Anal Cancers in Previously Screened Versus Unscreened Patients: Tumor Stage and Treatment Outcomes.

BACKGROUND: Targeted screening programs for patients at high risk for anal squamous-cell carcinoma have been proposed; however, the evidence in support of screening remains unclear. OBJECTIVE: This study aimed to determine whether screening high-risk patients (predominantly those living with HIV) detected squamous-cell carcinoma at an earlier stage compared to the routine practice of not screening. DESIGN: This is a cohort study. SETTINGS: This study was conducted at a quaternary care center in Canada. PATIENTS: Included patients were at least 18 years old with a pathologic diagnosis of invasive anal squamous-cell carcinoma between 2002 and 2022. INTERVENTIONS: Patients diagnosed through a high-risk screening program were compared to those who did not undergo screening. MAIN OUTCOME MEASURES: The primary outcome was clinical stage at presentation, categorized as T1N0M0 vs other. Secondary outcomes included treatments received, treatment failure, and overall survival. RESULTS: A total of 612 patients with anal squamous-cell carcinoma were included, with 26 of those patients diagnosed through a screening program. Patients with screen-detected cancers had greater odds of presenting with T1N0M0 tumors compared to unscreened patients (18 [69.2%] vs 84 [14.3%]; adjusted OR 9.95; 95% CI, 3.95-25.08). A propensity score-matched sensitivity analysis found similar results (OR 11.13; 95% CI, 4.67-26.52). Screened patients had greater odds of treatment with wide local excision alone, as opposed to any combination of chemotherapy, radiation therapy, and surgery (3 [12.5%] vs 18 [3.2%]; OR 4.38; 95% CI, 1.20-16.04). There were no statistically significant differences in treatment failure or overall survival between groups. LIMITATIONS: The small number of screened patients limits the power of the analysis. CONCLUSIONS: Screening for anal squamous-cell carcinoma among high-risk populations detects cancers at an earlier stage. Patients with screen-detected cancers also had a greater likelihood of being candidates for wide local excision alone, which may have spared them the morbidity associated with chemoradiotherapy or abdominoperineal resection. See Video Abstract. CNCERES DE ANO EN PACIENTES PREVIAMENTE DETECTADOS POR CRIBADO VERSUS NO DETECTADOS ESTADIO DEL TUMOR Y RESULTADOS DEL TRATAMIENTO: ANTECEDENTES:Se han propuesto programas de cribado dirigidos a pacientes con alto riesgo de carcinoma anal de células escamosas; sin embargo, la evidencia a favor de la detección sigue sin estar clara.OBJETIVO:Este estudio tuvo como objetivo determinar si el cribado de pacientes de alto riesgo (predominantemente aquellos que viven con el VIH) detectó el carcinoma de células escamosas en una etapa más temprana en comparación con la práctica habitual de no cribado.DISEÑO:Este es un estudio de cohortes.CONFIGURACIÓN:Este estudio se realizó en un centro de atención cuaternaria en Canadá.PACIENTES:Los pacientes incluidos tenían al menos 18 años con un diagnóstico patológico de carcinoma de células escamosas anal invasivo entre 2002 y 2022.INTERVENCIONES:Los pacientes diagnosticados mediante un programa de cribado de alto riesgo se compararon con aquellos que no se sometieron a cribado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el estadio clínico en la presentación, categorizado como T1N0M0 versus otro. Los resultados secundarios incluyeron los tratamientos recibidos, el fracaso del tratamiento y la supervivencia general.RESULTADOS:Se incluyeron un total de 612 pacientes con carcinoma anal de células escamosas, con 26 de esos pacientes diagnosticados a través de un programa de cribado. Los pacientes con cánceres detectados mediante cribado tenían mayores probabilidades de presentar tumores T1N0M0 en comparación con los pacientes no cribados (18 [69.2%] frente a 84 [14.3%]; razón de probabilidad ajustada 9.95; intervalo de confianza del 95 % 3.95 -25.08). Un análisis de sensibilidad emparejado por puntaje de propensión encontró resultados similares (odds ratio 11.13; intervalo de confianza del 95% 4.67 -26.52; p < 0.001). Los pacientes examinados tenían mayores probabilidades de recibir tratamiento con escisión local amplia sola, en comparación con cualquier combinación de quimioterapia, radiación y cirugía (3 [12.5%] frente a 18 [3.2%]; razón de probabilidad 4.38; intervalo de confianza del 95 % 1.20 -16.04). No hubo diferencias estadísticamente significativas en el fracaso del tratamiento o la supervivencia global entre los grupos.LIMITACIONES:El pequeño número de pacientes evaluados limita el poder del análisis.CONCLUSIONES:La detección del carcinoma anal de células escamosas entre las poblaciones de alto riesgo detecta los cánceres en una etapa más temprana. Los pacientes con cánceres detectados mediante cribado también tenían una mayor probabilidad de ser candidatos para una escisión local amplia sola, lo que puede haberles evitado la morbilidad asociada con la quimiorradioterapia o la resección abdominoperineal. (Traducción --Dr. Aurian Garcia Gonzalez ).

