Inhibition of cued but not executed task sets depends on cue-task compatibility and practice.

In task switching, processing a task cue is thought to activate the corresponding task representation ("task set"), thereby allowing for advance task preparation. However, the contribution of preparatory processes to the emergence of n-2 repetition costs as index of task set inhibition processes is debated. The present study investigated whether merely preparing for a task activates a corresponding task set, which needs to be inhibited in order to switch to a different task. To this end, we presented so-called task cue-only trials in trial n-2 and assessed subsequent n-2 repetition costs. The results revealed n-2 repetition costs following a task cue-only, but only for compatible cues with a transparent cue-task relation and only at the beginning of the experiment. In contrast, n-2 repetition costs following task execution in trial n-2 were absent. In a second experiment, we sought to rule out that the presence of n-2 repetition costs following a task cue-only and the corresponding absence following task execution were the consequence of a decay of task sets. This second experiment replicated the result pattern of the first experiment, with n-2 repetition costs following a task cue-only being present only at the beginning of the experiment and only for compatible cues. Hence, cue-induced task set inhibition effects depended on cue-task compatibility and practice. Furthermore, merely prepared task sets were more likely inhibited than executed task sets.

Coping with test anxiety using imagery rescripting: A two-session randomized controlled trial.

BACKGROUND: Up to 55 % of students experience test anxiety (TA), which is characterized by intense physiological and psychological symptoms before or during exams, such as anxiety, fear of failure, sweating, or increased heart rate. Furthermore, TA increases graduation times and can result in discontinuance of the graduate program all together. Previous research demonstrated the beneficial effects of combining cognitive behavioral therapy with imagery rescripting, however, treatment programs are comparably long. Hence, they do not account for the students´ time-sensitive schedules. Therefore, the present study investigates a two-session short-intervention using imagery rescripting to treat TA. METHODS: 44 students and pupils were randomly assigned to either the two-session imagery rescripting intervention (22 participants) or the waitlist-control condition (22 participants). One week before the intervention clinical interviews were conducted and self-report questionnaires on TA, self-efficacy, symptoms of depression, and intrusive prospective images were completed (T1). The same questionnaires were completed one week (T2) and six months after the intervention (T3). RESULTS: Test anxiety significantly decreased from T1 to T2, as well as from T1 to T3 within the intervention group. Furthermore, there were medium to large within and between group effects for situational test anxiety, self-efficacy, symptoms of depression, as well as prospective intrusive images, showing significant improvements for the intervention group at six months follow-up. LIMITATIONS: The study is limited to the comparably small sample size, as well as the sole usage of self-report measurements. CONCLUSIONS: The presented short-intervention provides a feasible treatment technique, which can be easily applied within school and university counseling centers.

Dynamics of task preparation processes revealed by effect course analysis on response times and error rates.

Cuing or executing a task impacts processing pathways for task-relevant information. While there is ample evidence that processing associated with task execution changes with practice, such evidence regarding cue-induced task preparation is scarce. Here we explored practice-related changes of processing pathways by task cuing in order to assess the plasticity of task preparation. We first developed and validated a new method for the study of practice-related changes, the effect course analysis. The effect course analysis is a model-free, non-parametric method designed to reveal effect changes within an experimental session on a continuous time scale. Then we applied this method to a new study in which cued task sets were supposed to remain activated during assessment of task-relevant pathways, as potential task execution was postponed at the end of the trial. The results showed that, with little practice, task cuing amplified task-relevant pathways, whereas this effect vanished with practice, suggesting that practice prompts fundamental changes of how task cues are used for task preparation. Hence, if one cannot be certain that cognitive processing is stationary, investigating the time course of experimental effects appears to be crucial to determine how cognitive processing is influenced by practice.

GenomeMUSter mouse genetic variation service enables multitrait, multipopulation data integration and analysis.

