Evaluation of Interprofessional Delivery of Diabetes Medication Management Training Among Family Medicine Residents.

OBJECTIVE: Diabetes-related care makes up approximately 24% of outpatient clinic visits. Therefore, confidence and understanding of diabetes management is necessary for family medicine residents. METHODS: We developed a combined lecture and simulation lab curriculum utilizing a registered nurse and pharmacist to deliver education to 20 family medicine learners. Pre and post surveys of the educational material were completed in 2 sections including one gauging medical knowledge and a second part gauging level of comfort. RESULTS: Of the learners who participated, fourteen completed the pre-post surveys. Most (53%) respondents improved their scores, while 20% scored the same 27% scored worse. The overall average score increased 57% to 70% and improvement was statistically significant (P < .05). All learners improved confidence by at least 1 point. CONCLUSION: An interprofessional team utilizing a lecture curriculum focusing on providing education on effective prescribing, medication safety profiles, and resource availability, showed improvement in confidence but mixed knowledge benefit. Further modifications to the curriculum may yield further educational gains.

Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.

Benefits of Cochlear Implantation for Older Adults With Asymmetric Hearing Loss.

OBJECTIVE(S): FDA-approved indications for cochlear implantation include patients with severe-to-profound unilateral hearing loss (UHL) or asymmetric hearing loss (AHL); however, these indications are not covered for Medicare beneficiaries. We assessed the outcomes of cochlear implant (CI) use for older adults with UHL or AHL. METHODS: Eighteen older adults (≥65 years of age at surgery) with UHL/AHL participated in a prospective, longitudinal investigation evaluating outcomes of CI use. Speech recognition for the affected ear was evaluated with consonant-nucleus-consonant (CNC) words. Spatial hearing was assessed with measures of sound source localization and sentence recognition in noise. The target sentence was presented from the front and the masker was either co-located with the target (SoNo), presented toward the affected ear (SoNci) or contralateral ear (SoNcontra). Perceived benefit was assessed with the Speech, Spatial, and Qualities of Hearing scale (SSQ) and the Tinnitus Handicap Inventory (THI). RESULTS: Participants experienced significant improvements with CI use for CNC words (mean [SD]; preop: 8% [10%], 1 yr: 51% [22%], 5 yr: 50% [19%]), masked sentence recognition (SoNcontra preop: 5% [6%], 1 yr: 22% [15%], 5 yr: 41% [14%]), and localization (preop: 76° [18°], 1 yr: 40° [11°], 5 yr: 41° [14°]), and reported significant improvements in hearing abilities (SSQ Spatial Hearing preop: 3 [1], 1 yr: 6 [2], 5 yr: 6 [2]) and tinnitus severity (THI preop: 16 [18], 1 yr: 4 [14], 5 yr: 6 [12]). CONCLUSION: Older adults with UHL/AHL experience significant improvements in speech recognition, spatial hearing, and subjective perceptions (e.g., hearing abilities and tinnitus severity) with a CI as compared to pre-operative abilities. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

A Cross-Sectional Analysis of Factors Promoting Intergenerational Resilience in Adolescent Youth With Refugee Status.

BACKGROUND: Adolescent youth occupy a critical and complex position in refugee families who resettle in a third country. OBJECTIVES: We examined the potential impact of health- and family-related factors on the social and behavioral adjustment outcomes of refugee adolescent youth. METHODS: Situated within an explanatory sequential mixed methods study, we used unadjusted and adjusted multinomial logistic regression to identify trauma, health, and socioecological characteristics of war-affected families associated with social and behavioral adjustment in 72 Karen adolescent youth resettled in the United States. RESULTS: Factors related to the health and well-being of war-affected families, including parent mental and physical health, youth-reported family function, housing, and parent employment demonstrated important associations with youth adjustment. CONCLUSION: These findings, originating within the complex dynamics of resettled war-affected families, demonstrated the interconnectedness of adolescent and parent experiences and opportunities to advance resilience in youth navigating integration and supporting their families through those same processes.

Trauma-Informed Professional Development: An Intervention Mapping Study.

