Regression of periventricular anastomosis after indirect revascularization in pediatric patients with moyamoya disease.

OBJECTIVE: The aim of this study was to evaluate whether indirect revascularization in pediatric patients with moyamoya disease leads to periventricular anastomosis (PVA) regression, which is markedly developed in moyamoya vessels and is regarded as a risk factor for hemorrhage. METHODS: Pediatric patients with moyamoya disease treated with indirect revascularization from 2011 to 2021 were included in this study. Magnetic resonance angiography and arterial spin labeling images acquired before and 1 year after surgery were assessed to obtain a visual scale of postoperative collateral artery formation, moyamoya vessels, PVA, and quantitative values of cerebral blood flow (CBF). The relationship between background information (age, sex, RNF213 p.R4810K variant status, and preoperative CBF) and postoperative collateral artery formation, as well as postoperative CBF improvement and regression of moyamoya vessels and PVA, was evaluated. RESULTS: Of 89 hemispheres in 58 patients (34 females; mean [SD] patient age 8.0 [3.4] years), 74.2% showed good postoperative collateral artery formation and a significant increase in CBF (p < 0.001). Postoperative PVA showed significant regression (postoperative score 1.46 [1.06] vs 2.02 [1.69], p = 0.001), especially in those arising from choroidal arteries (postoperative score 0.28 [0.50] vs 0.72 [0.67], p < 0.001). Compared with hemispheres without good collateral artery formation, those with good collateral artery formation were more likely to show a higher increase in CBF (9.74 [12.44] ml/min/100 g vs -4.86 [9.68] ml/min/100 g, p < 0.001) and regression of PVA (54.5% [36/66] vs 30.4% [7/23], p = 0.015). Although not statistically significant, patients with postoperative PVA progression were younger than those with regression (6.75 [3.03] years vs 8.18 [3.17] years, p = 0.188), and patients with the RNF213 p.R4810K variant were more likely to show regression (28/57 [49.1%] hemispheres vs 5/13 [38.5%] hemispheres, p = 0.069). CONCLUSIONS: Indirect revascularization in pediatric patients with moyamoya disease resulted in good collateral extracranial artery formation and an increase in CBF and PVA regression, especially of vessels arising from choroidal arteries. With good postoperative collateral artery development, patients were more likely to show improved CBF and regression of moyamoya vessels, including PVA. Whether postoperative PVA changes reduce future hemorrhage risk requires further investigation.

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study.

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.

Comparative analysis of metabolic risk factors for progression of non-alcoholic fatty liver disease.

AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD), a globally prevailing chronic liver condition, refers to a spectrum of disease ranging from bland steatosis to steatohepatitis causing fibrosis without significant alcohol intake. Prominent risk factors (RFs) include obesity, type 2 diabetes mellitus, and dyslipidemia. Currently, no established hierarchy exists for the influence of metabolic RFs on NAFLD progression. This retrospective cohort study investigated and ranked the independent and combined effects of three major RFs on NAFLD progression. MATERIAL AND METHODS: 652 NAFLD patients with ≥ 1 RF were categorized by RF combination to examine yearly changes in RF severity with liver stiffness measurement (LSM) over five years. Body mass index (BMI), hemoglo- bin A1c (HbA1c), total cholesterol (TC), and LSM were reviewed. RESULTS: In patients with any single improving RF, decreases in BMI were associated with a yearly LSM change of -1.26 kPa, while decreases in HbA1c and TC were associated with a change of -0.51 kPa and -0.56 kPa, respectively. In patients with any single worsening RF, increases in BMI were correlated with an LSM change of +0.74 kPa and increases in HbA1c and TC were correlated with a change of +0.43 kPa and +0.16 kPa, respectively. Patients with three RFs had the greatest LSM changes for both improving (-3.68 kPa) and worsening (+3.19 kPa) groups. The strongest predictors for LSM change were BMI and HbA1c, with standardized ß coefficients of 0.236 and 0.226 (p < 0.001), while TC had the least influence [0.112 (p < 0.01), F(3,647) = 11.458, p < 0.001, R 2 = 0.155]. CONCLUSIONS: Obesity was the most prominent RF. Treatment of all three RFs over a five-year period presented a high likelihood of fibrosis stage regression for NAFLD patients.

