Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state.

Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis.

Antibodies expand the scope of angiotensin receptor pharmacology.

G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody ('nanobody') antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

Modulation of prion protein expression through cryptic splice site manipulation.

Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in human PRNP's sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5' untranslated region. This exon is homologous to exon 2 in nonprimate species but contains a start codon that would yield an upstream open reading frame with a stop codon prior to a splice site if included in PRNP mRNA, potentially downregulating PrP expression through translational repression or nonsense-mediated decay. We establish a minigene transfection system and test a panel of splice site alterations, identifying mutants that reduce PrP expression by as much as 78%. Our findings nominate a new therapeutic target for lowering PrP.

Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

A single-cell map of antisense oligonucleotide activity in the brain.

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the central nervous system (CNS). By modulating RNA, they hold the promise of targeting root molecular causes of disease and hold potential to treat myriad CNS disorders. Realization of this potential requires that ASOs must be active in the disease-relevant cells, and ideally, that monitorable biomarkers also reflect ASO activity in these cells. The biodistribution and activity of such centrally delivered ASOs have been deeply characterized in rodent and non-human primate (NHP) models, but usually only in bulk tissue, limiting our understanding of the distribution of ASO activity across individual cells and across diverse CNS cell types. Moreover, in human clinical trials, target engagement is usually monitorable only in a single compartment, CSF. We sought a deeper understanding of how individual cells and cell types contribute to bulk tissue signal in the CNS, and how these are linked to CSF biomarker outcomes. We employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and NHPs treated with an ASO against PRNP. Pharmacologic activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target RNA suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect ASO pharmacodynamic effect in disease-relevant cells in a neuronal disorder. Our results provide a reference dataset for ASO activity distribution in the CNS and establish single nucleus sequencing as a method for evaluating cell type specificity of oligonucleotide therapeutics and other modalities.

Antisense oligonucleotide (ASO) drugs are a type of chemically modified DNA that can be injected into cerebrospinal fluid in order to enter brain cells and reduce the amount of RNA from a specific gene. The brain is a complex mixture of hundreds of billions of cells. When an ASO lowers a target gene's RNA by 50%, is that a 50% reduction in 100% of cells, or a 100% reduction in 50% of cells? Are the many different cell types of the brain affected equally? This new study uses single cell RNA sequencing to answer these questions, finding that ASOs are broadly active across cell types and individual cells, and linking reduction of target protein in cerebrospinal fluid to disease-relevant cells.

Metal cofactor stabilization by a partner protein is a widespread strategy employed for amidase activation.

Construction and remodeling of the bacterial peptidoglycan (PG) cell wall must be carefully coordinated with cell growth and division. Central to cell wall construction are hydrolases that cleave bonds in peptidoglycan. These enzymes also represent potential new antibiotic targets. One such hydrolase, the amidase LytH in Staphylococcus aureus, acts to remove stem peptides from PG, controlling where substrates are available for insertion of new PG strands and consequently regulating cell size. When it is absent, cells grow excessively large and have division defects. For activity, LytH requires a protein partner, ActH, that consists of an intracellular domain, a large rhomboid protease domain, and three extracellular tetratricopeptide repeats (TPRs). Here, we demonstrate that the amidase-activating function of ActH is entirely contained in its extracellular TPRs. We show that ActH binding stabilizes metals in the LytH active site and that LytH metal binding in turn is needed for stable complexation with ActH. We further present a structure of a complex of the extracellular domains of LytH and ActH. Our findings suggest that metal cofactor stabilization is a general strategy used by amidase activators and that ActH houses multiple functions within a single protein.

Neural Contributions to Reduced Fluid Intelligence across the Adult Lifespan.

