Family medicine residents' perspectives on shared decision-making: A mixed methods study.

OBJECTIVES: To 1) examine the willingness of residents to undertake shared decision-making and 2) explore whether the willingness to engage in shared decision-making is influenced by the perceived stakes of a clinical situation. METHODS: Sequential mixed methods design. Phase One: Family Medicine residents completed IncorpoRATE, a seven-item measure of clinician willingness to engage in shared decision making. Mean IncorpoRATE scores were calculated. Phase Two: We interviewed residents from phase one to explore their perceptions of high versus low stakes situations. Transcripts were analyzed using qualitative content analysis. RESULTS: IncorpoRATE scores indicated a greater willingness to engage in shared decision-making when the stakes of the decision were perceived as low (7.59 [2.0]) compared to high (4.38 [2.5]). Interviews revealed that residents held variable views of the stakes of similar clinical decisions. CONCLUSION: Residents are more willing to engage in shared decision-making when the stakes of the situation are perceived to be low. However, the interpretation of the stakes of clinical situations varies. PRACTICAL IMPLICATIONS: Further research is needed to explore how shared decision making is understood by residents in Family Medicine and when they view the process of shared decision-making to be most appropriate.

Small Molecule MIF Modulation Enhances Ferroptosis by Impairing DNA Repair Mechanisms.

Ferroptosis is a form of regulated cell death that can be modulated by small molecules and has the potential for the development of therapeutics for oncology. Although excessive lipid peroxidation is the defining hallmark of ferroptosis, DNA damage may also play a significant role. In this study, a potential mechanistic role for MIF in homologous recombination (HR) DNA repair is identified. The inhibition or genetic depletion of MIF or other HR proteins, such as breast cancer type 1 susceptibility protein (BRCA1), is demonstrated to significantly enhance the sensitivity of cells to ferroptosis. The interference with HR results in the translocation of the tumor suppressor protein p53 to the mitochondria, which in turn stimulates the production of reactive oxygen species. Taken together, the findings demonstrate that MIF-directed small molecules enhance ferroptosis via a putative MIF-BRCA1-RAD51 axis in HR, which causes resistance to ferroptosis. This suggests a potential novel druggable route to enhance ferroptosis by targeted anticancer therapeutics in the future.

Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults.

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

Implementation and evaluation of Exercise is Medicine in primary care clinics within a large academic health system.

OBJECTIVE: Exercise is Medicine (EIM) is a global initiative encouraging healthcare providers to routinely assess and promote physical activity (PA) among patients. The objective of this study was to evaluate the feasibility, adoption, implementation and effectiveness of EIM from patient, clinician and healthcare staff perspectives using a combination of electronic health record (EHR), survey and interview data. DESIGN: This study used a combination of the Practical Robust Implementation and Sustainability Model (PRISM) and the Learning Evaluation model to implement EIM. Data captured from the EHR, including Physical Activity Vital Sign (PAVS) scores, and data collected from qualitative surveys and interviews were used to evaluate the programme's Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM, which is embedded within PRISM) from provider, staff and patient perspectives. SETTING: Five primary care clinics within a large academic health system. PARTICIPANTS: A total of 24 443 patients from all participating clinics had at least one PAVS score during the study period. A total of 17 clinicians completed surveys, and 4 clinicians, 8 medical assistants and 9 patients completed interviews. RESULTS: Implementation fidelity metrics varied widely between components and across clinics but were generally consistent over time, indicating a high degree of programme maintenance. Fidelity was highest during the first 6 months of the COVID-19 pandemic when most visits were virtual. Mean PAVS scores increased from 57.7 (95% CI: 56 to 59.4) to 95.2 (95% CI: 91.6 to 98.8) min per week at 6 months for patients not meeting PA guidelines at baseline and decreased from 253.84 (95% CI: 252 to 255.7) to 208.3 (95% CI: 204.2 to 212.4) min per week at 6 months for patients meeting PA guidelines at baseline. After EIM implementation, clinician-estimated time spent discussing PA with patients increased for 35% of providers and stayed the same for 53%. CONCLUSION: Overall, this study established EIM's feasibility, adoption, implementation and maintenance in routine primary care practice within a large academic health system. From a population health perspective, EIM is a model to emulate to help primary care providers efficiently address healthy lifestyle behaviours in routine primary care visits.

