IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

Long-term Implications of Cosmetic Breast Surgeries on Subsequent Breast Reconstruction.

BACKGROUND: Cosmetic breast surgeries, such as augmentation, mastopexy, and reduction, are common aesthetic medical procedures for enhancing physical appearance. Despite their popularity, the influence of these surgeries on subsequent breast reconstruction for cancer patients remains underexplored. OBJECTIVES: This study seeks to investigate the effects of previous cosmetic breast surgeries on the outcomes of breast reconstruction. METHODS: A retrospective chart review was conducted from January 2011 to May 2023. This analysis compared patients with histories of implant augmentation, breast reduction, mastopexy, and augmentation-mastopexy against those receiving reconstruction without any cosmetic surgery history. Demographics, comorbidities, complications, revisions, and BREAST-Q surveys were collected. Statistical analysis was performed using SPSS, with significance set at p<0.05. RESULTS: The study included 124 patients (50 autologous, 74 implant) with a history of cosmetic breast surgery (102 implant augmentations, 17 breast reductions, five mastopexies, and nine augmentation mastopexies). They were analyzed against 1307 patients (683 autologous, 624 implant) without prior cosmetic breast surgery. Patients with prior cosmetic surgeries showed a higher incidence of hematoma with tissue expander placement. A preference for implant-based reconstruction was more common among patients with augmentation history (p<0.001), whereas autologous reconstruction was more common in those with history of breast reduction (p=0.047). Patients with history of breast augmentation had on average significantly more breast revisions (p <0.05). CONCLUSIONS: This study demonstrates a significantly higher hematoma rate and number of revisions compared to patients without a history of cosmetic surgery. Furthermore, it suggests that types of cosmetic breast surgery influence the decision-making process regarding implant versus autologous reconstruction.

Distinguishing Elements at the Sub-Nanometer Scale on the Surface of a High Entropy Alloy.

Materials in crystalline form possess translational symmetry (TS) when the unit cell is repeated in real space with long- and short-range orders. The periodic potential in the crystal regulates the electron wave function and results in unique band structures, which further define the physical properties of the materials. Amorphous materials lack TS due to the randomization of distances and arrangements between atoms, causing the electron wave function to lack a well-defined momentum. High entropy materials provide another way to break the TS by randomizing the potential strength at periodic atomic sites. The local elemental distribution has a great impact on physical properties in high entropy materials. It is critical to distinguish elements at the sub-nanometer scale to uncover the correlations between the elemental distribution and the material properties. Here, the use of synchrotron X-ray scanning tunneling microscopy (SX-STM) with sub-nm scale resolution in identifying elements on a high entropy alloy (HEA) surface is demonstrated. By examining the elementally sensitive X-ray absorption spectra with an STM tip to enhance the spatial resolution, the elemental distribution on an HEA's surface at a sub-nm scale is extracted. These results open a pathway towards quantitatively understanding high entropy materials and their material properties.

Deep learning reveals what facial expressions mean to people in different cultures.

Cross-cultural studies of the meaning of facial expressions have largely focused on judgments of small sets of stereotypical images by small numbers of people. Here, we used large-scale data collection and machine learning to map what facial expressions convey in six countries. Using a mimicry paradigm, 5,833 participants formed facial expressions found in 4,659 naturalistic images, resulting in 423,193 participant-generated facial expressions. In their own language, participants also rated each expression in terms of 48 emotions and mental states. A deep neural network tasked with predicting the culture-specific meanings people attributed to facial movements while ignoring physical appearance and context discovered 28 distinct dimensions of facial expression, with 21 dimensions showing strong evidence of universality and the remainder showing varying degrees of cultural specificity. These results capture the underlying dimensions of the meanings of facial expressions within and across cultures in unprecedented detail.

Complementary modulation of BMP signaling improves bone healing efficiency.

The bone morphogenetic protein (BMP) signaling pathway plays a crucial role in bone development and regeneration. While BMP-2 is widely used as an alternative to autograft, its clinical application has raised concerns about adverse side effects and deteriorated bone quality. Therefore, there is a need to develop more sophisticated approaches to regulate BMP signaling and promote bone regeneration. Here, we present a novel complementary strategy that targets both BMP antagonist noggin and agonist Trb3 to enhance bone defect repair without the application of exogenous BMP-2. In vitro studies showed that overexpression of Trb3 with simultaneous noggin suppression significantly promotes osteogenic differentiation of mesenchymal stem cells. This was accompanied by increased BMP/Smad signaling. We also developed sterosome nanocarriers, a non-phospholipid liposomal system, to achieve non-viral mediated noggin suppression and Trb3 overexpression. The gene-loaded sterosomes were integrated onto an apatite-coated polymer scaffold for in vivo calvarial defect implantation, resulting in robust bone healing compared to BMP-2 treatments. Our work provides a promising alternative for high-quality bone formation by regulating expression of BMP agonists and antagonists.

