[Three cases of occupational chronic chloropropene poisoning].

Chronic chloropropene poisoning is a disease mainly caused by peripheral nerve damage due to close contact with chloropropene in industrial production, its clinical manifestations include varying degrees of sensory, motor, or tendon reflex disorders in the distal limbs, and neuromyography can show neurogenic damage. This article analyzed and summarized the clinical characteristics, diagnosis and treatment methods of three patients with occupational chronic chloropropene poisoning, in order to enhance the clinical understanding of occupational chronic chloropropene poisoning and provide reference for clinical diagnosis and treatment.

An open-label 16-week study of liraglutide in adolescents with obesity post-sleeve gastrectomy.

BACKGROUND: Up to 50% of adolescents who undergo metabolic and bariatric surgery (MBS) have obesity 3 years post-MBS, placing them at continued risk for the consequences of obesity. OBJECTIVES: We conducted an open-label, 16-week pilot study of liraglutide in adolescents with obesity after sleeve gastrectomy (SG) to investigate liraglutide effects on weight and body mass index (BMI) post-SG. METHODS: Adolescents aged 12-20.99 years with obesity and a history of SG ≥1 year prior were enrolled. Liraglutide was initiated at 0.6 mg/day, escalated weekly to a maximum of 3 mg/day, with treatment duration 16 weeks. Fasting laboratory assessments and an oral glucose tolerance test were performed at baseline and end-treatment. RESULTS: A total of 43 participants were screened, 34 initiated liraglutide (baseline BMI 41.2 ± 7.7 kg/m2), and 31 (91%) attended the end-treatment visit. BMI decreased by 4.3% (p < 0.001) with liraglutide. Adolescents who had poor initial response to SG (<20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and haemoglobin A1C concentrations significantly decreased. There were no serious treatment-emergent adverse events reported. CONCLUSIONS: Liraglutide treatment was feasible and associated with a BMI reduction of 4.3% in adolescents who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone MBS.

[Comparison of the population covered by the 2024 version of the WHO's hepatitis B prevention and treatment guidelines and the Chinese antiviral treatment guidelines].

Objective: This study aims to compare the antiviral treatment similarities and differences in the population covered by the 2024 version of the World Health Organization's (WHO) hepatitis B prevention and treatment guidelines and the current Chinese hepatitis B prevention and treatment guidelines, so as to explore their impact on the indications for antiviral therapy in Chinese patients with chronic hepatitis B (CHB). Methods: The information of patients with chronic hepatitis B virus infection who did not receive antiviral treatment was collected through the registration database of the China Clinical Research Platform for Hepatitis B Elimination. Descriptive statistics were conducted on the demographic, blood, biochemical, and virological levels of patients according to the treatment recommendations of the two versions of the guidelines. The Mann-Whitney U test and χ2 test were used to compare the differences and proportional distribution of the treatment populations covered by the two guidelines. The χ2 test was used to analyze the coverage rate of different antiviral treatment indications. Results: A total of 21,134 CHB patients without antiviral treatment were enrolled. 69.4% of patients met the 2024 versions of the WHO guidelines' recommendations. 85.0% of patients met the current Chinese hepatitis B prevention and treatment guidelines. The WHO guidelines for antiviral therapy indications were met in younger patients with higher levels of ALT, AST, and APRI scores, as well as greater proportion of patients with higher viral loads (P<0.001). The WHO guidelines recommended a cut-off value of APRI>0.5, which raised the proportion of patients on antiviral therapy from 6.6% to 30.9%. 45.7% of patients met the antiviral indications for HBV DNA >2000 IU/ml with abnormal transaminase (ALT>30 U/L for males and ALT>19 U/L for females). The reduced APRI diagnostic cut-off value and ALT treatment threshold had further increased the treatment coverage rate by 91.6% in patients with chronic HBV infection in line with the 2024 versions of WHO guidelines. Conclusion: The reduction of the APRI diagnostic cut-off value and the ALT treatment threshold, based on the current hepatitis B guidelines of China, will further improve the treatment coverage of CHB patients.