Novel SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells.

Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca2+ uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca2+ level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.

Lipid profile in breast cancer: From signaling pathways to treatment strategies.

Breast cancer is the most prevalent cancer in women. Metabolic abnormalities, particularly increased lipid synthesis and uptake, impact the onset and progression of the disease. However, the influence of lipid metabolism in breast cancer varies according to the disease stage and patient's hormone status. In postmenopausal patients, obesity is associated with a higher risk and poor prognosis of luminal tumors, while in premenopausal individuals, it is correlated to BRCA mutated tumors. In fact, the tumor's lipid profile may be used to distinguish between HER2+, luminal and BRCA-mutated tumors. Moreover, drug resistance was associated with increased fatty acid synthesis and alterations in membrane composition, impacting its fluidity and spatial subdomains such as lipid rafts. Here, we discuss the subtype-specific lipid metabolism alterations found in breast cancer and the potentiality of its modulation in a clinical setting.

Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Up to an Hour of Donor Resuscitation Does Not Affect Pediatric Heart Transplantation Survival.

BACKGROUND: In pediatric heart transplantation, surgeons historically avoided donors requiring cardiopulmonary resuscitation (CPR), despite evidence that donor CPR does not change posttransplant survival (PTS). This study sought to determine whether CPR duration affects PTS. METHODS: All potential brain-dead donors aged <40 years from 2001 to 2021 consented for heart procurement were identified in the United Network for Organ Sharing database (n = 54,671). Organ acceptance was compared by CPR administration and duration. All recipients aged <18 years with donor CPR data were then identified (n = 5680). Survival analyses were conducted using increasing CPR duration as a cut point to identify the shortest duration beyond which PTS worsened. Additional analyses were performed with multivariable and cubic spline regression. RESULTS: Fifty-one percent of donors (28,012 of 54,671) received CPR. Donor acceptance was lower after CPR (54% vs 66%; P < .001) and across successive quartiles of CPR duration (P < .001). Of the transplant recipients, 48% (2753 of 5680) belonged to the no-CPR group, and 52% (2927 of 5680) belonged to the CPR group. Kaplan-Meier analyses of CPR duration attained significance at 55 minutes, after which PTS worsened (11.1 years vs 9.2 years; P = .025). There was no survival difference between the CPR ≤55 minutes group and the no-CPR group (11.1 years vs 11.2 years; P = .571). A cubic spline regression model confirmed that PTS worsened at more than 55 minutes of CPR. A Cox regression demonstrated that CPR >55 minutes predicted worsened PTS relative to no CPR (HR, 1.51; P = .007) but CPR ≤55 minutes did not (HR, 1.01; P = .864). CONCLUSIONS: Donor CPR decreases organ acceptance for transplantation; however, shorter durations (≤55 minutes) had equivalent PTS when controlling for other risk factors.

Novel crosstalk mechanisms between GluA3 and Epac2 in synaptic plasticity and memory in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease which accounts for the most cases of dementia worldwide. Impaired memory, including acquisition, consolidation, and retrieval, is one of the hallmarks in AD. At the cellular level, dysregulated synaptic plasticity partly due to reduced long-term potentiation (LTP) and enhanced long-term depression (LTD) underlies the memory deficits in AD. GluA3 containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are one of key receptors involved in rapid neurotransmission and synaptic plasticity. Recent studies revealed a novel form of GluA3 involved in neuronal plasticity that is dependent on cyclic adenosine monophosphate (cAMP), rather than N-methyl-d-aspartate (NMDA). However, this cAMP-dependent GluA3 pathway is specifically and significantly impaired by amyloid beta (Aß), a pathological marker of AD. cAMP is a key second messenger that plays an important role in modulating memory and synaptic plasticity. We previously reported that exchange protein directly activated by cAMP 2 (Epac2), acting as a main cAMP effector, plays a specific and time-limited role in memory retrieval. From electrophysiological perspective, Epac2 facilities the maintenance of LTP, a cellular event closely associated with memory retrieval. Additionally, Epac2 was found to be involved in the GluA3-mediated plasticity. In this review, we comprehensively summarize current knowledge regarding the specific roles of GluA3 and Epac2 in synaptic plasticity and memory, and their potential association with AD.

