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Background: The essential amino acid leucine (LEU) plays a crucial role in promoting resistance-training adaptations. Dileucine (DILEU), a LEU-LEU dipeptide, increases MPS rates, however its impact on resistance training outcomes remains unexplored. This study assessed the effects of DILEU supplementation on resistance training adaptations., Methods: Using a randomized, double-blind, placebo-controlled approach, 34 resistance-trained males (age: 28.3 ± 5.9 years) consumed 2 grams of either DILEU monohydrate (RAMPS™, Ingenious Ingredients, L.P.), LEU, or placebo (PLA) while following a 4-day per week resistance training program for 10 weeks. Changes in body composition, 1-repetition maximum (1RM) and repetitions to failure (RTF) for leg press (LP) and bench press (BP), anaerobic capacity, countermovement jump (CMJ), and maximal voluntary contraction (MVC) were assessed after 0 and 10 weeks., Results: Significant main effects for time (p < 0.001) were realized for LP and BP 1RM and RTF. A significant group × time interaction was identified for changes in LP 1RM (p = 0.02) and LP RTF (p = 0.03). Greater increases in LP 1RM were observed in DILEU compared to PLA (p = 0.02; 95% CI: 5.8, 73.2 kg), and greater increases in LP RTF in DILEU compared to LEU (p = 0.04; 95% CI: 0.58, 20.3 reps). No significant differences were found in other measures., Conclusions: DILEU supplementation at 2 grams daily enhanced lower body strength and muscular endurance in resistance-trained males more effectively than LEU or PLA. These findings suggest DILEU as a potentially effective supplement for improving adaptations to resistance training. NCT06121869 retrospectively registered., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: M.P and R.J are principals of Ingenious Ingredients, L.P., the sponsor of the study, and inventors of numerous patent applications for the use of dileucine but have not been involved in data collection or analysis. All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials as there are no restrictions on sharing data and/or materials., (Copyright: © 2024 Hagele et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more., Methods: This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0-2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M 2 , includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005)., Results: For 35 patients, 19 with 1-2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10-3; absolute neutrophil count > 8000/μl, HR = 4.95, P < 6.5x10-3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60-90)% of patients with 0-2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10-3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies., Conclusion: Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bruckner, De Jager, Knopf, Bassali, Book, Gurell, Nghiem, Schwartz and Hirschfeld.)

Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of energy drink (ED) or energy shot (ES) consumption on acute exercise performance, metabolism, and cognition, along with synergistic exercise-related performance outcomes and training adaptations. The following 13 points constitute the consensus of the Society and have been approved by the Research Committee of the Society: Energy drinks (ED) commonly contain caffeine, taurine, ginseng, guarana, carnitine, choline, B vitamins (vitamins B1, B2, B3, B5, B6, B9, and B12), vitamin C, vitamin A (beta carotene), vitamin D, electrolytes (sodium, potassium, magnesium, and calcium), sugars (nutritive and non-nutritive sweeteners), tyrosine, and L-theanine, with prevalence for each ingredient ranging from 1.3 to 100%. Energy drinks can enhance acute aerobic exercise performance, largely influenced by the amount of caffeine (> 200 mg or >3 mg∙kg bodyweight [BW -1 ]) in the beverage. Although ED and ES contain several nutrients that are purported to affect mental and/or physical performance, the primary ergogenic nutrients in most ED and ES based on scientific evidence appear to be caffeine and/or the carbohydrate provision. The ergogenic value of caffeine on mental and physical performance has been well-established, but the potential additive benefits of other nutrients contained in ED and ES remains to be determined. Consuming ED and ES 10-60 minutes before exercise can improve mental focus, alertness, anaerobic performance, and/or endurance performance with doses >3 mg∙kg BW -1 . Consuming ED and ES containing at least 3 mg∙kg BW -1 caffeine is most likely to benefit maximal lower-body power production. Consuming ED and ES can improve endurance, repeat sprint performance, and sport-specific tasks in the context of team sports. Many ED and ES contain numerous ingredients that either have not been studied or