Search

Presents a case study of the skin disease mycosis fungoides in a 39-year-old woman. Medical history of the patient; Symptoms and manifestation of the disease; Treatment of the disease.

Closed-loop arbutamine stress echocardiography has been shown to be safe and effective for detecting coronary artery disease (CAD) using a standardized infusion protocol and centralized core laboratory analyses. However, the accuracy of arbutamine stress echocardiography using local test interpretation has not been previously tested in a large population. The present study reports the safety, sensitivity, and specificity of arbutamine stress echocardiography in a multicenter trial allowing user-defined, nonstandardized protocols and local test interpretation. In all, 1,070 patients underwent arbutamine stress testing at 81 sites. Heart rate increased from 73 +/- 13 to 124 +/- 15 beats/min, systolic blood pressure from 144 +/- 24 to 174 +/- 25 mm Hg, and pressure rate product x 10(3) from 10.5 +/- 2.8 to 19.6 +/- 3.9. Among 1,070 patients, there were only 2 (0.2%) significant adverse events related to arbutamine, both of which resolved completely with appropriate therapy. There were no incidents of ventricular fibrillation, sustained ventricular tachycardia, or death related to testing. Among 242 patients who underwent arbutamine stress echocardiography and diagnostic coronary angiography within 12 weeks, sensitivity and specificity for detection of CAD were 71% (95% confidence interval 64% to 77%) and 67% (95% confidence interval 52% to 80%), respectively. Closed-loop arbutamine stress echocardiography is a safe and effective method for evaluating CAD in clinical practice. [ABSTRACT FROM AUTHOR]

Arbutamine stress echocardiography was performed in 81 patients with suspected coronary artery disease. Arbutamine infusion, using a dedicated closed-loop delivery device, provided comparable myocardial stress in patients receiving beta-1 blockers versus those who were not. [ABSTRACT FROM AUTHOR]

Introduction: The high output cardiac state (HOCS) [cardiac index (CI) >4 L/min/m2 ], primarily driven by abnormally low systemic vascular resistance (SVR), is a relatively under-recognized condition. Although, majority of these patients meet criteria for heart failure (HF), their treatment should be aimed at the primary pathology, as the majority of guideline directed HF therapies can reduce SVR further., Objectives: To characterize patients with HOCS and provide valuable insight into the condition., Methods: Patients investigated by right heart catheterization (RHC) at the St. Boniface Hospital, Winnipeg, Canada between January 2009 and November 2021 were reviewed. Two groups of patients were included: 1) HOCS [CI >4 L/min/m 2 ], and 2) pre-HOCS [CI between 3.8-4.0 L/min/m 2 ]. Their medical records were reviewed to identify plausible etiologies, relevant investigations, and outcomes., Results: 177/2950 (6 %) patients met criteria for inclusion: 144/177 (81 %) with HOCS [mean age 51 years (range 19 - 82); 67/144 (47 %) female] and 33/177 (19 %) with pre-HOCS [mean age 55 years (range 30 - 83); 6/33 (18 %) female]. The most common plausible etiologies for the HOCS included anemia (36 %), obesity (34 %), cirrhosis (17 %), and lung disease (32 %). Trans-thoracic echocardiography and magnetic resonance imaging findings were non-specific and predominantly described preserved left ventricular ejection fraction, and pulmonary hypertension. The population experienced high rates of hospitalization, and significantly high mortality [36/144 (25 %) of HOCS at a median follow-up of 31.5 months, and 13/33 (39 %) of pre-HOCS at a median follow-up of 17 months]., Conclusions: HOCS is not an uncommon condition and is associated with high mortality. Current HF guideline should incorporate such evaluation into the diagnostic criteria., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Iron deficiency anaemia (IDA) is common in patients with heart failure (HF) and is associated with advanced HF and increased mortality. Intravenous iron supplementation increases exercise tolerance, improves quality of life, and decreases symptoms among patients with HF with reduced ejection fraction (HFrEF) and iron deficiency. Despite this, many patients are not screened or treated for IDA. We aimed to increase rates of screening and treatment of IDA among HF patients through the introduction of curated materials to aid HF clinicians with appropriate screening and treatment., Methods: We conducted a retrospective chart review to identify the baseline number of HFrEF patients screened and treated for IDA at two ambulatory cardiology clinics in Toronto, Ontario. A quality improvement initiative was then introduced, which consisted of education and curated materials to aid clinicians in the screening and treatment of IDA among HFrEF patients. The proportion of patients screened and treated for IDA preintervention and postintervention were compared using χ 2 tests of Independence., Results: In the preintervention cohort, 36.3% (n=45) of patients with anaemia were screened for IDA. Among those screened, 64.4% (n=29) had IDA. Only 17.2% (n=5) of these were treated with IV iron. After implementation of the quality improvement initiative, 90.9% (n=60) of patients with anaemia were screened for IDA (p<0.001) and 90.3% (n=28) of those with IDA were treated with IV iron (p<0.001)., Conclusion: The introduction of curated materials to aid clinicians was associated with increased rates of screening and treatment of IDA among ambulatory HFrEF patients. Further work is required to identify barriers and implement strategies to increase screening and treatment rates of IDA among HFrEF patients., Competing Interests: Competing interests: YL and JC have received research funding from Octapharma and the Canadian Blood Services. SP has received research funding from Boehringer-Ingelheim and has participated in a clinical trial with Abbott within the past two years. SP is a member of a speakers’ bureau for Agence L.I.V., University of Toronto, and University Health Network. YL has acted as a consultant for Choosing Wisely Canada. SP is a member of a national heart failure advisory board that works with AstraZeneca, Boehringer-Ingelheim, Novartis, and Servier., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib., Patients and Methods: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR)., Results: Fifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes., Conclusions: Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population., (© 2023. The Author(s).)

