Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

Human distal airways contain a multipotent secretory cell that can regenerate alveoli.

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.

Helminth egg derivatives as proregenerative immunotherapies.

The immune system is increasingly recognized as an important regulator of tissue repair. We developed a regenerative immunotherapy from the helminth Schistosoma mansoni soluble egg antigen (SEA) to stimulate production of interleukin (IL)-4 and other type 2-associated cytokines without negative infection-related sequelae. The regenerative SEA (rSEA) applied to a murine muscle injury induced accumulation of IL-4-expressing T helper cells, eosinophils, and regulatory T cells and decreased expression of IL-17A in gamma delta (γδ) T cells, resulting in improved repair and decreased fibrosis. Encapsulation and controlled release of rSEA in a hydrogel further enhanced type 2 immunity and larger volumes of tissue repair. The broad regenerative capacity of rSEA was validated in articular joint and corneal injury models. These results introduce a regenerative immunotherapy approach using natural helminth derivatives.

Alkynes to (Free) Carbenes to Polycyclic Cyclopropanes.

Carbenes and carbenoids are commonly employed for the synthesis of cyclopropane-containing compounds. Here we report the metal-free, intramolecular cyclopropanation of tethered alkenes by free carbenes derived from alkynes to construct structurally unique multicyclic cyclopropanes with perfect atom economy. The nature of the tether influences both the rate of carbene formation and subsequent competing reaction events. Some of the substrates lead to metastable cyclopropane intermediates that further fragment to furnish interesting isomeric products by mechanistically novel processes. A removable siloxane tether can be utilized to achieve formal intermolecular cyclopropanations and to access cyclopropanol derivatives.

Applying the antecedent, behaviour, and consequence taxonomy to unintentional firearm injury as determined by a collaborative firearm injury database.

BACKGROUND: Unintentional firearm injury (UFI) remains a significant problem in the USA with respect to preventable injury and death. The antecedent, behaviour and consequence (ABC) taxonomy has been used by law enforcement agencies to evaluate unintentional firearm discharge. Using an adapted ABC taxonomy, we sought to categorise civilian UFI in our community to identify modifiable behaviours. METHODS: Using a collaborative firearm injury database (containing both a university-based level 1 trauma registry and a metropolitan law enforcement database), all UFIs from August 2008 through December 2021 were identified. Perceived threat (antecedent), behaviour and injured party (consequence) were identified for each incident. RESULTS: During the study period, 937 incidents of UFI were identified with 64.2% of incidents occurring during routine firearm tasks. 30.4% of UFI occurred during neglectful firearm behaviour such as inappropriate storage. Most injuries occurred under situations of low perceived threat. UFI involving children was most often due to inappropriate storage of weapons, while cleaning a firearm was the most common behaviour in adults. Overall, 16.5% of UFI involved injury to persons other than the one handling the weapon and approximately 1.3% of UFI resulted in mortality. CONCLUSIONS: The majority of UFI occurred during routine and expected firearm tasks such as firearm cleaning. Prevention programmes should not overlook these modifiable behaviours in an effort to reduce UFIs, complications and deaths.

Occupational therapy students' perceptions of their experience in a role-emerging Level II fieldwork within higher education student services.