BACKGROUND AND SIGNIFICANCE: Nurses are disproportionately affected by mental and physical health problems that are a result of exposure to traumatic events in the workplace. PURPOSE: The purpose of this study was to use intervention mapping strategies to construct interventions to address traumatic stress in nurses through trauma-informed professional development (TIPD) in a rehabilitation hospital. DESIGN: This study used a community-based participatory research design with an intervention mapping approach. Logic models were created through input from theory, evidence from the literature, and feedback from 12 focus groups with leaders, nursing professional development practitioners, and direct-care nurses. FINDINGS: Major themes in the logic models included safety, empowerment, peer support, and awareness. These findings were used to create specific TIPD interventions to be used with nurses in a rehabilitation hospital.

Speech Recognition and Subjective Hearing Abilities for Electric-Acoustic Stimulation Users With Unilateral Hearing Loss.

OBJECTIVE: Some cochlear implant (CI) recipients with unilateral hearing loss (UHL) have functional acoustic hearing in the implanted ear, warranting the fitting of an ipsilateral electric-acoustic stimulation (EAS) device. The present study assessed speech recognition and subjective hearing abilities over time for EAS users with UHL. STUDY DESIGN: Prospective, repeated-measures. SETTING: Tertiary referral center. PATIENTS: Adult CI recipients with normal-to-moderate low-frequency acoustic thresholds in the implanted ear and a contralateral pure-tone average (0.5, 1, and 2 kHz) ≤25 dB HL. MAIN OUTCOME MEASURES: Participants were evaluated preoperatively and at 1, 3, and 6 months post-activation. Speech recognition for the affected ear was evaluated with CNC words in quiet. Masked speech recognition in the bilateral condition was evaluated with AzBio sentences in a 10-talker masker (0 dB SNR) for three spatial configurations: target from the front and masker either colocated with the target or presented 90 degrees toward the affected or contralateral ear. Responses to the Speech, Spatial, and Qualities of Hearing Scale subscales were used to assess subjective hearing abilities. RESULTS: Participants experienced significant improvements in CNC scores ( F(3,13) = 14.90, p < 0.001), and masked speech recognition in the colocated ( F(3,11) = 3.79, p = 0.043) and masker toward the contralateral ear ( F(3,11) = 4.75, p = 0.023) configurations. They also reported significantly better abilities on the Speech Hearing ( F(3,13) = 5.19, p = 0.014) and Spatial Hearing ( F(3,13) = 10.22, p = 0.001) subscales. CONCLUSIONS: Adults with UHL and functional acoustic hearing in the implanted ear experience significant improvements in speech recognition and subjective hearing abilities within the initial months of EAS use as compared with preoperative performance and perceptions.

The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond.

Glioblastoma multiforme (GBM) is one of the deadliest human cancers with very limited treatment options available. The malignant behavior of GBM is manifested in a tumor which is highly invasive, resistant to standard cytotoxic chemotherapy, and strongly immunosuppressive. Immune checkpoint inhibitors have recently been introduced in the clinic and have yielded promising results in certain cancers. GBM, however, is largely refractory to these treatments. The immune checkpoint CD47 has recently gained attention as a potential target for intervention as it conveys a "don't eat me" signal to tumor-associated macrophages (TAMs) via the inhibitory SIRP alpha protein. In preclinical models, the administration of anti-CD47 monoclonal antibodies has shown impressive results with GBM and other tumor models. Several well-characterized oncogenic pathways have recently been shown to regulate CD47 expression in GBM cells and glioma stem cells (GSCs) including Epidermal Growth Factor Receptor (EGFR) beta catenin. Other macrophage pathways involved in regulating phagocytosis including TREM2 and glycan binding proteins are discussed as well. Finally, chimeric antigen receptor macrophages (CAR-Ms) could be leveraged for greatly enhancing the phagocytosis of GBM and repolarization of the microenvironment in general. Here, we comprehensively review the mechanisms that regulate the macrophage phagocytosis of GBM cells.

Feasibility of a new 'balanced binocular viewing' treatment for unilateral amblyopia in children aged 3-8 years (BALANCE): results of a phase 2a randomised controlled feasibility trial.

