The whole grain manifesto: From Green Revolution to Grain Evolution

Grains have historically represented a major component of human diets and were predominantly consumed in whole form until the first half of the 19th century, when a combination of technological innovations and market dynamics made refined grains, hitherto a premium product, affordable and available to the masses. Grains still account for more than half of the total caloric intake among vulnerable populations worldwide, and their dominant consumption in refined form turns a nutrient-dense, protective food into a nutrient-poor one contributing to growing rates of obesity and noncommunicable disease. Shifting a substantial portion of global grain consumption to whole grains is potentially one of the most significant and achievable improvements to diets and food systems worldwide. In countries with significant micronutrient deficiencies, a switch from refined to fortified whole grain foods can enable institutional channels such as school feeding programs to measurably improve diet quality in a budget-neutral way.

Response Adapted Ultra Low Dose Radiation Therapy for the Definitive Management of Orbital Indolent B-Cell Lymphoma

Radiation therapy (RT) to doses of 24-30 Gy is used for the treatment of indolent B-cell lymphoma (BCL);however, significant acute and late ocular effects are common. We aimed to develop a response adapted (RA) strategy that maintains excellent disease outcomes but reduces orbital morbidity. We performed a phase II prospective study of a RA strategy in 50 patients (pts) with stage I-IV orbital indolent BCL. Pts were treated with ultra-low dose (ULD) RT to 4 Gy in 2 fractions and assessed in 3-month intervals for response. Pts with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions. Pts that had a complete response (CR) to ULD RT were observed. We also evaluated this treatment strategy in a separate 55 pt retrospective cohort. From July 2015-January 2021 51 pts were enrolled. Fifty evaluable pts had follow-up for study inclusion. The median age was 63 years (29-88);62% were female (n=31). Pts had MALT lymphoma (n=32, 64%), follicular lymphoma (FL, n=16, 32%) and low grade BCL (n=6, 12%). Most pts (62%, n=31) had stage I disease limited to one (n=28) or both (n=3) orbits. Pts had newly diagnosed (n=36, 72%);relapsed (n=9, 18%) and refractory lymphoma (n=5, 10%). At a median follow up of 35 months [95% CI 22.2 – 37.4], 90% of pts (n=45) experienced a CR to RA RT, including 44 pts that had a CR to ULD RT (median time to CR 3.4 months) and 1 pt that had a CR after an additional 20 Gy. No local recurrences were observed. Treatment was well tolerated with no grade ≥3 toxicity. Five pts did not have a CR to planned RA therapy including 1 pt that refused additional RT, one pt treated with rituximab, one pt that had a PR on initial evaluation but has not returned for subsequent in person evaluations due to COVID, one pt being observed with stable disease and a final pt that received an additional 20 Gy to the orbit that has a persistent stable mass after the 20 Gy. In a planned subset analysis of 26 pts with newly diagnosed stage 1 disease (MALT, n=22;FL, n=3;low grade BCL, n=1);92.3% (n=24) had a CR to RA RT, with one pt requiring an additional 20 Gy. For all 26 pts with newly diagnosed stage 1 disease, the 3-year freedom from distant relapse rate was 90.4% with 3 distant relapses (contralateral orbit, n=2;paratracheal nodes, n=1). The median follow-up among the 55 pts (MALT, n=38;FL, n=13;low grade B-cell lymphoma, n=4) treated in the retrospective cohort between March 2013 and October 2021 was 28.7 months (95% CI 21.2 - 36.1);98% (n=54) of pts had a CR with RA RT, including 2 pts with a CR after an additional 20 Gy. The remaining pt went on to receive systemic therapy in lieu of additional RT for persistent disease. Among the 54 pts that had a CR with RA RT there was one local relapse in a pt with conjunctival FL 27.8 months after experiencing a CR to ULD RT. This pt received 20 Gy with resolution of the locally relapsed disease. We observed excellent disease control with negligible toxicity in the first prospective study assessing this novel approach of RA ULD RT for pts with indolent B-cell lymphoma. [ FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Quality of Sexual and Reproductive Health Services for Adolescents: Findings from A Survey of U.S. Physicians