Radiologic reporting of MRI-proven thoracolumbar epidural metastases on body CT: 12-Year single-institution experience.

RATIONALE AND OBJECTIVES: Metastatic epidural masses are an important radiological finding. The purpose of this study is to determine factors associated with non-reporting of thoracolumbar epidural metastases on body CT. MATERIALS AND METHODS: In a study population of 166 patients from a single institution over a 12-year period, 293 body CT examinations were identified which were performed within 30 days before or after a spine MRI diagnosis of epidural metastasis. Associations were sought between patient diagnosis, CT examination characteristics, reporting radiologist (n = 17), and lesion characteristics with respect to whether an epidural metastasis was reported on CT. RESULTS: In retrospective consensus review comprised of 3 radiologists, epidural metastases reported on spine MRI were clearly visible in 80.5% (236/293) of body CT examinations, however 65.3% (154/236) of the body CT reports omitted reporting their presence, even in cases where there was a preceding MRI diagnosis within 30 days (65.4%, 74/113). The identity of the reporting radiologist was statistically significantly associated with the accurate diagnostic reporting of epidural metastasis on body CT (p = 0.04). The only lesion features which were statistically significantly associated with CT reporting were lesion volume (p = 0.03) on noncontrast CT, and lesion volume (p = 0.006) and percentage of spinal canal stenosis (p = 0.001) on intravenous contrast-enhanced CT. The presence or absence of intravenous contrast was not significantly associated with CT reporting (p = 1.0). CONCLUSION: Using spine MRI as the reference standard for the presence of epidural tumor, the majority of body CT reports omit describing thoracolumbar epidural metastases which are clearly visible in retrospect.

Mothers' intentions to vaccinate their children for COVID-19.

Parents' intentions to vaccinate their children is an important area of investigation in light of the COVID-19 pandemic. There is a growing body of research examining factors that influence parents' vaccine intentions. The current study investigated factors that would influence maternal intent to vaccinate their children for COVID-19, shortly before the CDC approved vaccines for children 11 and younger. We had a sample of n = 176 mothers (Mchildage = 71.63 months, 52% White) from California fill out an online survey during February-April 2021. Our results suggest that perceived COVID-19 threat predicts mothers' intention to vaccinate their children (b = 0.370, p < 0.001), controlling for mothers' age, socioeconomic status, race, and child age. Child age (b = 0.027, p = 0.008), SES (b = 0.396, p = 0.018), and child previous flu shot (b = 0.725, p < 0.001) also positively predicted mothers' intention to vaccinate their children. Results are discussed in light of prior research on maternal vaccine intentions and hesitancy.

Atypical Seropositive Striated Muscle Antibody Myasthenia Gravis Presentation With Metastatic B1 Thymoma: A Rare Case.

The association between myasthenia gravis (MG) and thymomas is well-documented. Thymomas are rare epithelial cell tumors that arise from the thymus gland and occur in the mediastinum. Myasthenia gravis is a neuromuscular disorder that causes skeletal muscle weakness due to the presence of anti-acetylcholinesterase antibodies. Roughly 60% of thymomas are associated with MG, while only 10% of MG patients have thymomas. We present an atypical presentation of myasthenia gravis with an associated unusual metastatic thymoma. This case is of a young, previously healthy 26-year-old male with no previous medical history who presented with non-specific symptoms of fatigue, diarrhea, abdominal pain, back pain, blurry vision, and unintended weight loss. He underwent treatment with intravenous immunoglobulins (IVIG), had two surgical resections of the thymoma, and ultimately received radiotherapy. Based on our experience with this case, diagnosing myasthenia gravis by testing for specific muscle antibodies for patients with ptosis in the setting of non-specific complaints, including fatigue, vomiting, diarrhea, and abdominal or back pain, should be considered. Routine imaging should follow with a chest computed tomography to screen for thymomas if the specific anti-titin and anti-ryanodine receptor (anti-RyR) muscle antibodies are positive and myasthenia gravis is suspected. If a thymoma is confirmed, it is best to confirm; and mass characterizes with chest magnetic resonance imaging. A treatment approach of IVIG followed by surgical resection and possible debulking if the lesion is deemed metastatic could also be considered thereafter, especially in young patients with few comorbidities. Treatment with Pyridostigmine 30 mg twice daily for 25 days post-surgically and radiation for treatment of any remaining unresectable tumor should also be considered.

