Citations

Background: White matter hyperintensities (WMH) are associated with risk of dementia and stroke, so are an important therapeutic target for clinical trials. The cost of broad MRI screening to identify those individuals with significant WMH, however, limits the feasibility of designing clinical trials which target WMH presence and which test treatments that slow progression. Hypothesis: A low-cost retinal or clinical screening measure prior to an MRI screening stage reduces the cost of recruiting persons with significant WMH burden in a hypothetical clinical trial vs an MRI-only screening design. Method: Data were from participants in the Atherosclerosis Risk in Communities-Neurocognitive study with clinical, retinal and WMH measurements ( N = 1311) at ages 53-70 years. Significant WMH burden was defined as a Cardiovascular Health Study score >2. Three low-cost pre-screening measures were assessed: (1) retinal: a score incorporating multiple markers of abnormal retinal vasculature, (2) clinical: a score incorporating hypertension, diabetes, and age, (3) combined retinal-clinical: a score incorporating retinal and clinical factors. Given a prior published target sample for a WMH clinical trial (N= 646), we calculated a theoretical screening sample size based on the proportion of each pre-screening measure in the population multiplied by the proportion of significant WMH burden among those with a prevalent pre-screening feature. Total recruitment cost was calculated using standard retinal ($32.50) and MRI ($650) cost estimates. Results: Compared to the estimated cost of MRI-only screening (>$4.24M, requiring MRI screening 6,526 participants), pre-screening for a high clinical score reduced total cost to $2.47M, but increased the initial screening group to 52,778 participants, of whom 3,801 would be screened by MRI). A high retinal-clinical score cutoff reduced costs to $2.9M while only requiring 13,572 screened participants (of these only 3,801 would require MRI). Conclusion: A 2-stage recruitment design with a low-cost pre-screening retinal and clinical measure is a promising approach, resulting in a reduction of theoretical recruitment costs for recruiting persons with significant WMH burden compared to an MRI-only design.

AbstractDespite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor.Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

664 Background: Postoperative complications in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. Further, the impact of preoperative hypofractionated radiotherapy on postoperative outcomes is largely unknown. We sought to quantify perioperative morbidity among patients with pancreatic cancer who received neoadjuvant modified FOLFIRINOX chemotherapy with or without hypofractionated radiotherapy on a multicenter clinical trial. Methods: The A021501 phase 2 trial randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX then hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (Dec 31, 2016-Jan 1, 2019). Patients underwent resection according to defined operative standards at enrolling centers without specific requirements for either surgeon or hospital volume. Surgical complications and adverse events were assessed and captured at a single time point of 90 days after surgery and compared between treatment arms. Results: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n=32, Arm 1; n=19, Arm 2) at 28 institutions. Vascular resection was performed in 19 patients (37%). One patient in Arm 2 died within 90 days after surgery. Rates of any surgical complication were 19% (n=6) in Arm 1 and 42% (n=8) in Arm 2 (p=0.07). Median length of stay was 7 days (range 5-38 days). Five (10%) patients required reoperation within 90 days. Readmission rates were higher in Arm 2 than Arm 1 (16% vs. 42%, p=0.04) but there were no differences in rates of reoperation, pancreatic fistula or abscess requiring drainage, or wound infection between study arms. 54% of patients (n=26/48) experienced a grade 3 or higher adverse event, with no difference between treatment arms (47% versus 67%, p=0.7). Rates of initiation of adjuvant therapy did not differ between treatment arms (66% vs. 68%, p=0.4). Pancreatic fistula and abscess were associated with adjuvant therapy (p<0.01). No difference in overall survival was observed based on occurrence of surgical complications (HR 1.1; 95% CI 0.5-2.6). Conclusions: In this national cooperative group study of patients with borderline resectable pancreatic cancer,postoperative complications following neoadjuvant chemotherapy, radiation, and surgical resection were consistent with rates previously reported by high-volume institutions and using large datasets. Multimodality trials of preoperative therapy for locoregionally advanced pancreatic cancer may be safely performed in the cooperative group setting. Clinical trial information: NCT02839343 .

17 Background: Age-appropriate colon cancer screening has long demonstrated effectiveness in reducing colon cancer incidence and mortality. However, despite a gradual rise in compliance with colon cancer screening, significant disparities remain, particularly among patients with limited English proficiency (LEP). Multitarget stool DNA (MT-sDNA) testing (Exact Sciences, Madison, WI) has been available over the past decade in the United States as a lower-cost and non-invasive option for screening. In 2019, Exact Sciences began to offer patient navigation services comprising outbound phone, text, and e-mail reminders, and inbound phone support (>200 languages) with all MT-sDNA orders. In this study, we aimed to evaluate the disparity in successful MT-sDNA testing between LEP and EP patients in a time frame when patient navigation services were active. Methods: We performed a retrospective cohort study of patients 45-75 years old enrolled in the primary care setting of our institution who received an order for MT-sDNA screening during a period in which patient navigation services began to be offered. A multi-state Cox model was constructed with time to MT-sDNA or other CRC screening predicted by English proficiency accounting for age and gender. Wald tests were used to test the association of CRC screening completion and English proficiency. Rates of completion of MT-sDNA screening and other CRC screening following MT-sDNA test ordering were calculated using the Kaplan-Meier method. Results: Of the 5016 patients evaluated and referred for multitarget stool DNA testing from May 1st, 2021, and May 1st, 2022, 154 patients were of LEP, and 4862 were English proficient (EP). At 180 days following a MT-sDNA test order the rate of completion for the LEP patients was 50.2% (95% CI: 42.8-58.7%) versus 70.3% (95% 69.1-71.6%) for EP individuals (p=0.001). A small portion of individuals also completed another type of CRC screen, 3.3% for LEP and 2.5% for EP (p=0.99). Conclusions: This study is consistent with the existing research demonstrating LEP as a significant demographic group linked with decreased participation in cancer screening. Our findings indicated that despite the availability of patient navigation services, individuals with LEP were still less likely to complete an MT-sDNA test successfully when compared to those with EP. [Table: see text]

AbstractMorbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra‐rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346–3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Although the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.

Abstract The Infectious Diseases Society of America Training Program Directors Committee met in October 2022 and discussed an observed increase in clinical volume and acuity on infectious diseases (ID) services, and its impact on fellow education. Committee members sought to develop specific goals and strategies related to improving training program culture, preserving quality education on inpatient consult services and in the clinic, and negotiating change at the annual IDWeek Training Program Director meeting. This paper outlines a presentation of ideas brought forth at the meeting and is meant to serve as a reference document for infectious diseases training program directors seeking guidance in this area.