Abstract Apolipoprotein E (APOE) genotype influences onset age of Alzheimer's disease but effects on disease progression are less clear. We investigated amyloid-β (Aβ) levels and change in ...relationship to APOE genotype, using 2 different measures of Aβ in 2 different longitudinal cohorts. Aβ accumulation was measured using positron emission tomography (PET) imaging and11 C-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and cerebral spinal fluid (CSF) Aβ1-42 assays in 207 BIOCARD study participants (mean age 62 years; 195 normal, 12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3–2.4). PET-PiB retention increased and CSF Aβ1-42 declined longitudinally. APOE ε4 was significantly associated with higher PET-PiB retention and lower CSF Aβ1-42, independent of age and sex, but APOE genotype did not significantly affect Aβ change over time. APOE ε4 carriers may be further along in the disease process, consistent with earlier brain Aβ deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease.
Medical schools seeking to correct and reform curricula towards anti-racist perspectives need to address anti-Black forms of racism specifically and teach students critical upstander skills to ...interrupt manifestations of racism. We developed a course to teach preclinical medical students basic anti-racism competencies including recognition and awareness of anti-Black racism in medicine and upstander skills to advocate for patients and colleagues.IntroductionMedical schools seeking to correct and reform curricula towards anti-racist perspectives need to address anti-Black forms of racism specifically and teach students critical upstander skills to interrupt manifestations of racism. We developed a course to teach preclinical medical students basic anti-racism competencies including recognition and awareness of anti-Black racism in medicine and upstander skills to advocate for patients and colleagues.In 2021 and 2022, we designed, implemented, and evaluated an elective course for second-year medical students (N = 149) to introduce competencies of anti-racism focusing on upstander skills for addressing anti-Blackness. We designed three patient cases and one student-centered case to illustrate manifestations of anti-Black racism in medicine and used these cases to stimulate small-group discussions and guide students toward recognizing and understanding ways of responding to racism. We designed pre- and postassessments to evaluate the effectiveness of the course and utilized anonymous feedback surveys.MethodsIn 2021 and 2022, we designed, implemented, and evaluated an elective course for second-year medical students (N = 149) to introduce competencies of anti-racism focusing on upstander skills for addressing anti-Blackness. We designed three patient cases and one student-centered case to illustrate manifestations of anti-Black racism in medicine and used these cases to stimulate small-group discussions and guide students toward recognizing and understanding ways of responding to racism. We designed pre- and postassessments to evaluate the effectiveness of the course and utilized anonymous feedback surveys.Participants showed significant improvement in pre- to postassessment scores in both years of the course. The anonymous feedback survey showed that 97% of students rated the course at least somewhat effective, and the qualitative responses revealed five core themes: course timing, case complexity, learner differentiation, direct instruction, and access to resources.ResultsParticipants showed significant improvement in pre- to postassessment scores in both years of the course. The anonymous feedback survey showed that 97% of students rated the course at least somewhat effective, and the qualitative responses revealed five core themes: course timing, case complexity, learner differentiation, direct instruction, and access to resources.This course reinforces upstander competencies necessary for advancing anti-racism in medicine. It addresses a gap in medical education by reckoning with the entrenched nature of anti-Black racism in the culture of medicine and seeks to empower undergraduate medical students to advocate for Black-identifying patients and colleagues.DiscussionThis course reinforces upstander competencies necessary for advancing anti-racism in medicine. It addresses a gap in medical education by reckoning with the entrenched nature of anti-Black racism in the culture of medicine and seeks to empower undergraduate medical students to advocate for Black-identifying patients and colleagues.
Objective
This study aimed to test the efficacy of self‐monitoring and feedback (SM+FB) versus SM without FB (SM) in a behavioral weight‐loss intervention at 6 months.
Methods
This was a randomized ...clinical trial. Eligibility criteria included the following: ≥18 years of age, BMI ≥ 27 and ≤43, smartphone user, and ability to engage in moderate physical activity. All participants received a 90‐minute 1:1 counseling session, a Fitbit Charge 2, and a digital scale for SM. SM+FB participants were provided access to a customized smartphone application that provided three daily FB messages. The primary outcome was percentage of weight change from 0 to 6 months.