[Analysis of one-year outcomes after cochlear implantation in adults with single-sided deafness].

Objectives: To investigate the outcomes of cochlear implantation in Mandarin-speaking cochlear implant (CI) users with single-sided deafness (SSD). Methods: This study was a single-center prospective cohort study. Eleven Mandarin-speaking adult SSD patients who underwent CI implantation at Capital Medical University Beijing Tongren Hospital from August 2020 to October 2021 were recruited, including 6 males and 5 females, with the age ranging from 24 to 50 years old. In a sound field with 7 loudspeakers distributed at 180°, we measured root-mean-square error(RMSE)in SSD patients at the preoperative, 1-month, 3-month, 6-month, and 12-month after switch-on to assess the improvement of sound source localization. The Mandarin Speech Perception (MSP) was used in the sound field to test the speech reception threshold (SRT) of SSD patients under different signal-to-noise locations in a steady-state noise under conditions of CI off and CI on, to reflect the head shadow effect(SSSDNNH), binaural summation effect(S0N0) and squelch effect(S0NSSD). The Tinnitus Handicap Inventory (THI) and the Visual Analogue Scale (VAS) were used to assess changes in tinnitus severity and tinnitus loudness in SSD patients at each time point. The Speech, Spatial and Qualities of Hearing Scale(SSQ) and the Nijmegen Cochlear Implantation Scale (NCIQ) were used to assess the subjective benefits of spatial speech perception and quality of life in SSD patients after cochlear implantation. SPSS 19.0 software was used for statistical analysis. Results: SSD patients showed a significant improvement in the poorer ear in hearing thresholds with CI-on compared with CI-off; The ability to localize the sound source was significantly improved, with statistically significant differences in RMSE at each follow-up time compared with the preoperative period (P<0.05). In the SSSDNNH condition, which reflects the head shadow effect, the SRT in binaural hearing was significantly improved by 6.5 dB compared with unaided condition, and the difference was statistically significant (t=6.25, P=0.001). However, there was no significant improvement in SRT between the binaural hearing condition and unaided conditions in the S0N0 and S0NSSD conditions (P>0.05). The total score of THI and three dimensions were significant decreased (P<0.05). Tinnitus VAS scores were significantly lower in binaural hearing compared to the unaided condition (P<0.001). The total score of SSQ, and the scores of speech and spatial dimensions were significant improved in binaural hearing compared to the unaided condition (P<0.001). There was no statistical difference in NCIQ questionnaire scores between preoperative and postoperative (P>0.05), and only the self-efficacy subscore showed a significant increase(Z=-2.497,P=0.013). Conclusion: CI could help Mandarin-speaking SSD patients restore binaural hearing to some extent, improve sound localization and speech recognition in noise. In addition, CI in SSD patients could suppress tinnitus, reduce the loudness of tinnitus, and improve subjective perceptions of spatial hearing and quality of life.

The use of accelerometers to improve estimation of the thermic effect of food in whole room calorimetry studies.

