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A robust biomedical informatics infrastructure is essential for academic health centers engaged in translational research. There are no templates for what such an infrastructure encompasses or how it is funded. An informatics workgroup within the Clinical and Translational Science Awards network conducted an analysis to identify the scope, governance, and funding of this infrastructure. After we identified the essential components of an informatics infrastructure, we surveyed informatics leaders at network institutions about the governance and sustainability of the different components. Results from 42 survey respondents showed significant variations in governance and sustainability; however, some trends also emerged. Core informatics components such as electronic data capture systems, electronic health records data repositories, and related tools had mixed models of funding including, fee-for-service, extramural grants, and institutional support. Several key components such as regulatory systems (e.g., electronic Institutional Review Board [IRB] systems, grants, and contracts), security systems, data warehouses, and clinical trials management systems were overwhelmingly supported as institutional infrastructure. The findings highlighted in this report are worth noting for academic health centers and funding agencies involved in planning current and future informatics infrastructure, which provides the foundation for a robust, data-driven clinical and translational research program.
Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.
Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic.
MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment – Alzheimer's Association (ISTAART–AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden.
While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001).
MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.
The president woke up in a good mood on November 22, 1963. His back hurt more than usual, so he reinforced the corset he normally wore with a bandage-wrap for extra support. The discomfort did not darken his spirit, however; nor did the news of continued wrangling among leaders of the Democratic Party in Texas, particularly a squabble between conservative Governor John Connally and liberal Senator Ralph Yarborough that even Vice President Lyndon Johnson had been unable or unwilling to resolve. Despite this annoyance and his aching back, the president seemed more impressed by the large crowds and thunderous welcome that he and his wife had experienced during the first leg of their Texas trip. Even First Lady Jacqueline Kennedy, who normally disliked campaigning, was thrilled by their reception, and she and her husband had no reason to expect anything less from the day ahead. On the contrary, another enthusiastic crowd was already forming in the street below their hotel window. “I'll go anywhere with you,” said the first lady, as she watched a smile flash across the handsome face of her husband.
Nor was their mood darkened by a newspaper advertisement just published in the conservative Dallas Morning News. It began with sarcastic words welcoming President John F. Kennedy to the Lone Star State, but then launched a scurrilous attack, concealed in a series of leading questions, on the president's liberal policies at home and his supposedly soft stand on communism abroad. The ad revealed a degree of hostility toward the Kennedy administration that had been building for some time. Right-wing groups had physically and verbally assaulted Vice President Johnson and his wife when they campaigned in the state three years earlier, and similar groups had roughed up UN ambassador Adlai Stevenson during his visit to Dallas only a month before the president arrived. Stevenson was the darling of the liberal wing of the Democratic Party, a status that did not endear him to the increasingly conservative voters of Texas, who also viewed Johnson, a Texas native, as a traitor to his state for supporting the president's progressive agenda, especially on civil rights for African Americans.
All this was well known to Kennedy, as was the politics of the Dallas Morning News and its publisher and board chairman, E. M. Dealey.
As we have seen, Kennedy's thirty-five months in office, notably the policies he pursued and the way he and his wife comported themselves, had shaped his public identity. In fact, he and his wife had fashioned their own brand, basically a positive representation of themselves and the nation that most Americans found enormously appealing. That brand, moreover, would survive the president's death and become even more appealing, as evident in the way most people reacted to his assassination and what they said about his life. Indeed, it's impossible to understand Kennedy's commanding role in American memory without understanding the terrible shock of his death, both in the United States and around the world. People were shamed by what had happened. They felt a profound sense of guilt and personal loss, as if they had lost a friend as well as a champion who wanted to bring the blessings of liberty to those who did not enjoy them. These feelings account, in part, for why people would remember Kennedy so fondly and why their memories would long endure.
But this is not the whole story. In the United States, the assassination triggered a dark psychic state that contrasted sharply with the joyful exuberance, confidence, optimism, and hopefulness that most Americans associated with Kennedy's politics and personal style. The contrast alone made his remembrance more compelling. What is more, most people identified Kennedy with what was best in American life and his murder with a dangerous trend toward hatred and violence that was tearing at the nation's political fabric, destroying its social cohesion, and calling into question the shared identity of its citizens. As they saw it, the president had given his life trying to staunch the violence and heal divisions, which meant that his sacrifice could only be redeemed by honoring his memory and completing the unfinished work of his presidency. All of this explains why Kennedy's murder added luster to the image that he and his wife had constructed of themselves, why he would emerge from death as a larger-than-life figure, and why his brand, now overlaid with the sanctified mantle of a martyr, would become so deeply embedded in the collective memory of the American people.
