Large birth mark and unilateral swelling of the lower extremity in a young teenager.

We describe an early adolescent male who was diagnosed with vascular malformation associated with unilateral limb overgrowth based on the clinical findings of a persistent port-wine stain since birth and gradually progressing right lower limb oedema since early childhood. Clinicians should keep in mind to clinically evaluate such malformations in detail, as well as contemplate genetic testing in patients presenting with a large port-wine stain at birth, particularly if well demarcated and lateral in a lower extremity.

Improving explanation of motor disability with diffusion-based graph metrics at onset of the first demyelinating event.

BACKGROUND: Conventional magnetic resonance imaging (MRI) does not account for all disability in multiple sclerosis. OBJECTIVE: The objective was to assess the ability of graph metrics from diffusion-based structural connectomes to explain motor function beyond conventional MRI in early demyelinating clinically isolated syndrome (CIS). METHODS: A total of 73 people with CIS underwent conventional MRI, diffusion-weighted imaging and clinical assessment within 3 months from onset. A total of 28 healthy controls underwent MRI. Structural connectomes were produced. Differences between patients and controls were explored; clinical associations were assessed in patients. Linear regression models were compared to establish relevance of graph metrics over conventional MRI. RESULTS: Local efficiency (p = 0.045), clustering (p = 0.034) and transitivity (p = 0.036) were reduced in patients. Higher assortativity was associated with higher Expanded Disability Status Scale (EDSS) (ß = 74.9, p = 0.026) scores. Faster timed 25-foot walk (T25FW) was associated with higher assortativity (ß = 5.39, p = 0.026), local efficiency (ß = 27.1, p = 0.041) and clustering (ß = 36.1, p = 0.032) and lower small-worldness (ß = -3.27, p = 0.015). Adding graph metrics to conventional MRI improved EDSS (p = 0.045, ΔR2 = 4) and T25FW (p < 0.001, ΔR2 = 13.6) prediction. CONCLUSION: Graph metrics are relevant early in demyelination. They show differences between patients and controls and have relationships with clinical outcomes. Segregation (local efficiency, clustering, transitivity) was particularly relevant. Combining graph metrics with conventional MRI better explained disability.

Comparative anatomy of the caudate nucleus in canids and felids: Associations with brain size, curvature, cross-sectional properties, and behavioral ecology.

The evolutionary history of canids and felids is marked by a deep time separation that has uniquely shaped their behavior and phenotype toward refined predatory abilities. The caudate nucleus is a subcortical brain structure associated with both motor control and cognitive, emotional, and executive functions. We used a combination of three-dimensional imaging, allometric scaling, and structural analyses to compare the size and shape characteristics of the caudate nucleus. The sample consisted of MRI scan data obtained from six canid species (Canis lupus lupus, Canis latrans, Chrysocyon brachyurus, Lycaon pictus, Vulpes vulpes, Vulpes zerda), two canid subspecies (Canis lupus familiaris, Canis lupus dingo), as well as three felids (Panthera tigris, Panthera uncia, Felis silvestris catus). Results revealed marked conservation in the scaling and shape attributes of the caudate nucleus across species, with only slight deviations. We hypothesize that observed differences in caudate nucleus size and structure for the domestic canids are reflective of enhanced cognitive and emotional pathways that possibly emerged during domestication.

Effect of Varus-Producing Distal Femoral Osteotomy and High Tibial Osteotomy on Compartment Pressures and Contact Area at Varying Degrees of Knee Flexion.

