Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species.

In mouse peritoneal and other serous cavities, the transcription factor GATA6 drives the identity of the major cavity resident population of macrophages, with a smaller subset of cavity-resident macrophages dependent on the transcription factor IRF4. Here we showed that GATA6+ macrophages in the human peritoneum were rare, regardless of age. Instead, more human peritoneal macrophages aligned with mouse CD206+ LYVE1+ cavity macrophages that represent a differentiation stage just preceding expression of GATA6. A low abundance of CD206+ macrophages was retained in C57BL/6J mice fed a high-fat diet and in wild-captured mice, suggesting that differences between serous cavity-resident macrophages in humans and mice were not environmental. IRF4-dependent mouse serous cavity macrophages aligned closely with human CD1c+CD14+CD64+ peritoneal cells, which, in turn, resembled human peritoneal CD1c+CD14-CD64- cDC2. Thus, major populations of serous cavity-resident mononuclear phagocytes in humans and mice shared common features, but the proportions of different macrophage differentiation stages greatly differ between the two species, and dendritic cell (DC2)-like cells were especially prominent in humans.

Cutting Edge: Hepatic Stellate Cells Drive the Phenotype of Monocyte-derived Macrophages to Regulate Liver Fibrosis in Metabolic Dysfunction-associated Steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by infiltration of monocyte-derived macrophages (MdMs) into the liver; however, the function of these macrophages is largely unknown. We previously demonstrated that a population of MdMs, referred to as hepatic lipid-associated macrophages (LAMs), assemble into aggregates termed hepatic crown-like structures in areas of liver fibrosis. Intriguingly, decreasing MdM recruitment resulted in increased liver fibrosis, suggesting that LAMs contribute to antifibrotic pathways in MASH. In this study, we determined that hepatic crown-like structures are characterized by intimate interactions between activated hepatic stellate cells (HSCs) and macrophages in a collagen matrix in a mouse model of MASH. MASH macrophages displayed collagen-degrading capacities, and HSCs derived from MASH livers promoted expression of LAM marker genes and acquisition of a collagen-degrading phenotype in naive macrophages. These data suggest that crosstalk between HSCs and macrophages may contribute to collagen degradation MASH.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

The use of fractional radiofrequency in Asian patients to improve skin texture.

BACKGROUND AND OBJECTIVES: Fractional radiofrequency devices have been demonstrated to improve skin texture, such as smoothness, rhytides, brightness, and atrophic acne scars, by increasing dermal thickness, dermal collagen content, and dermal fibrillin content. The objective of the study is to assess the efficacy and adverse effects of this device on Asian patients of skin type III and IV with skin textural changes. MATERIALS AND METHODS: The study was designed as a prospective, open-labeled single-arm study, which was conducted with 20 Chinese patients aged 21-60 years and having irregularities in their skin texture, rhytides, and acne scars. The patients received six treatments at intervals of 4 weeks. Treatment was initiated with the maximum energy tolerated, which was then adjusted during the course of treatment if the patients felt excessive discomfort. A total of two passes were delivered in each session. Physician assessment results and standardized photographs were collected at the baseline, after all treatment visits, and at 1, 2, and 6 months after the final treatment visit. RESULTS: A total of 17 patients completed the study according to the established protocol. At the 6-month follow-up, 71% of patients were satisfied and 24% of patients were very satisfied with the received treatments, and the treatment physician reported varying degrees of improvement based on the global assessment scale in 60% of the subjects. While the anticipated side effects, such as erythema, edema, pinpoint bleeding, scab formation, and flare of acne, were noted in the patients, no serious adverse effects occurred. CONCLUSION: The use of fractional radiofrequency improves skin texture and is safe for use in Asian patients of skin type III and IV. No long-term serious adverse effects were noted.

Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

OBJECTIVE: Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. METHODS: It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. RESULTS: Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. CONCLUSION: To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

A case of recurrent systemic capillary leak syndrome triggered by influenza A infection associated with cardiogenic shock supported by veno-arterial extracorporeal membrane oxygenation.

Systemic capillary leak syndrome (SCLS) is a rare and under-recognized disease which is potentially fatal. We report a case of SCLS triggered by influenza A infection associated with fulminant cardiogenic shock, successfully supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Strong clinical suspicion with appropriate supportive treatment can be life-saving for patients with SCLS.

Translation and validation of the Traditional Chinese version of the COmprehensive Score for financial Toxicity-Functional Assessment of Chronic Illness Therapy (Version 2).