BACKGROUND: Role-emerging settings - those where occupational therapy (OT) services have not traditionally been provided - are common sites for practice placements of entry-level occupational therapy students. A growing body of literature has attempted to determine the value and drawbacks of such practice placements on the professional preparedness of OT students with mixed findings. Benefits have been identified, including increased cultural understanding, advocacy, creativity, initiative, and problem-solving skills. However, OT students have been reported to perceive such placement as limiting their professional growth and preparedness to practice compared to traditional placements. METHODS: A phenomenological study was conducted seeking the perceptions of OT students (n = 14) about their clinical placement at a role-emerging site. Recorded semi-structured interviews were conducted by trained interviewers within two weeks of the end of clinical placement. The recordings were transcribed verbatim and then coded using an iterative multi-coder inductive approach. Inter-coder agreement, reflectivity, and audit trail were maintained. RESULTS: Three themes emerged from the analysis: (1) integrating independence and support, (2) becoming occupational therapists, and (3) filling a gap. These themes reflect students' positive perceptions of their role-emerging clinical placement. They felt that this placement allowed them to develop self-confidence and professional identity as occupational therapists and learn new skills while simultaneously filling a gap in services for clients. Most importantly, they felt that this placement prepared them for their future OT practice. CONCLUSION: This finding and their resounding support of the experience suggest that OT students can perceive role-emerging placement as a solid foundation for clinical practice. Factors, included in this placement, that may have contributed to their experience include the level of support provided, time available for learning including space to make mistakes, and freedom from productivity and payor requirements.

External validation of the SI2NCAL2C score for outcomes following cerebral venous thrombosis.

OBJECTIVES: Prognostication for cerebral venous thrombosis (CVT) remains difficult. We sought to validate the SI2NCAL2C score in an international cohort. MATERIALS AND METHODS: The SI2NCAL2C score was originally developed to predict poor outcome (modified Rankin Scale (mRS) 3-6) at 6 months, and mortality at 30 days and 1 year using data from the International CVT Consortium. The SI2NCAL2C score uses 9 variables: the absence of any female-sex-specific risk factors, intracerebral hemorrhage, central nervous system infection, focal neurological deficits, coma, age, lower level of hemoglobin, higher level of glucose, and cancer. The ACTION-CVT study was an international retrospective study that enrolled consecutive patients across 27 centers. The poor outcome score was validated using 90-day mRS due to lack of follow-up at the 6-month time-point in the ACTION-CVT cohort. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plots. Missing data were imputed using the additive regression and predictive mean matching methods. Bootstrapping was performed with 1000 iterations. RESULTS: Mortality data were available for 950 patients and poor outcome data were available for 587 of 1,025 patients enrolled in ACTION-CVT. Compared to the International CVT Consortium, the ACTION-CVT cohort was older, less often female, and with milder clinical presentation. Mortality was 2.5% by 30 days and 6.0% by one year. At 90-days, 16.7% had a poor outcome. The SI2NCAL2C score had an AUC of 0.74 [95% CI 0.69-0.79] for 90-day poor outcome, 0.72 [0.60-0.82] for mortality by 30 days, and 0.82 [0.76-0.88] for mortality by one year. CONCLUSIONS: The SI2NCAL2C score had acceptable to good performance in an international external validation cohort. The SI2NCAL2C score warrants additional validation studies in diverse populations and clinical implementation studies.

Modified Broström vs Suture Tape Augmentation: A Systematic Review.

Ankle sprains are common musculoskeletal injuries which can develop into residual chronic lateral ankle instability. When non-surgical treatments fail, surgical intervention is often indicated. We performed a systematic review of the literature comparing outcome measures of modified Broström repair to suture tape augmentation for lateral ankle stabilization. All studies available in PubMed up to July 2023 were screened. Three randomized controlled trials involving 235 patients met inclusion criteria. All the studies reported on Foot and Ankle Ability Measure, two of the three studies found higher postoperative Sports Activity scores in the suture tape group. Two of the studies reported Foot and Ankle Outcome Score, neither were found to be significantly different. The third study analyzed return to pre-injury level of activity between the two surgical techniques and found a faster return to activity for suture tape compared to modified Broström procedure. Overall, outcome measures show no significant difference between modified Broström and suture tape augmentation.

Preconception paternal alcohol exposure decreases IVF embryo survival and pregnancy success rates in a mouse model.