Background: In patients with valgus alignment and degenerative changes in the lateral compartment, both distal femoral osteotomy (DFO) and high tibial osteotomy (HTO) can be used to unload the lateral compartment. Prior studies have shown that in valgus knees, the tibial wear is posterior and DFO exerts the greatest effect in extension; however, its effect is decreased as flexion angle rises. Hypothesis: Medial closing-wedge (MCW) HTO would significantly decrease contact area, mean contact pressure (MCP), and peak contact pressure (PCP) in the lateral knee compartment through knee flexion to a greater extent compared with lateral opening-wedge (LOW) DFO. Study Design: Controlled laboratory study. Methods: MCWHTO and LOWDFO were performed, correcting a mean of 8° of valgus alignment, in 10 cadaveric knees using plate fixation. Tibiofemoral contact pressure of the medial and lateral compartments was measured in 0°, 30°, 60°, and 90° of knee flexion before and after osteotomy using thin electronic sensors and load applied through an Instron device. PCP, MCP, and contact area were measured for each condition. Results: The lateral MCP was significantly decreased in the HTO state compared with the native state in 30° (P = .015), 60° (P = .0199), and 90° (P < .0001) of flexion. The lateral MCP was also significantly decreased in the HTO state when compared with the DFO state in 60° (P = .0093) and 90° of flexion (P < .0001). After DFO, the lateral MCP returned to that of the native state in 60° (P > .999) and 90° (P > .999) of flexion. The lateral PCP decreased for all test states in all degrees of flexion; the HTO state was significantly decreased when compared with the native state in 60° (P < .0001) and 90° (P < .0001). Conclusion: With varus corrections of 8°, MCWHTO was more effective at unloading the lateral compartment than LOWDFO. This effect was significant as the knee flexion angle increased. This study should be considered as one aspect of the surgical decision-making process. Clinical Relevance: In patients with mild to moderate valgus deformity without hypoplastic lateral femoral condyle and without significant joint line obliquity, MCWHTO may improve offloading of the lateral compartment in flexion.

Do maternal haemodynamics have a causal influence on treatment for gestational diabetes?

BACKGROUND: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM. METHODS: We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis. RESULTS: 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 - 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm, p = 0.014) and PWV (7.8 ± 1.04 vs. 8.4 ± 1.61 m/s, p = 0.029) were both significantly higher amongst the women requiring pharmacological management, though these relationships did not remain significant in causal logistic regression. CONCLUSIONS: Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment.

This observational study is the first to examine relationships between maternal haemodynamics and treatment requirement for gestational diabetes (GDM). This is also the first study to demonstrate a causative, rather than simply associational, relationship between maternal body mass index (BMI) and the need for pharmacological treatment of GDM, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12%. Maternal heart rate and pulse wave velocity were significantly higher among women with GDM requiring pharmacological management, but this finding did not remain significant in logistic regression analysis, and no causative relationships between maternal hemodynamics and treatment requirement were identified. Our findings highlight the importance of pre- and peri-conception weight control, but do not support a role for measurement of maternal hemodynamics in the prediction of women who are likely to require pharmacological management of GDM.

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BACKGROUND: Multiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. OBJECTIVE: To examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. METHODS: Thirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. RESULTS: Higher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). CONCLUSION: The association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

Outcomes of total shoulder arthroplasty in patients with prior anterior shoulder instability: minimum 5-year follow-up.

BACKGROUND: Patients with a history of anterior shoulder instability (ASI) commonly progress to glenohumeral arthritis or even dislocation arthropathy and often require total shoulder arthroplasty (TSA). The purposes of this study were to (1) report patient-reported outcomes (PROs) after TSA in patients with a history of ASI, (2) compare TSA outcomes of patients whose ASI was managed operatively vs. nonoperatively, and (3) report PROs of TSA in patients who previously underwent arthroscopic vs. open ASI management. METHODS: Patients were included if they had a history of ASI and had undergone TSA ≥5 years earlier, performed by a single surgeon, between October 2005 and January 2017. The exclusion criteria included prior rotator cuff repair, hemiarthroplasty, or glenohumeral joint infection before the index TSA procedure. Patients were separated into 2 groups: those whose ASI was previously operatively managed and those whose ASI was treated nonoperatively. This was a retrospective review of prospective collected data. Data collected was demographic, surgical and subjective. The PROs used were the American Shoulder and Elbow Surgeons score, Single Assessment Numerical Evaluation score, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) score, and 12-item Short Form physical component score. Failure was defined as revision TSA surgery, conversion to reverse TSA, or prosthetic joint infection. Kaplan-Meier survivorship analysis was performed. RESULTS: This study included 36 patients (27 men and 9 women) with a mean age of 56.4 years (range, 18.8-72.2 years). Patients in the operative ASI group were younger than those in the nonoperative ASI group (50.6 years vs. 64.0 years, P < .001). Operative ASI patients underwent 10 open and 11 arthroscopic anterior stabilization surgical procedures prior to TSA (mean, 2 procedures; range, 1-4 procedures). TSA failure occurred in 6 of 21 patients with operative ASI (28.6%), whereas no failures occurred in the nonoperative ASI group (P = .03). Follow-up was obtained in 28 of 30 eligible patients (93%) at an average of 7.45 years (range, 5.0-13.6 years). In the collective cohort, the American Shoulder and Elbow Surgeons score, Single Assessment Numerical Evaluation score, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) score, and 12-item Short Form physical component score significantly improved, with no differences in the postoperative PROs between the 2 groups. We found no significant differences when comparing PROs between prior open and prior arthroscopic ASI procedures or when comparing the number of prior ASI procedures. Kaplan-Meier analysis demonstrated a 79% 5-year survivorship rate in patients with prior ASI surgery and a 100% survivorship rate in nonoperatively managed ASI patients (P = .030). CONCLUSION: At mid-term follow-up, patients with a history of ASI undergoing TSA can expect continued improvement in function compared with preoperative values. However, TSA survivorship is decreased in patients with a history of ASI surgery compared with those without prior surgery.