Random noise arising from physical processes is an inherent characteristic of measurements and a limiting factor for most signal processing and data analysis tasks. Given the recent interest in generative adversarial networks (GANs) for data-driven modeling, it is important to determine to what extent GANs can faithfully reproduce noise in target data sets. In this paper, we present an empirical investigation that aims to shed light on this issue for time series. Namely, we assess two general-purpose GANs for time series that are based on the popular deep convolutional GAN architecture, a direct time-series model and an image-based model that uses a short-time Fourier transform data representation. The GAN models are trained and quantitatively evaluated using distributions of simulated noise time series with known ground-truth parameters. Target time series distributions include a broad range of noise types commonly encountered in physical measurements, electronics, and communication systems: band-limited thermal noise, power law noise, shot noise, and impulsive noise. We find that GANs are capable of learning many noise types, although they predictably struggle when the GAN architecture is not well suited to some aspects of the noise, e.g. impulsive time-series with extreme outliers. Our findings provide insights into the capabilities and potential limitations of current approaches to time-series GANs and highlight areas for further research. In addition, our battery of tests provides a useful benchmark to aid the development of deep generative models for time series.

Purpose: O 6 -methylguanine DNA methyltransferase ( MGMT )-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer., Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m 2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers., Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8 + tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2 ). Flow cytometry identified peripheral expansion of effector T cells., Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8 + TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations., Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations., (© 2023 The Authors; Published by the American Association for Cancer Research.)

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies., (© 2023. Springer Nature America, Inc.)

Single-nucleotide polymorphisms in the human juxtaposed with another zinc finger protein 1 ( JAZF1 ) gene have repeatedly been associated with both type 2 diabetes (T2D) and height in multiple genome-wide association studies (GWAS); however, the mechanism by which JAZF1 causes these traits is not yet known. To investigate the possible functional role of JAZF1 in growth and glucose metabolism in vivo, we generated Jazf1 knockout (KO) mice and examined body composition and insulin sensitivity both in young and adult mice by using 1 H-nuclear magnetic resonance and hyperinsulinemic-euglycemic clamp techniques. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were reduced in both young and adult Jazf1 KO mice, and young Jazf1 KO mice were shorter in stature than age-matched wild-type mice. Young Jazf1 KO mice manifested reduced fat mass, whereas adult Jazf1 KO mice manifested increased fat mass and reductions in lean body mass associated with increased plasma growth hormone (GH) concentrations. Adult Jazf1 KO manifested muscle insulin resistance that was further exacerbated by high-fat diet feeding. Gene set enrichment analysis in Jazf1 KO liver identified the hepatocyte hepatic nuclear factor 4 alpha (HNF4α), which was decreased in Jazf1 KO liver and in JAZF1 knockdown cells. Moreover, GH-induced IGF-1 expression was inhibited by JAZF1 knockdown in human hepatocytes. Taken together these results demonstrate that reduction of JAZF1 leads to early growth retardation and late onset insulin resistance in vivo which may be mediated through alterations in the GH-IGF-1 axis and HNF4α.

Background: Pregnancies complicated by type 1 diabetes (T1D) experience high levels of glycemic variability, which may be associated with adverse maternal and neonatal outcomes. Therefore, strategies that help pregnant women with T1D manage their glycemic control are of great interest., Methods: We examined associations with or without remote monitoring of Continuous Glucose Monitor (CGM) data by friends and family with indices of glycemic control and glycemic variability during pregnancies complicated by T1D in a pilot non-randomized trial ( n  = 28). During preconception or the first trimester, participants were placed in one of two groups based on device compatibility: (1) CGM Alone ( n  = 13): women without iPhone, iPad or iPod Touch; or (2) CGM Share ( n  = 15): women with iPhone, iPad, or iPod Touch and followers with devices compatible for data viewing. Linear mixed models were used to compare indices of glycemic control and glycemic variability over time between groups., Results: Participants using CGM Share had lower estimated HbA1c levels over time ( p  = .028), glucose management index ( p  = .041), and fewer glucose excursions >200 mg/dL in each trimester ( p  = .022) compared to those using CGM Alone. Participants using CGM Alone had higher high blood glucose index ( p  = .020), mean area under the curve ( p  = .026), and standard deviation ( p  = .046) compared to those using CGM Share. Other measures of glycemic variability did not differ between groups., Conclusion: In this non-randomized pilot study, use of CGM Share was associated with improvements in several indices of glycemic control and glycemic variability.

