Aims and Methods: Acute alcohol administration induces marked decreases in glucose metabolism throughout the human brain. However, the relationship between alcohol's effects on brain metabolism and ...the behavioural changes that occur with intoxication are still unclear. Here we assessed this association using principal component analysis for dimension reduction and canonical correlations to gauge inter-class relationships. We also used canonical correlations in the polynomial space to assess for possible nonlinear relationships. Results: After normalizing the regional measures to account for the large whole brain decreases observed with intoxication we show that the largest decreases occurred in occipital cortex and that there were relative increases in basal ganglia. Principal component analysis of the changes in the normalized measures revealed that 60% of the variance was accounted for by two factors; one that contrasted cerebellum versus frontal and anterior cingulate metabolism, and another that contrasted basal ganglia and insula. The square of the first factor was significantly correlated with the deterioration in cognitive performance. The second factor showed a significant linear correlation with self-reports of intoxication and with deterioration in cognitive and motor performance. Conclusions: These findings suggest that the contrasting effects of alcohol in basal ganglia versus the insula are involved in the perception of ‘feeling drunk’ and that its contrasting effects in cerebellum versus those in frontal and parietal cortices are involved in its motor incoordinating effects. On the other hand alcohol's impact on cognitive performance implicates a more complex pattern of brain effects that includes linear as well as non-linear associations.
Cognitive Profiles of Reading Disability Fletcher, Jack M; Shaywitz, Sally E; Shankweiler, Donald P ...
Journal of educational psychology,
03/1994, Letnik:
86, Številka:
1
Journal Article
Recenzirano
To examine the validity of distinguishing children with reading disabilities according to discrepancy and low-achievement definitions, we obtained four assessments of expected reading achievement and ...two assessments of actual reading achievement for 199 children, 7.5-9.5 years old. These assessments were used to subdivide the sample into discrepancy and low-achievement definitional groups who were compared on 9 cognitive variables related to reading proficiency. Results did not support the validity of discrepancy versus low achievement definitions. Although differences between children with impaired reading and children without impaired reading were large, differences between those children with impaired reading who met IQ-based discrepancy definitions and those who met low reading achievement definitions were small or not significant. Measures of phonological awareness were robust indicators of differences between children with impaired reading and children without impaired reading regardless of how reading disability was defined.
CONTEXT Physical activity is important for health, yet few studies have examined
the effectiveness of physical activity patient counseling in primary care. OBJECTIVE To compare the effects of 2 ...physical activity counseling interventions
with current recommended care and with each other in a primary care setting. DESIGN The Activity Counseling Trial, a randomized controlled trial with recruitment
in 1995-1997, with 24 months of follow-up. SETTING Eleven primary care facilities affiliated with 3 US clinical research
centers. PARTICIPANTS Volunteer sample of 395 female and 479 male inactive primary care patients
aged 35 to 75 years without clinical cardiovascular disease. INTERVENTIONS Participants were randomly assigned to 1 of 3 groups: advice (n = 292),
which included physician advice and written educational materials (recommended
care); assistance (n = 293), which included all the components received by
the advice group plus interactive mail and behavioral counseling at physician
visits; or counseling (n = 289), which included the assistance and advice
group components plus regular telephone counseling and behavioral classes. MAIN OUTCOME MEASURES Cardiorespiratory fitness, measured by maximal oxygen uptake
(O2max), and self-reported total physical activity, measured by a 7-day
Physical Activity Recall, compared among the 3 groups and analyzed separately
for men and women at 24 months. RESULTS At 24 months, 91.4% of the sample had completed physical activity and
77.6% had completed cardiorespiratory fitness measurements. For women at 24
months, O2max was significantly higher in the assistance
group than in the advice group (mean difference, 80.7 mL/min; 99.2% confidence
interval CI, 8.1-153.2 mL/min) and in the counseling group than in the advice
group (mean difference, 73.9 mL/min; 99.2% CI, 0.9-147.0 mL/min), with no
difference between the counseling and assistance groups and no significant
differences in reported total physical activity. For men, there were no significant
between-group differences in cardiorespiratory fitness or total physical activity. CONCLUSIONS Two patient counseling interventions differing in type and number of
contacts were equally effective in women in improving cardiorespiratory fitness
over 2 years compared with recommended care. In men, neither of the 2 counseling
interventions was more effective than recommended care.