News of the assassination shot like a thunderbolt across the country.
In his new book, Michael J. Hogan, a leading historian of the American presidency, offers a new perspective on John Fitzgerald Kennedy, as seen not from his life and times but from his afterlife in American memory. The Afterlife of John Fitzgerald Kennedy considers how Kennedy constructed a popular image of himself, in effect, a brand, as he played the part of president on the White House stage. The cultural trauma brought on by his assassination further burnished that image and began the process of transporting Kennedy from history to memory. Hogan shows how Jacqueline Kennedy, as the chief guardian of her husband's memory, devoted herself to embedding the image of the slain president in the collective memory of the nation, evident in the many physical and literary monuments dedicated to his memory. Regardless of critics, most Americans continue to see Kennedy as his wife wanted him remembered: the charming war hero, the loving husband and father, and the peacemaker and progressive leader who inspired confidence and hope in the American people.
The rededication of the Kennedy Presidential Library and Museum in 1993, one year before Jacqueline Kennedy's death, marked the culmination of her efforts to freeze in public memory the romantic image of her husband as the ideal American. The rededication followed a major renovation of the Columbia Point complex. Just as the Kennedys had once performed the presidency on the White House stage, the former first lady would now use the renovated museum, much like a theater, to reproduce her husband's life – not in all aspects, to be sure, but as she wanted others to see him. As before, the goal was to control the president's identity, define his legacy, and make him worthy of remembrance. With that goal in mind, a familiar narrative unfolded inside the museum, set amidst the usual props, precious artifacts, costumes, and symbols of the Kennedy presidency, but with little room left over for counternarratives or alternative memories. In its own way, the library half of the complex pursued the same goal. Family and friends still protected the president's memory, as they defined it, by limiting access to his records, favoring some scholars over others, and punishing those who would tarnish the sanctified image of the fallen hero. Not surprisingly, all of this led to yet another round of controversy between the library and the community of scholars who wanted to tell their own story of Kennedy's life and administration.
As this suggests, the library's purpose and that of the museum had not changed much, if at all, over the years. Nor, for that matter, had the ongoing debates, in both media commentary and historical scholarship, over how to define Kennedy and his place in American history. In the twenty years following the rededication of the Columbia Point complex, the old orthodoxy, once so aggressively championed by Jacqueline Kennedy, had only a little to add to what Schlesinger and Sorensen had said in the 1960s. Much the same was true of left-wing revisionism, which had its heyday in the 1970s and 1980s but faded thereafter. Some conservative critics, in their own version of revisionism, still denounced Kennedy as a weak and ineffective liberal while others made a tortuous effort to redefine the president as a virtuous conservative and precursor of Ronald Reagan.
As we have seen, President Kennedy's assassination and funeral marked a period of acute cultural trauma notable not only for its widespread feelings of grief, shock, and insecurity but also for its many “flashbulb” memories – of a child's adoring salute to his father, of a daughter's loving embrace of his casket, of a widow's strength and courage, of the eternal flame. For those on hand, not to mention the millions watching on television, these individual memories quickly folded into a collective memory that would last a lifetime. In this sense, the president's funeral served not only to calm a nervous nation, or even to burnish further the idealized image of the president and first lady as both had performed their parts on the White House stage. It also served as a frame of reference through which so many Americans would remember John F. Kennedy in the years following his tragic death.
Memories of the late president would quickly take on a sacred quality; his character would be ennobled and his virtues celebrated as those at the heart of the nation's identity. Here was the president as hero, the larger-than-life figure who was one of us, as Arthur G. Neal put it, but also the best of us. Here was the ideal American president, the man of charm and good humor, the optimistic and confident leader who inspired hope in the American people and the conviction that they could do anything. Here was the devoted husband and loving father, the tolerant and pragmatic idealist, the seeker of peace through security, the champion of social justice and human rights. Here was the decorated navy veteran who had given his life in service to the nation and from whose death would spring a new birth of American democracy.
This basically conventional narrative of national redemption through the blood sacrifice of a fallen leader became, for the Kennedy family and most Americans, the approved story of the president's life.