Results
The sample (N = 502) was 45 (SD 14.4) years old, BMI was 33.7 (SD 4.00) kg/m2, 79.5% of participants were female (n = 399), and 84.3% were White (n = 423). At 6 months, there was 85.86% retention and a significant percentage of weight change in both groups (SM+FB: −3.16%, 95% CI: −3.85% to −2.47%, p < 0.0001; SM: −3.20%, 95% CI: −3.86% to −2.54%, p < 0.0001) but no significant between‐group mean difference (−0.04%, 95% CI: −0.99% to 0.91%, p = 0.940). A ≥5% weight loss was achieved by 31.9% of the SM+FB group and 28.3% of the SM group.
Conclusions
There was no significant between‐group difference in weight loss at 6 months.
Purpose
The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters
123
I-iodide,
131
I-iodide and
99m
Tc-pertechnetate. ...However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate
18
F-labelled tetrafluoroborate (
18
FTFB) for PET imaging of hNIS.
Methods
18
FTFB was prepared by isotopic exchange of BF
4
−
with
18
Ffluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition.
Results
18
FTFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate.
Conclusion
18
FTFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans.
Hummingbirds are nature's masters of aerobatic manoeuvres. Previous research shows that hummingbirds and insects converged evolutionarily upon similar aerodynamic mechanisms and kinematics in ...hovering. Herein, we use three-dimensional kinematic data to begin to test for similar convergence of kinematics used for escape flight and to explore the effects of body size upon manoeuvring. We studied four hummingbird species in North America including two large species (magnificent hummingbird, Eugenes fulgens, 7.8 g, and blue-throated hummingbird, Lampornis clemenciae, 8.0 g) and two smaller species (broad-billed hummingbird, Cynanthus latirostris, 3.4 g, and black-chinned hummingbirds Archilochus alexandri, 3.1 g). Starting from a steady hover, hummingbirds consistently manoeuvred away from perceived threats using a drastic escape response that featured body pitch and roll rotations coupled with a large linear acceleration. Hummingbirds changed their flapping frequency and wing trajectory in all three degrees of freedom on a stroke-by-stroke basis, likely causing rapid and significant alteration of the magnitude and direction of aerodynamic forces. Thus it appears that the flight control of hummingbirds does not obey the 'helicopter model' that is valid for similar escape manoeuvres in fruit flies. Except for broad-billed hummingbirds, the hummingbirds had faster reaction times than those reported for visual feedback control in insects. The two larger hummingbird species performed pitch rotations and global-yaw turns with considerably larger magnitude than the smaller species, but roll rates and cumulative roll angles were similar among the four species.
Medical school can be a socially isolating experience, particularly for students underrepresented in medicine. Social isolation and perceptions of not belonging can negatively impact students' ...academic performance and well-being. Therefore, interventions are needed to support students and these efforts should be appealing, brief, and low-burden.
Guided by evidence-based approaches, we developed the Build & Belong intervention for medical students as a brief peer-to-peer approach that consisted of four components. First, M3 and M4 students wrote reflections on belonging in medical school. Second, M3 and M4 students video recorded messages for M1 and M2 students using their written reflections. Third, M1 and M2 students watched and discussed the videos in small groups. Fourth, the M1 and M2 students wrote letters to future students. Our intervention differs from previous student belonging interventions in the peer delivery of messages.
The Build & Belong intervention aimed to improve medical students' social belongingness. Using a longitudinal observational study design, the intervention was piloted at a medical school in the Mid-Atlantic United States in 2017-2018. Students completed surveys before and after the intervention. Paired samples tests (t-tests and Wilcoxon) assessed pre- to post-intervention changes in social isolation, social connectedness, and social assurance.
Among 63 medical students, with 25.9% from backgrounds underrepresented in medicine, we assessed follow-up outcomes in 38 students. Social isolation scores significantly decreased from baseline (M = 54.8, SD = 7.06) to follow-up (M = 51.3, SD = 6.67; p < .001). Social isolation changes were evident regardless of sex, although males reported a greater reduction (M Δ = −5.32, p < .001) than females (M Δ = −2.79, p = .014). Black/African American students had the largest reduction in social isolation (M Δ = −7.24, p = .010). Social assurance and connectedness scores did not change significantly between baseline and follow-up. Medical students appeared to resonate with messages delivered by more experienced peers (M3s and M4s), particularly messages that normalized feelings of not belonging and strategies to reduce those feelings.