Fluid intelligence, the ability to solve novel, complex problems, declines steeply during healthy human aging. Using fMRI, fluid intelligence has been repeatedly associated with activation of a frontoparietal brain network, and impairment following focal damage to these regions suggests that fluid intelligence depends on their integrity. It is therefore possible that age-related functional differences in frontoparietal activity contribute to the reduction in fluid intelligence. This paper reports on analysis of the Cambridge Center for Ageing and Neuroscience data, a large, population-based cohort of healthy males and females across the adult lifespan. The data support a model in which age-related differences in fluid intelligence are partially mediated by the responsiveness of frontoparietal regions to novel problem-solving. We first replicate a prior finding of such mediation using an independent sample. We then precisely localize the mediating brain regions, and show that mediation is specifically associated with voxels most activated by cognitive demand, but not with voxels suppressed by cognitive demand. We quantify the robustness of this result to potential unmodeled confounders, and estimate the causal direction of the effects. Finally, exploratory analyses suggest that neural mediation of age-related differences in fluid intelligence is moderated by the variety of regular physical activities, more reliably than by their frequency or duration. An additional moderating role of the variety of nonphysical activities emerged when controlling for head motion. A better understanding of the mechanisms that link healthy aging with lower fluid intelligence may suggest strategies for mitigating such decline.SIGNIFICANCE STATEMENT Global populations are living longer, driving urgency to understand age-related cognitive declines. Fluid intelligence is of prime importance because it reflects performance across many domains, and declines especially steeply during healthy aging. Despite consensus that fluid intelligence is associated with particular frontoparietal brain regions, little research has investigated suggestions that under-responsiveness of these regions mediates age-related decline. We replicate a recent demonstration of such mediation, showing specific association with brain regions most activated by cognitive demand, and robustness to moderate confounding by unmodeled variables. By showing that this mediation model is moderated by the variety of regular physical activities, more reliably than by their frequency or duration, we identify a potential modifiable lifestyle factor that may help promote successful aging.

The M3 Muscarinic Acetylcholine Receptor Can Signal through Multiple G Protein Families.

The M3 muscarinic acetylcholine receptor (M3R) is a G protein-coupled receptor (GPCR) that regulates important physiologic processes, including vascular tone, bronchoconstriction, and insulin secretion. It is expressed on a wide variety of cell types, including pancreatic beta, smooth muscle, neuronal, and immune cells. Agonist binding to the M3R is thought to initiate intracellular signaling events primarily through the heterotrimeric G protein Gq. However, reports differ on the ability of M3R to couple to other G proteins beyond Gq. Using members from the four primary G protein families (Gq, Gi, Gs, and G13) in radioligand binding, GTP turnover experiments, and cellular signaling assays, including live cell G protein dissociation and second messenger assessment of cAMP and inositol trisphosphate, we show that other G protein families, particularly Gi and Gs, can also interact with the human M3R. We further show that these interactions are productive as assessed by amplification of classic second messenger signaling events. Our findings demonstrate that the M3R is more promiscuous with respect to G protein interactions than previously appreciated. SIGNIFICANCE STATEMENT: The study reveals that the human M3 muscarinic acetylcholine receptor (M3R), known for its pivotal roles in diverse physiological processes, not only activates intracellular signaling via Gq as previously known but also functionally interacts with other G protein families such as Gi and Gs, expanding our understanding of its versatility in mediating cellular responses. These findings signify a broader and more complex regulatory network governed by M3R and have implications for therapeutic targeting.

The impact of sickle cell disease and its treatment on ovarian reserve in reproductive-aged Black women.

We compared serum anti-Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80-2.76 vs. 4.12, 95% CI 3.11-5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43-76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist.

A Long-Lived Alpine Perennial Advances Flowering under Warmer Conditions but Not Enough to Maintain Reproductive Success.

AbstractAssessing whether phenological shifts in response to climate change confer a fitness advantage requires investigating the relationships among phenology, fitness, and environmental drivers of selection. Despite widely documented advancements in phenology with warming climate, we lack empirical estimates of how selection on phenology varies in response to continuous climate drivers or how phenological shifts in response to warming conditions affect fitness. We leverage an unusual long-term dataset with repeated, individual measurements of phenology and reproduction in a long-lived alpine plant. We analyze phenotypic plasticity in flowering phenology in relation to two climate drivers, snowmelt timing and growing degree days (GDDs). Plants flower earlier with increased GDDs and earlier snowmelt, and directional selection also favors earlier flowering under these conditions. However, reproduction still declines with warming and early snowmelt, even when flowering is early. Furthermore, the steepness of this reproductive decline increases dramatically with warming conditions, resulting in very little fruit production regardless of flowering time once GDDs exceed approximately 225 degree days or snowmelt occurs before May 15. Even though advancing phenology confers a fitness advantage relative to stasis, these shifts are insufficient to maintain reproduction under warming, highlighting limits to the potential benefits of phenological plasticity under climate change.