OBJECTIVES: This study aimed to evaluate the safety of dichoptic balanced binocular viewing (BBV) for amblyopia in children, plus feasibility, adherence, acceptability, trial methodology and clinical measures of visual function. DESIGN: We carried out an observer-masked parallel-group phase 2a feasibility randomised controlled trial. SETTING: Two study sites, a secondary/tertiary and a community site. PARTICIPANTS: We enrolled 32 children aged 3-8 years with unilateral amblyopia who had completed optical adaptation where indicated. 20 children attended the 16-week exit visit (retention 63%). INTERVENTIONS: Children were randomised to BBV (movies customised to interocular acuity difference at baseline) for 1 hour a day (active intervention) or standard management as per parental choice (part-time occlusion or atropine blurring, control). All interventions were used at home, daily for 16 weeks. PRIMARY OUTCOME MEASURE: 'VacMan suppression test' of interocular balance at 16 weeks from randomisation. SECONDARY OUTCOME MEASURES: feasibility outcomes (recruitment and retention ratios, adherence with the allocated intervention); safety outcomes at other time points (changes in prevalence of diplopia, manifest strabismus, suppression/interocular balance on a range of tests); efficacy outcomes (clinical measures of visual function, such as best-corrected visual acuity, BCVA). Outcome measures were identical to those planned in the protocol. RESULTS: Primary outcome: At baseline, values for the interocular balance point were higher (indicating greater suppression of the amblyopic eye) in the occlusion group than in the BBV group. These values shifted downwards on average for the occlusion group, significantly decreasing from baseline to week 16 (t8=4.49, p=0.002). Balance values did not change between baseline and week 16 for the BBV group (t9=-0.82, p=0.435). At 16 weeks, there was no statistical difference in interocular balance/suppression change over time between the two arms. The difference at follow-up between the arms, adjusted for baseline, was -0.02 (95% CI -0.28 to 0.23, p=0.87). FEASIBILITY: We prescreened 144 records of potentially eligible children. Between 28 October 2019 and 31 July 2021, including an interruption due to the COVID-19 pandemic, 32 children were screened and randomised (recruitment rate 22%), 16 to BBV and 16 to standard treatment. 20 children attended the 16-week exit visit (retention 63%). Mean adherence with BBV as proportion of viewing time prescribed was 56.1% (SD36) at 8 and 57.9% (SD 30.2) at 16 weeks. Mean adherence with prescribed occlusion time was 90.1% (SD 19.7) at 8 and 59.2% (SD 24.8) at 16 weeks. SECONDARY SAFETY/EFFICACY OUTCOMES: One child in the BBV arm reported transient double vision, which resolved; two reported headaches, which led to withdrawal. BCVA improved from mean 0.47 (SD0.18) logMAR at randomisation to 0.26 (0.14) with standard treatment, and from 0.55 (0.28) to 0.32 (0.26) with BBV. Outcomes at 16 weeks did not differ between treatments. PARTICIPANT EXPERIENCE: Families were generally positive about BBV, but families found both patching and BBV difficult to integrate into family routines. CONCLUSIONS: Recruitment rates indicate that a future phase 3 trial will require multiple sites or a longer enrolment period. Retention and adherence rates were lower than anticipated, which will influence future study designs. Dichoptic treatment may be equal to occlusion treatment in safety and efficacy; headaches may lead to discontinuation. Integration into family routines may constitute a barrier to implementation. TRIAL REGISTRATION NUMBER: NCT03754153.

HIV BG505 SOSIP.664 trimer with 3M-052-AF/alum induces human autologous tier-2 neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140, formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding and immunogenicity in a first-in-healthy adult (n=17), randomized, placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, B-cell and CD4+ T-cell responses emerged post-vaccination. Five vaccinees developed serum autologous tier-2 nAbs (ID50 titer, 1:28-1:8647) after 2-3 doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B-cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes. KEY TAKEAWAY/TAKE-HOME MESSAGES: HIV BG505 SOSIP.664 trimer with novel 3M-052-AF/alum adjuvant in humans appears safe and induces serum neutralizing antibodies to matched clade A, tier 2 virus, that map to diverse Env epitopes with relatively high titers. The novel adjuvant may be an important mediator of vaccine response.

Misspellings or "miscellings"-Non-verifiable and unknown cell lines in cancer research publications.