Increasingly, couples struggling with fertility turn to assisted reproductive techniques, including IVF, to have children. Despite the demonstrated influence of periconception male health and lifestyle choices on offspring development, studies examining IVF success rates and child health outcomes remain exclusively focused on maternal factors. Using a physiologically relevant mouse model, we tested the hypothesis that chronic paternal preconception alcohol intake adversely affects IVF success and negatively impacts IVF offspring fetoplacental growth. Using a voluntary, binge-like mouse model, we exposed sexually mature C57BL/6J males to three preconception treatments (0% (Control), 6% EtOH or 10% EtOH) for 6 weeks, isolated and cryopreserved caudal sperm from treated males, and then used these samples to fertilize oocytes before assessing IVF embryo developmental outcomes. We found that preconception paternal alcohol use reduced IVF embryo survival and pregnancy success rates in a dose-dependent manner, with the pregnancy success rate of the 10% EtOH treatment falling to half those of the Controls. Mechanistically, we found that preconception paternal alcohol exposure disrupts embryonic gene expression, including Fgf4 and Egfr, two critical regulators of trophectoderm stem cell growth and placental patterning, with lasting impacts on the histological organization of the late-term placenta. The changes in placental histoarchitecture were accompanied by altered regulation of pathways controlling mitochondrial function, oxidative phosphorylation and some imprinted genes. Our studies indicate that male alcohol use may significantly impede IVF success rates, increasing the couple's financial burden and emotional stress, and highlights the need to expand prepregnancy messaging to emphasize the reproductive dangers of alcohol use by both parents.

Computation-guided optimization of split protein systems.

Splitting bioactive proteins into conditionally reconstituting fragments is a powerful strategy for building tools to study and control biological systems. However, split proteins often exhibit a high propensity to reconstitute, even without the conditional trigger, limiting their utility. Current approaches for tuning reconstitution propensity are laborious, context-specific or often ineffective. Here, we report a computational design strategy grounded in fundamental protein biophysics to guide experimental evaluation of a sparse set of mutants to identify an optimal functional window. We hypothesized that testing a limited set of mutants would direct subsequent mutagenesis efforts by predicting desirable mutant combinations from a vast mutational landscape. This strategy varies the degree of interfacial destabilization while preserving stability and catalytic activity. We validate our method by solving two distinct split protein design challenges, generating both design and mechanistic insights. This new technology will streamline the generation and use of split protein systems for diverse applications.

Gender-Based Discrimination Among Medical Students: A Cross-Sectional Study in Brazil.

INTRODUCTION: Gender-based discrimination (GBD) creates a hostile environment during medical school, affecting students' personal life and academic performance. Little is known about how GBD affects the over 204,000 medical students in Brazil. This study aims to explore the patterns of GBD experienced by medical students in Brazil. METHODS: This is a cross-sectional study using an anonymous, Portuguese survey disseminated in June 2021 among Brazilian medical students. The survey was composed of 24 questions to collect data on GBD during medical school, formal methods for reporting GBD, and possible solutions for GBD. RESULTS: Of 953 responses, 748 (78%) were cisgender women, 194 (20%) were cisgender men, and 11 (1%) were from gender minorities. 65% (616/942) of respondents reported experiencing GBD during medical school. Women students experienced GBD more than men (77% versus 22%; P < 0.001). On comparing GBD perpetrator roles, both women (82%, 470/574) and men (64%, 27/42) reported the highest rate of GBD by faculty members. The occurrence of GBD by location differed between women and men. Only 12% (115/953) of respondents reported knowing their institution had a reporting mechanism for GBD. CONCLUSIONS: Most respondents experienced GBD during medical school. Cisgender women experienced GBD more than cisgender men. Perpetrators and location of GBD differed for men and women. Finally, an alarming majority of students did not know how to formally report GBD in their schools. It is imperative to adopt broad policy changes to diminish the rate of GBD and its a consequential burden on medical students.

Gas-phase stability and thermodynamics of ligand-bound, binary complexes of chloramphenicol acetyltransferase reveal negative cooperativity.