Low Energy Availability and Increased Risk of Relative Energy Deficiency in Sport (RED-S) During a 3767-km Thru-Hike on the Pacific Crest Trail: A Case Study.

Long-distance "thru-hiking" has extraordinary physical demands and has become increasingly popular. This report describes a man (55 y) who thru-hiked the Pacific Crest Trail in 2021 and was at risk of developing the relative energy deficiency in sport (RED-S) syndrome. Hiking distance was 3767 km over 128 d. Eighty-eight days (69%) were full days of hiking, covering 38±8 km/d (mean±SD) in 7.9±1.6 h/d. Exercise energy expenditure above rest (heart rate vs indirect calorimetry regression method) was 2834±1518 kcal/d, total energy expenditure was 5702±1323 kcal/d, and energy intake was 4141 kcal/d. Body mass decreased by 9%, and fat mass (dual-energy X-ray absorptiometry) decreased by 46%. Energy availability (energy intake minus exercise energy expenditure) was 19.3 kcal/d/kg fat-free mass, indicating low energy availability (defined as <30 kcal/d/kg). Dual-energy X-ray absorptiometry-measured spine bone mineral density (BMD) decreased by 8.6%, with little to no decrease in total hip (-1.0%) and femoral neck (-1.5%) BMD. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides increased by 24, 39, and 57%, respectively. Within 8 mo after the hike, BMD and serum lipids nearly or fully returned to baseline. No changes in high-density lipoprotein cholesterol, glycemia, or blood pressure were observed. According to guidelines, these observations are consistent with a moderate risk of RED-S, and a medical evaluation and treatment plan are advisable in order to avoid clinical manifestations (eg, stress fractures, anemia, psychological disturbances). To minimize RED-S risk, it may be prudent for thru-hikers to optimize energy availability by moderating daily hiking distances and/or increasing food intake.

Effect of Huperzine A on Cognitive Function and Perception of Effort during Exercise: A Randomized Double-Blind Crossover Trial.

Huperzine A has shown the ability to acutely improve cognitive function in certain populations, and therefore is commonly added to pre-workout supplements. However, its effects have not been studied in exercise-trained individuals. OBJECTIVE: We hypothesized that acute consumption of huperzine A would improve cognitive function during exercise, which may be beneficial for exercise performance. METHODS: From January to April, 2018, 15 exercise-trained individuals (11 women [height 166 ± 2 cm, weight 60.5 ± 3.0 kg] and 4 men [height 173 ± 4 cm, weight 82.0 ± 11.0 kg], BMI 23.5 ± 1.4 kg/m2, age 30.4 ± 3.6 years) were studied in a double blind randomized-sequence cross-over study, in which they underwent tests for cognitive function (digit span, verbal/word fluency, and Stroop), neuromuscular performance (sharpened Romberg and dart throwing), and exercise performance (estimated aerobic capacity, hand-grip strength, vertical jump, and push-up) after acute ingestion of huperzine A (200 mcg) or placebo. One week separated the two trials. RESULTS: No measures of cognitive function differed between placebo and huperzine A trials (all p ≥ 0.296). Heart rates (157 ± 4 vs. 158 ± 4 bpm; p = 0.518) and ratings of perceived exertion (13.7 ± 0.56 vs. 13.9 ± 0.61; p = 0.582) did not differ between placebo and huperzine A trials, respectively. Ratings of subjective difficulty post-exercise (0-10 scale) were significantly higher (5.7 ± 0.38 vs. 6.8 ± 0.38; p = 0.002) in the huperzine A trial than the placebo trial. No differences were observed for neuromuscular or exercise performance measures between groups (all p ≥ 0.497). CONCLUSIONS: Huperzine A does not enhance cognitive function during exercise despite it being marketed as a cognitive enhancer. Because of its inability to enhance cognitive function, its inclusion in pre-workout supplements warrants reconsideration. Other more practical and effective strategies should be considered.