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense variant resource by harmonizing multiple data sets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extendable to other model organisms. The result is a web- and programmatically accessible data service called GenomeMUSter, comprising single-nucleotide variants covering 657 strains at 106.8 million segregating sites. Interoperation with phenotype databases, analytic tools, and other resources enable a wealth of applications, including multitrait, multipopulation meta-analysis. We show this in cross-species comparisons of type 2 diabetes and substance use disorder meta-analyses, leveraging mouse data to characterize the likely role of human variant effects in disease. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

Longitudinal Reoperation Risk After Apical Prolapse Procedures in Women Aged 65 Years and Older.

OBJECTIVE: To describe longitudinal reoperation risk among older women undergoing surgery for apical pelvic organ prolapse (POP) and to compare risk of reoperation for prolapse and complications among different surgical approaches. METHODS: This nationwide, retrospective cohort study evaluated older adult women (aged 65 years and older) within the Centers for Medicare & Medicaid Services' (CMS) 5% LDS (Limited Data Set) who underwent sacrocolpopexy, uterosacral ligament suspension (USLS), sacrospinous ligament fixation (SSLF), or colpocleisis, or their uterine-preserving equivalents, from January 1, 2011, to December 31, 2018, with follow-up through 2019. The primary outcome was overall reoperation, and secondary outcomes included reoperation for POP and for complications. Rates were compared using χ 2 tests for categorical variables, Wilcoxon rank-sum for continuous variables and Kaplan Meier estimates of cumulative incidence. Death and exit from CMS insurance were considered as censoring events. We used cumulative incidence to calculate reoperation risk as a function of time at 1 year or more, 3 years or more, and 7 years or more. RESULTS: This cohort included 4,089 women who underwent surgery to treat apical POP from 2011 to 2018: 1,034 underwent sacrocolpopexy, 717 underwent USLS, 1,529 underwent SSLF, and 809 underwent colpocleisis. Demographics varied among patients for each POP surgery. Patients who underwent the different surgeries had differences in age ( P <.01), Charlson Comorbidity Index score ( P <.01), diabetes ( P <.01), chronic obstructive pulmonary disease ( P <.01), hypertension ( P <.01), chronic pain ( P =.01), congestive heart failure ( P <.01), and concomitant hysterectomy ( P <.01). Reoperation rates were low and increased over time. The overall reoperation risk through 7 years was 7.3% for colpocleisis, 10.4% for USLS, 12.5% for sacrocolpopexy, and 15.0% for SSLF ( P <.01). Reoperation for recurrent POP through 7 years was 2.9% for colpocleisis, 7.3% for sacrocolpopexy, 7.7% for USLS, and 9.9% for SSLF ( P <.01). Reoperation for complications through 7 years was 5.3% for colpocleisis, 8.2% for sacrocolpopexy, 6.4% for USLS, and 8.2% for SSLF ( P <.01). CONCLUSION: The type of surgical repair is significantly associated with long-term risk of reoperation. Colpocleisis offers the least likelihood of reoperation for prolapse, followed by sacrocolpopexy; colpocleisis followed by USLS has the least risk of long-term reoperation for complication.

Aon: a service to augment Alliance Genome Resource data with additional species.

OBJECTIVE: Cross-species comparative genomics requires access to accurate homology data across the entire range of annotated genes. The Alliance of Genome Resources (AGR) provides an open-source and comprehensive database of homology data calculated using a wide array of algorithms at differing stringencies to elucidate orthologous relationships. However, the current AGR application program interface (API) is limited to five homology endpoints for nine species. While AGR provides a robust resource for several canonical species, its utility can be greatly enhanced by increased filtering and data processing options and incorporating additional species. RESULTS: Here, we describe a novel API tool, AON, that expands access to the AGR orthology resource by creating a data structure that supports 50 additional endpoints. More importantly, it provides users with a framework for adding bespoke endpoints, custom species, and additional orthology data. We demonstrate AON's functionality by incorporating the service into the GeneWeaver ecosystem for supporting cross-species data analysis.

Mouse phenome database: curated data repository with interactive multi-population and multi-trait analyses.