BACKGROUND: Cancer patients often experience severe financial distress due to the high cost of their treatment, and strategies are needed to objectively measure this financial distress. The COmprehensive Score for financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT) is one instrument used to measure such financial distress. This study aimed to translate the COST-FACIT (Version 2) [COST-FACIT-v2] instrument into traditional Chinese (COST-FACIT-v2 [TC]) and evaluate its psychometric properties. METHODS: The Functional Assessment of Chronic Illness Therapy (FACIT) translation method was adopted. The translated version was reviewed by an expert panel and by 20 cancer patients for content validity and face validity, respectively, and 640 cancer patients, recruited from three oncology departments, completed the translated scale. Its reliability was evaluated in terms of internal consistency and test-retest reliability. Confirmatory factor analysis has been used to evaluate the one- and two-factor structures of the instrument reported in the literature. The convergent validity was examined by the correlation with health-related quality of life (HRQoL) and psychological distress. Known-group validity was examined by the difference in the COST-FACIT-v2 (TC) total mean score between groups with different income levels and frequency of health care service use. RESULTS: The COST-FACIT-v2 (TC) showed good content and face validity and demonstrated high internal consistency (Cronbach's alpha, 0.86) and acceptable test-retest reliability (intraclass correlation coefficient, 0.71). Confirmatory factor analysis showed that the one- and two-factor structures of the instrument that have been reported in the literature could not be satisfactorily fitted to the data. Psychological distress correlated significantly with the COST-FACIT-v2 (TC) score (r = 0.47; p < 0.001). HRQOL showed a weak to moderate negative correlation with the COST-FACIT-v2 (TC) score (r = - 0.23 to - 0.46; p < 0.001). Significant differences were seen among the COST-FACIT-v2 (TC) scores obtained in groups of different income level and frequency of health care service use. CONCLUSIONS: The COST-FACIT-v2 (TC) showed some desirable psychometric properties to support its validity and reliability for assessing cancer patients' level of financial toxicity.

Identifying a cut-off score for the COST measure to indicate high financial toxicity and low quality of life among cancer patients.

PURPOSE: To identify a cut-off score for the COmprehensive Score for financial Toxicity (COST) to predict a clinical implication of a high level of financial toxicity (FT). METHODS: A total of 640 cancer patients were recruited from three regional hospitals in Hong Kong. They completed a questionnaire comprising the COST measure and the Functional Assessment of Cancer Therapy - General (FACT-G) instrument. The cut-off score for the COST that predicts the lowest quartile of the FACT-G total score was identified by receiver operating characteristic (ROC) analysis. The sample was then stratified by this cut-off score, and characteristics were compared using Fisher's exact, chi-squared or independent sample t-test. RESULTS: The mean scores were 20.1 ± 8.8 for the COST and 71.6 ± 15.5 for the FACT-G. The ROC analysis suggested that the cut-off of 17.5 yielded an acceptable sensitivity and specificity. Characteristics of patients with a higher level of FT included being younger, having a monthly household income of < 10,000 HKD (approximately 1290 USD), being more likely not employed, having stage IV cancer and receiving targeted and/or immunotherapy. In terms of financial support, a higher proportion of these patients had discussed financial issues with health care professionals and had received financial assistance. In addition, fewer of them were covered by private health insurance. CONCLUSION: Our findings suggest a cut-off for the COST that can be used to screen for FT in clinical settings. In addition, while a considerable proportion of high-FT patients received targeted therapy, they often received financial assistance. There is a gap between financial hardship and assistance that warrants attention.

Fractional 1064 nm Picosecond Laser in Treatment of Melasma and Skin Rejuvenation in Asians, A Prospective Study.

BACKGROUND AND OBJECTIVES: Facial melasma is a disfiguring pigmentation and occurs frequently with aging skin. Topical treatment alone was often suboptimal. A recent study showed that fractional picosecond laser has promising result in benign pigmentary lesions. This study aims to investigate the efficacy and safety of 1064 nm picosecond laser in treatment of facial melasma and skin rejuvenation in Asian skin. STUDY DESIGN/MATERIALS AND METHODS: Patients of Asian descent seeking treatment for facial melasma and skin rejuvenation were screened and recruited. Each patient received up to nine laser treatments at 4-6 weeks intervals with a fractionated nonablative 1064 nm picosecond laser. Baseline and posttreatment modified Melasma Area Severity Index (mMASI) and Global Aesthetic Improvement Scale (IGAS) were assessed by blinded investigators based on the clinical photographs. Subject overall satisfaction was assessed by the questionnaires after treatment. All adverse events were documented. RESULTS: Twenty patients were recruited with a median age of 52.7 ± 8.2 years. Three subjects had Fitzpatrick skin type III and 17 had skin type IV. All subjects received nine laser sessions. Over 70% of patients were satisfied with the treatment outcomes. There was a statistically significant improvement in mMASI which reduced from 10.8 at baseline to 2.7 and 3.6 at 6 and 12 weeks post-treatment, respectively (both P < 0.01). For skin rejuvenation, 70% reported at least a moderate improvement at 6 weeks of post-treatment. No major side-effect was reported. Erythema was the most frequent transient response, while some reported edema (1.1%). Both resolved spontaneously. None reported hypo- or hyperpigmentation after treatment. The overall mean pain scare (VAS) was 1.92. CONCLUSION: Fractionated non-ablative 1064 nm picosecond laser was effective in treatment of melasma and skin rejuvenation. It was also safe and well tolerated. Importantly, there was no hypo or hyperpigmentation reported. Lasers Surg. Med. 00:00-00, 2021. © 2021 Wiley Periodicals LLC.

