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Objective: Duplex ultrasound (US) of the lower extremities is commonly used to assess patients with lower extremity atherosclerosis. Arterial calcification can often be visualized in these images; however, efforts to quantify its extent have been limited. We, thus, sought to develop a new scoring system to measure calcification on duplex US studies of the femoral artery and correlate it with standard computed tomography (CT)-based methods. We then made preliminary attempts to correlate US-based femoral artery calcification scores with limb-specific outcomes in patients with peripheral arterial disease. Methods: Patients who underwent CT evaluation of the lower extremities and arterial duplex US of either lower extremity within 6 months of each examination were included in the study. CT-based calcium scores of the femoral artery were generated using calcium scoring software. To determine the US score, five standard arterial segments (ie, common femoral artery, proximal superficial femoral artery [SFA], mid-SFA, distal SFA, and above the knee popliteal artery) were scored using a scale of 0 to 2 (0, a completely normal vessel segment; 1, a vessel with hyperechoic irregularities of the vessel wall; and 2, clear anechoic shadowing). The available scores were then averaged to yield a single femoral calcium score for each leg. Predictors of femoral calcification scores were then assessed and compared with the CT-based methods. The correlation between the US- and CT-based femoral calcification was assessed, and then the association between the US-based femoral calcification score and limb outcomes was evaluated. Results: A total of 113 patients met the inclusion criteria and were included in the final analysis. US-based calcification scores were increased in patients with diabetes, renal failure, and the presence of chronic limb threatening ischemia similar to CT-based femoral calcification. The US- and CT-based calcification scores showed a moderate to strong correlation (r = 0.64). An elevated US-based femoral artery calcification score was associated with decreased amputation-free survival. Conclusions: A novel US-based method shows promise as a simple method for quantifying the extent of femoral artery calcification in patients with peripheral arterial disease. The US-based method correlates with standard CT-based methods. Preliminary studies show that it could be useful for predicating outcomes for patients with peripheral arterial disease.

Background: With hospital inpatient capacity increasingly limited and primary total joint arthroplasty (TJA) rapidly transitioning to outpatient settings, the feasibility of outpatient aseptic revision and conversion TJA (rTJA) has been considered. Before the widespread adoption of outpatient rTJA, guidelines must be established to prevent patient harm. To this end, this study describes our initial experience with same-day-discharge (SDD) aseptic rTJA. Methods: All aseptic rTJAs performed between May 8, 2015, and December 30, 2021, were retrospectively reviewed. Revision indications, patient selection criteria, and outcomes including SDD success rate, predischarge complications, all-cause emergency department visits, inpatient readmissions, and unplanned clinic encounters within 90 days of surgery were recorded. Results: Thirty-five SDD aseptic rTJAs were performed. Conversion total hip arthroplasty (55.0%) and instability (27.3%) were the most common indications for hip revision. Instability (50%) and conversion total knee arthroplasty (20.8%) were most common for knee revision. SDD was achieved in 97% (34/35) of cases. One hip patient failed SDD due to persistent hypoxia requiring an overnight hospital stay and also underwent closed reduction for dislocation in the emergency department within 90 days of discharge. Two additional patients had unplanned clinic encounters within 90 days of the index procedure. There were no hospital readmissions or reoperations within 90 days. Conclusions: Our initial experience suggests SDD aseptic rTJA can be safe and effective when modern perioperative outpatient protocols and surgical techniques are implemented. Future studies should further define patient selection criteria to optimize outcomes and minimize complications in this population.