Biomechanical Analysis Evaluating Meniscal Extrusion After Knotless Suture Anchor Fixation for Segmental Medial Meniscal Allograft Transplantation.

Background: Segmental medial meniscal allograft transplantation (MAT) has been shown to restore knee biomechanics; however, stable fixation of the transplantation is critical to avoid extrusion and maximize healing. Purpose: To evaluate the degree of meniscal extrusion and biomechanical function of segmental medial MAT performed with meniscocapsular sutures versus repair augmentation with knotless suture anchors. Study Design: Controlled laboratory study. Methods: Segmental midbody medial meniscectomy and subsequent segmental medial MAT were performed on 10 fresh-frozen cadaveric knees. The knees were then loaded in a dynamic tensile testing machine to 1000 N for 60 seconds at 0°, 30°, 60°, and 90° of flexion, and 4 conditions were tested: (1) intact, (2) segmental defect, (3) inside-out segmental repair, and (4) anchor plus inside-out segmental repair of the medial MAT. Meniscal extrusion was measured using high-fidelity ultrasound imaging. The mean contact area and the mean and peak contact pressures were assessed with submeniscal pressure-mapping sensors. Data from testing conditions were compared with 2-way repeated-measures analysis of variance, with pairwise comparison using the Bonferroni method. Results: At 90° of flexion, the segmental defect state showed a higher degree of meniscal extrusion compared with all other states (P ≤ .012). There was no difference in the degree of meniscal extrusion between the intact state and the inside-out repair or anchor plus inside-out segmental repair states at all knee flexion angles (P > .05). There was no significant difference in the mean and peak contact pressures among the 4 states at all flexion angles except that at 0° of knee flexion there was significantly lower peak contact pressure at the medial compartment after anchor plus inside-out segmental repair compared with the segmental defect state (P = .048). Conclusion: Meniscal extrusion was not significantly increased at any flexion angle after segmental resection. The addition of knotless anchors did not improve meniscal extrusion or contact pressures/area compared with capsular repair alone. The addition of knotless anchors did improve contact mechanics from the segmental defect state, but only at 0° of flexion. Clinical Relevance: The addition of knotless suture anchors to segmental meniscal transplantation increased stabilization of the meniscus at full extension compared with repair with sutures alone. This increased stabilization may lead to better long-term outcomes.

Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.

A collaborative approach to improving representation in viral genomic surveillance.

The lack of routine viral genomic surveillance delayed the initial detection of SARS-CoV-2, allowing the virus to spread unfettered at the outset of the U.S. epidemic. Over subsequent months, poor surveillance enabled variants to emerge unnoticed. Against this backdrop, long-standing social and racial inequities have contributed to a greater burden of cases and deaths among minority groups. To begin to address these problems, we developed a new variant surveillance model geared toward building 'next generation' genome sequencing capacity at universities in or near rural areas and engaging the participation of their local communities. The resulting genomic surveillance network has generated more than 1,000 SARS-CoV-2 genomes to date, including the first confirmed case in northeast Louisiana of Omicron, and the first and sixth confirmed cases in Georgia of the emergent BA.2.75 and BQ.1.1 variants, respectively. In agreement with other studies, significantly higher viral gene copy numbers were observed in Delta variant samples compared to those from Omicron BA.1 variant infections, and lower copy numbers were seen in asymptomatic infections relative to symptomatic ones. Collectively, the results and outcomes from our collaborative work demonstrate that establishing genomic surveillance capacity at smaller academic institutions in rural areas and fostering relationships between academic teams and local health clinics represent a robust pathway to improve pandemic readiness.