Functional brain connectivity during social attention predicts individual differences in social skill.

Social attention involves selectively attending to and encoding socially relevant information. We investigated the neural systems underlying the wide range of variability in both social attention ability and social experience in a neurotypical sample. Participants performed a selective social attention task, while undergoing fMRI and completed self-report measures of social functioning. Using connectome-based predictive modeling, we demonstrated that individual differences in whole-brain functional connectivity patterns during selective attention to faces predicted task performance. Individuals with more cerebellar-occipital connectivity performed better on the social attention task, suggesting more efficient social information processing. Then, we estimated latent communities of autistic and socially anxious traits using exploratory graph analysis to decompose heterogeneity in social functioning between individuals. Connectivity strength within the identified social attention network was associated with social skills, such that more temporal-parietal connectivity predicted fewer challenges with social communication and interaction. These findings demonstrate that individual differences in functional connectivity strength during a selective social attention task are related to varying levels of self-reported social skill.

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

Unravelling the signaling power of pollutants.

Exposure to environmental pollutants contributes to diverse pathologies, including pulmonary disease, lower respiratory infections, cancer, and stroke. Pollutants' entry can occur through inhalation, traversing endothelial and epithelial barriers, and crossing the blood-brain barrier, leading to a wide distribution throughout the human body via systemic circulation. Pollutants cause cellular damage by multiple mechanisms encompassing oxidative stress, mitochondrial dysfunction, (neuro)inflammation, and protein instability/proteotoxicity. Sensing pollutants has added a new dimension to disease progression and drug failure. Understanding the molecular pathways and potential receptor binding/signaling that underpin 'sensing' could contribute to ways to combat the detrimental effects of pollutants. We highlight key points of pollutant signaling, crosstalk with receptors acting as drug targets for chronic diseases, and discuss the potential for future therapeutics.

Identification and characterization of a small molecule that activates thiosulfate sulfurtransferase and stimulates mitochondrial respiration.

The enzyme Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), is a positive genetic predictor of diabetes type 2 and obesity. As increased TST activity protects against the development of diabetic symptoms in mice, an activating compound for TST may provide therapeutic benefits in diabetes and obesity. We identified a small molecule activator of human TST through screening of an inhouse small molecule library. Kinetic studies in vitro suggest that two distinct isomers of the compound are required for full activation as well as an allosteric mode of activation. Additionally, we studied the effect of TST protein and the activator on TST activity through mitochondrial respiration. Molecular docking and molecular dynamics (MD) approaches supports an allosteric site for the binding of the activator, which is supported by the lack of activation in the Escherichia coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption.

Mitochondrial transplantation rescues neuronal cells from ferroptosis.

Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that preventing mitochondrial dysfunction can rescue cells from ferroptotic cell death. However, the complexity of mitochondrial dysfunction and the timing of therapeutic interventions make it difficult to develop an effective treatment strategy against ferroptosis in neurodegeneration conditions. In this study, we explored the use of mitochondrial transplantation as a novel therapeutic approach for preventing ferroptotic neuronal cell death. Our data showed that isolated exogenous mitochondria were incorporated into both healthy and ferroptotic immortalized hippocampal HT-22 cells and primary cortical neurons (PCN). The mitochondrial incorporation was accompanied by increased metabolic activity and cell survival through attenuating lipid peroxidation and mitochondrial superoxide production. Further, the function of mitochondrial complexes I, III and V activities contributed to the neuroprotective activity of exogenous mitochondria. Similarly, we have also showed the internalization of exogenous mitochondria in mouse PCN; these internalized mitochondria were found to effectively preserve the neuronal networks when challenged with ferroptotic stimuli. The administration of exogenous mitochondria into the axonal compartment of a two-compartment microfluidic device induced mitochondrial transportation to the cell body, which prevented fragmentation of the neuronal network in ferroptotic PCN. These findings suggest that mitochondria transplantation may be a promising therapeutic approach for protecting neuronal cells from ferroptotic cell death.