The Mouse Phenome Database continues to serve as a curated repository and analysis suite for measured attributes of members of diverse mouse populations. The repository includes annotation to community standard ontologies and guidelines, a database of allelic states for 657 mouse strains, a collection of protocols, and analysis tools for flexible, interactive, user directed analyses that increasingly integrates data across traits and populations. The database has grown from its initial focus on a standard set of inbred strains to include heterogeneous mouse populations such as the Diversity Outbred and mapping crosses and well as Collaborative Cross, Hybrid Mouse Diversity Panel, and recombinant inbred strains. Most recently the system has expanded to include data from the International Mouse Phenotyping Consortium. Collectively these data are accessible by API and provided with an interactive tool suite that enables users' persistent selection, storage, and operation on collections of measures. The tool suite allows basic analyses, advanced functions with dynamic visualization including multi-population meta-analysis, multivariate outlier detection, trait pattern matching, correlation analyses and other functions. The data resources and analysis suite provide users a flexible environment in which to explore the basis of phenotypic variation in health and disease across the lifespan.

GenomeMUSter mouse genetic variation service enables multi-trait, multi-population data integration and analyses.

Hundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait - variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web- and programmatically-accessible data service called GenomeMUSter ( https://muster.jax.org ), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

Functional design of experiment for potency assay optimization and in-silico simulation.

For biotherapeutic analytics, robust and reliable potency assays are required. Design of experiment (DoE) approaches are used to investigate the impact of multiple assay parameters. Currently, specific assay features (e.g., half effective concentration) are modelled independently from each other. A joint interpretation of several assay features is thus difficult. In our functional DoE approach, we use the functional relationship of the assay features to describe the sigmoidal dose-response curve. With the composed functional form, the direct impact of assay parameters on the dose-response curve shape was modelled. Moreover, a multivariate desirability was defined and used for assay optimization. We believe that functional modelling contributes to understanding the joint influence of assay parameters and helps to design robust biotherapeutic analytics.

Effects of Same-Day Discharge on 30-Day Readmission Rates in Women Aged 65 Years and Older Undergoing Minimally Invasive Pelvic Organ Prolapse Surgery.

OBJECTIVE: To compare the effects of same-day discharge on 30-day readmission after minimally invasive pelvic organ prolapse (POP) surgery in older patients. METHODS: This retrospective cohort study examined all minimally invasive POP surgeries performed and included in the national Centers for Medicare & Medicaid Services 5% Limited Data Set (2011-2018). Our primary outcome was 30-day hospital readmission, and our secondary outcome was 30-day emergency department (ED) visits. RESULTS: Of the 7,278 patients undergoing surgery, patients who had same-day discharge were older (73.5 years vs 73.1 years, P =.04) and less likely to undergo concomitant hysterectomy (9.5% vs 34.9%, P <.01) or midurethral sling (36.8% vs 40.1%, P =.02). Same-day discharge increased over the study period from 15.7% in 2011 to 25.5% in 2018 ( P <.01). On propensity score-matching multiple logistic regression, the adjusted difference was statistically significant, with same-day discharge increasing the odds of 30-day readmission compared with next-day discharge (adjusted odds ratio [OR] 1.57, 95% CI 1.19-2.08). There was no difference (OR 0.81, 95% CI 0.63-1.05) for 30-day ED visits on propensity score-matching multiple logistic regression. CONCLUSION: After minimally invasive POP surgery, older women have low rates of readmission and ED visits within 30 days. After propensity score matching and adjustment for perioperative factors, there may be increased odds in readmission and no difference in ED visits risk in those who had same-day discharge. When considering patient factors, same-day discharge after minimally invasive POP surgery may be effective for older patients.

Electrophysiological correlates of response time outliers: Outlier related potentials.