The biological role of the bacterial chloramphenicol (Chl)-resistance enzyme, chloramphenicol acetyltransferase (CAT), has seen renewed interest due to the resurgent use of Chl against multi-drug-resistant microbes. This looming threat calls for more rationally designed antibiotic derivatives that have improved antimicrobial properties and reduced toxicity in humans. Herein, we utilize native ion mobility spectrometry-mass spectrometry (IMS-MS) to investigate the gas-phase structure and thermodynamic stability of the type I variant of CAT from Escherichia coli (EcCATI) and several EcCATI:ligand-bound complexes. EcCATI readily binds multiple Chl without incurring significant changes to its gas-phase structure or stability. A non-hydrolyzable acetyl-CoA derivative (S-ethyl-CoA, S-Et-CoA) was used to kinetically trap EcCATI and Chl in a ternary, ligand-bound state (EcCATI:S-Et-CoA:Chl). Using collision-induced unfolding (CIU)-IMS-MS, we find that Chl dissociates from EcCATI:S-Et-CoA:Chl complexes at low collision energies, while S-Et-CoA remains bound to EcCATI even as protein unfolding occurs. Gas-phase binding constants further suggest that EcCATI binds S-Et-CoA more tightly than Chl. Both ligands exhibit negative cooperativity of subsequent ligand binding in their respective binary complexes. While we observe no significant change in structure or stability to EcCATI when bound to either or both ligands, we have elucidated novel gas-phase unfolding and dissociation behavior and provided a foundation for further characterization of alternative substrates and/or inhibitors of EcCATI.

α-Synuclein is the major platelet isoform but is dispensable for activation, secretion, and thrombosis.

Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via Soluble NSF Attachment Protein Receptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (i.e. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α-Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein's role in platelet secretion is uncharacterized. In this study, immunofluorescence showed that α-synuclein was present on punctate structures that co-stained with markers for α-granules and lysosomes and in a cytoplasmic pool. We analyzed the phenotype of α-synuclein-/- mice and their platelets. Platelets from knockout mice had a mild, agonist-dependent secretion defect but aggregation and spreading in vitro were unaffected. Consistently, thrombosis/hemostasis were unaffected in the tail-bleeding, FeCl3 carotid injury and jugular vein puncture models. None of the platelet secretory machinery examined, e.g. the v-SNAREs, were affected by α-synuclein's loss. The results indicate that, despite its abundance, α-synuclein has only a limited role in platelet function and thrombosis.

What did we know? The N-terminus of α-Synuclein affects SNARE-complex assembly, fusion pore opening, and granule docking.Microvascular bleeding is seen in Parkinson Disease patients where α-synuclein has a pathological role.What did we discover? α-Synuclein colocalizes with P-selectin (α-granules) and LAMP-1 (lysosomes) in platelets.The loss of α-synuclein has only a mild, agonist-dependent effect on platelet secretion.The loss of α-synuclein had no effect on thrombosis/hemostasis in 3 injury models.What is the impact? Despite its abundance, α-synuclein is not required for platelet secretion.α-Synuclein is not required for hemostasis or thrombosis.

The complementary roles of VAMP-2, -3, and -7 in platelet secretion and function.

Platelet secretion requires Soluble N-ethylmaleimide Sensitive Attachment Protein Receptors (SNAREs). Vesicle SNAREs/Vesicle-Associated Membrane Proteins (v-SNAREs/VAMPs) on granules and t-SNAREs in plasma membranes mediate granule release. Platelet VAMP heterogeneity has complicated the assessment of how/if each is used and affects hemostasis. To address the importance of VAMP-7 (V7), we analyzed mice with global deletions of V3 and V7 together or platelet-specific deletions of V2, V3, and global deletion of V7. We measured the kinetics of cargo release, and its effects on three injury models to define the context-specific roles of these VAMPs. Loss of V7 minimally affected dense and α granule release but did affect lysosomal release. V3-/-7-/- and V2Δ3Δ7-/- platelets showed partial defects in α and lysosomal release; dense granule secretion was unaffected. In vivo assays showed that loss of V2, V3, and V7 caused no bleeding or occlusive thrombosis. These data indicate a role for V7 in lysosome release that is partially compensated by V3. V7 and V3, together, contribute to α granule release, however none of these deletions affected hemostasis/thrombosis. Our results confirm the dominance of V8. When it is present, deletion of V2, V3, or V7 alone or in combination minimally affects platelet secretion and hemostasis.