Purpose: An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors., Clinical Context: An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection., Provisional Clinical Opinion: Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel-based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK ) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker-linked options relative to other approved or investigational treatments.Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines., Competing Interests: Debyani ChakravartyConsulting or Advisory Role: Medendi Medical Travel Jeffrey SklarStock and Other Ownership Interests: PrecipioResearch Funding: Jilin Zixin (Inst) Kathleen MooreHonoraria: Research To Practice, Prime Oncology, Physicans' Education Resource, Great Debates and UpdatesConsulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, TESARO (Inst), VBL Therapeutics, Merck, Aravive, Eisai, Vavotar Life Sciences, Mersana (Inst), Myriad Genetics, Alkemeres (Inst), Blueprint Pharmacetuicals (Inst), GlaxoSmithKline/Tesaro (Inst), I-Mab (Inst), InxMed (Inst), Mereo BioPharma (Inst)Research Funding: PTC Therapeutics (Inst), Lilly (Inst), Merck (Inst), Tesaro (Inst), Genentech (Inst), Clovis Oncology (Inst), Lilly Foundation (Inst), Regeneron (Inst), Advaxis (Inst), Bristol Myers Squibb (Inst), Verastem (Inst), Novartis Pharmaceuticals UK Ltd (Inst), AstraZeneca (Inst), Agenus (Inst), Takeda (Inst), Forty Seven (Inst), Stem CentRx (Inst), Immunogen (Inst), Bayer (Inst), Novogen (Inst), AbbVie/Stemcentrx (Inst)Other Relationship: GOG Partners (Inst) Shridar GanesanEmployment: Merck (I)Stock and Other Ownership Interests: Ibris, Inspirata, Merck (I), SilageneConsulting or Advisory Role: Inspirata, Novartis, Roche, Foghorn Therapeutics, Foundation Medicine, Merck Sharp & Dohme, Silagene, EQRx, EMD Serono, KayoTheraResearch Funding: M2Gen (Inst)Patents, Royalties, Other Intellectual Property: I hold 2 patents for digital imaging that may be licensed to Ibris Inc and Inspirata IncOther Relationship: NIH/NCI Christine M. LovlyHonoraria: Takeda, Pfizer, Cepheid, Foundation Medicine, AstraZeneca, Blueprint Medicines, Lilly, Genentech, Syros Pharmaceuticals, Amgen, Roche, EMD Serono, Daiichi Sankyo/AstraZeneca, Puma BiotechnologyConsulting or Advisory Role: Novartis, Foundation Medicine, Pfizer, Takeda, Cepheid, AstraZeneca, Blueprint Medicines, Syros Pharmaceuticals, Genentech, Lilly, Amgen, EMD Serono, Daiichi Sankyo/AstraZeneca, Puma BiotechnologyResearch Funding: Novartis, Xcovery, AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Takeda, Foundation Medicine, Novartis, Cepheid, Genentech Stacy W. GrayStock and Other Ownership Interests: Magenta Therapeutics (I)Honoraria: Triptych Health PartnersConsulting or Advisory Role: Magenta Therapeutics (I) Jimmy HwangConsulting or Advisory Role: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Caris Centers of Excellence, Pfizer, QED Therapeutics, Deciphera, IncyteSpeakers' Bureau: Bristol Myers Squibb, Deciphera, IncyteResearch Funding: Caris Centers of Excellence (Inst), Boehringer Ingelheim (Inst) Christopher LieuConsulting or Advisory Role: Ipsen (Inst), HalioDx (Inst), Pfizer (Inst)Research Funding: Merck (Inst) Fabrice AndréStock and Other Ownership Interests: PegacsyResearch Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Roche (Inst), Daiichi (Inst)Travel, Accommodations, Expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca Nilofer AzadConsulting or Advisory Role: AMAG Pharmaceuticals, Taiho Pharmaceutical, QED Therapeutics, Merck, Incyte, Helsinn Therapeutics/QED TherapeuticsResearch Funding: Celgene (Inst), Genentech (Inst), Astex Pharmaceuticals (Inst), Agios (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Syndax (Inst), Array BioPharma (Inst), Intensity Therapeutics (Inst), Bayer (Inst), EMD Serono, Debiopharm Group (Inst), Incyte (Inst), Loxo/Lilly (Inst), AtlasMedx (Inst) Mitesh BoradStock and Other Ownership Interests: Gilead Sciences, AVEO, Intercept Pharmaceuticals, Spectrum PharmaceuticalsConsulting or Advisory Role: G1 Therapeutics, Fujifilm (Inst), Agios (Inst), Insys Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celgene (Inst), Inspyr Therapeutics, Halozyme (Inst), Pieris Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, ImvaxResearch Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), MedImmune (Inst), BiolineRx (Inst), Agios (Inst), Halozyme (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray Industries (Inst), Dicerna (Inst), Sillajen (Inst), Eisai (Inst), Taiho Pharmaceutical (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun Biopharma (Inst), ARIAD (Inst), ImClone Systems (Inst), QED Therapeutics (Inst), Incyte (Inst), Puma Biotechnology (Inst), Adaptimmune (Inst), Merck Serono (Inst), RedHill Biopharma (Inst), Basilea (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Laura TafeStock and Other Ownership Interests: Exact Sciences, GlaxoSmithKlineResearch Funding: Biocartis (Inst)Other Relationship: College of American Pathologists, Association for Molecular Pathology Mark RobsonConsulting or Advisory Role: Change HealthCareResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Merck (Inst)Other Relationship: Research to Practice, Clinical Care Options, Physicans' Education Resource, Pfizer, MyMedEd, Clinical Education AllianceUncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic Sciences, Artios, Tempus, Zenith PharmaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summary Funda Meric-BernstamEmployment: MD Anderson Cancer CenterHonoraria: Rutgers Cancer Institute of New JerseyConsulting or Advisory Role: Samsung Bioepis, Xencor, Debiopharm Group, Silverback Therapeutics, IBM Watson Health, Roche, PACT Pharma, eFFECTOR Therapeutics, Kolon Life Sciences, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes, Infinity Pharmaceuticals, AbbVie, Black Diamond Therapeutics, Eisai, OnCusp Therapeutics, Lengo Therapeutics, Tallac Therapeutics, Karyopharm Therapeutics, BiovicaSpeakers' Bureau: Chugai PharmaResearch Funding: Novartis (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Genentech (Inst), Calithera Biosciences (Inst), Debiopharm Group (Inst), Bayer (Inst), Aileron Therapeutics (Inst), PUMA Biotechnology (Inst), CytomX Therapeutics (Inst), Jounce Therapeutics (Inst), Zymeworks (Inst), Curis (Inst), Pfizer (Inst), eFFECTOR Therapeutics (Inst), AbbVie (Inst), Boehringer Ingelheim (I), Guardant Health (Inst), Daiichi Sankyo (Inst), GlaxoSmithKline (Inst), Seattle Genetics (Inst), Taiho Pharmaceutical (Inst), Klus Pharma (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Beth Israel Deaconess Medical CenterNo other potential conflicts of interest were reported.