Longitudinal Changes in Skin Microbiome Associated with Change in Skin Status in Patients with Psoriasis.

The aim of this study was to identify key microbes associated with change in skin status (lesional vs normal). Longitudinal changes in the skin microbiome between patients with psoriasis and healthy family controls living in the same household were studied using whole genome metagenomic shotgun sequencing at 4 time-points. There were significant changes in abundance of the pathogen Campylobacter jejuni and its higher taxonomic levels when the skin status of patients with psoriasis changed. There were significant longitudinal variations in alpha diveristy (p < 0.001) and beta diversity (p < 0.05) of the skin microbiome in patients with psoriasis, but not in the healthy control group, which indicated composition of skin microbiome in patients with psoriasis was different from healthy control and was dynamically less stable. This study will serve as the basis for future temporal studies of the skin microbiome and probiotic therapeutics.

A Prospective Study in the Treatment of Lentigines in Asian Skin Using 532 nm Picosecond Nd:YAG Laser.

BACKGROUND AND OBJECTIVE: To evaluate safety and efficacy of treatment with the picosecond Nd:YAG 532 nm for lentigines in Asian skin. STUDY DESIGN/MATERIALS AND METHODS: This was a prospective, open-label cohort study, using a novel picosecond 532-nm laser for the treatment of facial lentigines. Subjects received up to three laser treatments every 4-6 weeks and were assessed at 4 and 12 weeks after final treatment. Primary endpoint was degree of improvement in lentigines at 12 weeks after the final treatment, assessed by treating investigator based on Physicians Global Assessment. Secondary end-points included degree of improvement in lentigines at 12 weeks after final treatment, assessed by subject (Subject's Global Assessment), and change in mean relative Melanin index (MI) value at 3 months after final treatment as compared to baseline as assessed by mexameter measurement. RESULTS: A total of 20 patients (3 male, and 17 female) of Asian-descent with Fitzpatrick skin type III and IV, with lentigines on the face were included in this study. A total of 89 lesions were treated with the laser setting of 532-nm, 750 picoseconds, fluence of 0.2-0.5 J/cm 2 , and spot size of 4 mm. One hundred and thirty-seven treatment sessions were given in total. Eighteen patients (90%) achieved a moderate to significant improvement at 12-week follow-up based on a 5-grade physician global assessment scale. The improvement rate of relative MI (MI in the lesion minus normal skin) was 33.30 ± 18.71 and 37.63 ± 19.25% at 4- and 12-week follow-up. Post-inflammatory hyperpigmentation (PIH) occurred in 14 of 137 sessions (10.2%), and hypopigmentation occurred in one patient with five lesions (3.6%). CONCLUSION: This study demonstrates that using picosecond Nd:YAG laser 532 nm for removal of solar lentigines in darker skin type appears to be safe and effective. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc. LIMITATIONS: Small study group.

The effects of therapeutic hip exercise with abdominal core activation on recruitment of the hip muscles.