An unusual case of colonic duplication cyst in an adult with dysplasia.

Duplication cysts are rare benign congenital malformations typically identified in children by the age of 2 years. We report a rare case of colonic duplication cyst with dysplasia in an adult. A 32-year-old male was diagnosed with non-specific abdominal symptoms. Abdominopelvic computed tomography scan demonstrated a submucosal cystic lesion in the right colon. He underwent laparoscopic right hemicolectomy. Histopathology showed colonic duplication cyst with low grade dysplasia. He is due for a surveillance colonoscopy in 3 years. Duplication cyst in an adult colon with dysplasia is extremely rare. They are usually present in the terminal ileum. They have non-specific abdominal symptoms or can be asymptomatic. They are often identified incidentally or intraoperatively. Imaging may demonstrate a cystic lesion. Histopathology is required for definitive diagnosis. There are no guidelines or consensus on managing duplication cysts in adults. We recommend an oncological resection of the involved colon. Surveillance with routine colonoscopy is advisable.

Deep learning reveals what vocal bursts express in different cultures.

Human social life is rich with sighs, chuckles, shrieks and other emotional vocalizations, called 'vocal bursts'. Nevertheless, the meaning of vocal bursts across cultures is only beginning to be understood. Here, we combined large-scale experimental data collection with deep learning to reveal the shared and culture-specific meanings of vocal bursts. A total of n = 4,031 participants in China, India, South Africa, the USA and Venezuela mimicked vocal bursts drawn from 2,756 seed recordings. Participants also judged the emotional meaning of each vocal burst. A deep neural network tasked with predicting the culture-specific meanings people attributed to vocal bursts while disregarding context and speaker identity discovered 24 acoustic dimensions, or kinds, of vocal expression with distinct emotion-related meanings. The meanings attributed to these complex vocal modulations were 79% preserved across the five countries and three languages. These results reveal the underlying dimensions of human emotional vocalization in remarkable detail.

A review of clinical efficacy data supporting emergency use authorization for COVID-19 therapeutics and lessons for future pandemics.

Emergency Use Authorization (EUA) allows the US Food and Drug Administration (FDA) to expedite the availability of therapeutics in the context of a public health emergency. To date, an evidentiary standard for clinical efficacy to support an EUA has not yet been established. This review examines the clinical data submitted in support of EUA for antiviral and anti-inflammatory therapeutics for coronavirus disease 2019 (COVID-19) through December of 2021 and the resilience of the authorization as new clinical data arose subsequent to the authorization. In the vast majority of cases, EUA was supported by at least one well-powered randomized controlled trial (RCT) where statistically significant efficacy was demonstrated. This included branded medications already approved for use outside of the context of COVID-19. When used, the standard of a single RCT seemed to provide adequate evidence of clinical efficacy, such that subsequent clinical studies generally supported or expanded the EUA of the therapeutic in question. The lone generic agent that was granted EUA (chloroquine/hydroxychloroquine) was not supported by a well-controlled RCT, and the EUA was withdrawn within 3 months time. This highlighted not only the ambiguity of the EUA standard, but also the need to provide avenues through which high quality clinical evidence for the efficacy of a generic medication could be obtained. Therefore, maintaining the clinical trial networks assembled during the COVID-19 pandemic could be a critical component of our preparation for future pandemics. Consideration could also be given to establishing a single successful RCT as regulatory guidance for obtaining an EUA.

Synthesis, Characterization, and Hydrogen Evolution Activity of Metallo-meso-(4-fluoro-2,6-dimethylphenyl)porphyrin Derivatives.

Zn(II), Cu(II), and Ni(II) 5,10,15,20-tetrakis(4-fluoro-2,6-dimethylphenyl)porphyrins (TFPs) have been synthesized and characterized. The electronic spectroscopy and cyclic voltammetry of these compounds, along with the free-base macrocycle (2H-TFP), have been determined; 2H-TFP was also structurally characterized by X-ray crystallography. The Cu(II)TFP exhibits catalytic activity for the hydrogen evolution reaction (HER). The analysis of linear sweep voltammograms shows that the HER reaction of Cu(II)TFP with benzoic acid is first-order in proton concentration with an average apparent rate constant for HER catalysis of k app = 5.79 ± 0.47 × 103 M-1 s-1.