evaluated in combination with other nutrients contained in the ED or ES. For this reason, these products need to be studied to demonstrate efficacy of single- and multi-nutrient formulations for physical and cognitive performance as well as for safety. Limited evidence is available to suggest that consumption of low-calorie ED and ES during training and/or weight loss trials may provide ergogenic benefit and/or promote additional weight control, potentially through enhanced training capacity. However, ingestion of higher calorie ED may promote weight gain if the energy intake from consumption of ED is not carefully considered as part of the total daily energy intake. Individuals should consider the impact of regular coingestion of high glycemic index carbohydrates from ED and ES on metabolic health, blood glucose, and insulin levels. Adolescents (aged 12 through 18) should exercise caution and seek parental guidance when considering the consumption of ED and ES, particularly in excessive amounts (e.g. > 400 mg), as limited evidence is available regarding the safety of these products among this population. Additionally, ED and ES are not recommended for children (aged 2-12), those who are pregnant, trying to become pregnant, or breastfeeding and those who are sensitive to caffeine. Diabetics and individuals with preexisting cardiovascular, metabolic, hepatorenal, and/or neurologic disease who are taking medications that may be affected by high glycemic load foods, caffeine, and/or other stimulants should exercise caution and consult with their physician prior to consuming ED. The decision to consume ED or ES should be based upon the beverage's content of carbohydrate, caffeine, and other nutrients and a thorough understanding of the potential side effects. Indiscriminate use of ED or ES, especially if multiple servings per day are consumed or when consumed with other caffeinated beverages and/or foods, may lead to adverse effects. The purpose of this review is to provide an update to the position stand of the International Society of Sports Nutrition (ISSN) integrating current literature on ED and ES in exercise, sport, and medicine. The effects of consuming these beverages on acute exercise performance, metabolism, markers of clinical health, and cognition are addressed, as well as more chronic effects when evaluating ED/ES use with exercise-related training adaptions.

Position Statement: The International Society of Sports Nutrition (ISSN) presents this position based on a critical examination of literature surrounding the effects of essential amino acid (EAA) supplementation on skeletal muscle maintenance and performance. This position stand is intended to provide a scientific foundation to athletes, dietitians, trainers, and other practitioners as to the benefits of supplemental EAA in both healthy and resistant (aging/clinical) populations. EAAs are crucial components of protein intake in humans, as the body cannot synthesize them. The daily recommended intake (DRI) for protein was established to prevent deficiencies due to inadequate EAA consumption. The following conclusions represent the official position of the Society: 1. Initial studies on EAAs' effects on skeletal muscle highlight their primary role in stimulating muscle protein synthesis (MPS) and turnover. Protein turnover is critical for replacing degraded or damaged muscle proteins, laying the metabolic foundation for enhanced functional performance. Consequently, research has shifted to examine the effects of EAA supplementation - with and without the benefits of exercise - on skeletal muscle maintenance and performance. 2. Supplementation with free-form EAAs leads to a quick rise in peripheral EAA concentrations, which in turn stimulates MPS. 3. The safe upper limit of EAA intake (amount), without inborn metabolic disease, can easily accommodate additional supplementation. 4. At rest, stimulation of MPS occurs at relatively small dosages (1.5-3.0 g) and seems to plateau at around 15-18 g. 5. The MPS stimulation by EAAs does not require non-essential amino acids. 6. Free-form EAA ingestion stimulates MPS more than an equivalent amount of intact protein. 7. Repeated EAA-induced MPS stimulation throughout the day does not diminish the anabolic effect of meal intake. 8. Although direct comparisons of various formulas have yet to be investigated, aging requires a greater proportion of leucine to overcome the reduced muscle sensitivity known as "anabolic resistance." 9. Without exercise, EAA supplementation can enhance functional outcomes in anabolic-resistant populations. 10. EAA requirements rise in the face of caloric deficits. During caloric deficit, it's essential to meet whole-body EAA requirements to preserve anabolic sensitivity in skeletal muscle.