What did we know? V8 is the primary VAMP isoform for platelet granule secretion, but V2 and V3 play compensatory roles.V3 is important for platelet endocytosis.V7 plays a minimal role in secretion and does not affect hemostasis.What did we discover? The loss of both V3 and V7 increases α and lysosomal secretion defects.Platelet-specific deletion of V2 and V3 with global V7-deletion causes defective α and lysosomal release.Secretion deficiencies in V3^−/−7^−/− and V2^Δ3^Δ7^−/− have no effect on hemostasis or thrombosis.What is the impact? We show that endosomal v-SNAREs (V3 and V7) play minor roles in secretion.V3^−/−7^−/− and platelet-specific V2^Δ3^Δ7^−/− mice are viable and will be valuable in in vivo studies of membrane trafficking.

Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging.

BACKGROUND: Perfusion weighted imaging (PWI) is critical for determining whether stroke patients presenting in an extended time window are candidates for mechanical thrombectomy. However, PWI is not always available. Fluid-attenuated inversion recovery hyperintense vessels (FHVs) are seen in patients with a PWI lesion. We investigated whether a scale measuring the extent FHV could serve as a surrogate for PWI to determine eligibility for thrombectomy. METHODS: The National Institutes of Health (NIH) FHV score was developed to quantify the burden of FHV and applied to magnetic resonance imaging scans of stroke patients with fluid-attenuated inversion recovery and perfusion imaging. The NIH-FHV was combined with the diffusion weighted image volume to estimate the diffusion-perfusion mismatch ratio. Linear regression was used to compare PWI volumes and mismatch ratios with estimates from the NIH-FHV score. Receiver operating characteristic analysis was used to test the ability of the NIH-FHV score to identify a significant mismatch. RESULTS: There were 101 patients included in the analysis, of whom 78% had a perfusion deficit detected on PWI with a mean lesion volume of 47 (±59) mL. The NIH-FHV score was strongly associated with the PWI lesion volume (P<0.001; R2=0.32; ß-coefficient, 0.57). When combined with diffusion weighted image lesion volume, receiver operating characteristic analysis testing the ability to detect a mismatch ratio ≥1.8 using the NIH-FHV score resulted in an area under the curve of 0.94. CONCLUSIONS: The NIH-FHV score provides an estimate of the PWI lesion volume and, when combined with diffusion weighted imaging, may be helpful when trying to determine whether there is a clinically relevant diffusion-perfusion mismatch in situations where perfusion imaging is not available. Further studies are needed to validate this approach.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study.

BACKGROUND: A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort. METHODS: This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups. RESULTS: Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P=0.02). CONCLUSIONS: In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Impact of breakthrough COVID-19 cases during the omicron wave on vascular health and cardiac autonomic function in young adults.

We and others have previously shown that COVID-19 results in vascular and autonomic impairments in young adults. However, the newest variant of COVID-19 (Omicron) appears to have less severe complications. Therefore, we investigated whether recent breakthrough infection with COVID-19 during the Omicron wave impacts cardiovascular health in young adults. We hypothesized that measures of vascular health and indices of cardiac autonomic function would be impaired in those who had the Omicron variant of COVID-19 when compared with controls who never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7 females). Macro- and microvascular function were assessed using flow-mediated dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were assessed as indices of cardiac autonomic function. FMD was not different between control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive hyperemia (P = 0.884) and arterial stiffness were not different between groups (e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367). Finally, measures of HR variability and cardiac BRS were not different between groups (all, P > 0.05). Collectively, these data suggest preserved vascular health and cardiac autonomic function in young, otherwise healthy adults who had breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show for the first time that breakthrough cases of COVID-19 during the Omicron wave does not impact vascular health and cardiac autonomic function in young adults. These are promising results considering earlier research showing impaired vascular and autonomic function following previous variants of COVID-19. Collectively, these data demonstrate that the recent Omicron variant is not detrimental to cardiovascular health in young, otherwise healthy, vaccinated adults.