Dataset of testicular germ cell tumors (TGCT) risk associated with serum polychlorinated biphenyl (PCB) by age at diagnosis and histologic types.

In a population-based case control study of testicular germ cell tumors (TGCT), we reported a strong positive association between serum levels of Wolff's Group 1 (potentially estrogenic) polychlorinated biphenyl (PCBs) and risk of TGCT, and the observed associations were similar for both seminoma and non-seminoma. While the observed specific associations between TGCT and Wolff's Group 1 PCBs cannot be easily explained by bias or confounding, a question can still be asked, that is, could the relationship between PCBs and TGCT differ by age at diagnosis? PCBs tend to bioaccumulate, with more heavily chlorinated PCB congeners tending to have longer half-lives. Half-lives of PCB congeners were reported ranging from 4.6 years for PCB-28 to 41.0 years for PCB-156. The half-life for the heavy PCB congeners (17.8 years) was found to be approximately twice that for the light PCBs (9.6 years) in early studies. Therefore, the same PCB concentration measured in a 20-year-old vs. a 55-year-old is unlikely to represent the same lifetime PCB exposure or type of PCB exposure. In this analysis, we stratified the data by median age of diagnosis of TGCT and further stratified by histologic type of TGCT (seminoma vs non-seminoma) to explore if the risk of TGCT associated with PCB exposures differs by age.

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts.

The incidence rate of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last several decades. Some epidemiologic studies have reported that the endocrine disrupting polychlorinated biphenyls (PCBs) in serum may be associated with TGCT risk, but the evidence is inconsistent. Our goal was to investigate whether serum levels of PCBs are associated with the increase of TGCT risk. We conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCBs congeners were measured using gas chromatography and unconditional logistic regression model was used to evaluate the risk of TGCT associated with total PCBs exposure, groups of PCBs categorized by Wolff's functional groups, and individual PCB congeners. The results showed that there was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.) = 1.0 (0.6-1.9), ρ trend = 0.9). However, strong positive association was observed between total serum levels of Wolff's Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR = 2.5, 95% CI = 1.3-4.7, ρ trend <0.05) as well as seminoma and non-seminoma subtypes. Wolff's Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177. Considering the continuing increase of TGCT, these associations should be replicated in different populations with larger sample size.

Tocilizumab for severe COVID-19 in solid organ transplant recipients: a matched cohort study.

The safety and efficacy of tocilizumab for the treatment of severe respiratory symptoms due to COVID-19 remain uncertain, in particular among solid organ transplant (SOT) recipients. Thus, we evaluated the clinical characteristics and outcomes of 29 hospitalized SOT recipients who received tocilizumab for severe COVID-19, compared to a matched control group who did not. Among a total of 117 total SOT recipients hospitalized with COVID-19, 29 (24.8%) received tocilizumab. The 90-day mortality was significantly higher among patients who received tocilizumab (41%) compared to those who did not (20%, P = .03). When compared to control patients matched by age, hypertension, chronic kidney disease, and administration of high dose corticosteroids, there was no significant difference in mortality (41% vs 28%, P = .27), hospital discharge (52% vs 72%, P = .26), or secondary infections (34% vs 24%, P = .55). Among patients who received tocilizumab, there was also no difference in mortality based on the level of oxygen support (intubated vs not intubated) at the time of tocilizumab initiation. In this matched cohort study, tocilizumab appeared to be safe but was not associated with decreased 90-day mortality. Larger randomized studies are needed to identify whether there are subsets of SOT recipients who may benefit from tocilizumab for treatment of COVID-19.

Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large U.S. Cohort.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) has been associated with acute liver injury (ALI) manifested by increased liver enzymes in reports worldwide. Prevalence of liver injury and associated clinical characteristics are not well defined. We aim to identify the prevalence of and risk factors for development of COVID-19-associated ALI in a large cohort in the United States. APPROACH AND RESULTS: In this retrospective cohort study, all patients who underwent SARS-CoV-2 testing at three hospitals in the NewYork-Presbyterian network were assessed. Of 3,381 patients, 2,273 tested positive and had higher initial and peak alanine aminotransferase (ALT) than those who tested negative. ALI was categorized as mild if ALT was greater than the upper limit of normal (ULN) but <2 times ULN, moderate if ALT was between 2 and 5 times the ULN, and severe if ALT was >5 times the ULN. Among patients who tested positive, 45% had mild, 21% moderate, and 6.4% severe liver injury (SLI). In multivariable analysis, severe ALI was significantly associated with elevated inflammatory markers, including ferritin (odds ratio [OR], 2.40; P < 0.001) and interleukin-6 (OR, 1.45; P = 0.009). Patients with SLI had a more severe clinical course, including higher rates of intensive care unit admission (69%), intubation (65%), renal replacement therapy (RRT; 33%), and mortality (42%). In multivariable analysis, peak ALT was significantly associated with death or discharge to hospice (OR, 1.14; P = 0.044), controlling for age, body mass index, diabetes, hypertension, intubation, and RRT. CONCLUSIONS: ALI is common in patients who test positive for SARS-CoV-2, but is most often mild. However, among the 6.4% of patients with SLI, a severe disease course should be anticipated.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Effect of interventions using physical activity trackers on physical activity in people aged 60 years and over: a systematic review and meta-analysis.

BACKGROUND: Older people are at high risk of physical inactivity. Activity trackers can facilitate physical activity. We aimed to investigate the effect of interventions using activity trackers on physical activity, mobility, quality of life and mental health among people aged 60+ years. METHODS: For this systematic review, we searched eight databases, including MEDLINE, Embase and CENTRAL from inception to April 2018. Randomised controlled trials of interventions that used activity trackers to promote physical activity among people aged 60+ years were included in the analyses. The study protocol was registered with PROSPERO, number CRD42017065250. RESULTS: We identified 23 eligible trials. Interventions using activity trackers had a moderate effect on physical activity (23 studies; standardised mean difference (SMD)=0.55; 95% CI 0.40 to 0.70; I2=86%) and increased steps/day by 1558 (95% CI 1099 to 2018 steps/day; I2=92%) compared with usual care, no intervention and wait-list control. Longer duration activity tracker-based interventions were more effective than short duration interventions (18 studies, SMD=0.70; 95% CI 0.47 to 0.93 vs 5 studies, SMD=0.14; 95% CI -0.26 to 0.54, p for comparison=0.02). Interventions that used activity trackers improved mobility (three studies; SMD=0.61; 95% CI 0.31 to 0.90; I2=10%), but not quality of life (nine studies; SMD=0.09; 95% CI -0.07 to 0.25; I2=45%). Only one trial included mental health outcomes and it reported similar effects of the activity tracker intervention compared with control. CONCLUSIONS: Interventions using activity trackers improve physical activity levels and mobility among older people compared with control. However, the impact of activity tracker interventions on quality of life, and mental health is unknown.

Drug-induced Liver Injury Secondary to Herbal and Dietary Supplements.

The use of herbal and dietary supplements (HDS) is increasing in the United States and worldwide. Its significant association with liver injury has become a concern, particularly because rates of hepatotoxicity caused by HDS are increasing. There are variety of HDS available, ranging from multi-ingredient substances, to anabolic steroids for bodybuilding purposes, to individual ingredients for purposes of supplementing a diet. This article reviews the impact of liver injury cause by HDS and explores the hepatotoxic potential of such products and their individual ingredients.

Prolonged Serum Alanine Aminotransferase Elevation Associated with Isotretinoin Administration.

