For the want of a nail: the Western Allies quest to synchronize maneuver and logistics during operations Torch and Overlord

Doctor of PhilosophyDepartment of HistoryDonald J. MrozekUnderstanding why the Western Allies failed to penetrate the western border of Germany in the fall of 1944 is a longer and more involved story than most histories of the topic imply. Allied performance in the European Theater of Operations during World War II is directly linked to their performance in the Mediterranean Theater of Operations (MTO) and before that, in the North African theater. This study focuses on how the Western Allies conducted campaigns – how they ran combined headquarters in order to plan and supervise joint, theater-level operations, and how those activities changed over time as the key leaders involved gained combat experience. After looking at the efforts of the Allied over this longer window of time, a new conclusion about why the pursuit phase of Overlord failed to penetrate the Westwall becomes clear. LTG J. C. H. Lee’s Communication’s Zone (COMZ) was unprepared to fulfill the logistical requirements of the Allied fall campaign in France in 1944, contributing directly to disappointment over the outcome of the campaign. For those who expected two years of combat experience to result in more effective performance in subsequent action, the failure was surely surprising. This study examines why COMZ could not manage the theater’s logistics and distribution system, and how Supreme Headquarters, Allied Expeditionary Force (SHAEF) failed to correct this shortcoming as it sought to synchronize joint operations with logistical requirements and the limitations they imposed. By contrasting the operational methods used by the United States (U.S.) and United Kingdom (U.K). and by looking at how Torch and Overlord unfolded, this study reaches three conclusions. First, COMZ was woefully unprepared to execute its combat mission in August 1944, and its failures lengthened the war considerably. Second, this failure was directly linked to the U.S. Army’s inability to integrate lessons learned at European Theater of Operations, U.S. Army (ETOUSA). Third, the work demonstrates how critical the integration of maneuver and sustainment is at the operational level of war and how U.S. doctrine and practice predating the war made this difficult to recognize. Finally, successful command at the theater and operational level relies upon consensus and cooperation, unlike the more directive nature of tactical control. COMZ and SHAEF were not prepared to fulfil their roles in August and September because the U.S. experience in World War One and the doctrine that emerged from that experience resulted in the adoption of a model for theater command that was eventually rejected in 1944. Although useful lessons were gained during Torch and implemented at Allied Force Headquarters (AFHQ), ETOUSA and Lee’s Service of Supply (SOS) did not integrate them. Those lessons were obscured when key personalities rotated or the org chart changed -- it took time for AFHQ, North African Theater of Operations, U.S. Army (NATOUSA), and the functional components to gel. ETOUSA and SOS faced different challenges, were busy with Bolero, and suffered through personnel turnover and restrictions of their own. A final round of reorganization swept through the U.K. over the winter of 1943 and 1944 when much of the command team relocated from the MTO to London. These organizational changes left in question who exactly was in charge of the various aspects of the sustainment mission during Overlord. Lee proved less effective than his peers when it came to producing results that were valued by the operational commands, and SHAEF and the army groups gradually poached ownership of planning and integrating logistical support from SOS/COMZ as a result. Lee held on to running the communications zone in France, but then he did not properly prepare for the mission. By the time SHAEF realized COMZ did not know how to do its job, it was too late to save the fall campaign. Just how bad things had gotten by October and November was masked by poor recordkeeping during the pursuit, confusion over what was really happening within the subordinate commands, and a narrative advanced by Eisenhower in January 1945 designed to paint a more flattering picture of recent events. Eisenhower manipulated facts in a report submitted to the Combined Chiefs of Staff in order to justify his decisions in France, dismiss any reported “mistakes” made during the fall, and ensure he retained personal control over the three army groups rather than reappointing a subordinate overall ground commander. In the process, Eisenhower initiated the cover-up that would make it so difficult to establish why the pursuit broke down

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts

Background: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. Methods: The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case control cohorts. We used these resources (31K SCZ cases, 41K controls; 248K MDD cases, 563K controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and nine methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) are compared. Results: Compared to PC+T, the other nine methods give higher prediction statistics, MegaPRS, LDPred2 and SBayesR significantly so, up to 9.2% variance in liability for SCZ across 30 target cohorts, an increase of 44%. For MDD across 26 target cohorts these statistics were 3.5% and 59%, respectively. Conclusions: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparison and are recommended in applications to psychiatric disorders