Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics

The relationship between white matter microstructure and general cognitive ability in patients with schizophrenia and healthy participants in the ENIGMA Consortium

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants. Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition. Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges’ g]=0.27, CI=0.17–0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05–0.35) and healthy participant groups (effect size=0.32, CI=0.18–0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18–0.37), the patient group (effect size=0.23, CI=0.09–0.38), and the healthy participant group (effect size=0.31, CI=0.18–0.44). Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain

Uniportal Video-Assisted Thoracoscopic Lung Resection: A Single-Surgeon Experience and Comparison with Multiportal Technique in the Veteran Population

Uniportal video-assisted thoracoscopic surgery (VATS) has been shown to offer improved postoperative outcomes compared with multiportal technique. Shorter operative time has rarely been described. Our objective was to compare operative time and clinical outcomes between uniportal and multiportal VATS approaches for lung resection. This is a retrospective review of patients that underwent video-assisted thoracoscopic lung resection at United States Veterans Affairs centers between 2008 and 2018 using the Veteran Affairs Surgical Quality Improvement Program. Cases were assigned to uniportal (single surgeon) or multiportal cohorts. Multivariable analysis of clinical outcomes was performed, adjusting for preoperative confounding covariates. Temporal trend in operative time in uniportal cohort was analyzed in the context of cumulative operative volume using Spearman\u27s rank correlation coefficient, rho (). In total, 8,212 cases were selected from 2008 to 2018 at Veterans Affairs centers: 176 (2.1%) uniportal and 8036 (97.9%) multiportal cases. Uniportal cohort was significantly associated with shorter operative time (1.7 hours versus 3.1 hours,  \u3c .001), higher adjusted odds of surgical site infection (adjusted odds ratio = 2.76;  = .005), and longer length of stay (6 days versus 5 days;  = .04). Uniportal cohort operative time decreased over time ( = -0.474), with most significant change corresponding with increased cumulative operative volume from 25 to 44 cases. Uniportal technique offered shorter operative duration in veterans compared with multiportal approach, validating its technical advantages. Operative time decreased as cumulative operative volume increased, demonstrating a learning curve. Future studies should prospectively investigate any association between operative time and clinical outcomes after thoracoscopic lung resection

Clinical Outcomes and Technical Approach of Thymectomy in the Veterans Health Administration

BACKGROUND: Thymectomy is traditionally performed through a transsternal incision, but less invasive modalities have emerged, including transcervical, thoracoscopic, and robotic approaches. Despite the advantages of video-assisted thoracoscopic surgery (VATS) over thoracotomy, most thymectomies are performed through sternotomy. This study compared the use and 30-day postoperative outcomes of transsternal, transcervical, and VATS thymectomy in the Veterans Health Administration. METHODS: This was a retrospective review of veterans who underwent thymectomy through the Veterans Affairs Surgical Quality Improvement Program. Their 30-day outcomes were compared among techniques, by adjusting for confounding covariates. Temporal trends were analyzed using the Spearman\u27 rank correlation coefficient, rho(ρ). RESULTS: From 2008 to 2019, 594 thymectomies were performed: 376 (63.3%) transsternal, 113 (19.0%) VATS (including robotic approaches), and 105 (17.7%) transcervical cases. VATS use increased from 0% in 2008 to 61% of case volume in 2019. Relative to the transsternal technique, VATS thymectomy was associated with decreased odds of pulmonary complications (adjusted odds ratio, 0.06; P = .028) and shorter hospital stay (2.9 ± 0.4 days shorter; P \u3c .001). No difference in outcomes was detected between VATS and transcervical thymectomy. The postoperative complication rate decreased from 17.7% in 2008 to 5.6% in 2019 (ρ = -0.101; P = .014). Length of stay decreased from median 4 days in 2008 to 3 days in 2019 (ρ = -0.093; P = .026). In thymic cancer, VATS 5-year overall survival was noninferior to the transsternal approach (71.3% vs 74.6%; P = .54). CONCLUSIONS: The transsternal approach comprised most thymectomy cases in veterans, whereas VATS thymectomy use increased over time and was associated with favorable outcomes. The 30-day outcomes after thymectomy improved over time, which may reflect a trend toward wider use of less invasive approaches. Future studies should examine long-term outcomes

Hospital Operative Volume and Esophagectomy Outcomes in the Veterans Affairs System

INTRODUCTION: Previous studies reported that increased hospital case volume improves outcomes after esophagectomy. Yet, the standard for high and low-volume hospitals varies in the literature. This study attempts to define the relationship between hospital operative volume and 30-day post-operative outcomes of esophagectomy in the Veterans Affairs (VA) system. METHODS: This is a retrospective review of patients that underwent esophagectomy from 2008 to 2019 utilizing the Veterans Affairs Surgical Quality Improvement Program Database. Receiver operating characteristic (ROC) analysis quantified an inflection point of optimal association between 30-day morbidity and mortality by facility volume. This point was used to separate cohorts for comparison of outcomes using 1:1 propensity score matching (PSM) to account for confounding covariates. RESULTS: Two thousand two hundred and twelve esophagectomies were performed from 2008 to 2019 and ROC analysis identified an inflection point at 43 cases (4 cases/y) where bidirectional operative volume significantly affected outcomes. Subsequent PSM resulted in 1718 cases utilized for analysis (n = 859 per cohort). Facility volume ≥4 cases/y was significantly associated with decreased odds of 30-day mortality (odds ratio(OR) = 0.57; P = 0.03), shorter length of stay (median 13 versus 14 d; P = 0.04) and longer operative times (6.5 versus 6.0 h; P \u3c 0.001). CONCLUSIONS: VA hospitals that averaged ≥4 esophagectomies/y had significantly lower rates of mortality and length of stay. This volume threshold may serve as a benchmark to determine the optimal setting for esophageal resection. However, our findings also may reflect the benefits of cumulative operating room and multidisciplinary team experience at VA centers in conjunction with dedicated surgeons. Future studies should focus on long-term outcomes after esophagectomy in relation to hospital operative volume