BACKGROUND: Core stabilization has been utilized for rehabilitation and prevention of lower limb musculoskeletal injuries. Previous studies showed that activation of the abdominal core muscles enhanced the hip muscle activity in hip extension and abduction exercises. However, the lack of the direct measurement and quantification of the activation level of the abdominal core muscles during the execution of the hip exercises affect the level of evidence to substantiate the proposed application of core exercises to promote training and rehabilitation outcome of the hip region. The aim of the present study was to examine the effects of abdominal core activation, which is monitored directly by surface electromyography (EMG), on hip muscle activation while performing different hip exercises, and to explore whether participant characteristics such as gender, physical activity level and contractile properties of muscles, which is assessed by tensiomyography (TMG), have confounding effect to the activation of hip muscles in enhanced core condition. METHODS: Surface EMG of bilateral internal obliques (IO), upper gluteus maximus (UGMax), lower gluteus maximus (LGMax), gluteus medius (GMed) and biceps femoris (BF) of dominant leg was recorded in 20 young healthy subjects while performing 3 hip exercises: Clam, side-lying hip abduction (HABD), and prone hip extension (PHE) in 2 conditions: natural core activation (NC) and enhanced core activation (CO). EMG signals normalized to percentage of maximal voluntary isometric contraction (%MVIC) were compared between two core conditions with the threshold of the enhanced abdominal core condition defined as >20%MVIC of IO. RESULTS: Enhanced abdominal core activation has significantly promoted the activation level of GMed in all phases of clam exercise (P < 0.05), and UGMax in all phases of PHE exercise (P < 0.05), LGMax in eccentric phases of all 3 exercises (P < 0.05), and BF in all phases of all 3 exercises except the eccentric phase of PHE exercise (P < 0.05). The %MVIC of UGMax was significantly higher than that of LGMax in all phases of clam and HABD exercises under both CO and NC conditions (P < 0.001) while the %MVIC of LGMax was significantly higher than UGMax in concentric phase of PHE exercise under NC condition (P = 0.003). Gender, physical activity level and TMG parameters were not major covariates to activation of hip muscles under enhanced core condition. CONCLUSIONS: Abdominal core activation enhances the hip muscles recruitment in Clam, HABD and PHE exercises, and this enhancement is correlated with higher physical activity and stiffer hip muscle. Our results suggest the potential application of abdominal core activation for lower limb rehabilitation since the increased activation of target hip muscles may enhance the therapeutic effects of hip strengthening exercises.

Alternative reading frame selection mediated by a tRNA-like domain of an internal ribosome entry site.

The dicistrovirus intergenic region internal ribosome entry site (IRES) utilizes a unique mechanism, involving P-site tRNA mimicry, to directly assemble 80S ribosomes and initiate translation at a specific non-AUG codon in the ribosomal A site. A subgroup of dicistrovirus genomes contains an additional stem-loop 5'-adjacent to the IRES and a short open reading frame (ORFx) that overlaps the viral structural polyprotein ORF (ORF2) in the +1 reading frame. Using mass spectrometry and extensive mutagenesis, we show that, besides directing ORF2 translation, the Israeli acute paralysis dicistrovirus IRES also directs ORFx translation. The latter is mediated by a UG base pair adjacent to the P-site tRNA-mimicking domain. An ORFx peptide was detected in virus-infected honey bees by multiple reaction monitoring mass spectrometry. Finally, the 5' stem-loop increases IRES activity and may couple translation of the two major ORFs of the virus. This study reveals a novel viral strategy in which a tRNA-like IRES directs precise, initiator Met-tRNA-independent translation of two overlapping ORFs.

Lobe-specific calmodulin binding to different ryanodine receptor isoforms.

Ryanodine receptors (RyRs) are large ion channels that are responsible for the release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum. Calmodulin (CaM) is a Ca(2+) binding protein that can affect the channel open probability at both high and low Ca(2+) concentrations, shifting the Ca(2+) dependencies of channel opening in an isoform-specific manner. Here we analyze the binding of CaM and its individual domains to three different RyR regions using isothermal titration calorimetry. We compared binding to skeletal muscle (RyR1) and cardiac (RyR2) isoforms, under both Ca(2+)-loaded and Ca(2+)-free conditions. CaM can bind all three regions in both isoforms, but the binding modes differ appreciably in two segments. The results highlight a Ca(2+)/CaM and apoCaM binding site in the C-terminal fifth of the channel. This binding site is the target for malignant hyperthermia and central core disease mutations in RyR1, which affect the energetics and mode of CaM binding.