The Build & Belong intervention appears to reduce social isolation scores among medical students. This pilot test of the Build & Belong intervention provides initial evidence of the effectiveness of a brief, low-cost intervention. Build & Belong may provide a scalable strategy to reduce medical students' social isolation. Our peer-based approach is distinct from administrator-led strategies; peers were seen as trusted and reliable sources of information about belonging and ways to overcome the challenges experienced during medical school.
Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological ...impact. This survey study aimed to characterize these methods.
A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children.
Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality.
Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers.
Certain genomic features, such as del(11q), expression of unmutated immunoglobulin heavy-chain variable region (IGHV) gene, or complex karyotype, predict poorer outcomes to chemotherapy in patients ...with chronic lymphocytic leukemia (CLL).
We examined the pooled long-term follow-up data from PCYC-1115 (RESONATE-2), PCYC-1112 (RESONATE), and CLL3001 (HELIOS), comprising a total of 1238 subjects, to determine the prognostic significance of these markers in patients treated with ibrutinib.
With a median follow-up of 47 months, ibrutinib-treated patients had longer progression-free survival (PFS) than patients treated in the comparator arm, regardless of genomic risk factors. Among patients treated with ibrutinib, we found that high-risk genomic features were not associated with shorter PFS (63-75% across all subgroups at 42 months) or overall survival (79-83% across all subgroups at 42 months). Surprisingly, we observed that ibrutinib-treated patients with del(11q) actually had a significantly longer PFS than ibrutinib-treated patients without del(11q) (42-month PFS rate 70% vs. 65%, P = .02).
These analyses not only demonstrate that genomic risk factors previously associated with poor outcomes lose their adverse prognostic significance but also that del(11q) can be associated with a superior PFS with ibrutinib therapy.
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A pooled analysis of 1238 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma from three phase 3 studies found that genomic risk factors were not associated with shorter progression-free survival (PFS) or overall survival for patients treated with ibrutinib. Ibrutinib-treated patients with del(11q) were found to have a longer PFS than those without del(11q). These results suggest less prognostic relevance for certain genomic risk factors with ibrutinib treatment.
The mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC) is negatively regulated by reversible phosphorylation. BCKDC kinase (BDK) inhibitors that augment BCKDC flux have been shown ...to reduce branched-chain amino acid (BCAA) concentrations in vivo. In the present study, we employed high-throughput screens to identify compound 3,6-dichlorobenzobthiophene-2-carboxylic acid (BT2) as a novel BDK inhibitor (IC50 = 3.19 μm). BT2 binds to the same site in BDK as other known allosteric BDK inhibitors, including (S)-α-cholorophenylproprionate ((S)-CPP). BT2 binding to BDK triggers helix movements in the N-terminal domain, resulting in the dissociation of BDK from the BCKDC accompanied by accelerated degradation of the released kinase in vivo. BT2 shows excellent pharmacokinetics (terminal T½ = 730 min) and metabolic stability (no degradation in 240 min), which are significantly better than those of (S)-CPP. BT2, its analog 3-chloro-6-fluorobenzobthiophene-2-carboxylic acid (BT2F), and a prodrug of BT2 (i.e. N-(4-acetamido-1,2,5-oxadiazol-3-yl)-3,6-dichlorobenzobthiophene-2-carboxamide (BT3)) significantly increase residual BCKDC activity in cultured cells and primary hepatocytes from patients and a mouse model of maple syrup urine disease. Administration of BT2 at 20 mg/kg/day to wild-type mice for 1 week leads to nearly complete dephosphorylation and maximal activation of BCKDC in heart, muscle, kidneys, and liver with reduction in plasma BCAA concentrations. The availability of benzothiophene carboxylate derivatives as stable BDK inhibitors may prove useful for the treatment of metabolic disease caused by elevated BCAA concentrations.
Background: Branched-chain amino acids (BCAA) are elevated in maple syrup urine disease, obesity, and type 2 diabetes.
Results: We show that benzothiophene carboxylate derivatives are allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase (BDK).
Conclusion: These BDK inhibitors robustly augment BCAA oxidation in mice, resulting in lower plasma BCAA.
Significance: The BDK inhibitors are potentially useful for treatment of the above disorders.
To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 ...high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10−4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 × 10−13 overall; P = 6.9 × 10−12 replication), and rs16892766, at 8q23.3 (P = 3.3 × 10−18 overall; P = 9.6 × 10−17 replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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