Reproducible laboratory research relies on correctly identified reagents. We have previously described gene research papers with wrongly identified nucleotide sequence(s), including papers studying miR-145. Manually verifying reagent identities in 36 recent miR-145 papers found that 56% and 17% of papers described misidentified nucleotide sequences and cell lines, respectively. We also found 5 cell line identifiers in miR-145 papers with misidentified nucleotide sequences and cell lines, and 18 cell line identifiers published elsewhere, that did not represent indexed human cell lines. These 23 identifiers were described as non-verifiable (NV), as their identities were unclear. Studying 420 papers that mentioned 8 NV identifier(s) found 235 papers (56%) that referred to 7 identifiers (BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803, and MGC-823) as independent cell lines. We could not find any publications describing how these cell lines were established. Six cell lines were sourced from cell line repositories with externally accessible online catalogs, but these cell lines were not indexed as claimed. Some papers also stated that short tandem repeat (STR) profiles had been generated for three cell lines, yet no STR profiles could be identified. In summary, as NV cell lines represent new challenges to research integrity and reproducibility, further investigations are required to clarify their status and identities.

Effect of Age and Unaided Acoustic Hearing on Pediatric Cochlear Implant Users' Ability to Distinguish Yes/No Statements and Questions.

PURPOSE: The purpose of this study was to evaluate the ability to discriminate yes/no questions from statements in three groups of children: bilateral cochlear implant (CI) users, nontraditional CI users with aidable hearing preoperatively in the ear to be implanted, and controls with normal hearing. Half of the nontraditional CI users had sufficient postoperative acoustic hearing in the implanted ear to use electric-acoustic stimulation, and half used a CI alone. METHOD: Participants heard recorded sentences that were produced either as yes/no questions or as statements by three male and three female talkers. Three raters scored each participant response as either a question or a statement. Bilateral CI users (n = 40, 4-12 years old) and normal-hearing controls (n = 10, 4-12 years old) were tested binaurally in the free field. Nontraditional CI recipients (n = 22, 6-17 years old) were tested with direct audio input to the study ear. RESULTS: For the bilateral CI users, performance was predicted by age but not by 125-Hz acoustic thresholds; just under half (n = 17) of the participants in this group had measurable 125-Hz thresholds in their better ear. For nontraditional CI recipients, better performance was predicted by lower 125-Hz acoustic thresholds in the test ear, and there was no association with participant age. Performance approached that of the normal-hearing controls for some participants in each group. CONCLUSIONS: Results suggest that a 125-Hz acoustic hearing supports discrimination of yes/no questions and statements in pediatric CI users. Bilateral CI users with little or no acoustic hearing at 125 Hz develop the ability to perform this task, but that ability emerges later than for children with better acoustic hearing. These results underscore the importance of preserving acoustic hearing for pediatric CI users when possible.

COVID-19 Vaccine Efficacy in Participants With Weakened Immune Systems From 4 Randomized Controlled Trials.

BACKGROUND: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. RESULTS: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.

Travel surveillance uncovers dengue virus dynamics and introductions in the Caribbean.

Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced more frequent outbreaks, and all four dengue virus (DENV) serotypes have been reported in the region, leading to hyperendemicity and increased rates of severe disease. However, there is significant variability regarding virus surveillance and reporting between islands, making it difficult to obtain an accurate understanding of the epidemiological patterns in the Caribbean. To investigate this, we used travel surveillance and genomic epidemiology to reconstruct outbreak dynamics, DENV serotype turnover, and patterns of spread within the region from 2009-2022. We uncovered two recent DENV-3 introductions from Asia, one of which resulted in a large outbreak in Cuba, which was previously under-reported. We also show that while outbreaks can be synchronized between islands, they are often caused by different serotypes. Our study highlights the importance of surveillance of infected travelers to provide a snapshot of local introductions and transmission in areas with limited local surveillance and suggests that the recent DENV-3 introductions may pose a major public health threat in the region.

Demographic Representation in Clinical Research Relative to a Cochlear Implant Patient Population.

OBJECTIVES: Research samples that are representative of patient populations are needed to ensure the generalizability of study findings. The primary aim was to assess the efficacy of a study design and recruitment strategy in obtaining a participant sample that was representative of the broader cochlear implant (CI) patient population at the CI center. A secondary aim was to review whether the CI recipient population was representative of the state population. METHODS: Demographic variables were compared for a research participant sample (n = 79) and the CI patient population (n = 338). The participant sample was recruited from the CI patient population. The study design included visits that were at the same location and frequency as the recommended clinical follow-up intervals. The demographics for the combined group (participant sample and patient population) were then compared to the reported demographics for the population in North Carolina. RESULTS: There were no significant differences between the participant sample and patient population for biological sex, age at implantation, racial distribution, socioeconomic position, degree of urbanization, or drive time to the CI center (p ≥ 0.086). The combined CI recipient population was significantly different from the North Carolina population for the distributions of race, ethnicity, and degree of urbanization (p < 0.001). CONCLUSION: The study design and recruitment strategy allowed for recruitment of a participant sample that was representative of the CI patient population. Disparities in access to cochlear implantation persist, as supported by the significant differences in the combined CI recipient population and the population for our state. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:4101-4110, 2024.