Membrane inflammasome activation by choriodecidual Ureaplasma parvum infection without intra-amniotic infection in a Non-Human Primate model†.

Intrauterine infection is a significant cause of neonatal morbidity and mortality. Ureaplasma parvum is a microorganism commonly isolated from cases of preterm birth and preterm premature rupture of membranes (pPROM). However, the mechanisms of early stage ascending reproductive tract infection remain poorly understood. To examine inflammation in fetal (chorioamnionic) membranes we utilized a non-human primate (NHP) model of choriodecidual U. parvum infection. Eight chronically catheterized pregnant rhesus macaques underwent maternal-fetal catheterization surgery at ~105-112 days gestation and choriodecidual inoculation with U. parvum (105 CFU/mL, n =4) or sterile media (controls; n = 4) starting at 115-119 days, repeated at 5-day intervals until C-section at 136-140 days (term=167 days). The average inoculation to delivery interval was 21 days, and Ureaplasma infection of the amniotic fluid (AF) was undetectable in all animals. Choriodecidual Ureaplasma infection resulted in increased fetal membrane expression of MMP-9 and PTGS2, but did not result in preterm labor or increased concentrations of AF pro-inflammatory cytokines. However, membrane expression of inflammasome sensors, NLRP3, NLRC4, AIM2, and NOD2, and adaptor ASC (PYCARD) gene expression were significantly increased. Gene expression of IL-1ß, IL-18, IL-18R1  , CASPASE-1, and pro-CASPASE-1 protein increased with Ureaplasma infection. Downstream inflammatory genes MYD88 and NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells) were also significantly upregulated. These results demonstrate that choriodecidual Ureaplasma infection, can cause activation of inflammasome complexes and pathways associated with pPROM and preterm labor prior to microbes being detectable in the AF.

Cefepime-taniborbactam activity against antimicrobial-resistant clinical isolates of Enterobacterales and Pseudomonas aeruginosa: GEARS global surveillance programme 2018-22.

OBJECTIVES: Taniborbactam is a boronate-based ß-lactamase inhibitor in clinical development in combination with cefepime. METHODS: Cefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs ≥ 16 mg/L underwent WGS. ß-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing. RESULTS: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes;  ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs ≥ 16 mg/L. CONCLUSIONS: Cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.

Analysis of non-human primate models for evaluating prion disease therapeutic efficacy.

Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene (PRNP). While no disease-modifying therapy is currently available, genetic and pharmacological proofs of concept support development of therapies that lower PrP levels in the brain. In light of proposals for clinical testing of such drugs in presymptomatic individuals at risk for genetic prion disease, extensive nonclinical data are likely to be required, with extra attention paid to choice of animal models. Uniquely, the entire prion disease process can be faithfully modeled through transmission of human prions to non-human primates (NHPs), raising the question of whether NHP models should be used to assess therapeutic efficacy. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. Using this dataset, we assess prion strain, route of administration, endpoint, and passage number to characterize the relationship of tested models to currently prevalent human subtypes of prion disease. We analyze the incubation times observed across diverse models and perform power calculations to assess the practicability of testing prion disease therapeutic efficacy in NHPs. We find that while some models may theoretically be able to support therapeutic efficacy studies, pilot studies would be required to confirm incubation time and attack rate before pivotal studies could be designed, cumulatively requiring several years. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. Our findings indicate that it would be challenging to conduct efficacy studies in NHPs in a paradigm that honors the potential advantages of NHPs over other available models, on a timeframe that would not risk unduly delaying patient access to promising drug candidates.

Evaluation of biofilm assembly and microbial diversity on a freshwater, ferrous-hulled shipwreck.