Introduction
Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm arising from dendritic cells of the lymphoid follicles. The inciting event that leads to the development of ...malignancy remains unknown. The prevalent therapeutic approach involves surgical excision with the possibility of radiation therapy. However, most initial responders develop eventual recurrence. Furthermore, due to the rarity of the malignancy, there are no official recommendations for optimal FDCS therapy. To further elucidate possible therapies for FDCS, we assessed the effects of multiple agents in vitro on the cell viability of patient primary cells and employed our patient-derived xenograft (PDX) model to validate the efficacy of these agents in an in vivo model system.
Methods
A 53-year-old female with highly metastatic FDCS, who had been refractory to multiple treatments, presented at the hospital with hypotension, weakness, and anorexia. FDCS samples were isolated from the patient's pleural fluid, and an in vitro primary patient cell culture was established and a subset of the patient cells were engrafted into SCID mice implanted with a human fetal bone chip to create the PDX model. A series of in vitro drug screens conducted with MTS cell viability and Annexin V apoptosis assays identified the therapies that decreased the cell viability of these cells. After passaging the cells for 3 generations, and based on the in vitro results, the mice were administered intravenous treatment with DMSO control (1%, n=2), bortezomib (0.5 mg/kg, n=3), carfilzomib (1 mg/kg, n=3), or combination bortezomib with CTX (0.5 mg/kg and 10 mg/kg, respectively, n=3) twice a week for 3 weeks. The average days of survival, tumor volume, and tumor mass were determined in vivo.
Results
The clinical pathology report showed that the FDCS case was rare, with the immunophenotypes CD21- CD23- and weakly positive CD35, which was also confirmed in our PDX model. The MTS assay demonstrated that the proteasome inhibitors carfilzomib and bortezomib as well as Bruton's tyrosine kinase inhibitor ibrutinib and the SINE XP01 antagonist KPT-330 inhibited the growth of the freshly isolated FDCS cells derived from either the patient or the PDX mice. The Annexin V-binding assay demonstrated carfilzomib, bortezomib, and KPT-330 significantly induced apoptosis of both the patient and PDX-derived FDCS cells. CTX is the primary chemotherapy drug administered to FDCS patients; therefore, we combined CTX with bortezomib, the most effective anti-tumor drug observed in our in vitro studies, to investigate the therapeutic effects of this novel combination in our PDX model. Our in vivo results validated the in vitro data and demonstrated that the bortezomib and CTX combination therapy significantly inhibited tumor growth in PDX mice compared with the proteasome inhibitors bortezomib or carfilzomib alone.
Conclusion
The data presented here suggest the potential of utilizing parallel in vitro drug screening and in vivo PDX tumor studies to determine possible therapies for rare malignancies. The combination therapy of bortezomib and CTX is a promising modality to treat relapsed FDCS. However, the patient died of hypotension and weakness after receiving bortezomib plus CHOP.
Pham:Amgen, Onyx, Millennium: Research Funding. Wang:Janssen: Honoraria; Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding.
•Ibrutinib ± rituximab was effective and well tolerated as first-line MCL therapy; outcomes were worse in patients with high-risk disease.•Novel approaches are needed for patients with high-risk MCL ...and those with progressive disease after first-line ibrutinib.
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During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio HR, 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.
1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual ...differences in motor, mnemonic and reward functions. To identify "cis"-acting genetic mechanisms for these individual differences, we have sought variants in 5' aspects of the human DAT gene and identified the haplotypes that these variants define. 2. We report (i) significant relationships between 5' DAT haplotypes and human individual differences in ventral striatal DAT expression assessed in vivo using (11)C cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum using (3)H carboxyflurotropane binding. 3. These observations support the idea that cis-acting variation in 5' aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5' DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes.
Abstract
Background
Pneumonia is the most common infectious cause of morbidity and excess mortality complicating hematopoietic cell transplantation (HCT) and treatment of hematologic malignancy. ...Standard bronchoscopic and noninvasive microbiologic testing identify causative pathogens in less than half of cases. The Karius Test, a plasma next-generation sequencing assay of microbial cell-free DNA, may improve diagnostic yield in these patients.