Background:. Unicompartmental and total knee arthroplasty (UKA and TKA) have demonstrated excellent mid- and long-term outcomes and have been compared in clinical series for decades; however, to our knowledge, no study has sufficiently matched UKA and TKA cohorts on preoperative osteoarthritis severity. The purpose of this study was to evaluate patient-reported outcomes of radiographically and demographically matched UKA and TKA cohorts. Methods:. One hundred and thirty-five UKAs and 135 TKAs were matched by patient age, sex, body mass index, and American Society of Anesthesiologists Physical Status (ASA-PS) classification as well as preoperative osteoarthritis severity in medial and lateral tibiofemoral and patellofemoral compartments (Kellgren-Lawrence grading system). Patient-reported outcome measures for pain, function, activity level, and satisfaction were evaluated at minimum 1-year follow-up via components of the modern Knee Society Score, the University of California Los Angeles (UCLA) activity-level score, and a Likert satisfaction scale. Results:. The patients in the UKA group reported significantly less pain, a higher activity level, and greater satisfaction while performing several functional activities and could walk for a longer amount of time before stopping due to knee discomfort compared with those in the TKA group (p ≤ 0.038). In addition, a greater proportion of patients in the UKA than in the TKA group were “satisfied or very satisfied” with their knee replacement surgery at minimum 1-year follow-up (90% versus 81%; p = 0.043). Conclusions:. With minimum 1-year follow-up, patients who underwent UKA reported significantly higher function, less pain, and a greater level of patient satisfaction than a radiographically and demographically matched TKA cohort. Level of Evidence:. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

RASopathy is caused by dysfunction in the MAPK pathway, and include syndromes like Noonan syndrome (NS), NS with multiple lentigines (formerly known as Leopard syndrome), cardiofaciocutaneous (CFC), Legius syndrome, capillary malformation–arteriovenous malformation, neurofibromatosis type 1, and Costello syndrome. When counted together, RASopathies affect 1/1000 live births, and are characterized by cardiovascular manifestations, short stature, developmental delay, renal, urogenital, skin/skeletal abnormalities, and dysmorphic appearance. NS—one of the most common RASopathies—occurs in 1/1000 to 1/2500 live births. On the other hand, the frequency of CFC is unknown, but it is one of the rarest RASopathies, with estimates of only a few hundred cases worldwide. However, its phenotype overlaps with that of NS. In this case series, we describe 5 patients with a clinical and genetic diagnosis of RASopathy—either NS or CFC—all of whom were also diagnosed with isolated sagittal synostosis (ISS). Medical records from ophthalmology, cardiology, plastic surgery, medical genetics, cleft craniofacial, and neurosurgery were used to determine patient history. In our cohort, late presentation of ISS was the predominant form of ISS presentation. We hope this report further characterizes the burgeoning relationship between RASopathy and ISS. Furthermore, these findings support including sagittal synostosis among the presenting features in the clinical phenotype of RASopathies. Ethical approval was obtained from the university’s institutional review board.

Background: Greater quadriceps strength has been associated with lower risk of symptomatic knee osteoarthritis (OA) in older adults. However, factors that confer elevated risk of knee OA (eg, sedentary lifestyle, obesity, and knee injury) also contribute to a reduced tolerance of resistance training programs at ≥60% 1-repetition maximum (1RM). Therefore, the current study assessed whether concurrent application of blood flow restriction (BFR) to low-load resistance training is an efficacious and tolerable means of improving quadriceps strength in men at risk of symptomatic knee OA. Methods: Men older than age 45, with a history of knee injury or elevated body mass index (BMI), were randomized to low-load resistance training (30% 1RM) either with or without concurrent BFR. Isotonic double-leg press strength and isokinetic knee extensor strength were assessed before and after 4 weeks of training 3 times/wk. Knee pain (Knee Osteoarthritis Outcome Score) was assessed for tolerance. Results: Of the 42 men (mean age 56.1 ± 7.7 years) who were randomized, 41 completed the program. There were no significant intergroup differences in age, BMI, knee pathology, or muscle strength at baseline. Although leg press 1RM improved in both control and BFR groups, there were no significant intergroup differences in primary or secondary measures of muscle strength. The BFR was not associated with worsening of knee pain, but there was a significant improvement in knee pain in the control group. Conclusions: In comparison with training without BFR, addition of BFR to 30% 1RM resistance training for 4 weeks did not confer significantly greater increases in leg press or quadriceps strength in older men with risk factors for symptomatic knee OA.