Purpose: Quality sexual and reproductive health (SRH) care for adolescents includes implementation of youth-friendly clinical practices (e.g., practices that support minor’s rights to confidential care) and provision of recommended clinical services (e.g., access to the full range of contraceptive methods). There is limited data from providers regarding the quality of SRH care for adolescents in the United States. This analysis examines physician-reported prevalence of youth-friendly practices and SRH services overall and by physician specialty to inform focused improvement efforts. Methods: Data were from the DocStyles online panel survey administered with U.S. healthcare providers September-October 2020. The survey assessed whether the following youth-friendly practices were in place just before the COVID-19 pandemic: walk-in hours, evening/weekend hours, time alone with a provider at every visit, confidentiality policy communicated at every visit, and routine encouragement of parent-adolescent communication. SRH services assessed included long-acting reversible contraception (LARC) insertion and removal, clinic-based sexually transmitted infection (STI) testing, and counseling about STI prevention at contraception initiation. We restricted the analytic sample to family practitioners (n=364), internists (n=247), pediatricians (n=180), and obstetricians/gynecologists (n=213) primarily working in outpatient settings who reported providing family planning or STI services to at least one patient aged 15-19 years per week just before the pandemic. Descriptive statistics were calculated overall and for each physician specialty, and chi-squared tests were used to examine differences. We also explored associations between physician-report of adolescent SRH quality improvement (QI) efforts in the year just before the pandemic and each youth-friendly practice and SRH service. Generalized linear models were used to produce adjusted prevalence ratios (APR) controlling for physician specialty, individual versus group practice, and adolescent patient volume for SRH services. Results: Among physicians who provided SRH services to adolescents overall, the proportion with youth-friendly practices in place ranged from 44.7% for weekend/evening hours available to 60.5% for routine encouragement of parent-adolescent communication. Walk-in hours and evening/weekend hours available were highest for pediatricians and lowest for obstetricians/gynecologists. Nearly three-quarters of pediatricians and obstetricians/gynecologists reported always providing time alone and communicating the confidentiality policy whereas only about half of family physicians and one-third of internists reported each of these practices. Overall, 37.6% reported their practice provided LARC placement and removal, 79.3% provided clinic-based STI testing, and 66.3% always discussed STI prevention with adolescents initiating contraception. Across these services, prevalence was consistently highest for obstetricians/gynecologists and lowest for internists, although the proportion of internists and pediatricians providing LARC services was similarly low (12.2% and 13.3%, respectively). Overall, about one-quarter (28.5%) of physicians reported that adolescent SRH QI efforts were conducted in the past year, and QI was associated with increased likelihood of having youth-friendly practices in place and providing SRH services for all indicators except weekend/evening hours and LARC services (APR range: 1.10-1.55). Conclusions: Findings suggest opportunities to improve youth-friendly practices and delivery of SRH services for adolescents, which vary by physician specialty. Implementing adolescent-focused SRH QI initiatives may be one approach to strengthening certain youth-friendly practices and clinical services. Sources of Support: None.

Opportunities for fellowship education: the first year of the Medical Biochemical Genetics Clinical Core Seminar Series