The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

The TNFR1 antagonist Atrosimab reduces neuronal loss, glial activation and memory deficits in an acute mouse model of neurodegeneration.

Tumor necrosis factor alpha (TNF-α) and its key role in modulating immune responses has been widely recognized as a therapeutic target for inflammatory and neurodegenerative diseases. Even though inhibition of TNF-α is beneficial for the treatment of certain inflammatory diseases, total neutralization of TNF-α largely failed in the treatment of neurodegenerative diseases. TNF-α exerts distinct functions depending on interaction with its two TNF receptors, whereby TNF receptor 1 (TNFR1) is associated with neuroinflammation and apoptosis and TNF receptor 2 (TNFR2) with neuroprotection and immune regulation. Here, we investigated the effect of administering the TNFR1-specific antagonist Atrosimab, as strategy to block TNFR1 signaling while maintaining TNFR2 signaling unaltered, in an acute mouse model for neurodegeneration. In this model, a NMDA-induced lesion that mimics various hallmarks of neurodegenerative diseases, such as memory loss and cell death, was created in the nucleus basalis magnocellularis and Atrosimab or control protein was administered centrally. We showed that Atrosimab attenuated cognitive impairments and reduced neuroinflammation and neuronal cell death. Our results demonstrate that Atrosimab is effective in ameliorating disease symptoms in an acute neurodegenerative mouse model. Altogether, our study indicates that Atrosimab may be a promising candidate for the development of a therapeutic strategy for the treatment of neurodegenerative diseases.

Augmenting TCR signal strength and ICOS costimulation results in metabolically fit and therapeutically potent human CAR Th17 cells.

IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4+ T cells, the degree to which T cell antigen receptor (TCR) and costimulation signal strength influences Th17 immunity remains unknown. We discovered that decreasing TCR/costimulation signal strength by incremental reduction of αCD3/costimulation beads progressively altered Th17 phenotype. Moreover, Th17 cells stimulated with αCD3/inducible costimulator (ICOS) beads produced more IL-17A, IFNγ, IL-2, and IL-22 than those stimulated with αCD3/CD28 beads. Compared with Th17 cells stimulated with the standard, strong signal strength (three beads per T cell), Th17 cells propagated with 30-fold fewer αCD3/ICOS beads were less reliant on glucose and favored the central carbon pathway for bioenergetics, marked by abundant intracellular phosphoenolpyruvate (PEP). Importantly, Th17 cells stimulated with weak αCD3/ICOS beads and redirected with a chimeric antigen receptor that recognizes mesothelin were more effective at clearing human mesothelioma. Less effective CAR Th17 cells generated with high αCD3/ICOS beads were rescued by overexpressing phosphoenolpyruvate carboxykinase 1 (PCK1), a PEP regulator. Thus, Th17 therapy can be improved by using fewer activation beads during manufacturing, a finding that is cost effective and directly translatable to patients.

Collagen type I alters the proteomic signature of macrophages in a collagen morphology-dependent manner.

Idiopathic pulmonary fibrosis is a progressive lung disease that causes scarring and loss of lung function. Macrophages play a key role in fibrosis, but their responses to altered morphological and mechanical properties of the extracellular matrix in fibrosis is relatively unexplored. Our previous work showed functional changes in murine fetal liver-derived alveolar macrophages on fibrous or globular collagen morphologies. In this study, we applied differential proteomics to further investigate molecular mechanisms underlying the observed functional changes. Macrophages cultured on uncoated, fibrous, or globular collagen-coated plastic were analyzed by liquid chromatography-mass spectrometry. The presence of collagen affected expression of 77 proteins, while 142 were differentially expressed between macrophages grown on fibrous or globular collagen. Biological process and pathway enrichment analysis revealed that culturing on any type of collagen induced higher expression of enzymes involved in glycolysis. However, this did not lead to a higher rate of glycolysis, probably because of a concomitant decrease in activity of these enzymes. Our data suggest that macrophages sense collagen morphologies and can respond with changes in expression and activity of metabolism-related proteins. These findings suggest intimate interactions between macrophages and their surroundings that may be important in repair or fibrosis of lung tissue.