The aim was to investigate the construct validity and internal consistency of the Swedish version of the Consumer Emergency Care Satisfaction Scale. The sample comprised 157 persons from an emergency department and an observation ward. The results showed satisfactory reliability, and an explorative factor analysis revealed 3 factors: Caring, Teaching, and Clinical Competence. The Swedish version of the scale seems reliable and may be a useful tool for measuring satisfaction in different acute care settings. [ABSTRACT FROM AUTHOR]

Hospitals continue to experience high nurse turnover rates. Based on the need to retain skilled nurses, differences in job satisfaction of experienced medical-surgical and critical care nurses were examined. [ABSTRACT FROM AUTHOR]

Dementia patients' caregivers often provide information about patients' daily functioning, but little is known about factors influencing caregivers' perceptions. Baseline data from an intervention trial were used to compare caregiver estimates of dementia patients' performance with their actual performance of instrumental activities of daily living (IADLs) and to assess relationships between measures of caregiver responses to caregiving, self-perceived sense of self-efficacy, and depression. We also assessed patient cognition, overall function and behavioral disturbance, and caregivers' perceptions of their patients' behavior as manipulative or deliberate. Disparities between these estimates and actual patient performance on structured IADL tasks were unrelated to any caregiver, patient, or relationship factor that we measured [ABSTRACT FROM AUTHOR]

Having reliable and valid instruments is a necessity for nurses and others measuring concepts such as patient satisfaction. The purpose of this article is to describe the use of convergence to test the construct validity of the Davis Consumer Emergency Care Satisfaction Scale (CECSS). Results indicate convergence of the CECSS with the Risser Patient Satisfaction Scale and 2 single-item visual analogue scales, therefore supporting construct validity. Persons measuring patient satisfaction with nurse behaviors in the emergency department can confidently use the CECSS. [ABSTRACT FROM AUTHOR]

The purpose of this descriptive, comparative study was to compare stress levels of families of terminally ill patients who have advance directives with stress levels of families of terminally ill patients without advance directives. A convenience sample of 105 family members or healthcare surrogates completed the Horowitz Impact of Event Scale. Significant differences were found between the two groups on the total scale (t = -3.44, df = 100, P = .001) and the two subscales of intrusion (t = -3.35, df = 101, P = .001) and avoidance (t = -2.12, df = 100, P = .036). Families of patients with advance directives reported less stress than families of patients without advance directives. Nurses need to provide opportunities and guidance to terminally ill patients and their families regarding the need to discuss end-of-life issues and development of advance directives. [ABSTRACT FROM AUTHOR]

This study was an attempt to improve the quality of the relationship between dementia caregivers and their loved ones by decreasing the gap between caregivers' expectations and patients' actual functional abilities and by teaching supportive skills. Although a group of 49 caregiver-patient dyads were recruited, the outcome measures of only those dyads (47) that completed the week seven session were used for analysis. Half of the dyads were randomized to an intervention group and the other half to a waiting list. The intervention group (N = 24) completed a four-session caregiver training program in which caregivers first watched investigators administering to their loved ones the Texas Functional Living Scale and later progressed to helping their loved ones by appropriate cueing to perform the tasks involved. Comparisons were made between baseline scores, scores at seven weeks, and scores at the end of 17 weeks on the congruence between caregiver estimates and patients' actual performance on the Independent Living Scale and measures of cognition, function, preillness quality of relationship, caregiver mood, feeling of self-efficacy, and several other measures. We were not able to increase the congruence between caregiver estimates and patients' actual performance and found no change in any other measure. We didfind the expected relationship between depression and caregiver sense of self-efficacy. [ABSTRACT FROM AUTHOR]

Major developmental events occurring in the hippocampus during the third trimester of human gestation and neonatally in altricial rodents include rapid and synchronized dendritic arborization and astrocyte proliferation and maturation. We tested the hypothesis that signals sent by developing astrocytes to developing neurons modulate dendritic development in vivo . We altered neuronal development by neonatal (third trimester-equivalent) ethanol exposure in mice; this treatment increased dendritic arborization in hippocampal pyramidal neurons. We next assessed concurrent changes in the mouse astrocyte translatome by translating ribosomal affinity purification (TRAP)-seq. We followed up on ethanol-inhibition of astrocyte Chpf2 and Chsy1 gene translation because these genes encode for biosynthetic enzymes of chondroitin sulfate glycosaminoglycan (CS-GAG) chains (extracellular matrix components that inhibit neuronal development and plasticity) and have not been explored before for their roles in dendritic arborization. We report that Chpf2 and Chsy1 are enriched in astrocytes and their translation is inhibited by ethanol, which also reduces the levels of CS-GAGs measured by Liquid Chromatography/Mass Spectrometry. Finally, astrocyte-conditioned medium derived from Chfp2 -silenced astrocytes increased neurite branching of hippocampal neurons in vitro . These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulates dendritic arborization in developing neurons., Competing Interests: Disclosure All the authors reported no biomedical financial interests or potential conflicts of interest.