Low-Level Anorectal HIV Shedding despite Effective Antiretroviral Therapy Is Not Driven by Mucosal Inflammation.

Although antiretroviral treatment (ART) suppresses HIV RNA in blood and prevents transmission, low-level anorectal HIV RNA shedding persists in some ART-treated men who have sex with men. We collected anorectal biopsies and swabs from 55 men who have sex with men on effective ART, hypothesizing that anorectal shedding would be linked to microbiota-driven mucosal T cell activation. Lymphocytes were assessed by flow cytometry, soluble immune factors by multiplex immunoassay, neutrophils and epithelial integrity by immunofluorescence microscopy, and the anorectal microbiome by quantitative PCR and 16S rRNA gene sequencing. Unexpectedly, we found no evidence that anorectal HIV shedding was associated with the parameters of mucosal inflammation, including T cell activation, inflammatory cytokines, the density of neutrophils, or epithelial integrity. Moreover, the anorectal bacterial load was actually lower in the shedding group, with no major differences in bacterial composition. Instead, the strongest mucosal immune correlates of HIV shedding were an increase in central memory cell frequency and Ki67 expression as well as higher concentrations of the cytokine IL-7 in anorectal secretions. Anorectal HIV RNA shedding during effective ART was not driven by local inflammation; the associations seen with local homeostatic T cell proliferation will require further confirmation.

The effects of substance use and physical activity on cognition: The impact of incongruent health behaviors.

BACKGROUND: Cognitive functioning refers to storage and manipulation of information and includes executive functioning (EF) and attention (ATT). While physical activity (PA) improves cognitive functioning, decrements are associated with frequent substance use. This study examined PA on cognitive functioning within the context of past-year substance use. METHODS: Using NESARC-III data (N = 36,309), cross-sectional analysis examined interactions between self-reported past-year PA and substance use in relation to cognitive functioning. RESULTS: As hypothesized, light-to-moderate, vigorous, and total PA conditional main effects were positively associated with both facets of cognition, while frequent substance use conditional main effects were negatively associated with ATT and EF. The positive association between PA and cognition was diminished by substance use. Frequent binge drinking, marijuana, cocaine, and opioid use weakened the impact of light-to-moderate PA on EF, and only frequent cocaine use lessened the relationship between vigorous PA on EF. When PA intensities were combined, frequent binge drinking and cocaine use weakened the PA and EF association. Infrequent stimulant use reduced the association between all levels of PA and ATT, while infrequent marijuana use unexpectedly enhanced the relation between vigorous PA and ATT. CONCLUSIONS: Overall, PA enhanced two facets of cognitive functioning across six substances. However, these benefits are reduced in the context of frequency of substance use. The positive association between light-to-moderate PA and EF appears to be more sensitive in the context of frequent substance use than vigorous PA. Implications for public health messaging and PA as cognitive remediation treatment for substance use disorders are discussed.

Correction: The Effect of Protandim® Supplementation on Athletic Performance and Oxidative Blood Markers in Runners.

[This corrects the article DOI: 10.1371/journal.pone.0160559.].

Anal dysplasia and HIV shedding in ART-treated men.