Nanobodies for Medical Imaging: About Ready for Prime Time?

Recent advances in medical treatments have been revolutionary in shaping the management and treatment landscape of patients, notably cancer patients. Over the last decade, patients with diverse forms of locally advanced or metastatic cancer, such as melanoma, lung cancers, and many blood-borne malignancies, have seen their life expectancies increasing significantly. Notwithstanding these encouraging results, the present-day struggle with these treatments concerns patients who remain largely unresponsive, as well as those who experience severely toxic side effects. Gaining deeper insight into the cellular and molecular mechanisms underlying these variable responses will bring us closer to developing more effective therapeutics. To assess these mechanisms, non-invasive imaging techniques provide valuable whole-body information with precise targeting. An example of such is immuno-PET (Positron Emission Tomography), which employs radiolabeled antibodies to detect specific molecules of interest. Nanobodies, as the smallest derived antibody fragments, boast ideal characteristics for this purpose and have thus been used extensively in preclinical models and, more recently, in clinical early-stage studies as well. Their merit stems from their high affinity and specificity towards a target, among other factors. Furthermore, their small size (~14 kDa) allows them to easily disperse through the bloodstream and reach tissues in a reliable and uniform manner. In this review, we will discuss the powerful imaging potential of nanobodies, primarily through the lens of imaging malignant tumors but also touching upon their capability to image a broader variety of nonmalignant diseases.

Eligibility and Radiologic Assessment for Adjuvant Clinical Trials in Kidney Cancer.

PURPOSE: To harmonize the eligibility criteria and radiologic disease assessment definitions in clinical trials of adjuvant therapy for renal cell carcinoma (RCC). METHOD: On November 28, 2017, US-based experts in RCC clinical trials, including medical oncologists, urologic oncologists, regulators, biostatisticians, radiologists, and patient advocates, convened at a public workshop to discuss eligibility for trial entry and radiologic criteria for assessing disease recurrence in adjuvant trials in RCC. Multiple virtual meetings were conducted to address the issues identified at the workshop. RESULTS: The key workshop conclusions for adjuvant RCC therapy clinical trials were as follows. First, patients with non-clear cell RCC could be routinely included, preferably in an independent cohort. Second, patients with T3-4, N+M0, and microscopic R1 RCC tumors may gain the greatest advantages from adjuvant therapy. Third, trials of agents not excreted by the kidney should not exclude patients with severe renal insufficiency. Fourth, therapy can begin 4 to 16 weeks after the surgical procedure. Fifth, patients undergoing radical or partial nephrectomy should be equally eligible. Sixth, patients with microscopically positive soft tissue or vascular margins without gross residual or radiologic disease may be included in trials. Seventh, all suspicious regional lymph nodes should be fully resected. Eighth, computed tomography should be performed within 4 weeks before trial enrollment; for patients with renal insufficiency who cannot undergo computed tomography with contrast, noncontrast chest computed tomography and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be performed. Ninth, when feasible, biopsy should be undertaken to identify any malignant disease. Tenth, when biopsy is not feasible, a uniform approach should be used to evaluate indeterminate radiologic findings to identify what constitutes no evidence of disease at trial entry and what constitutes radiologic evidence of disease. Eleventh, a uniform approach for establishing the date of recurrence should be included in any trial design. Twelfth, patient perspectives on the use of placebo, conditions for unblinding, and research biopsies should be considered carefully during the conduct of an adjuvant trial. CONCLUSIONS AND RELEVANCE: The discussions suggested that a uniform approach to eligibility criteria and radiologic disease assessment will lead to more consistently interpretable trial results in the adjuvant RCC therapy setting.

Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in Bladder Cancer.