We tested whether spontaneous physical activity (SPA) from accelerometers could be used in a whole room calorimeter to estimate thermic effect of food (TEF). Eleven healthy participants (n = 7 females; age: 27 ± 4 yr; body mass index: 22.8 ± 2.6 kg/m2) completed two 23-h visits in randomized order: one "fed" with meals provided and one "fasted" with no food. SPA was measured by ActivPAL and Actigraph accelerometers. Criterion TEF was calculated as the difference in total daily energy expenditure (TDEE) between fed and fasted visits and compared with three methods of estimating TEF: 1) SPA-adjusted TEF (adjTEF)-difference in TDEE without SPA between visits, 2) Wakeful TEF-difference in energy expenditure obtained from linear regression and basal metabolic rate during waking hours, 3) 24-h TEF-increase in TDEE above SPA and sleeping metabolic rate. Criterion TEF was 9.4 ± 4.5% of TDEE. AdjTEF (difference in estimated vs. criterion TEF: activPAL: -0.3 ± 3.3%; Actigraph: -1.8 ± 8.0%) and wakeful TEF (activPAL: -0.9 ± 6.1%; Actigraph: -2.8 ± 7.6%) derived from both accelerometers did not differ from criterion TEF (all P > 0.05). ActivPAL-derived 24-h TEF overestimated TEF (6.8 ± 5.4%, P = 0.002), whereas Actigraph-derived 24-h TEF was not significantly different (4.3 ± 9.4%, P = 0.156). TEF estimations using activPAL tended to show better individual-level agreement (i.e., smaller coefficients of variation). Both accelerometers can be used to estimate TEF in a whole room calorimeter; wakeful TEF using activPAL is the most viable option given strong group-level accuracy and reasonable individual agreement.NEW & NOTEWORTHY Two research-grade accelerometers can effectively estimate spontaneous physical activity and improve the estimation of thermic effect of food (TEF) in whole room calorimeters. The activPAL demonstrates strong group-level accuracy and reasonable individual-level agreement in estimating wakeful TEF, whereas a hip-worn Actigraph is an acceptable approach for estimating 24-h TEF. These results highlight the promising potential of accelerometers in advancing energy balance research by improving the assessment of TEF within whole room calorimeters.

Beyond day and night: The importance of ultradian rhythms in mouse physiology.

Our circadian world shapes much of metabolic physiology. In mice ∼40% of the light and ∼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.

The thermoneutral zone in women takes an "arctic" shift compared to men.

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.

Youth's energy intake during a laboratory-based loss-of-control eating paradigm: Associations with reported current dieting.

Dieting is theorized as a risk factor for loss-of-control (LOC)-eating (i.e., feeling a sense of lack of control while eating). Support for this association has largely relied on retrospective self-report data, which does not always correlate with objectively assessed eating behavior in youth. We hypothesized that during a laboratory-based LOC-eating paradigm, children and adolescents who reported current (at the time of the visit) dieting would consume meals consistent with LOC-eating (greater caloric intake, and intake of carbohydrates and fats, but less intake of protein). Participants were presented with a buffet-style meal and instructed to "Let yourself go and eat as much as you want." Current dieting (i.e., any deliberate change to the amount or type of food eaten to influence shape or weight, regardless of how effective the changes are) was assessed via interview. General linear models were adjusted for fat mass (%), lean mass (kg), height, sex, protocol, race and ethnicity, pre-meal hunger and minutes since consumption of a breakfast shake. Of 337 participants (Mage 12.8 ± 2.7y; 62.3 % female; 45.7 % non- Hispanic White and 26.1 % non-Hispanic Black; MBMIz 0.78 ± 1.11), only 33 (9.8 %) reported current dieting. Current dieting was not significantly associated with total energy intake (F = 1.63, p = .20, ηp2 = 0.005), or intake from carbohydrates (F = 2.45, p = .12, ηp2 = 0.007), fat (F = 2.65, p = .10, ηp2 = 0.008), or protein (F = 0.39, p = .53, ηp2 = 0.001). Contrary to theories that dieting promotes LOC-eating, current dieting was not associated with youth's eating behavior in a laboratory setting. Experimental approaches for investigating dieting are needed to test theories that implicate dieting in pediatric LOC-eating.

Lower subjective social status is associated with increased adiposity and self-reported eating in the absence of hunger due to negative affect among children reporting teasing distress.