Advanced central nervous system imaging biomarkers in radiologically isolated syndrome: a mini review.

Radiologically isolated syndrome is characterised by central nervous system white-matter hyperintensities highly suggestive of multiple sclerosis in individuals without a neurological history of clinical demyelinating episodes. It probably represents the pre-symptomatic phase of clinical multiple sclerosis but is poorly understood. This mini review summarises our current knowledge regarding advanced imaging techniques in radiologically isolated syndrome that provide insights into its pathobiology and prognosis. The imaging covered will include magnetic resonance imaging-derived markers of central nervous system volumetrics, connectivity, and the central vein sign, alongside optical coherence tomography-related metrics.

Inflammatory and Immunologic Contributions in Femoroacetabular Impingement Syndrome.

Femoroacetabular impingement (FAI) is one of the most common causes of labral and early cartilage damage in the nondysplastic hip. FAI is increasingly recognized as a cause for hip and groin pain in the young, active patient, and the surgical treatment of FAI with hip arthroscopy has risen exponentially. Although our understanding of FAI and the progression to degenerative osteoarthritis of the hip has historically been considered a mechanical "wear-and-tear" disease of an imperfectly shaped, aspherical, femoral head within a deep or overcovering acetabulum leading to cartilage injury, our understanding of the intrinsic pathophysiologic mechanisms underlying the development of FAI and joint degeneration of the hip remains poor. For example, many patients with FAI morphology may never develop hip pain or osteoarthritis; there remains more to discover regarding the pathophysiology of arthritis in the setting of FAI. Recent work has begun to identify a strong inflammatory and immunologic component to the FAI disease process that affects the hip synovium, labrum, and cartilage and may be detectable from peripheral clinical samples (blood and urine). This review highlights our current understanding of the inflammatory and immunologic contributions to FAI and potential therapeutic strategies to supplement and augment the surgical management of FAI.

First-line immunosuppression in neuromuscular diseases.

Autoimmune neuromuscular diseases are common and often treatable causes for peripheral nervous system dysfunction. If not optimally managed, they result in meaningful impairments and disability. The treating neurologist should aim to maximise clinical recovery with minimal iatrogenic risk. This requires careful patient and medication selection, appropriate counselling and close monitoring of clinical efficacy and safety. Here, we summarise our consensus departmental approach to first-line immunosuppression in neuromuscular diseases. We combine multispecialty evidence and expertise with a focus on autoimmune neuromuscular diseases to create guidance on starting, dosing and monitoring for toxic effects of the commonly used drugs. These include corticosteroids, steroid-sparing agents and cyclophosphamide. We also provide efficacy monitoring advice, as clinical response informs dosage and drug choice. The principles of this approach could be applied across much of the spectrum of immune-mediated neurological disorders where there is significant therapeutic crossover.

Use of Computed Tomography in the Evaluation of Anterior Shoulder Instability: Possible Effect on Surgical Management.

BACKGROUND: Glenoid bone loss is a critical factor in the management of anterior shoulder instability (ASI). Computed tomography (CT) is often considered the gold standard to evaluate glenoid bone loss, but it is associated with negative factors such as radiation. Thus, interest exists as to when orthopaedic surgeons need a CT scan to guide decision-making when treating ASI. PURPOSE: To determine whether information gained from a shoulder CT scan alters orthopaedic surgeons' management plan for ASI and, secondarily, to determine whether surgeon- and patient-specific factors affect whether a CT scan changes treatment and which clinical factors are most important in surgical decision-making. STUDY DESIGN: Cross-sectional study. METHODS: A questionnaire composed of 24 ASI vignettes was administered to Herodicus Society members, American Shoulder and Elbow Surgeons Neer Circle members, and sports medicine fellowship-trained orthopaedic surgeons. Participants chose their recommended surgical treatment from the options of arthroscopic Bankart repair, open Bankart repair, bony reconstruction procedure, or other based on patient history, radiographs, and magnetic resonance imaging. Participants were then shown CT images and asked whether their treatment plan changed and, if not, whether the CT scan was not necessary or had reinforced their decision. Generalized linear mixed-effects logistic regression modeling was performed to assess the influence of vignette and respondent characteristics on treatment decisions. RESULTS: A total of 74 orthopaedic surgeons completed the survey; 96% were fellowship trained (sports medicine, 50%; shoulder and elbow surgery, 41%), and 66% practiced in academic settings. CT imaging did not change the selected treatment strategy in 75.6% of responses. In cases when management did not change, surgeons reported that the CT scan reinforced their decision in 53.4% of responses and was not necessary for decision-making in 22.2% of responses. Decision-making was more likely to be changed after CT in male patients and those with off-track lesions. CONCLUSION: Information gained from a CT scan did not alter treatment decision-making in three-quarters of vignettes among surgeons experienced in the management of ASI. The finding that CT scans did alter the treatment plan in nearly a quarter of cases is not insignificant, and it appears that in patients with borderline glenoid track status and few other risk factors for recurrence after arthroscopic stabilization, CT imaging is more likely to change management.