Objective: To harmonize eligibility criteria and radiographic disease assessments in clinical trials of adjuvant therapy for muscle-invasive bladder cancer (MIBC). Methods: National experts in bladder cancer clinical trial research, including medical and urologic oncologists, radiologists, biostatisticians, and patient advocates, convened at a public workshop on November 28, 2017, to discuss eligibility, radiographic entry criteria, and assessment of disease recurrence in adjuvant clinical trials in patients with MIBC. Results: The key workshop conclusions for adjuvant MIBC clinical trials included the following points: (1) patients with urothelial carcinoma with divergent histologic differentiation should be allowed to enroll; (2) neoadjuvant chemotherapy is defined as at least 3 cycles of neoadjuvant cisplatin-based combination chemotherapy; (3) patients with muscle-invasive, upper-tract urothelial carcinoma should be included in adjuvant trials of MIBC; (4) patients with severe renal insufficiency can enroll into trials using agents that are not renally excreted; (5) patients with microscopic surgical margins can be included; (6) patients should undergo a standard bilateral lymph node dissection prior to enrollment; (7) computed tomographic (CT) imaging should be performed within 4 weeks prior to enrollment. For patients with renal insufficiency who cannot undergo CT imaging with contrast, noncontrast chest CT and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be done; (8) biopsy of indeterminate lesions to evaluate for malignant disease should be done when feasible; (9) a uniform approach to evaluate indeterminate radiographic lesions when biopsy is not feasible should be included in any trial design; (10) a uniform approach to determining the date of recurrence is important in interpreting adjuvant trial results; and (11) new high-grade, upper-tract primary tumors and new MIBC tumors should be considered recurrence events. Conclusions and Relevance: A uniform approach to eligibility criteria, definitions of no evidence of disease, and definitions of disease recurrence may lead to more consistent interpretations of adjuvant trial results in MIBC.

Long-Term Parathyroid Hormone 1-34 Replacement Therapy in Children with Hypoparathyroidism.

OBJECTIVE: To determine whether multiple daily injections of parathyroid hormone (PTH) 1-34 are safe and effective as long-term therapy for children with hypoparathyroidism. STUDY DESIGN: Linear growth, bone accrual, renal function, and mineral homeostasis were studied in a long-term observational study of PTH 1-34 injection therapy in 14 children. METHODS: Subjects were 14 children with hypoparathyroidism attributable to autoimmune polyglandular syndrome type 1 (N = 5, ages 7-12 years) or calcium receptor mutation (N = 9, ages 7-16 years). Mean daily PTH 1-34 dose was 0.75 ± 0.15 µg/kg/day. Treatment duration was 6.9 ± 3.1 years (range 1.5-10 years). Patients were evaluated semiannually at the National Institutes of Health Clinical Center. RESULTS: Mean height velocity and lumbar spine, whole body, and femoral neck bone accretion velocities were normal throughout the study. In the first 2 years, distal one-third radius bone accrual velocity was reduced compared with normal children (P < .003). Serum alkaline phosphatase correlated with PTH 1-34 dose (P < .006) and remained normal (235.3 ± 104.8 [SD] U/L, N: 51-332 U/L). Mean serum and 24-hour urine calcium levels were 2.05 ± 0.11 mmol/L (N: 2.05-2.5 mmol/L) and 6.93 ± 1.3 mmol/24 hour (N: 1.25-7.5 mmol/24 hour), respectively-with fewer high urine calcium levels vs baseline during calcitriol and calcium treatment (P < .001). Nephrocalcinosis progressed in 5 of 12 subjects who had repeated renal imaging although renal function remained normal. CONCLUSIONS: Twice-daily or thrice-daily subcutaneous PTH 1-34 injections provided safe and effective replacement therapy for up to 10 years in children with hypoparathyroidism because of autoimmune polyglandular syndrome type 1 or calcium receptor mutation.

CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.

Melorheostosis (MEL) is a rare disease of high bone mass with patchy skeletal distribution affecting the long bones. We recently reported somatic mosaic mutations in MAP2K1 in 8 of 15 patients with the disease. The unique anatomic distribution of melorheostosis is of great interest. The disease remains limited to medial or lateral side of the extremity with proximo-distal progression. This pattern of distribution has historically been attributed to sclerotomes (area of bone which is innervated by a single spinal nerve level). In a further analysis of our study on MEL, 30 recruited patients underwent whole body CT scans to characterize the anatomic distribution of the disease. Two radiologists independently reviewed these scans and compared it to the proposed map of sclerotomes. We found that the disease distribution conformed to the distribution of a single sclerotome in only 5 patients (17%). In another 12 patients, the lesions spanned parts of contiguous sclerotomes but did not involve the entire extent of the sclerotomes. Our findings raise concerns about the sclerotomal hypothesis being the definitive explanation for the pattern of anatomic distribution in MEL. We believe that the disease distribution can be explained by clonal proliferation of a mutated skeletal progenitor cell along the limb axis. Studies in mice models on clonal proliferation in limb buds mimic the patterns seen in melorheostosis. We also support this hypothesis by the dorso-ventral confinement of melorheostotic lesion in a patient with low allele frequency of MAP2K1-positive osteoblasts and low skeletal burden of the disease. This suggests that the mutation occurred after the formation of dorso-ventral plane. Further studies on limb development are needed to better understand the etiology, pathophysiology and pattern of disease distribution in all patients with MEL.