Background: The Medical Biochemical Genetics (MBG) Fellowship is an Accreditation Council of Graduate Medical Education (ACGME) subspecialty,one-year training program designed to prepare ClinicalMedical Genetics and Genomics graduates for practice in the diagnosis and treatment of inborn errors of metabolism (IEM). The ACGMErequires each program to provide “structured education, includingformal coursework in the basic sciences and clinical areas pertinent tobiochemical genetics”. There are currently 19 programs around theUnited States (US). Most have only one fellow per year. An average of18 MBG fellows every two years sit for the board examination. Eachprogram has a separate, individual curriculum. This puts a potentiallylarge burden on faculty to generate and teach didactic lectures for asingle fellow per year, and limits the fellow to learn in isolation,without interaction with the greater US IEM community. In 2020,amidst the COVID-19 pandemic, faculty at the University of Coloradoapproached the program directors of the individual MBG programsacross the US to establish a unified MBG curriculum to meet the“formal coursework” requirement. Twelve MBG programs opted totake part.Methods: A curriculum, designated as the MBG Clinical Core SeminarSeries (CCSS),was established to included 13 lectures covering contentfrom the American Board of Medical Genetics and GenomicsBiochemical Genetics Blueprint. Sessions were held weekly fromAugust through November of 2020 using a virtual platform (https://zoom.us/). Each session was designated to be 90 minutes: 75 min fordidactic teaching and 15 min for questions/interaction with the facultyspeaker and one another. Lectures were taught by expert faculty,boarded in Medical/Clinical Biochemical Genetics and well-known inthe field for the lecture subject matter. Invitations were sent out toMBG programs nationwide, and responding participants were addedto an email listserv that was kept through the MBG program at theUniversity of Colorado. Attendance was not limited to MBG fellows,but faculty were instructed to focus on MBG fellows as the primaryaudience. After each lecture, opportunity was given to all participantsto engage in a brief survey to evaluate the class using 3 generalquestions (see below) and response both by free text and using a Likertscale (5 = Strongly Agree to 1 = Strongly Disagree). Lectures wererecorded on ZOOM, and recordings with accompanying referencematerialwere distributed to the entire listserv using a Dropbox link, aswell as uploaded and stored on the Society for Inherited MetabolicDisease website.Results: The number of participants on the listservwas 217 by the endof the lecture series. Synchronous participation included an average of75 participants per session. In total, there were 98 responses to thethree questions in the survey. Respondents include both MBG andClinical Biochemical Genetics (CBG) fellows (22 responses), as well asattending physicians, genetics/pediatrics residents, genetic counselors,advanced practice providers, and nurses. Participants scored thethree questions as follows: “This session will improve my ability todiagnose and manage metabolic patients” (4.60 ± 0.59);“This sessionmade me feel more connected to the larger metabolic community”(4.62 ± 0.65);and “This session was high-yield given breadth anddepth of content and time allotted” (4.61 ± 0.65). Of note, MBG andCBG fellow responses to the three questions were 4.73 ± 0.54,4.36 ± 0.83, and 4.77 ± 0.41, respectively. Free text comments weregenerally positive, with the major critiques being the large amount ofcontent for time allotted and the desire for board-related practicequestions.Conclusions: The MBG-CCSS endeavored to create a unique opportunityfor trainees to network, facilitate teaching by nationallyrecognized experts, and minimize duplication of effort in individualtraining programs. These goals were all achieved with great success.An unexpected finding was the level of interest from a much largernumber of individuals than expected, far more than th US cohort ofMBG fellows. This points to a significant unmet demand for IEMfocusededucation at all levels around the country. Evaluation scoresfrom fellows, as well as comments, indicate several areas forimprovement including 1) less content per session 2) more participantinteraction 3) incorporated board practice questions and 4) formalassessment of knowledge using a written final exam. We will alsostrive to improve fellow-fellow and fellow-faculty dialogue through interactive questions and smaller fellow-faculty-only discussions.Moving forward, we will continue to build on the success of the firstyear, to prepare and inspire IEM providers for independent clinicalpractice

Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma

Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. [Formula presented] Disclosures: Nikolaenko: Pfizer: Research Funding;Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau;Amgen: Consultancy, Speakers Bureau;Pharmacyclics: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;AbbVie: Membership on an entity's Board of Directors or advisor committees;CBM Biopharma: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Research Funding;Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy;Kymera: Consultancy;Karyopharm: Consultancy;AbbVie: Consultancy;Seagen Inc.: Research Funding;Allogene Therapeutics: Consultancy;Astra-Zeneca: Consultancy;Incyte Corporation: Consultancy;BeiGene: Consultancy;Bluebird Bio: Consultancy;Genmab: Consultancy;EMD Serono: Consultancy;Bristol-Myers Squibb Company: Consultancy, Research Funding;C4 Therapeutics: Consultancy;Morphosys: Consultancy;Kite Pharma: Consultancy;Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy;Shoreline Biosciences, Inc.: Consultancy;Tubulis: Consultancy;Verastem: Research Funding;ONO Pharmaceuticals: Consultancy;Myeloid Therapeutics: Consultancy;SecuraBio: Consultancy, Research Funding;Trillium Therapeutics: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Millennium /Takeda: Consultancy, Research Funding;Kura Oncology: Consultancy;Janssen: Consultancy;Kyowa Hakko Kirin: Consultancy, Research Funding;Forty Seven, Inc.: Research Funding;Daiichi Sankyo: Research Funding;C4 Therapeutics: Consultancy;Celgene: Research Funding;Aileron: Research Funding;Affimed: Research Funding;Acrotech Biopharma: Consultancy;ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding;Teva: Consultancy;Janssen: Honoraria, Research Funding;Bayer: Consultancy, Honoraria, Research Funding;Genentech, Inc.: Consultancy, Honoraria, Research Funding;Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;IGM Biosciences: Research Funding;Merck: Consultancy;Juno Therapeutics: Consultancy;TG Therapeutics: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Research Funding;Memorial Sloan Kettering Cancer Center: Current Employment;Pharmacyclics: Honoraria, Research Funding;Daiichi Sankyo: Consultancy;ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria;Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding;Morphosys: Consultancy;Targeted Oncology: Consultancy;Medscape: Consultancy;Pharmacyclics: Consultancy, Research Funding;Janssen: Consultancy, Honoraria;Epizyme: Consultancy. OffLabel Disclosure: CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis

Preliminary activity of devimistat (CPI 613) in patients with relapsed or refractory burkitt lymphoma/leukemia

Introduction: Patients (pts) with primary refractory or relapsed Burkitt lymphoma/leukemia (BL) or high-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit, DHL) and/or BCL6 (triple hit, THL) have a dismal prognosis. A dysregulated MYC oncogene has downstream effects on proliferation and highly glycolytic metabolism with tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. Devimistat is a non-redox active analogue of lipoic acid, a required cofactor for two key TCA cycle mitochondrial enzymes: pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption results in a shutdown of ATP and biosyntheticintermediate production leading to cancer cell death. In a phase I trial (n = 26) a pt with multiply refractory BL had a partial remission sustained over one year prior to resection. She remains in remission 7 years later. As of March 2021, 20 clinical studies in over 700 pts with various cancers have been conducted (ongoing/completed) with devimistat. We initiated a phase II trial to further explore efficacy. Methods: NCT03793140 is a multicenter study enrolling 17 patients on each of two cohorts BL or DHL/THL. Pts must have had one prior therapy or are refusing standard of care, measurable disease or isolated bone marrow involvement, and must not be within 3 months of a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks and the maintenance intrathecal/intraOmmaya therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance every 21 days. Pts are evaluable for response if they receive at least 4/5 days of the first cycle. At least 1response in the first 9 pts by cycle 3 was needed to expand to 17 pts in total in that cohort. Results: 9 pts were enrolled in the DHL/THL arm. Number of prior therapies was 3(1-6). No responses and only 1 stable disease resulted in cohort closure. Thus far, 8 BL pts were enrolled. Number of prior therapies was 3 (2-4). 2 pts were inevaluable. 1/6 pts had a response. This HIV+ pt had a thigh mass having received 4 prior therapies. He had a near complete metabolic remission after 3 cycles of devimistat. PET/CT assessment: Thigh lesion baseline October 19, 2020: 10.8 x 6.5 cm SUV 24. After cycle 3: unmeasurable, SUV 2. He is currently in cycle 7, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of March 03, 2021, no serious AEs related to study drug. 4 pts had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the near complete remission in this patient is promising in a disease where no viable treatment options exist.