Reversible Hydrosulfide (HS-) Binding Using Exclusively C-H Hydrogen-Bonding Interactions in Imidazolium Hosts.

H2S is a physiologically important signaling molecule with complex roles in biology and exists primarily as HS- at physiological pH. Despite this anionic character, few investigations have focused on the molecular recognition and reversible binding of this important biological anion. Using a series of imidazole and imidazolium host molecules, we investigate the role of preorganization and charge on HS- binding. Using a macrocyclic bis-imidazolium receptor, we demonstrate the unexpected 2:1 host-guest binding of HS-, which was characterized both in solution and by X-ray crystallography. To the best of our knowledge, this is the first example of this binding stoichiometry for HS- binding. Moreover, the short C-H···S distances of 2.53, 2.54, 2.76, and 2.79 Å are well within the sum of the van der Waals radii of the interacting atoms, which is consistent with strong C-H···S interactions.

Single-cell RNA sequencing of a new transgenic t(8;21) preleukemia mouse model reveals regulatory networks promoting leukemic transformation.

T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.

Complex epistatic interactions between ELF3, PRR9, and PRR7 regulate the circadian clock and plant physiology.

Circadian clocks are endogenous timekeeping mechanisms that coordinate internal physiological responses with the external environment. EARLY FLOWERING3 (ELF3), PSEUDO RESPONSE REGULATOR (PRR9), and PRR7 are essential components of the plant circadian clock and facilitate entrainment of the clock to internal and external stimuli. Previous studies have highlighted a critical role for ELF3 in repressing the expression of PRR9 and PRR7. However, the functional significance of activity in regulating circadian clock dynamics and plant development is unknown. To explore this regulatory dynamic further, we first employed mathematical modeling to simulate the effect of the prr9/prr7 mutation on the elf3 circadian phenotype. These simulations suggested that simultaneous mutations in prr9/prr7 could rescue the elf3 circadian arrhythmia. Following these simulations, we generated all Arabidopsis elf3/prr9/prr7 mutant combinations and investigated their circadian and developmental phenotypes. Although these assays could not replicate the results from the mathematical modeling, our results have revealed a complex epistatic relationship between ELF3 and PRR9/7 in regulating different aspects of plant development. ELF3 was essential for hypocotyl development under ambient and warm temperatures, while PRR9 was critical for root thermomorphogenesis. Finally, mutations in prr9 and prr7 rescued the photoperiod-insensitive flowering phenotype of the elf3 mutant. Together, our results highlight the importance of investigating the genetic relationship among plant circadian genes.

Finding social need-les in a haystack: ascertaining social needs of Medicare patients recorded in the notes of care managers.

BACKGROUND: Unmet social needs may impair health and access to health care, and intervening on these holds particular promise in high-risk patient populations, such as those with multiple chronic conditions. Our objective was to identify social needs in a patient population at significant risk-Medicare enrollees with multiple chronic illnesses enrolled in care management services-and measure their prevalence prior to any systematic screening. METHODS: We partnered with Renova Health, an independent Medicare Chronic Care Management (CCM) provider with patients in 10 states during our study period (January 2017 through August 2020). Our data included over 3,000 Medicare CCM patients, representing nearly 20,000 encounters. We used a dictionary-based natural language processing approach to ascertain the prevalence of six domains of barriers to care (food insecurity, housing instability, utility hardship) and unmet social needs (health care affordability, need for supportive services, transportation) in notes taken during telephonic Medicare CCM patient encounters. RESULTS: Barriers to care, specifically need for supportive services (2.4%) and health care affordability (0.8%), were the most prevalent domains identified. Transportation as a barrier to care came up relatively less frequently in CCM encounters (0.1%). Unmet social needs were identified at a comparatively lower rate, with potential housing instability (0.3%) flagged most followed by potential utility hardship (0.2%) and food insecurity (0.1%). CONCLUSIONS: There is substantial untapped opportunity to systematically screen for social determinants of health and unmet social needs in care management.