OBJECTIVES: Low social standing and teasing are independently associated with increased body mass index (BMI) and overeating in children. However, children with low social status may be vulnerable to teasing. METHODS: We tested the statistical interaction of subjective social status (SSS) and subjective socioeconomic status (SSES) and teasing distress on BMI, fat mass index (FMI), and eating in the absence of hunger (EAH) in children (Mage = 13.09 years, SD = 2.50 years; 27.8% overweight/obese). Multiple linear regressions identified the main effects of self-reported SSS (compared to peers in school), distress due to teasing, and their interaction on BMI (n = 115), FMI (n = 114), and child- (n = 100) and parent-reported (n = 97) EAH. RESULTS: Teasing distress was associated with greater BMI, FMI, and child-reported EAH due to negative affect (a subscale of EAH) and total EAH scores. There were no associations of SSS with these outcomes. However, there was an interaction between SSS and teasing distress for BMI, FMI, and EAH from negative affect such that lower SSS was associated with higher BMI, FMI, and EAH from negative affect in the presence of teasing distress. However, there were no main effects or interactions (with teasing distress) of SSES on the outcomes. CONCLUSIONS: These findings suggest that the relationship between lower SSS and increased adiposity and overeating behaviors may be exacerbated by other threats to social standing, such as teasing. Children exposed to multiple social threats may be more susceptible to eating beyond physiological need and obesity than those who experience a single form of perceived social disadvantage.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

[Advances in the role of infection in the development of benign tracheal stenosis].

Benign tracheal stenosis (BTS) is a refractory disease with a complex pathogenesis and limited therapeutic drug effects. The management of benign tracheal stenosis remains a major challenge for the interventional physiologist. In recent years, the role of infection in the occurrence and development of tracheal stenosis has attracted some attention, but there is still some controversy. A clear understanding of the relationship between infection and tracheal stenosis is essential to elucidate the pathogenic mechanism of BTS, and then to improve early prevention and management of BTS. This article reviewed the research progress on BTS associated with infection to explore new effective interventions that can reduce the BTS.

[Clinical characteristics and associated factors of mild cognitive impairment in patients with common cardiovascular diseases].

Objective: To analyze the clinical characteristics of patients with common cardiovascular diseases (CVD, including hypertension, coronary heart disease, atrial fibrillation, and heart failure) combined with mild cognitive impairment (MCI) and explore the potential risk factors of MCI in patients with CVD. Methods: A total of 2 294 patients with common cardiovascular diseases who met the criteria at Cardiology Medical Center in Beijing Anzhen Hospital, Capital Medical University, from June 1, 2021, to January 5, 2022, were retrospectively included. The patients were divided into the normal cognitive function group (1 107 cases) and the MCI group (1 187 cases). Demographic information and CVD status were collected. The information of cognitive function were collected using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) scales. The difference between normal cognitive function and MCI were compared and analyzed. The logistic regression analysis was used to explored risk factors of MCI in CVD patients. Results: A total of 2 294 patients aged (60.6±10.4) years were included, among whom there were 29.99% (688 cases) females. Compared with patients in the normal cognitive function group, patients in the MCI group were older [ (57.9±11.4) vs (63.1±8.9) years old, P<0.001], with a higher proportion of women [26.47% (293 cases) vs 33.28% (395 cases), P<0.001]; there was a higher proportion of patients suffering from hypertension in the MCI group [59.62% (660 cases) vs 64.62% (767 cases), P=0.014ï¼½, and more components of CVD [(1.68±0.62) vs (1.74±0.65) components, P=0.017]. The risk factors of MCI in patients with common CVD were increased age, increased depression score, combined with hypertension, and ≥3 common components of CVD, with OR (95%CI) of 1.043 (1.032-1.054), 1.021 (1.004-1.037), 1.151 (1.142-3.439), and 1.137 (1.023-1.797), respectively (all P values <0.05). Increasing education level was observed to be associated with reduced risk of MCI with OR (95%CI) of 0.319 (0.271-0.378) (P<0.05). Conclusions: The incidence of MCI was high in CVD patients. The risk factors of MCI in CVD patients included hypertension and≥3 common components of CVD.

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

Does Wrist-Worn Accelerometer Wear Compliance Wane over a Free-Living Assessment Period? An NHANES Analysis.