Many baseball pitching studies have used inverse dynamics to assess throwing arm kinetics as high and repetitive kinetics are thought to be linked to pitching injuries. However, prior studies have not used participant-specific body segment inertial parameters (BSIPs), which are thought to improve analysis of high-acceleration motions and overweight participants. This study's objectives were to (1) calculate participant-specific BSIPs using dual energy X-ray absorptiometry (DXA) measures, (2) compare inverse dynamic calculations of kinetics determined by DXA-calculated BSIPs (full DXA-driven inverse dynamics) against kinetics using the standard inverse dynamics approach with scaled BSIPs (scaled inverse dynamics), and (3) examine associations between full DXA-driven kinetics and overweight indices: body mass index (BMI) and segment mass index (SMI). Eighteen participants (10-11 years old) threw 10 fastballs that were recorded for motion analysis. DXA scans were used to calculate participant-specific BSIPs (mass, center of mass, radii of gyration) for each pitching arm segment (upper arm, forearm, hand), BMI, and SMI. The hypotheses were addressed with t-tests and linear regression analyses. The major results were that (1) DXA-calculated BSIPs differed from scaled BSIPs for each pitching arm segment; (2) calculations for shoulder, but not elbow, kinetics differed between the full DXA-driven and scaled inverse dynamics analyses; and (3) full DXA-driven inverse dynamics calculations for shoulder kinetics were more often associated with SMI than BMI. Results suggest that using participant-specific BSIPs and pitching arm, SMIs may improve evidence-based injury prevention guidelines for youth pitchers., (Copyright © 2022 by ASME.)

