Experimental Design: Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts., Results: Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response., Conclusions: Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features., (©2015 American Association for Cancer Research.)

Tumors are typically sequenced to depths of 75-100× (exome) or 30-50× (whole genome). We demonstrate that current sequencing paradigms are inadequate for tumors that are impure, aneuploid or clonally heterogeneous. To reassess optimal sequencing strategies, we performed ultra-deep (up to ~312×) whole genome sequencing (WGS) and exome capture (up to ~433×) of a primary acute myeloid leukemia, its subsequent relapse, and a matched normal skin sample. We tested multiple alignment and variant calling algorithms and validated ~200,000 putative SNVs by sequencing them to depths of ~1,000×. Additional targeted sequencing provided over 10,000× coverage and ddPCR assays provided up to ~250,000× sampling of selected sites. We evaluated the effects of different library generation approaches, depth of sequencing, and analysis strategies on the ability to effectively characterize a complex tumor. This dataset, representing the most comprehensively sequenced tumor described to date, will serve as an invaluable community resource (dbGaP accession id phs000159).

Background: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted., Patients and Methods: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome., Results: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival., Conclusions: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.