Long-Term Visual Outcomes in Neovascular Age-Related Macular Degeneration Eyes With Baseline Macular Atrophy on Anti-Vascular Endothelial Growth Factor Treatment.

BACKGROUND AND OBJECTIVE: This study explores the connection between macular atrophy (MA) status at baseline and best visual acuity (BVA) after 5 to 7 years of anti-vascular endothelial growth factor (anti-VEGF) injections on eyes with neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: This retrospective study included patients with neovascular age-related macular degeneration receiving anti-VEGF injections at least twice-yearly for 5+ years at Cole Eye Institute. Analyses of variance and linear regressions explored the connection between MA status, baseline MA intensity, and 5-year BVA change. RESULTS: Of 223 included patients, 5-year BVA change was not statistically significant between MA status groups or from baseline. The population's average 7-year BVA change was -6.3 Early Treatment Diabetic Retinopathy Study letters. Type and frequency of anti-VEGF injections were comparable between MA status groups (P > 0.05). CONCLUSION: Regardless of MA status, 5- and 7-year BVA change lacked clinical relevance. If receiving regular treatment for 5+ years, patients with baseline MA achieve comparable visual outcomes to those without MA, with similar treatment and visit burdens. [Ophthalmic Surg Lasers Imaging Retina 2023;54:223-230.].

Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype.

Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavß2a expression (ß2a-Tg mice) showed increased cytosolic CM Ca2+, and modest levels of CM hypertrophy, and fibrosis. This study aimed to determine if ß2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, high-fat diet (HFD) and Nω-nitro-l-arginine methyl ester (l-NAME, LN). Four-month-old wild-type (WT) and ß2a-Tg mice were given either normal chow (WT-N, ß2a-N) or HFD and/or l-NAME (WT-HFD, WT-LN, WT-HFD-LN, ß2a-HFD, ß2a-LN, and ß2a-HFD-LN). Some animals were treated with the histone deacetylase (HDAC) (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (ß2a-HFD-LN-SAHA). Echocardiography was performed monthly. After 4 mo of treatment, terminal studies were performed including invasive hemodynamics and organs weight measurements. Cardiac tissue was collected. Four months of HFD plus l-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. ß2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased atrial natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M2-macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model, by attenuating these effects. The 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and increased M2-macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies.NEW & NOTEWORTHY Our study shows that three independent pathological stressors (increased Ca2+ influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M2-macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This "3-Hit" mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF.

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation.

BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study.

The relationship between structural connectivity (SC) and functional connectivity (FC) captured from magnetic resonance imaging, as well as its interaction with disability and cognitive impairment, is not well understood in people with multiple sclerosis (pwMS). The Virtual Brain (TVB) is an open-source brain simulator for creating personalized brain models using SC and FC. The aim of this study was to explore SC-FC relationship in MS using TVB. Two different model regimes have been studied: stable and oscillatory, with the latter including conduction delays in the brain. The models were applied to 513 pwMS and 208 healthy controls (HC) from 7 different centers. Models were analyzed using structural damage, global diffusion properties, clinical disability, cognitive scores, and graph-derived metrics from both simulated and empirical FC. For the stable model, higher SC-FC coupling was associated with pwMS with low Single Digit Modalities Test (SDMT) score (F=3.48, P$\lt$0.05), suggesting that cognitive impairment in pwMS is associated with a higher SC-FC coupling. Differences in entropy of the simulated FC between HC, high and low SDMT groups (F=31.57, P$\lt$1e-5), show that the model captures subtle differences not detected in the empirical FC, suggesting the existence of compensatory and maladaptive mechanisms between SC and FC in MS.