OBJECTIVES: Anal human papillomavirus (HPV) infection is highly prevalent among men who have sex with men (MSM). HPV-associated anal dysplasia has been linked with anal HIV RNA shedding despite antiretroviral therapy (ART). Since mucosal HIV levels are a key determinant of sexual transmission of the virus, this would have important public health implications. Therefore, we assessed the association between anal dysplasia and HIV shedding in ART-treated MSM from Toronto, Canada. METHODS: In 54 HIV-infected men on effective ART, we assessed anal HIV RNA shedding by PCR, HPV infection by microsphere-based genotyping and anal dysplasia by high-resolution anoscopy. All participants were enrolled between May 2017 and October 2018. RESULTS: The median duration of ART at the time of study enrolment was 18 years, with most participants being on an integrase inhibitor-based ART regimen. Low-level anal HIV RNA shedding was present in 15/54 (27.8%) participants. Neither the detection of shedding nor the level of HIV RNA was associated with anal dysplasia, HPV infection or antiretroviral regimen. CONCLUSIONS: HPV-associated anal dysplasia was not associated with anal HIV RNA shedding in this relatively small cohort of men on effective ART. While anal HIV RNA was detected more often than anticipated, shedding was low level and unlikely to cause HIV transmission. However, the immunological drivers of anal HIV RNA shedding in ART-treated individuals may merit further study.

Short Term High-Repetition Back Squat Protocol Does Not Improve 5-km Run Performance.

The purpose of this study was to evaluate the hypothesis that a novel high-repetition, low-resistance back squat training protocol, designed to stimulate high-intensity interval training, improves 5-km run performance. Fifteen runners [4 male, 11 female; 150 + minutes of endurance exercise/week; age = 22.7 ± 2.0 y; 21.5 ± 2.2 kg/m2 BMI] in this single-group test-retest design completed two weeks of back squats consisting of three sets of 15-24 repetitions at 60% of estimated one-repetition max (1RM), three times per week (1-2 days of rest between sessions). Outcome tests included a 5-km outdoor timed run, laboratory indirect calorimetry to quantify substrate oxidation rates during steady-state submaximal exercise (60% and 70% heart rate max (HRmax)), and estimated 1RM for back squats. Back squat estimated 1RM increased by 20% (58.3 ± 18.5 to 70.2 ± 16.7 kg, P < 0.001). However, 5-km run times due to the back squat protocol did not significantly change (Pre-Squats: 23.9 ± 5.0 vs. Post-Squats: 23.7 ± 4.3 minutes, P = 0.71). Likewise, the squat training program did not significantly alter carbohydrate or lipid oxidation rates during steady-state submaximal exercise at 60% or 70% of HRmax (P values ranged from 0.36 - 0.99). Short term high-repetition back squat training does not appear to impact 5-km run performance or substrate utilization during submaximal exercise.

Short-Term Mediterranean Diet Improves Endurance Exercise Performance: A Randomized-Sequence Crossover Trial.

Objective: Healthful dietary patterns have constituents that are known to improve exercise performance, such as antioxidants, nitrates, and alkalizing effects. However, ergogenic effects of such diets have not been evaluated. We hypothesized that a short-term Mediterranean diet results in better exercise performance, as compared to a typical Western diet. Methods: Eleven recreationally active women (n = 7) and men (n = 4) (body mass index, 24.6 ± 3.2 kg/m2; age 28 ± 3 years) were studied in a randomized-sequence crossover study, in which they underwent exercise performance testing on one occasion after 4 days of a Mediterranean diet and on another occasion after 4 days of a Western diet. A 9- to 16-day washout period separated the two trials. Endurance exercise performance was evaluated with a 5-km treadmill time trial. Anaerobic exercise performance tests included a Wingate cycle test, a vertical jump test, and hand grip dynamometry. Results: Five-kilometer run time was 6% ± 3% shorter (faster) in the Mediterranean diet trial than in the Western diet trial (27.09 ± 3.55 vs 28.59 ± 3.21 minutes; p = 0.030) despite similar heart rates (160 ± 5 vs 160 ± 4 beats/min; p = 0.941) and ratings of perceived exertion (14.6 ± 0.5 vs 15.0 ± 0.5; p = 0.356). No differences between the diet conditions were observed for anaerobic exercise tests, including peak and mean power from the Wingate test (both p ≥ 0.05), the vertical jump test (p = 0.19), and the hand grip strength test (p = 0.69). Conclusions: Our findings extend existing evidence of the health benefits of the Mediterranean diet by showing that this diet is also effective for improving endurance exercise performance in as little as 4 days. Further studies are warranted to determine whether a longer-term Mediterranean diet provides greater benefits and whether it might also be beneficial for anaerobic exercise performance and muscle strength and power.