Abstract: There are many types of cysts in the leg; the most common is a popliteal (Baker's) cyst. This occurs when synovial fluid fills the tissue plane between the medial head of the gastrocnemius and the semimembranosus muscle and is often associated with intraarticular knee pathology. Treatment for various types of cysts includes aspiration with or without fenestration, injections with corticosteroids, dextrose, or various sclerosing agents, and surgical excision. This case describes a 58-yr-old man with a large cyst measuring 14.7 × 2.7 × 3.1 cm in size in the lateral calf, within the lateral gastrocnemius, with atypical size and location for a calf cyst. Computed tomography arthrogram showed intraarticular communication with the knee. The cyst recurred after two aspirations and injections with 25% dextrose/lidocaine. Aspiration and injection with doxycycline resulted in temporary relief followed by recurrence. Complete cyst resolution occurred after final aspiration without injectate. The cyst was likely synovial based on location, intraarticular communication, and fluid analysis. We suspect that complete resolution may have been due to repeated aspiration and injection, essentially performing longitudinal cyst fenestration, with possible contribution from doxycycline injection. Further study of intracyst doxycycline injection with reaspiration after 10 mins for treatment of refractory cysts may be warranted., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Genetic variation in the TCF4 (transcription factor 4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of autism spectrum disorder called Pitt-Hopkins syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models has been shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking., Methods: To model PTHS, we differentiated human cortical neurons from human induced pluripotent stem cells that were derived from patients with PTHS and neurotypical individuals. To identify pathophysiology and disease mechanisms, we assayed cortical neurons with whole-cell electrophysiology, Ca 2+ imaging, multielectrode arrays, immunocytochemistry, and RNA sequencing., Results: Cortical neurons derived from patients with TCF4 mutations showed deficits in spontaneous synaptic transmission, network excitability, and homeostatic plasticity. Transcriptomic analysis indicated that these phenotypes resulted in part from altered expression of genes involved in presynaptic neurotransmission and identified the presynaptic binding protein RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons., Conclusions: Taken together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Preeclampsia is a hypertensive disorder of pregnancy that affects ∼2%-5% of all pregnancies, contributes to 4 of the top 10 causes of pregnancy-related deaths, and remains a long-term risk factor for cardiometabolic diseases. Yet, little is still known about the molecular mechanisms that lead to this disease. There is evidence that some cases have a genetic cause. However, it is well appreciated that harmful factors in the environment, such as poor nutrition, stress, and toxins, may lead to epigenetics changes that can contribute to this disease. DNA methylation is one of the epigenetic modifications known to be fairly stable and impact gene expression. Using DNA from buccal swabs, we analyzed global DNA methylation among three groups of individuals: mothers who experienced 1 ) early-stage preeclampsia (<32 wk), 2 ) late-stage preeclampsia (>37 wk), or 3 ) no complications during their pregnancies, as well as the children from these three groups. We found significant differentially methylated regions (DMRs) between mothers who experienced preeclampsia compared with those with no complications adjacent or within genes that are important for placentation, embryonic development, cell adhesion, and inflammation (e.g., the cadherin pathway). A significant portion of DMR genes showed expression in tissues relevant to preeclampsia (i.e., the brain, heart, kidney, uterus, ovaries, and placenta). As this study was performed on DNA extracted from cheek swabs, this opens the way to future studies in different tissues, aimed at identifying possible biomarkers of risk and early detection, developing targeted interventions, and reducing the progression of this life-threatening disease. NEW & NOTEWORTHY Preeclampsia is a life-threatening hypertensive disorder, affecting 2%-5% of pregnancies, that remains poorly understood. This study analyzed DNA methylation from buccal swabs from mothers who experienced early and late-stage preeclampsia and those with uncomplicated pregnancies, along with their children. Differentially methylated regions were found near and within genes crucial for placental function, embryonic development, and inflammation. Many of these genes are expressed in preeclampsia-related tissues, offering hope for future biomarker development for this condition.