PURPOSE: Accelerometers are used to objectively measure physical behaviors in free-living environments, typically for seven consecutive days or more. We examined whether participants experience "wear fatigue," a decline in wear time day over day, during typical assessment period acquired in a nationally representative sample of 6- to 80-yr-olds in the United States. METHODS: Participants were instructed to wear an ActiGraph GT3X+ on their nondominant wrist continuously for seven consecutive days. Participants with seven complete days of recorded data, regardless of wear status, were included in the analyses ( N = 13,649). Wear was scored with the sleep, wake, and nonwear algorithm. RESULTS: Participants averaged 1248 ± 3.6 min·d -1 (mean ± SE) of wear over the assessment, but wear time linearly decreased from day 1 (1295 ± 3.2 min) to day 7 (1170 ± 5.3 min), resulting in a wear fatigue of -18.1 ± 0.7 min·d -1 ( ß ± SE). Wear fatigue did not differ by sex but varied by age-group-highest in adolescents (-26.8 ± 2.4 min·d -1 ) and lowest in older adults (-9.3 ± 0.9 min·d -1 ). Wear was lower in evening (1800-2359 h) and early morning (0000-0559 h) compared with the middle of the day and on weekend days compared with weekdays. We verified similar wear fatigue (-23.5 ± 0.7 min·d -1 ) in a separate sample ( N = 14,631) with hip-worn devices and different wear scoring. Applying minimum wear criteria of ≥10 h·d -1 for ≥4 d reduced wear fatigue to -5.3 and -18.7 min·d -1 for the wrist and hip, respectively. CONCLUSIONS: Patterns of wear suggest noncompliance may disproportionately affect estimates of sleep and sedentary behavior, particularly for adolescents. Further study is needed to determine the effect of wear fatigue on longer assessments.

Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.

OBJECTIVE: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and ß-cell function after therapy in AA Y-T2D. METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. ß-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI. CONCLUSION: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance ß-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Phase II clinical trial of neoadjuvant anti-PD-1 (toripalimab) combined with axitinib in resectable mucosal melanoma.

BACKGROUND: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. PATIENTS AND METHODS: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. RESULTS: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. CONCLUSIONS: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.

Dietary linoleic acid lowering alone does not lower arachidonic acid or endocannabinoids among women with overweight and obesity: A randomized, controlled trial.

The linoleic acid (LA)-arachidonic acid (ARA)-inflammatory axis suggests dietary LA lowering benefits health because it lowers ARA and ARA-derived endocannabinoids (ECB). Dietary LA reduction increases concentrations of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DHA derived ECB. The aim of this study was to examine targeted reduction of dietary LA, with and without EPA and DHA, on plasma EPA and DHA and ECB (2-arachidonoyl glycerol [2-AG], anandamide [AEA], and docosahexaenoyl ethanolamide [DHA-EA]). Healthy, pre-menopausal women (n = 62, BMI 30 ± 3 kg/m2 , age 35 ± 7 years; mean ± SD) were randomized to three 12-week controlled diets: (1) high LA, low omega-3 EPA and DHA (H6L3); (2) low LA, low omega-3 EPA and DHA (L6L3); or (3) low LA, high omega-3 EPA and DHA (L6H3). Baseline plasma fatty acids and ECB were similar between diets. Starting at 4 weeks, L6L3 and L6H3 lowered plasma LA compared to H6L3 (p < 0.001). While plasma ARA changed from baseline by 8% in L6L3 and -8% in L6H3, there were no group differences. After 4 weeks, plasma EPA and DHA increased from baseline in women on the L6H3 diet (ps < 0.001) and were different than the H6L3 and L6L3 diets. No differences were found between diets for AEA or 2-AG, however, in L6L3 and L6H3, AEA increased by 14% (ps < 0.02). L6H3 resulted in 35% higher DHA-EA (p = 0.013) whereas no changes were seen with the other diets. Lowering dietary LA did not result in the expected changes in fatty acids associated with the LA-ARA inflammatory axis in women with overweight and obesity.