Impact of COVID-19 on cardiac autonomic function in healthy young adults: potential role of symptomatology and time since diagnosis.

Emerging evidence suggests that COVID-19 may affect cardiac autonomic function; however, the limited findings in young adults with COVID-19 have been equivocal. Notably, symptomology and time since diagnosis appear to influence vascular health following COVID-19, but this has not been explored in the context of cardiac autonomic regulation. Therefore, we hypothesized that young adults who had persistent symptoms following COVID-19 would have lower heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) compared with those who had COVID-19 but were asymptomatic at testing and controls who never had COVID-19. Furthermore, we hypothesized that there would be relationships between cardiac autonomic function measures and time since diagnosis. We studied 27 adults who had COVID-19 and were either asymptomatic (ASYM; n = 15, 6 females); 21 ± 4 yr; 8.4 ± 4.0 wk from diagnosis) or symptomatic (SYM; n = 12, 9 females); 24 ± 3 yr; 12.3 ± 6.2 wk from diagnosis) at testing, and 20 adults who reported never having COVID-19 (24 ± 4 yr, 11 females). Heart rate and beat-to-beat blood pressure were continuously recorded during 5 min of rest to assess HRV and cardiac BRS. HRV [root mean square of successive differences between normal heartbeats (RMSSD); control, 73 ± 50 ms; ASYM, 71 ± 47 ms; and SYM, 84 ± 45 ms; P = 0.774] and cardiac BRS (overall gain; control, 22.3 ± 10.1 ms/mmHg; ASYM, 22.7 ± 12.2 ms/mmHg; and SYM, 24.3 ± 10.8 ms/mmHg; P = 0.871) were not different between groups. However, we found correlations with time since diagnosis for HRV (e.g., RMSSD, r = 0.460, P = 0.016) and cardiac BRS (overall gain, r = 0.470, P = 0.014). These data suggest a transient impact of COVID-19 on cardiac autonomic function that appears mild and unrelated to persistent symptoms in young adults.NEW & NOTEWORTHY The potential role of persistent COVID-19 symptoms on cardiac autonomic function in young adults was investigated. We observed no differences in heart rate variability or cardiac baroreflex sensitivity between controls who never had COVID-19 and those who had COVID-19, regardless of symptomology. However, there were significant relationships between measures of cardiac autonomic function and time since diagnosis, suggesting that COVID-19-related changes in cardiac autonomic function are transient in young, otherwise healthy adults.

Infant brain imaging using magnetoencephalography: Challenges, solutions, and best practices.

The excellent temporal resolution and advanced spatial resolution of magnetoencephalography (MEG) makes it an excellent tool to study the neural dynamics underlying cognitive processes in the developing brain. Nonetheless, a number of challenges exist when using MEG to image infant populations. There is a persistent belief that collecting MEG data with infants presents a number of limitations and challenges that are difficult to overcome. Due to this notion, many researchers either avoid conducting infant MEG research or believe that, in order to collect high-quality data, they must impose limiting restrictions on the infant or the experimental paradigm. In this article, we discuss the various challenges unique to imaging awake infants and young children with MEG, and share general best-practice guidelines and recommendations for data collection, acquisition, preprocessing, and analysis. The current article is focused on methodology that allows investigators to test the sensory, perceptual, and cognitive capacities of awake and moving infants. We believe that such methodology opens the pathway for using MEG to provide mechanistic explanations for the complex behavior observed in awake, sentient, and dynamically interacting infants, thus addressing core topics in developmental cognitive neuroscience.