High-quality recordings of radio frequency (RF) emissions from commercial communication hardware in realistic environments are often needed to develop and assess spectrum-sharing technologies and practices, e.g., for training and testing spectrum sensing algorithms and for interference testing. Unfortunately, the time-consuming, expensive nature of such data collections together with data-sharing restrictions pose significant challenges that limit data set availability. Furthermore, developing accurate models of real-world RF emissions from first principles is often very difficult because system parameters and implementation details are at best only partially known, and complex system dynamics are difficult to characterize. Hence, there is a need for flexible, data-driven methods that can leverage existing data sets to synthesize additional similar waveforms. One promising machine-learning approach is unsupervised deep generative modeling with generative adversarial networks (GANs). To date, GANs for RF communication signals have not been studied thoroughly. In this paper, we present the first in-depth investigation of generated signal fidelity for GANs trained with baseband orthogonal frequency-division multiplexing (OFDM) signals, where each subcarrier is digitally modulated with quadrature amplitude modulation (QAM). Building on prior GAN methods, we developed two novel GAN models and evaluated their performance using simulated data sets with known ground truth. Specifically, we investigated model performance with respect to increasing data set complexity over a range of OFDM parameters and conditions, including fading channels. The findings presented here inform the feasibility of use cases and provide a foundation for further investigations into deep generative models for RF communication signals.

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination-directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA -mutated PARP inhibitor-resistant high-grade serous ovarian cancer (HGSOC)., Patients and Methods: Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks)., Results: Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor-resistant HGSOC, one achieved PR (-90%) and five had SD ranging 16-72 weeks (CBR 86%)., Conclusion: Olaparib with ceralasertib demonstrated preliminary activity in ATM -mutated tumors and in PARP inhibitor-resistant BRCA1/2 -mutated HGSOC. These data warrant additional studies to further confirm activity in these settings., Competing Interests: Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported. Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols., Patients and Methods: Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared., Results: Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so., Conclusion: We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.

Low concordance between studies that examine the role of microbiota in human diseases is a pervasive challenge that limits the capacity to identify causal relationships between host-associated microorganisms and pathology. The risk of obtaining false positives is exacerbated by wide interindividual heterogeneity in microbiota composition 1 , probably due to population-wide differences in human lifestyle and physiological variables 2 that exert differential effects on the microbiota. Here we infer the greatest, generalized sources of heterogeneity in human gut microbiota profiles and also identify human lifestyle and physiological characteristics that, if not evenly matched between cases and controls, confound microbiota analyses to produce spurious microbial associations with human diseases. We identify alcohol consumption frequency and bowel movement quality as unexpectedly strong sources of gut microbiota variance that differ in distribution between healthy participants and participants with a disease and that can confound study designs. We demonstrate that for numerous prevalent, high-burden human diseases, matching cases and controls for confounding variables reduces observed differences in the microbiota and the incidence of spurious associations. On this basis, we present a list of host variables that we recommend should be captured in human microbiota studies for the purpose of matching comparison groups, which we anticipate will increase robustness and reproducibility in resolving the members of the gut microbiota that are truly associated with human disease.

Background: The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology., Methods: Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA-targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial., Results: At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround)., Conclusions: The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients., (© The Author(s) 2019. Published by Oxford University Press.)

Background: Atrial myxomas are generally considered benign neoplasms. The majority of tumors are sporadic and less than 10% are associated with an autosomal dominant condition known as the Carney complex, which is most often caused by germline mutation in the gene PRKAR1A. Whether this gene plays a role in the development of sporadic myxomas has been an area of debate, although recent studies have suggested that some fraction of sporadic tumors also carry mutations in PRKARIA. Extra-cardiac complications of atrial myxoma include dissemination of tumor to the brain; however, the dissemination of viable invasive tumor cells is exceedingly rare., Case Presentation: We present here a 48-year-old white woman who developed multiple intracranial hemorrhagic lesions secondary to tumor embolism that progressed to 'false' aneurysm formation and invasion through the vascular wall into brain parenchyma 7 months after resection of an atrial myxoma. Whole exome sequencing of her tumor revealed multiple mutations in PRKAR1A not found in her germline deoxyribonucleic acid (DNA), suggesting that the myxoma in this patient was sporadic., Conclusions: Our patient illustrates that mutations in PRKAR1A may be found in sporadic lesions. Whether the presence of this mutation affects the clinical behavior of sporadic tumors and increases risk for metastasis is not clear. Regardless, the protein kinase A pathway which is regulated by PRKAR1A represents a possible target for treatment in patients with metastatic cardiac myxomas harboring mutations in the PRKARIA gene.

The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor ( EGFR ). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation. Activating EGFR mutations in cancers other than lung are uncommon, but when present may predict response to EGFR tyrosine kinase inhibitors (TKIs). Development of the T790M mutation in this case suggests that EGFR-targeted TKIs may follow similar patterns of resistance regardless of tumor type. Although actionable mutations are detected infrequently in PDAC, this case illustrates the potential benefit of offering genomic analysis to all patients with advanced disease., (Copyright © 2017 by the National Comprehensive Cancer Network.)