In response time (RT) research, RTs which largely deviate from the RT distribution are considered "outliers". Outliers are typically excluded from RT analysis building upon the implicit assumption that cognitive processing is distorted in outlier trials. The present study aims to test this assumption by comparing cognitive processing indexed by event-related potentials (ERP) of trials with outliers and valid trials in two different tasks. To this end, we compared stimulus- and response-locked ERPs for outliers identified by nine different methods with valid trials, using cluster-based permutation tests. Consistently across outlier exclusion methods and tasks, the late positive complex (P3) associated with response-related processes was reduced in outliers. Analyses of response-locked ERPs related this P3 attenuation to a slower and temporally more extended increase of the P3, possibly indexing reduced evidence accumulation speed in outliers. P3 peak amplitude in response-locked ERPs was similar between outliers and valid trials, suggesting that the absolute amount of evidence required for a response remained comparable. Furthermore, in addition to these more general ERP correlates of outliers, the contingent negative variation (CNV) ERP component was reduced in outliers as a function of preparatory demands of the task. Hence, electrophysiological correlates, and thus cognitive processing, are altered in outliers compared to valid trials. In order to avoid distortion of observed ERP differences between conditions, the RT outlier distribution should be considered for the analysis of ERPs in combined ERP and RT studies.

Academic training increases grounding of scientific concepts in experiential brain systems.

Scientific concepts typically transcendent our sensory experiences. Traditional approaches to science education therefore assume a shift towards amodal or verbal knowledge representations during academic training. Grounded cognition approaches, in contrast, predict a maintenance of grounding of the concepts in experiential brain networks or even an increase. To test these competing approaches, the present study investigated the semantic content of scientific psychological concepts and identified the corresponding neural circuits using functional magnetic resonance imaging (fMRI) in undergraduate psychology students (beginners) and in graduated psychologists (advanced learners). During fMRI scanning, participants were presented with words denoting scientific psychological concepts within a lexical decision task (e.g. "conditioning", "habituation"). The individual semantic property content of each concept was related to brain activity during abstract concept processing. In both beginners and advanced learners, visual and motor properties activated brain regions also involved in perception and action, while mental state properties increased activity in brain regions also recruited by emotional-social scene observation. Only in advanced learners, social constellation properties elicited brain activity overlapping with emotional-social scene observation. In line with grounded cognition approaches, the present results highlight the importance of experiential information for constituting the meaning of abstract scientific concepts during the course of academic training.

Task cue influences on lexical decision performance and masked semantic priming effects: The role of cue-task compatibility.

Recent research demonstrated that mere presentation of a task cue influences subsequent unconscious semantic priming by attentional sensitization of related processing pathways. The direction of this influence depended on task-set dominance. Dominant task sets with a compatible cue-task mapping were supposed to be rapidly suppressed, while weak task sets showed more sustainable activation. Building on this research, we manipulated cue-task compatibility as instance of task-set dominance in two experiments and tested how masked semantic priming was influenced by actually performing the cued task (induction-task trials) or by mere cue presentation (task cue-only trials). In induction-task trials, the results of earlier research were replicated; semantic priming was larger following a semantic induction task compared to a perceptual induction task. In task cue-only trials, priming effects were reversed compared to induction-task trials in both experiments. Priming was larger for a perceptual compared to a semantic task set in task cue-only trials, indicating suppression of task sets following mere cue presentation in preparation for the upcoming lexical decision task. This notion of an inhibition of task sets after mere cue presentation was further supported by switching-related costs and changes of task-set implementation throughout the experiment. The absence of a moderator role of cue-task compatibility for task cue effects on priming in the present study suggests that the precise time course of task-set activation and inhibition in response to task cues as a function of cue-task compatibility might depend on specific experimental settings.

Total Synthesis of the Antimycobacterial Natural Product Chlorflavonin and Analogs via a Late-Stage Ruthenium(II)-Catalyzed ortho-C(sp2)-H-Hydroxylation.

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization's (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3'-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 µm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure-activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.

Long-term reoperation risk after apical prolapse repair in female pelvic reconstructive surgery.