Abandoned shipwrecks are sitting at the bottom of oceans, lakes, and rivers around the world. Over time, microbial-comprised biofilms can help protect wrecks against chemical corrosion or contribute to their deterioration through microbiologically influenced corrosion (MIC) by organisms including iron-oxidizing bacteria (FeOB) and sulfate-reducing bacteria (SRB). Assessing the community assembly of these biofilms will give us a better understanding of the role these microbes play in MIC and the factors that influence it. Here, we determine if microbial community composition differs across a shallow freshwater ferrous-hulled shipwreck environment. Results suggest that there was a statistically significant difference among the sample types indicating the wreck environments around Accomac influenced the community composition. This is consistent with previous observations within an estuarine, shallow-water wreck environment. Bacteroidota, Chloroflexota, and Cyanobacteriota were the primary taxa responsible for differences among these wreck environments. Interestingly, port-side biofilm communities were significantly different than those on the starboard side suggesting physical factors of the environment drove niche partitioning on each side of the wreck. Similarly, FeOB enrichments and known FeOB taxa were found across the entire wreck but were primarily found in samples associated with the port side of the wreck. Amplicon sequencing identified both known FeOB and SRB taxa with a higher proportion of FeOB than SRB. Overall, these results indicate that there is niche partitioning of the microbial communities as well as with corrosion-causing taxa within a shallow freshwater wreck site which may lead to variation in how microbes may contribute to the protection or deterioration of these ferrous-hulled wrecks. IMPORTANCE: The overall structure, abundance, and diversity of microbial communities on shipwrecks have recently been studied in marine aquatic environments. While previous studies have looked at the microbial communities associated with shallow-water ferrous-hulled wrecks in marine environments, studies focusing on freshwater wreck systems are limited. The purpose of this study was to determine microbial community diversity and composition trends across the Accomac shipwreck environment. Furthermore, shipwrecks are colonized by corrosion-causing taxa, such as iron-oxidizing bacteria and sulfate-reducing bacteria which have been shown to influence the biocorrosion of ferrous-hulled structures. Identification of various microbes in biofilms, as well as corrosion-causing microbes, can help researchers identify the role they play in aquatic ecosystem development and persistence as well as artificial reef integrity. Understanding how microbes assemble on wrecks will provide insight into preservation strategies to prevent deterioration of these wrecks over time, as well as limiting biocorrosion of similar structures.

Single-Center Incidence and Patterns of Stroke in Early Renal Anhydramnios After Serial Amnioinfusions.

The Renal Anhydramnios Fetal Therapy (RAFT) trial is a study of serial amnioinfusions to prevent lethal neonatal pulmonary hypoplasia from early renal anhydramnios. Infant neurologic outcomes were not originally evaluated. We describe the high incidence of stroke observed among infants in the treatment arm of the trial at our center.

7 T characterization of excitatory and inhibitory systems of acute pain in healthy female participants.

Current understanding of the physiological underpinnings of normative pain processing is incomplete. Enhanced knowledge of these systems is necessary to advance our understanding of pain processes as well as to develop effective therapeutic interventions. Previous neuroimaging research suggests a network of interrelated brain regions that seem to be implicated in the processing and experience of pain. Among these, the dorsal anterior cingulate cortex (dACC) plays an important role in the affective aspects of pain signals. The current study leveraged functional MRS to investigate the underlying dynamic shifts in the neurometabolic signature of the human dACC at rest and during acute pain. Results provide support for increased glutamate levels following acute pain administration. Specifically, a 4.6% increase in glutamate was observed during moderate pressure pain compared with baseline. Exploratory analysis also revealed meaningful changes in dACC gamma aminobutyric acid in response to pain stimulation. These data contribute toward the characterization of neurometabolic shifts, which lend insight into the role of the dACC in the pain network. Further research in this area with larger sample sizes could contribute to the development of novel therapeutics or other advances in pain-related outcomes.

Deprescribing bisphosphonates for older adults with dementia: perspectives of caregivers.