In response to a university-based serogroup B meningococcal disease outbreak, the serogroup B meningococcal vaccine Trumenba was recommended for students, a rare instance in which a specific vaccine brand was recommended. This outbreak highlights the challenges of using molecular and immunologic data to inform real-time response.

On September 30, 2015, the New Jersey Department of Health (NJDOH) was notified by an out-of-state health services company that an experienced nurse had reused syringes for multiple persons earlier that day. This occurred at an employee influenza vaccination clinic on the premises of a New Jersey business that had contracted with the health services company to provide influenza vaccinations to its employees. The employees were to receive vaccine from manufacturer-prefilled, single-dose syringes. However, the nurse contracted by the health services company brought three multiple-dose vials of vaccine that were intended for another event. The nurse reported using two syringes she found among her supplies to administer vaccine to 67 employees of the New Jersey business. She reported wiping the syringes with alcohol and using a new needle for each of the 67 persons. One of the vaccine recipients witnessed and questioned the syringe reuse, and brought it to the attention of managers at the business who, in turn, reported the practice to the health services company contracted to provide the influenza vaccinations.

DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells. Conventional DNase sequencing (DNase-seq) for genome-wide DHSs profiling is limited by the requirement of millions of cells. Here we report an ultrasensitive strategy, called single-cell DNase sequencing (scDNase-seq) for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single-cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and enhancers associated with multiple active histone modifications display constitutive DHS whereas chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply scDNase-seq to pools of tumour cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded tissue slides from patients with thyroid cancer, and detect thousands of tumour-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one mutation (chr18: 52417839G>C) in the tumour cells of a patient with follicular thyroid carcinoma, which affects the binding of the tumour suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, scDNase-seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis both for basic and for translational research, and may provide critical information for personalized medicine.

Background: In 2013-2014, an outbreak of serogroup B meningococcal disease occurred among persons linked to a New Jersey university (University A). In the absence of a licensed serogroup B meningococcal (MenB) vaccine in the United States, the Food and Drug Administration authorized use of an investigational MenB vaccine to control the outbreak. An investigation of the outbreak and response was undertaken to determine the population at risk and assess vaccination coverage., Methods: The epidemiologic investigation relied on compilation and review of case and population data, laboratory typing of meningococcal isolates, and unstructured interviews with university staff. Vaccination coverage data were collected during the vaccination campaign held under an expanded-access Investigational New Drug protocol., Results: Between March 25, 2013, and March 10, 2014, 9 cases of serogroup B meningococcal disease occurred in persons linked to University A. Laboratory typing results were identical for all 8 isolates available. Through May 14, 2014, 89.1% coverage with the 2-dose vaccination series was achieved in the target population. From the initiation of MenB vaccination through February 1, 2015, no additional cases of serogroup B meningococcal disease occurred in University A students. However, the ninth case occurred in March 2014 in an unvaccinated close contact of University A students., Conclusions: No serogroup B meningococcal disease cases occurred in persons who received 1 or more doses of 4CMenB vaccine, suggesting 4CMenB may have protected vaccinated individuals from disease. However, the ninth case demonstrates that carriage of serogroup B Neisseria meningitidis among vaccinated persons was not eliminated., (Copyright © 2015 by the American Academy of Pediatrics.)

Unlabelled: Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage., Significance: A chimeric fusion RNA, PAX3-FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis., (©2013 AACR.)

This article offers a new evaluation of Michael Balint's history. It starts with his growing up in Hungary and examines the central concepts of his writing: the analytic pair, regression and the basic fault and creativity, up to and including his renowned work on the eponymous Balint groups (which forged a unique link between psychoanalysis and medicine). While his name is, of course, well known, this article aims to bring his ideas to the attention of a modern analytic audience. Having trained in the 1920s with Ferenczi, Balint brought Ferenczi's literary inheritance to England where he lived until his death in 1970. His connections to Klein, Winnicott and Lacan, all of whom respected his analytic stance, are also examined. Furthermore, this article argues that his ideas were filtered through the theoretical lens of his first wife Alice Balint and later through Enid Balint, both of whom played a key - and rarely recognised - role in the development of his thought. It ends with a brief discussion of his ideas on analytic training and his quest, successful only after his death, to publish the complete Freud-Ferenczi correspondence, together with Ferenczi's diary., (Copyright © 2012 Institute of Psychoanalysis.)

Personalized medicine in the treatment of cancer is based on the recognition that molecularly targeted therapies are most effective in patients whose tumors carry specific genetic or genomic alterations. These alterations, which often activate oncogenes that encode the components of signal transduction pathways, serve as predictive markers for sensitivity or resistance of individual tumors to drugs that target such pathways. In the recent past, individual mutations and other changes within tumors have been assayed to determine the likelihood of response or nonresponse to specific targeted therapies. However, with the development of increasing numbers of molecularly targeted drugs, attention has shifted to high-throughput testing of tumors for dozens of predictive markers. This approach to predictive testing has been termed molecular tumor profiling. This review describes the background to this field, the principal markers analyzed, and the methodologies that are being utilized or are under development for tumor profiling.