Impact of carbohydrate quantity and quality on maternal and pregnancy outcomes in gestational diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the impact of carbohydrate quantity and quality on maternal and pregnancy outcomes in gestational diabetes mellitus. METHODS: Using a pre-defined search strategy, two researchers systematically searched MEDLINE, CINAHL Plus, and PubMed for randomized controlled trials comparing low-carbohydrate, low-glycaemic index, or low-glycaemic load diets with usual care in gestational diabetes mellitus. Mean differences and risk ratios were extracted. RESULTS: Thirteen studies with 877 participants were included. Low-carbohydrate diet did not significantly differ from usual care for fasting blood glucose (3 studies; mean difference: 1.60 mmol/L; 95 % confidence interval: -1.95, 5.15), insulin requirement (2 studies; risk ratio: 1.01; 95 % confidence interval: 0.31, 3.05), birthweight (4 studies; mean difference: -0.23 kg; 95 % confidence interval: -1.90, 1.45), caesarean delivery (5 studies; risk ratio: 1.11; 95 % confidence interval: 0.66, 1.85), macrosomia (3 studies; risk ratio: 0.35; 95 % confidence interval: 0.00, 2130.64), large-for-gestational-age (2 studies; risk ratio: 0.46; 95 % confidence interval: 0.03, 7.20), and small-for-gestational-age infants (2 studies; risk ratio: 0.94; 95 % confidence interval: 0.00, 231.18). Low-glycaemic index diet did not significantly differ from usual care for the above outcomes either. However, low-glycaemic load diet reduced macrosomia risk (2 studies; risk ratio: 0.51; 95 % confidence interval: 0.43, 0.59). CONCLUSIONS: Low-carbohydrate and low-glycaemic index diets do not differ from usual care for most maternal and foetal outcomes in gestational diabetes mellitus. But low-glycaemic load diet may reduce macrosomia risk.

Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma.

Primary liver cancer (PLC) includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma and is the sixth most common cancer worldwide with poor prognosis. PLC is characterized by an abundant stromal reaction in which cancer-associated fibroblasts (CAFs) are one of the major stromal components. Solid evidence has demonstrated the crucial role of CAFs in tumor progression, and CAF abundance is often correlated with poor clinical outcomes. Although CAFs are regarded as an attractive and promising target for PLC treatment, a poor understanding of CAF origins and heterogeneity and a lack of specific CAF markers are the major hurdles to efficient CAF-specific therapy. In this review, we examine recent advances in the understanding of CAF diversity in the context of biomarkers, subtypes, and functions in PLC. The regulatory roles of CAFs in extracellular matrix remodeling, metastasis, cancer stemness, and therapeutic resistance are summarized. With an increasing link between CAF abundance and reduced antitumor immune responses, we provide updated knowledge on the crosstalk between CAFs and immune cells within the tumor microenvironment, which leads to immune resistance. In addition, we present current CAF-targeted therapies and describe some future perspectives. A better understanding of CAF biology will shed light on a novel therapeutic strategy against PLC.

Success Rate of Transcranial Doppler Scanning of Cerebral Arteries at Different Transtemporal Windows in Healthy Elderly Individuals.

This study measured the rates of success in applying transcranial Doppler (TCD) scanning at the middle, posterior and anterior temporal windows (MTW, PTW and ATW) in the elderly. A hand-held 1.6-MHz pulsed-wave TCD transducer was used to search for cerebral arteries at MTW, PTW and ATW locations. Physical attributes of the head, including head circumference and the distance between tragi on both sides ("tragus-to-tragus arc length"), were also measured to explore the associations with successful rates. Among 396 healthy elderly participants (aged 62.6 ± 6.0 y, 140 men), 81.1% (n = 321; 127 men) had one or more temporal windows penetrable by TCD ultrasound (n = 286 [72.2%] at MTW, n = 195 [49.2%] at PTW and n = 106 [26.8%] at ATW). Regression analysis revealed that successful scanning increased significantly in male participants at three window locations. Younger age significantly increased successful scanning at the MTW and ATW. Smaller tragus-to-tragus arc length increased successful scanning at the MTW, but unsuccessful scanning at the ATW. Our findings support using MTW as the first location when positioning the TCD transducer for the scanning of cerebral arteries in the elderly population. When performing TCD scanning on two temporal windows, we propose choosing the MTW and PTW.

Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

Mitochondrial Pyruvate Carrier Inhibition Attenuates Hepatic Stellate Cell Activation and Liver Injury in a Mouse Model of Metabolic Dysfunction-associated Steatotic Liver Disease.

Hepatic stellate cells (HSC) are non-parenchymal liver cells that produce extracellular matrix comprising fibrotic lesions in chronic liver diseases. Prior work demonstrated that mitochondrial pyruvate carrier (MPC) inhibitors suppress HSC activation and fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis (MASH). In the present study, pharmacologic or genetic inhibition of the MPC in HSC decreased expression of markers of activation in vitro. MPC knockdown also reduced the abundance of several intermediates of the TCA cycle, and diminished α-ketoglutarate played a key role in attenuating HSC activation by suppressing hypoxia inducible factor-1α signaling. On high fat diets, mice with HSC-specific MPC deletion exhibited reduced circulating transaminases, numbers of HSC, and hepatic expression of markers of HSC activation and inflammation compared to wild-type mice. These data suggest that MPC inhibition modulates HSC metabolism to attenuate activation and illuminate mechanisms by which MPC inhibitors could prove therapeutically beneficial for treating MASH.