AMONDYS 45 (casimersen) is an antisense oligonucleotide therapy used to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by a mutation in the DMD gene. Symptoms include progressive muscle weakness, respiratory and cardiac complications, and premature death. Casimersen targets a specific mutation in the DMD gene that results in the absence of dystrophin protein, a key structural component of muscle fibers. While there is currently no cure for DMD, exon-skipping therapy works by restoring the reading frame of the mutated gene, allowing the production of a partially functional dystrophin protein. Clinical trials of casimersen have shown promising results in increasing dystrophin production, as measured by polymerase chain reaction (PCR) droplets when compared to placebo. In a randomized double-blind trial, patients who received casimersen had significantly higher dystrophin levels when compared to those who received placebo. Casimersen therapy is administered through repeated intravenous infusions, although the optimal dosage and duration of treatment are still under investigation. Based on the completed and ongoing clinical trials, casimersen has been well tolerated, with most adverse events being mild and unrelated to casimersen. In 2021, AMONDYS 45 (casimersen) received approval from the US Food and Drug Administration (FDA) for the treatment of Duchene muscular dystrophy in patients with a mutation of the DMD gene that is amenable to exon 45 skipping. These collective findings indicate that casimersen has the potential to elicit functional changes in individuals with DMD, although further studies are necessary to comprehensively evaluate the specific functional improvements. Regardless, the FDA approval and ongoing clinic trials mark a significant milestone in the development of DMD treatments and offer hope for those affected by this debilitating disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Vasterling et al.)

In a way analogous to human vision, the fruit fly D. melanogaster and many other flying insects generate smooth and saccadic movements to stabilize and shift their gaze in flight, respectively. It has been hypothesized that this combination of continuous and discrete movements benefits both flight stability and performance, particularly at high frequencies or speeds. Here we develop a hybrid control system model to explore the effects of saccades on the yaw stabilization reflex of D. melanogaster. Inspired from experimental data, the model includes a first order plant, a Proportional-Integral (PI) continuous controller, and a saccadic reset system that fires based on the integrated error of the continuous controller. We explore the gain, delay and switching threshold parameter space to quantify the optimum regions for yaw stability and performance. We show that the addition of saccades to a continuous controller provides benefits to both stability and performance across a range of frequencies. Our model suggests that Drosophila operates near its optimal switching threshold for its experimental gain set. We also show that based on experimental data, D. melanogaster operates in a region that trades off performance and stability. This trade-off increases flight robustness to compensate for internal perturbations such as wing damage., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis., (© 2023. The Author(s).)

Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene expression and is both inherited and modified by environmental exposures throughout life. Prenatal development is a particularly vulnerable time period during which exposure to maternal asthma increases asthma risk in offspring. How maternal asthma affects DNA methylation in offspring and what the consequences of differential methylation are in subsequent generations are not fully known. In this study, we tested the effects of grandmaternal house dust mite (HDM) allergen sensitization during pregnancy on airway physiology and inflammation in HDM-sensitized and challenged second-generation mice. We also tested the effects of grandmaternal HDM sensitization on tissue-specific DNA methylation in allergen-naïve and -sensitized second-generation mice. Descendants of both allergen- and vehicle-exposed grandmaternal founders exhibited airway hyperreactivity after HDM sensitization. However, grandmaternal allergen sensitization significantly potentiated airway hyperreactivity and altered the epigenomic trajectory in second-generation offspring after HDM sensitization compared with HDM-sensitized offspring from vehicle-exposed founders. As a result, biological processes and signaling pathways associated with epigenetic modifications were distinct between lineages. A targeted analysis of pathway-associated gene expression found that Smad3 was significantly dysregulated as a result of grandmaternal allergen sensitization. These data show that grandmaternal allergen exposure during pregnancy establishes a unique epigenetic trajectory that reprograms allergen responses in second-generation offspring and may contribute to asthma risk. NEW & NOTEWORTHY Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. This study shows that maternal allergen exposure during pregnancy promotes unique epigenetic trajectories in second-generation offspring at baseline and in response to allergen sensitization, which is associated with the potentiation of airway hyperreactivity. These effects are one mechanism by which maternal asthma may influence the inheritance of asthma risk.