Purpose: The effects of creatine supplementation on muscle metabolism and exercise performance during a simulated endurance road race was investigated., Methods: Twelve adult male (27.3 +/- 1.0 yr, 178.6 +/- 1.4 cm, 78.0 +/- 2.5 kg, 8.9 +/- 1.1 %fat) endurance-trained (53.3 +/- 2.0 ml* kg-1* min-1, cycling ~160 km/wk) cyclists completed a simulated road race on a cycle ergometer (Lode), consisting of a two-hour cycling bout at 60% of peak aerobic capacity (VO2peak) with three 10-second sprints performed at 110% VO2 peak every 15 minutes. Cyclists completed the 2-hr cycling bout before and after dietary creatine monohydrate or placebo supplementation (3 g/day for 28 days). Muscle biopsies were taken at rest and five minutes before the end of the two-hour ride., Results: There was a 24.5 +/- 10.0% increase in resting muscle total creatine and 38.4 +/- 23.9% increase in muscle creatine phosphate in the creatine group (P < 0.05). Plasma glucose, blood lactate, and respiratory exchange ratio during the 2-hour ride, as well as VO2 peak, were not affected by creatine supplementation. Submaximal oxygen consumption near the end of the two-hour ride was decreased by approximately 10% by creatine supplementation (P < 0.05). Changes in plasma volume from pre- to post-supplementation were significantly greater in the creatine group (+14.0 +/- 6.3%) than the placebo group (-10.4 +/- 4.4%; P < 0.05) at 90 minutes of exercise. The time of the final sprint to exhaustion at the end of the 2-hour cycling bout was not affected by creatine supplementation (creatine pre, 64.4 +/- 13.5s; creatine post, 88.8 +/- 24.6s; placebo pre, 69.0 +/- 24.8s; placebo post 92.8 +/- 31.2s: creatine vs. placebo not significant). Power output for the final sprint was increased by ~33% in both groups (creatine vs. placebo not significant)., Conclusions: It can be concluded that although creatine supplementation may increase resting muscle total creatine, muscle creatine phosphate, and plasma volume, and may lead to a reduction in oxygen consumption during submaximal exercise, creatine supplementation does not improve sprint performance at the end of endurance cycling exercise.

Chimeric gene products, most often resulting from chromosome translocations, have been considered unique features of cancer, or at least of cells at high risk for becoming cancerous. Chimeric JAZF1-JJAZ1 mRNA transcribed from DNA spanning the site of recombination in the (7;17)(p15;q21) chromosomal translocation found in half of endometrial stromal sarcomas and most cases of benign stromal nodules is one such example. The recent finding that chimeric JAZF1-JJAZ1 mRNA can also be detected in normal endometrial stromal cells suggests that chimeric gene products are not limited to cancer or pre-cancerous cells. The JAZF1-JJAZ1 mRNA and the protein encoded by it appear to be identical to that synthesized from the gene fusion in neoplastic cells. In cultured cells, the chimeric protein has anti-apoptotic properties and is pro-proliferative when unrearranged JJAZ1 alleles are silenced, as they are in endometrial stromal sarcomas but not in the stromal nodules. These observations are consistent with the conclusion that chromosomal rearrangements and gene fusions in neoplastic cells may represent mechanisms for the deregulated expression of chimeric gene products that are generated at specific stages in cell development and have physiologic functions in normal cells. Furthermore, it may be possible that other means for abnormal production of chimeric gene products, such as hyperactive transsplicing of RNA, may be another mechanism underlying the neoplastic properties of tumor cells.

An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Chromosomal rearrangements that create gene fusions are common features of human tumors. The prevailing view is that the resultant chimeric transcripts and proteins are abnormal, tumor-specific products that provide tumor cells with a growth and/or survival advantage. We show that normal endometrial stromal cells contain a specific chimeric RNA joining 5' exons of the JAZF1 gene on chromosome 7p15 to 3' exons of the Polycomb group gene JJAZ1/SUZ12 on chromosome 17q11 and that this RNA is translated into JAZF1-JJAZ1, a protein with anti-apoptotic activity. The JAZF1-JJAZ1 RNA appears to arise from physiologically regulated trans-splicing between precursor messenger RNAs for JAZF1 and JJAZ1. The chimeric RNA and protein are identical to those produced from a gene fusion found in human endometrial stromal tumors. These observations suggest that certain gene fusions may be pro-neoplastic owing to constitutive expression of chimeric gene products normally generated by trans-splicing of RNAs in developing tissues.