Microvascular proliferation in arteriovenous malformation of the hand worsens during pregnancy: a case report.

Arteriovenous malformations (AVMs) are rare congenital disorders characterized by episodes of disproportionate growth that can cause pain and severe bleeding, with microvascular proliferation (MVP) associated with these episodes. Hormonal influences can also worsen the symptoms in patients with AVM. Case presentation: This case report presents a female patient with congenital vascular malformations of the left hand since birth, whose symptoms worsened during puberty and pregnancy, ultimately leading to amputation of the left hand due to unbearable pain and loss of function. Pathologic analysis revealed substantial MVP activity within the tissues of the AVM, with an expression of receptors for estrogen, growth hormone, and follicle-stimulating hormone in the vessels of the AVM, including MVP areas. Resected materials not related to pregnancy revealed chronic inflammation and fibrosis but hardly any MVP. Discussion and conclusion: These findings suggest a role for MVP in the progressive growth of AVM during pregnancy, with a potential role for hormonal influences. The case highlights the relationship between AVM symptoms and size during pregnancy and the pathological findings of MVP areas within the AVM with hormone receptor expression on proliferating vessels in resected materials.

Differing prevalence of microcephaly and macrocephaly in male and female fetuses.

Objective: To compare the proportion of female and male fetuses classified as microcephalic (head circumference [HC] < 3rd percentile) and macrocephalic (>97th percentile) by commonly used sex-neutral growth curves. Methods: For fetuses evaluated at a single center, we retrospectively determined the percentile of the first fetal HC measurement between 16 and 0/7 and 21-6/7 weeks using the Hadlock, Intergrowth-21st, and NICHD growth curves. The association between sex and the likelihood of being classified as microcephalic or macrocephalic was evaluated with logistic regression. Results: Female fetuses (n = 3,006) were more likely than male fetuses (n = 3,186) to be classified as microcephalic using the Hadlock (0.4% male, 1.4% female; odds ratio female vs. male 3.7, 95% CI [1.9, 7.0], p < 0.001), Intergrowth-21st (0.5% male, 1.6% female; odds ratio female vs. male 3.4, 95% CI [1.9, 6.1], p < 0.001), and NICHD (0.3% male, 1.6% female; odds ratio female vs. male 5.6, 95% CI [2.7, 11.5], p < 0.001) curves. Male fetuses were more likely than female fetuses to be classified as macrocephalic using the Intergrowth-21st (6.0% male, 1.5% female; odds ratio male vs. female 4.3, 95% CI [3.1, 6.0], p < 0.001) and NICHD (4.7% male, 1.0% female; odds ratio male vs. female 5.1, 95% CI [3.4, 7.6], p < 0.001) curves. Very low proportions of fetuses were classified as macrocephalic using the Hadlock curves (0.2% male, < 0.1% female; odds ratio male vs. female 6.6, 95% CI [0.8, 52.6]). Conclusion: Female fetuses were more likely to be classified as microcephalic, and male fetuses were more likely to be classified as macrocephalic. Sex-specific fetal head circumference growth curves could improve interpretation of fetal head circumference measurements, potentially decreasing over- and under-diagnosis of microcephaly and macrocephaly based on sex, therefore improving guidance for clinical decisions. Additionally, the overall prevalence of atypical head size varied using three growth curves, with the NICHD and Intergrowth-21st curves fitting our population better than the Hadlock curves. The choice of fetal head circumference growth curves may substantially impact clinical care.