Isotretinoin is a highly effective oral retinoid derivative for severe forms of acne. Despite its high margin of safety, isotretinoin carries a risk of teratogenicity and mild to massive elevations of serum cholesterol and triglyceride levels, as well as infrequent transaminitis. Liver dysfunction induced by isotretinoin is rare but it poses a management dilemma. We describe a 16-year-old male in whom alanine aminotransferase (ALT) rose from a baseline of 13 to 288 U/L after 20 weeks of treatment with 1.0-1.4 mg/kg of oral isotretinoin daily. Though the patient remained asymptomatic, ALT levels did not return to normal limits for approximately 8 months after discontinuation of therapy, an observation that has not been documented in the literature. When oral isotretinoin was readministered for intractable facial acne 3 years later, liver enzymes remained normal throughout the course of therapy. Although the pathogenesis and prognosis of retinoid-induced hepatotoxicity are unknown, this case illustrates that isotretinoin may be safely readministered after normalization of liver function tests.

Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK(®) Weight Loss Products: Results from the DILIN Prospective Study.

INTRODUCTION: Herbal and dietary supplements (HDS) have been increasingly recognized as a cause for acute liver injury (Navarro et al. Hepatology 60(4):1399-1408, 2014; Bailey et al. J Nutr 141:261-266, 2011). HDS products frequently contain numerous ingredients, and are marketed under various product names. A perusal of marketed weight loss products indicates that green tea extract (GTE) is a common ingredient in many. We aimed to describe the course and outcome of six patients who developed liver injury attributed to SLIMQUICK(®) weight loss products. METHODS: Patients with suspected drug-induced liver injury were enrolled in a prospective study of the Drug-Induced Liver Injury Network (DILIN) and causality was assessed by a panel of hepatologists. During the period under study, 6 of 1091 cases of liver injury were attributed to a SLIMQUICK(®) product and were assigned causality scores of probable, highly likely, or definite. RESULTS: Six cases of acute liver injury attributed to SLIMQUICK(®) products were enrolled in the DILIN prospective study between 2007 and 2011. All were women aged 22 to 58 years. Two had a normal body weight and four were mildly obese (body mass index 22.9-32.2 kg/m(2)). All were taking SLIMQUICK(®) products for weight loss and no patient reported prior use. Laboratory tests revealed a hepatocellular pattern of injury, with initial alanine aminotransferase (ALT) levels above 1000 U/L in all but one patient. Three patients were hospitalized and one underwent successful liver transplantation. No patients died of liver injury. GTE and/or its component catechins were listed among the ingredients for five of the six products. CONCLUSIONS: SLIMQUICK(®) products can lead to severe acute hepatocellular liver injury, which may result in transplantation. Given the frequency of GTE as a component in weight loss products, this ingredient should be studied further as a possible cause for liver injury.

Liver Injury from Herbal, Dietary, and Weight Loss Supplements: a Review.

Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.

The role of vision in odor-plume tracking by walking and flying insects.

The walking paths of male cockroaches, Periplaneta americana, tracking point-source plumes of female pheromone often appear similar in structure to those observed from flying male moths. Flying moths use visual-flow-field feedback of their movements to control steering and speed over the ground and to detect the wind speed and direction while tracking plumes of odors. Walking insects are also known to use flow field cues to steer their trajectories. Can the upwind steering we observe in plume-tracking walking male cockroaches be explained by visual-flow-field feedback, as in flying moths? To answer this question, we experimentally occluded the compound eyes and ocelli of virgin P. americana males, separately and in combination, and challenged them with different wind and odor environments in our laboratory wind tunnel. They were observed responding to: (1) still air and no odor, (2) wind and no odor, (3) a wind-borne point-source pheromone plume and (4) a wide pheromone plume in wind. If walking cockroaches require visual cues to control their steering with respect to their environment, we would expect their tracks to be less directed and more variable if they cannot see. Instead, we found few statistically significant differences among behaviors exhibited by intact control cockroaches or those with their eyes occluded, under any of our environmental conditions. Working towards our goal of a comprehensive understanding of chemo-orientation in insects, we then challenged flying and walking male moths to track pheromone plumes with and without visual feedback. Neither walking nor flying moths performed as well as walking cockroaches when there was no visual information available.