Freud early in the history of analysis viewed hysteria in relation to trauma. This became a subject of great interest to Ferenczi particularly in his clinical activities in trying to find the balance between fantasy and trauma. The enactment in the body, as a psychosomatic symptom, is a way of unconsciously drawing attention to that which cannot be processed emotionally. A young man with a long-standing obsessional character had a sudden onset of motor disturbance. A recent set of family calamities triggered a psychosomatic defence against his having to be affectively in touch with a breakdown, which first occurred when he was 2 years old, and which he had never mourned. It was only after the development of a severe body tic following the family disruption that the possibility of finding lost affect and the capacity for an integration of the psychic and somatic became available through the analytic process.

Polycomb group genes (PcGs) have been implicated in cancer based on altered levels of expression observed in certain tumors and the behavior of cultured cells containing inserted PcG transgenes. Endometrial stromal tumors provide evidence for a direct causal relationship because they contain several chromosomal translocations and resultant gene fusions involving PcGs, the most common of which joins portions of the JAZF1 gene to the PcGJJAZ1/SUZ12. We show here that both benign and malignant forms of this tumor have the JAZF1-JJAZ1 fusion but only the malignant form also exhibits exclusion of the unrearranged JJAZ1 allele. To evaluate the effects of both the JJAZ1/SUZ12 fusion and allelic exclusion on functions related to cell growth, we studied HEK293 cells that were modified with respect to JJAZ1 expression. We found that the JAZF1-JJAZ1 fusion restored levels of the polycomb protein EZH2 and histone 3 lysine 27 trimethylation, which were reduced by knockdown of endogenous JJAZ1. At the same time, the presence of JAZF1-JJAZ1 markedly inhibited apoptosis and induced above normal proliferation rates, although the latter effect occurred only when normal JJAZ1 was suppressed. Our findings suggest a genetic pathway for progression of a benign precursor to a sarcoma involving increased cell survival associated with acquisition of a PcG rearrangement, followed by accelerated cellular proliferation upon allelic exclusion of the unrearranged copy of that gene. Furthermore, these results indicate the likely functional importance of allelic exclusion of genes disrupted by chromosomal translocations, as seen in a variety of other cancers.

Placental site trophoblastic tumor is a neoplasm of extravillous intermediate trophoblast at the implantation site, preceded in the majority of cases by a female gestational event. Our pilot investigation suggested that the development of this tumor might require a paternally derived X chromosome and the absence of a Y chromosome. Twenty cases of placental site trophoblastic tumor were included in this study. Genotyping at 15 polymorphic loci and one sex determination locus was performed by multiplex PCR followed by capillary electrophoresis. X chromosome polymorphisms were determined by PCR amplification of exon 1 of the human androgen receptor gene using primers flanking the polymorphic CAG repeats within this region. Genotyping at 15 polymorphic loci was informative and paternal alleles were present in all tumors, confirming the trophoblastic origin of the tumors. The presence of an X chromosome and the absence of a Y chromosome were observed in all tumors. Among 13 cases in which analysis of the X chromosome polymorphism was informative, all but one demonstrated at least two X alleles and seven cases showed one identifiable paternal X allele. These results confirm a unique pathogenetic mechanism in placental site trophoblastic tumor, involving an exclusion of the Y chromosome from the genome and, therefore, a tumor arising from the trophectoderm of a female conceptus. As epigenetic regulations of imprinting during X chromosome inactivation are of significant biological implications, placental site trophoblastic tumor may provide an important model for studying the sex chromosome biology and the proliferative advantage conferred by the paternal X chromosome.

Daily diary methods were used to examine changes in pain and negative mood over the first 6 weeks of rehabilitation after surgical reconstruction of the anterior cruciate ligament (ACL). Participants (58 men and 33 women) completed measures of personal factors (i.e., age, athletic identity, neuroticism, optimism) before surgery and indices of daily pain, negative mood, and stress for 42 days after surgery. Multilevel modeling revealed that, as would be expected, daily pain ratings decreased significantly over the course of the study and that the rate of decline in pain ratings decreased over time. Age and daily negative mood were positively associated with daily pain ratings. Daily negative mood also decreased significantly over the course of the study and was positively associated with neuroticism, daily pain, and daily stress. Athletic identity and optimism interacted with time since surgery in predicting daily negative mood such that participants with high levels of athletic identity and low levels of optimism reported greater decreases in daily negative mood over time. Overall, the findings reveal a pattern of improved psychological functioning over the early stages of post-operative ACL rehabilitation.

Several clinical vignettes express the unconscious use of the patient's body as containing and enacting a somatic defense until free association enables affect to be found in the clinical setting. In this paper, there is a plea to take the body of the patient as seriously as the mind and language. As Ferenczi eloquently remarked "one needs to have lived through an affective experience, to have, so to speak, felt it in ones body, in order to gain conviction."