BACKGROUND: Although several different apical suspension procedures are available to women with pelvic organ prolapse, data on long-term efficacy and safety profiles are limited. OBJECTIVE: The primary aim of this study was to analyze longitudinal reoperation risk for recurrent prolapse among the 4 apical suspension procedures over 2 to 15 years. Secondary aims included evaluation of all-cause reoperation, defined as a repeated surgery for the indications of recurrent prolapse and adverse events, and total retreatment rate, which included a repeated treatment with another surgery or a pessary. STUDY DESIGN: This was a multicenter, retrospective cohort study within Kaiser Permanente Southern California that included women who underwent sacrocolpopexy, uterosacral ligament suspension, sacrospinous ligament fixation, or colpocleisis from January 2006 through December 2018. Women who underwent concomitant rectal prolapse repair or vaginal prolapse repair with mesh augmentation were excluded. Data were abstracted using procedural and diagnostic codes through July 2021, with manual review of 10% of each variable. Patient demographics and pessary use were compared using analysis of variance or chi square tests for continuous and categorical variables, respectively. Time-to-event analysis was used to contrast reoperation rates. A Cox regression model was used to perform an adjusted multivariate analysis of the following predictors of reoperation for recurrence: index surgery, concomitant procedures, patient demographics, baseline comorbidities, and year of index surgery. Censoring events included exit from the health maintenance organization and death. RESULTS: The cohort included 9681 women with maximum follow-up of 14.8 years. The overall incidence of reoperation for recurrent prolapse was 7.4 reoperations per 1000 patient-years, which differed significantly by type of apical suspension (P<.0001). The incidence of reoperation was lower after colpocleisis (1.4 events per 1000 patient-years) and sacrocolpopexy (4.8 events per 1000 patient-years) when compared with uterosacral ligament suspension (9 events per 1000 patient-years) and sacrospinous ligament fixation (13.9 events per 1000 patient-years). All pairwise comparisons between procedures were significant (P=.0003-.0018) after correction for multiplicity, except for uterosacral ligament suspension or uterosacral ligament hysteropexy vs sacrospinous ligament fixation or sacrospinous ligament hysteropexy (P=.05). The index procedure was the only significant predictor of reoperation for recurrence (P=.0003-.0024) on multivariate regression analysis. Reoperations for complications or sequelae (overall 2.9 events per 1000 patient-years) also differed by index procedure (P<.0001) and were highest after sacrocolpopexy (4.4 events per 1000 patient-years). The incidence of all-cause reoperation for recurrence and adverse events after sacrocolpopexy, however, was comparable to that of the other reconstructive procedures (P=.1-.4) in pairwise comparisons with Bonferroni correction. Similarly, frequency of pessary use differed by index procedure (P<.0001) and was highest after sacrospinous ligament fixation at 9.3% (43/464). CONCLUSION: Among nearly 10,000 patients undergoing prolapse surgery within a large managed care organization, colpocleisis and sacrocolpopexy offered the most durable obliterative and reconstructive prolapse repairs, respectively. All-cause reoperation rates were lowest after colpocleisis by a large margin, but similar among reconstructive apical suspension procedures.

Ground Contact Time Estimating Wearable Sensor to Measure Spatio-Temporal Aspects of Gait.

Inpatient gait analysis is an essential part of rehabilitation for foot amputees and includes the ground contact time (GCT) difference of both legs as an essential component. Doctors communicate improvement advice to patients regarding their gait pattern based on a few steps taken at the doctor's visit. A wearable sensor system, called Suralis, consisting of an inertial measurement unit (IMU) and a pressure measuring sock, including algorithms calculating GCT, is presented. Two data acquisitions were conducted to implement and validate initial contact (IC) and toe-off (TO) event detection algorithms as the basis for the GCT difference determination for able-bodied and prosthesis wearers. The results of the algorithms show a median GCT error of -51.7 ms (IMU) and 14.7 ms (sensor sock) compared to the ground truth and thus represent a suitable possibility for wearable gait analysis. The wearable system presented, therefore, enables a continuous feedback system for patients and, above all, a remote diagnosis of spatio-temporal aspects of gait behaviour based on reliable data collected in everyday life.

Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma.

Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5-50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.

Implementation of a Spatially-Variant and Tissue-Dependent Positron Range Correction for PET/CT Imaging.

Aim: To develop and evaluate a new approach for spatially variant and tissue-dependent positron range (PR) correction (PRC) during the iterative PET image reconstruction. Materials and Methods: The PR distributions of three radionuclides (18F, 68Ga, and 124I) were simulated using the GATE (GEANT4) framework in different material compositions (lung, water, and bone). For every radionuclide, the uniform PR kernel was created by mapping the simulated 3D PR point cloud to a 3D matrix with its size defined by the maximum PR in lung (18F) or water (68Ga and 124I) and the PET voxel size. The spatially variant kernels were composed from the uniform PR kernels by analyzing the material composition of the surrounding medium for each voxel before implementation as tissue-dependent, point-spread functions into the iterative image reconstruction. The proposed PRC method was evaluated using the NEMA image quality phantom (18F, 68Ga, and 124I); two unique PR phantoms were scanned and evaluated following OSEM reconstruction with and without PRC using different metrics, such as contrast recovery, contrast-to-noise ratio, image noise and the resolution evaluated in terms of full width at half maximum (FWHM). Results: The effect of PRC on 18F-imaging was negligible. In contrast, PRC improved image contrast for the 10-mm sphere of the NEMA image quality phantom filled with 68Ga and 124I by 33 and 24%, respectively. While the effect of PRC was less noticeable for the larger spheres, contrast recovery still improved by 5%. The spatial resolution was improved by 26% for 124I (FWHM of 4.9 vs. 3.7 mm). Conclusion: For high energy positron-emitting radionuclides, the proposed PRC method helped recover image contrast with reduced noise levels and with improved spatial resolution. As such, the PRC approach proposed here can help improve the quality of PET data in clinical practice and research.

Systematic Review of Gossypol/AT-101 in Cancer Clinical Trials.

The potential of gossypol and of its R-(-)-enantiomer (R-(-)-gossypol acetic acid, AT-101), has been evaluated for treatment of cancer as an independent agent and in combination with standard chemo-radiation-therapies, respectively. This review assesses the evidence for safety and clinical effectiveness of oral gossypol/AT-101 in treating various types of cancer. The databases PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov were examined. Phase I and II trials as well as single arm and randomized trials were included in this review. Results were screened to determine if they met inclusion criteria and then summarized using a narrative approach. A total of 17 trials involving 759 patients met the inclusion criteria. Overall, orally applied gossypol/AT-101 at low doses (30 mg daily or lower) was determined as well tolerable either as monotherapy or in combination with chemo-radiation. Adverse events should be strictly monitored and were successfully managed by dose-reduction or treating symptoms. There are four randomized trials, two performed in patients with advanced non-small cell lung cancer, one in subjects with head and neck cancer, and one in patients with metastatic castration-resistant prostate cancer. Thereby, standard chemotherapy (either docetaxel (two trials) or docetaxel plus cisplatin or docetaxel plus prednisone) was tested with and without AT-101. Within these trials, a potential benefit was observed in high-risk patients or in some patients with prolongation in progression-free survival or in overall survival. Strikingly, the most recent clinical trial combined low dose AT-101 with docetaxel, fluorouracil, and radiation, achieving complete responses in 11 of 13 patients with gastroesophageal carcinoma (median duration of 12 months) and a median progression-free survival of 52 months. The promising results shown in subsets of patients supports the need of further specification of AT-101 sensitive cancers as well as for the establishment of effective AT-101-based therapy. In addition, the lowest recommended dose of gossypol and its precise toxicity profile need to be confirmed in further studies. Randomized placebo-controlled trials should be performed to validate these data in large cohorts.