Little is known about caregivers' perspectives on deprescribing bisphosphonates for older adults with dementia. Caregivers agreed that fracture prevention was important for maintaining functional independence but acknowledged that changing goals of care may justify deprescribing. Conversations grounded in "what matters most" can align fracture prevention treatment with goals of care. PURPOSE: The long-term fracture prevention benefits of bisphosphonates may begin to be overshadowed by the potential burden of adverse effects and polypharmacy for older adults living with dementia as the disease progresses. We characterized factors that influence caregiver decision-making for continuing versus deprescribing bisphosphonates for persons living with dementia. METHODS: We conducted 11 interviews with family or informal caregivers of older adults living with dementia in the community or in long-term care who had been treated with bisphosphonates. Interviews focused on experiences caring for someone who has experienced a fracture, perceived benefits and harms of bisphosphonates, and experiences with deprescribing. Analyses were conducted using a qualitative framework methodology guided by the Health Belief Model. RESULTS: Most caregivers were male (n = 8), younger than 65 (n = 8) and were an adult child caregiver (n = 8). Three caregivers were Black and five were Latino/a. Attempts to maintain functional independence despite high likelihood of falls was frequently discussed as contributing to fracture risk, in this population. Many caregivers perceived fracture prevention treatment as important, while several noted that it may become less important near the end of life. Perceived benefits of fracture prevention treatment for persons with dementia included improved quality of life and maintaining independence. Although most indicated that bisphosphonates were well tolerated, gastrointestinal adverse effects, preference for fewer treatments, and dementia-related behaviors that interfere with medication administration may be reasons for deprescribing. CONCLUSION: Conversations grounded in caregiver experiences and "what matters most" may help optimize fracture prevention treatment for older adults with dementia.

Complexities of Physician Workforce Projection: Call for a Unified National Healthcare Workforce Policy.

Ensuring an adequate supply of physicians is paramount in securing the future of healthcare. To do so, accurate physician workforce predictions are needed to inform policymakers. However, the United States lacks such predictions from reliable sources. Several non-governmental organizations have actively been involved in attempting to quantify workforce needs, but they often employ opaque methodologies and are deeply conflicted, leading to potentially unreliable or biased results. Moreover, while federal and state entities invest approximately $15 billion annually in graduate medical education (GME) payments, they have very little control over how the funding is used to shape the future physician workforce. In this article, we review physician workforce predictions from both an international and a domestic perspective and finally discuss how the creation of an apolitical, data-driven, expert-led panel at the federal level with sufficient authority to influence broader workforce policy is the optimal solution for ensuring an adequate supply of physicians for generations to come.

Opt-Out Syphilis Screening at an Urgent Care Center in Atlanta: Evaluation of a Pilot Program.

BACKGROUND: Human immunodeficiency virus (HIV) and syphilis disproportionately impact communities with low access to primary care, who often utilize urgent care centers (UCCs) for sexual health care. UCC visits represent an opportunity for identification and treatment of syphilis and linkage to HIV testing and prevention services. We describe a universal, opt-out syphilis screening program pilot at an Atlanta UCC. METHODS: A chart review was performed on patients 18 years and older who were offered opt-out syphilis screening and had a rapid plasma reagin (RPR) test collected from September 1, 2021 to December 31, 2021. Demographic data, syphilis stage and treatment, and HIV testing and serostatus were abstracted from the electronic health record. Patients with reactive RPRs were contacted by a study physician for syphilis staging and treatment, counseling, and referral for HIV preexposure prophylaxis (PrEP) or treatment. RESULTS: From September 1, 2021 to December 31, 2021, 5794 patients were triaged and 1381 underwent RPR screening (23.8%). Eighty (5.8%) had reactive RPRs, and 42 (52.5%) had active syphilis. Of those with active syphilis, 39 (92.9%) received any treatment, and 35 (83.3%) completed treatment. Patients with late syphilis were less likely to complete syphilis treatment (adjusted odds ratio, 0.03; P = 0.009; 95% confidence interval, 0.002-0.42). Among 955 offered PrEP, 41 (4.3%) expressed interest in PrEP, and 7 (0.7%) completed PrEP clinic intake. Univariate analysis did not identify any factors associated with interest in PrEP. CONCLUSIONS: In a UCC setting, routine, opt-out syphilis testing resulted in increased syphilis identification and treatment. It also provided an opportunity for PrEP counseling and referral, although few patients completed PrEP clinic intake.

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer.

OBJECTIVE: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. METHODS: Lkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. RESULTS: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. CONCLUSION: In Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.