Methods
Patients with active hematologic malignancy or recent HCT undergoing bronchoscopy for suspected pneumonia were prospectively enrolled in this observational study conducted at 10 United States medical centers. A panel of expert clinicians blinded to Karius Test results reviewed a standardized panel of microbiologic and molecular testing from bronchoalveolar lavage and blood samples for bacterial and fungal testing, nasopharyngeal swab for respiratory viral testing, imaging results, clinical documentation, and any additional microbiologic or molecular testing collected per usual standard of care to adjudicate a probable cause of pneumonia. The panel then adjudicated whether a probable cause of pneumonia or other clinically relevant infection was identified by the Karius Test.
Results
Between January 3, 2020 and February 4, 2022, 257 patients were enrolled. A planned interim analysis of the first 69 sequentially enrolled patients in the per protocol population was conducted. An adjudicated probable cause of pneumonia was identified by standard care in 18/69 (26%) patients. The Karius Test identified an adjudicated probable cause of pneumonia in 10/51 (20%) patients when no cause of pneumonia was identified by standard care testing. The combination of standard care and the Karius Test together identified a probable cause of pneumonia in 28/69 (41%) patients. At least one additional pathogen adjudicated as a probable cause of pneumonia was identified by the Karius Test in 6/18 (33%) of patients with positive standard care testing.
Conclusion
The Karius Test notably increased the probability of identifying a pathogenic cause of pneumonia among immunocompromised patients undergoing bronchoscopy. The additive diagnostic value of the Karius Test may significantly enhance management of this common condition.
Disclosures
Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support Radha Duttagupta, PhD, Karius Inc: Stocks/Bonds Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Ghady Haidar, MD, Karius, Allovir, and AstraZeneca: Grant/Research Support Alfred Luk, MD, Karius: Grant/Research Support Jamie Todd, MD, Altavant Sciences: Advisor/Consultant|AstraZeneca: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|CareDx: Grant/Research Support|Cellarity: Advisor/Consultant|Natera: Advisor/Consultant Genovefa Papanicolaou, MD, AlloVir: Board Member|AlloVir: Serve as member of DSMC|Amplyx: Board Member|Amplyx: Serve as member of DSMC|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|CSL Behring: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Investigator for Merck|MSD: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Board Member|Octapharma: Serve as EAC member|Partners RX: Advisor/Consultant|SymBio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Takeda: Investigator for Takeda|Vera: Board Member|Vera: Serve as member of DSMC Elena Nemirovich-Danchenko, MD PhD, Karius: Stocks/Bonds Mona Mughar, BS, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Sudeb Dalai, MD, Karius: Stocks/Bonds Yuen Cho, MS, CLS(CA-DPH), Karius: Stocks/Bonds Asim A. Ahmed, MD, Karius: Employee|Karius: Stocks/Bonds Desiree Hollemon, MSN, MPH, Karius: Stocks/Bonds David K. Hong, MD, Janssen Pharmaceutical Companies of Johnson & Johnson: Employee|Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Marla Lay Vaughn, BS, MT(ASCP), Karius: Employee|Karius: Stocks/Bonds Tim Blauwkamp, PhD, Karius: Board Member|Karius: Ownership Interest Zivjena Vucetic, MD, Karius: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Rina Romano, BS, Karius Inc: Stocks/Bonds|Karius Inc: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant.
We used Tellegen's Multidimensional Personality Questionnaire (MPQ) harm avoidance (fear) scale and the constraint superfactor as personality measures of inhibitory control and examined their ...association with glucose metabolism in the orbitofrontal gyrus at rest in 14 recently abstinent methamphetamine-dependent subjects and 22 comparison subjects. Higher MPQ scores were associated with higher relative orbitofrontal gyrus metabolism in the methamphetamine-dependent subjects. There was a tendency towards a negative association for the comparison subjects (test of coincidence of regression lines for the two subject groups: F = 3.3, df = 2,32; = 0.051). These results suggest that the role of the orbitofrontal cortex in inhibitory control can be manifested in stable personality predispositions and further implicate this region in the core characteristics of drug addiction.
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