Congenital chylous ascites (CCA) is a rare condition seen in the neonatal period. The pathogenesis is primarily related to congenital intestinal lymphangiectasis. Conservative treatment of chylous ascites involves paracentesis, total parenteral nutrition (TPN), medium-chain triglyceride (MCT)-based milk formula, use of somatostatin analogue and octreotide. Surgical treatment is considered when conservative treatment fails. We describe a laparoscopic treatment of CCA using the fibrin glue technique. A male infant, in whom foetal ascites was detected at 19 weeks of gestation, was born by caesarean section at 35 weeks of gestation weighing 3760 g. There was evidence of hydrops in the foetal scan. A diagnosis of chylous ascites was made by abdominal paracentesis. A magnetic resonance scan was suggestive of gross ascites, and no lymphatic malformation was identified. TPN and octreotide infusion was started and continued for 4 weeks, but the ascites persisted. The failure of conservative treatment led us to perform laparoscopic exploration. Intraoperatively, chylous ascites and multiple prominent lymphatic vessels around the root of the mesentery were noted. The fibrin glue was applied over the leaking mesenteric lymphatic vessels in the duodenopancreatic region. Oral feeding was started from post-operative day 7. After 2 weeks of the MCT formula, ascites progressed. Thus, laparoscopic exploration was necessary. We introduced an endoscopic applicator for fibrin glue and applied it into the place of leakage. The patient was doing well with no appearance of ascites reaccumulating and was discharged on the 45 th post-operative day. Follow-up ultrasonography (1 st , 3 rd and 9 th months after discharge) showed a small amount of ascitic fluid but with no clinical significance. Laparoscopic localisation and ligation of leakage sites could be difficult, especially in newborns and young infants due to the small size of lymphatic vessels. The use of fibrin glue to seal the lymphatic vessels is quite promising.

Background and Purpose: To determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID-19)-infected subjects in seven U.S. and four European hospitals., Methods: This is a retrospective study of COVID-19-positive subjects with the following inclusion criteria: age >18, lab-confirmed COVID-19 infection, and acute NI findings (NI+) attributed to COVID-19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID-19-positive (TN) subjects were assessed., Results: A total of 37,950 COVID-19-positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States., Conclusion: This multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID-19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID-19., (© 2023 American Society of Neuroimaging.)

Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet)., Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use., Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years)., Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: This study was designed to demonstrate the safety and feasibility of episcleral brachytherapy (ESB) for the treatment of anti-vascular endothelial growth factor (anti-VEGF) resistant neovascular age-related macular degeneration (nAMD) in a 6-subject cohort adjunct to anti-VEGF therapy., Methods: Six eyes of six subjects with anti-VEGF resistant nAMD (persistent fluid or hemorrhage despite frequent anti-VEGF treatment) were treated with ESB between May 2018 and July 2018 as part of a larger early feasibility trial. Baseline and follow-up exams with multi-modal imaging were conducted., Results: In this analysis, six eyes were included. The mean age was 74.7 years; 33% were female; 67% had polypoidal choroidal vasculopathy. The mean number of lifetime anti-VEGF injections received prior to the study enrollment was 33.9 injections and 10 injections in the year prior to the study enrollment. In the first and second years following ESB, the mean number of injections was 8.5 and 8, respectively. No evidence of radiation-induced toxicity through 2 years following ESB was observed. The mean baseline VA was 55.3 letters. At 1 year, the mean VA increased by 3.2 letters and 1.7 letters at year 2. At 2 years, the mean change in vascular complex on ICGA was - 18%, - 43% on OCTA, and - 5% on FA. The subjects also experienced a mean decrease in CRT on OCT of 21% after 2 years., Conclusions: The results from this six-subject