The historical context and scientific legacy of John O. Holloszy.

John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.

Low-carbohydrate, ketogenic diet impairs anaerobic exercise performance in exercise-trained women and men: a randomized-sequence crossover trial.

BACKGROUND: Low-carbohydrate, ketogenic diets cause mild, subclinical systemic acidosis. Anaerobic exercise performance is limited by acidosis. Therefore, we evaluated the hypothesis that a low-carbohydrate, ketogenic diet impairs anaerobic exercise performance, as compared to a high-carbohydrate diet. METHODS: Sixteen men and women (BMI, 23±1 kg/m2, age 23±1 years) participated in a randomized-sequence, counterbalanced crossover study in which they underwent exercise testing after 4 days of either a low-carbohydrate, ketogenic diet (LC; <50 g/day and <10% of energy from carbohydrates) or a high-carbohydrate diet (HC; 6-10 g/kg/day carbohydrate). Dietary compliance was assessed with nutrient analysis of diet records, and with measures of urine pH and ketones. Anaerobic exercise performance was evaluated with the Wingate anaerobic cycling test and the yo-yo intermittent recovery test. RESULTS: The diets were matched for total energy (LC: 2333±158 kcal/d; HC: 2280±160 kcal/d; P=0.65) but differed in carbohydrate content (9±1% vs. 63±2% of energy intake; P<0.001). LC resulted in lower urine pH (5.9±0.1 vs. 6.3±0.2, P=0.004) and the appearance of urine ketones in every participant. LC resulted in 7% lower peak power (801±58 watts vs. 857±61 watts, P=0.008) and 6% lower mean power (564±50 watts vs. 598±51 watts, P=0.01) during the Wingate Test. Total distance ran in the yo-yo intermittent recovery test was 15% less after LC diet (887±139 vs. 1045±145 meters, P=0.02). CONCLUSIONS: Short-term low-carbohydrate, ketogenic diets reduce exercise performance in activities that are heavily dependent on anaerobic energy systems. These findings have clear performance implications for athletes, especially for high-intensity, short duration activities and sports.

Sex-specific effects of dehydroepiandrosterone (DHEA) on bone mineral density and body composition: A pooled analysis of four clinical trials.

OBJECTIVE: Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat-free mass in older women and men enrolled in four similar clinical trials. DESIGN: Pooled analyses of data from four double-blinded, randomized controlled trials. PARTICIPANTS: Women (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. MEASUREMENTS: Twelve-month changes in BMD, fat mass, fat-free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin-like growth factor-1 (IGF-1). RESULTS: Women on DHEA had increases (mean ± SD; all P < 0.001 vs placebo) in DHEAS (231 ± 164 µg/dL), testosterone (18.6 ± 20.9 µg/dL), (17)estradiol (8.7 ± 11.0 pg/mL) and IGF-1 (25.1 ± 52.3 ng/mL), and men had increases in DHEAS (269.0 ± 177 µg/dL; P < 0.01), (17)estradiol (4.8 ± 12.2 pg/m; P < 0.01) and IGF-1 (6.3 ± 41.4 ng/mL; P < 0.05). Women on DHEA had increases in lumbar spine (1.0% ± 3.4%) and trochanter (0.5% ± 3.8%) BMD and maintained total hip BMD (0.0% ± 2.8%); men had no BMD benefit and a decrease in fat mass (-0.4 ± 2.6 kg; all P < 0.01 vs placebo). CONCLUSIONS: Dehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit-to-risk profile for women than oestrogen therapy.

Adropin: An endocrine link between the biological clock and cholesterol homeostasis.

OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. RESULTS: In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-ß-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. CONCLUSIONS: In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.