cohort with 2-year data support additional investigations of ESB for nAMD, specifically those with persistent disease activity and treatment resistant nAMD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival., Methods: Analyses evaluate predictive blood tests to identify patients who often survive 1 and 2 years. A four-test model includes: albumin, absolute neutrophil count, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio. Individual tests include: alkaline phosphatase, lymphocytes, white blood count, platelet count, and hemoglobin. Eligible patients have advanced: resistant 3rd line colorectal, and both resistant and new pancreatic and intrahepatic bile duct cancers. Eligibility characteristics include: biopsy-proven, measurable metastatic disease, NCI grade 0-2 blood tests, Karnofsky Score 100-50, and any adult age. Drugs are given at 1/4-1/3 of their standard dosages biweekly: gemcitabine, irinotecan, fluorouracil, leucovorin, and day 2 oxaliplatin every 2 weeks. In case of progression, Docetaxel is added (except colon cancer), with or without Mitomycin C, and next cetuximab (except pancreatic and KRAS BRAF mutation cancers). Bevacizumab is substituted for cetuximab in case of another progression or ineligibility. Consent was written and conforms with Helsinki, IRB, and FDA criteria (FDA #119005)., Results: Median survival is 14.5 months. Of 205 patients, 60% survive 12, and 37% survive 24 months (95% CI ± 8%). Survival is > 24, 13, and 3.8 months for patients with 0, 1-2, and 3-4 unfavorable tests, respectively. Individual "favorable and unfavorable" tests predict long and short survival. Neither age nor prior therapy discernibly affects survival. Net rates of clinically significant toxicities are less than 5%., Conclusion: Treatments reproduce predictable, greater than 12 and 24-month chances of survival for the aged and for patients with drug-resistant tumors. Evaluation of blood tests may change practice, expand eligibility, and personalize treatments. Findings support investigation of drug combinations and novel dosages to reverse resistance and improve safety., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Amidst the COVID-19 pandemic, telemedicine has emerged as a safe and cost-effective alternative to traditional ophthalmology clinic visits. This study evaluated patient attitudes towards telemedicine at a full-service, retina-only practice to identify areas for growth in implementation., Methods: A survey was distributed to established patients at University Retina and Macula Associates following the completion of a telemedicine encounter in July 2021. On a 5-point Likert scale, patients compared telemedicine to in-person visits for six domains: ability to ease COVID-related anxiety, efficiency, patient education, quality of care, fulfillment of personal needs, and convenience. Pearson's χ 2 and Fisher's exact test were used to assess correlations between demographic factors and patient attitudes or preference towards telemedicine., Results: Among 103 respondents, two-thirds (68.7%) preferred in-person compared to telemedicine encounters. Overall, patients had a neutral attitude towards telemedicine [mean Likert rating (SD) = 3.11/5 ± 0.82]. Questions assessing "patient education" and "telemedicine efficiency" received the greatest proportion of positive and negative responses, respectively. Positive attitudes were more frequent among patients with prior telemedicine experience (87.5%) compared to never-users (71.8%; p = 0.046). Patients ≥ 75 years old tended to negatively assess telemedicine regarding reduction of COVID-19-related anxiety, efficiency, patient education, and physician facetime (p < 0.05 for all). A positive but non-significant trend was observed between higher education level and positive attitude towards telemedicine (p = 0.18). Telehealth never-users more often negatively rated receiving adequate facetime with the physician virtually (54.7%) compared to prior users (25.6%; p = 0.004). Younger age, prior history of telemedicine use, and higher education level were associated with increased preference for telemedicine (p < 0.05 for all)., Conclusion: Our findings revealed hesitance remains among patients towards adoption of telemedicine. Targeting age-, experience-, and education-related barriers will be invaluable for increasing acceptance of this healthcare delivery model., (© 2022. The Author(s).)