The effects of the Covid-19 pandemic on ecotourism, a study from West of Iran.

Most tourism researchers agree on the effects of the COVID-19 on ecotourism. The present study aims to assess the effects of the COVID-19 pandemic on the ecotourism status in Lorestan province in Iran. To this aim, 29 effects were identified using Delphi technique. According to results, the effects were divided into six categories including the decreased number of incoming tourists, the reduced activity of hotels and resorts, the declined income of goods and service suppliers for tourists, the decreased activity of travel agencies and tourist tours, as well as positive and negative environmental effects. Generally, the results provide new knowledge in the field of ecotourism crisis management. In addition, the identified effects provide the basis for further research on the method of reducing the negative effects.

AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome.

Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies.

Interventions with Music in PECTus excavatum treatment (IMPECT trial): a study protocol for a randomised controlled trial investigating the clinical effects of perioperative music interventions.

INTRODUCTION: Pectus excavatum repair is associated with substantial postoperative pain, despite the use of epidural analgesia and other analgesic regimens. Perioperative recorded music interventions have been shown to alleviate pain and anxiety in adults, but evidence for children and adolescents is still lacking. This study protocol describes a randomised controlled trial that evaluates the effects of recorded music interventions on postoperative pain relief in children and adolescents after pectus excavatum repair. METHODS: A multicentre randomised controlled trial was set up comparing the effects of perioperative recorded music interventions in addition to standard care with those of standard care only in patients undergoing a Nuss procedure for pectus excavatum repair. One hundred and seventy subjects (12-18 years of age) will be included in three centres in the Netherlands. Patient inclusion has started in November 2018, and is ongoing. The primary outcome is self-reported perceived pain measured on the visual analogue scale. Secondary outcomes are anxiety level, analgesics consumption, vital parameters such as heart rate, blood pressure and respiratory rate, length of hospital stay, postoperative complications, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NL6863.

The Influence of Pain on the Outcome of Extracorporeal Shockwave Lithotripsy.

INTRODUCTION: The aim of this study was to determine the predictive value of pain scores on the efficacy of extracor-poreal shockwave lithotripsy (ESWL) and to identify other predictive risk factors for treatment success. MATERIALS AND METHODS: A total of 476 patients who underwent ESWL (piezoelectric lithotripsy) for urolithiasis between September 2011 and December 2015 were identified. The primary end-point of this study was success rate, which was evaluated 4 months after ESWL. The secondary outcome was the occurrence of complications as a result of ESWL. RESULTS: The average pain perception was reported at 5 on a scale from 0 to 10. The overall success rate of ESWL was found to be 43.9% and the success rate after the first ESWL was 35.1%. Univari-ate analysis showed no significant correlation between pain score and success of ESWL (p = 0.135). The level of intensity was correlated with pain scores (Pearson correlation -0.423, p < 0.001). Univariate analysis identified five predictive factors: sex, stone location, stone size, hydronephrosis and the use of tamsulosin. Multivariate logistic regression analysis showed that sex, stone location and size independently in-fluenced the success of ESWL (p = 0.045, p = 0.001 and p < 0.001). CONCLUSION: No correlation was found between the pain scores and efficacy of ESWL. Despite this absence, pain scores during ESWL sessions remain high and additional analgesia would improve patient satisfaction.

Associations between the HEXACO model of personality and gambling involvement, motivations to gamble, and gambling severity in young adult gamblers.

Background and aims Substantial research has examined the role of personality in disordered gambling. The predominant model in this work has been the five-factor model (FFM) of personality. In this study, we examined the personality correlates of gambling engagement and gambling severity using a six-dimensional framework known as the HEXACO model of personality, which incorporates FFM characteristics with the addition of honesty-humility. In addition, the potential mediating role of gambling motives in the personality and gambling severity relationship was explored. Methods A sample of undergraduate gamblers (n = 183) and non-gamblers (n = 143) completed self-report measures of the Problem Gambling Severity Index (PGSI) and the Gambling Motives Questionnaire-Financial, as well as self- and observer report forms of the HEXACO-100. Results Logistic regression results revealed that scores on honesty-humility were positively associated with non-gambling over gambling status. Furthermore, it was also found that honesty-humility, agreeableness, and conscientiousness were each uniquely associated with PGSI severity scores. The results of the mediational analyses suggest that each personality factor has different gambling motivational paths leading to PGSI gambling severity. Discussion and conclusions The findings of this study contribute to the literature on behavioral addictions by providing an increased understanding of individual personality factors associated with likelihood of gambling, overall gambling severity, and gambling motives. Ultimately, these findings suggest that the honesty-humility dimension may be a target for the prevention efforts against problematic gambling outcomes.

Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects.

Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence and fatigue were frequently reported. Other adverse events included headache and nausea. Muscular weakness was reported at a higher incidence only with the highest almorexant dose. The pharmacokinetic profile of almorexant was characterized by a median time to the maximum concentration of 1.5 hours, quick disposition with a distribution half-life of 1.6 hours, and rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours. Objective pharmacodynamic measures showed decreases in saccadic peak velocity and adaptive tracking performance and increases in body sway with the 400-mg dose of almorexant. Subjective assessments revealed a dose-dependent decrease in alertness. Almorexant had no effects on mood, calmness, subjective internal and external perception, and feeling high. These findings provide a solid basis to study the effects of almorexant in elderly patients with insomnia.

Increased impact of a contraceptive vaginal ring with ethinyl estradiol and nestorone on C-reactive protein.

UNLABELLED: OBJECTIVE & STUDY DESIGN: In a parallel design, 23 and 22 healthy pre-menopausal women were randomly administered a contraceptive vaginal ring (CVR) delivering 150/15 µg Nestorone®/ethinyl estradiol (EE) daily or an oral contraceptive (OC) containing levonorgestrel and EE (150/30 µg) for three cycles, to compare the effects on C-reactive protein and other markers of inflammation. ANCOVA was performed with baseline values as covariate. RESULTS: The CVR caused [estimate of difference (95% CI), 109% (16-275%)] higher levels of CRP than the OC, while no difference was observed for leukocyte 1% (-13/+17%) and monocyte counts 6% (-9/+23%). The greater increase in CRP was confined to CVR recipients exhibiting low pre-treatment CRP-levels, whereas no difference was observed in the increases for recipients in the highest tertile of pre-treatment CRP levels. CONCLUSION: The difference in CRP rise in CVR and OC users does not correspond with the effects on other markers of inflammation and is most likely due to a specific difference in the effect of ethinyl-estradiol combined with nestorone in cases with low CRP.

Discriminant analysis of the metabolic effects of a new combined contraceptive vaginal ring containing Nestorone/EE vs. a second-generation oral contraceptive containing levonorgestrel/EE.

BACKGROUND: Discriminant analysis (DA) was performed on data of two combined hormonal contraceptives (CHC) differing in estrogen ratio to explore whether a combination of variables rather than a single variable distinguishes CHCs better. STUDY DESIGN: Data were used of a parallel study in premenopausal women treated for three cycles (21 days on, 7 days off) with a contraceptive vaginal ring delivering Nestorone and ethinyl estradiol (EE) or an oral contraceptive containing levonorgestrel and EE. DA was performed on the change from baseline (CFB) and the end-of-treatment values at 3 months for lipids, sex-hormone binding globulin (SHBG), C-reactive protein, angiotensinogen, blood pressure and hemostasis variables, and on the hemostasis variables only. RESULTS: For the complete set, the CFB for factor VII (FVII), SHBG and plasminogen (PLG), or end-of-treatment SHBG- and FVII level discriminated the treatments best. Maximal discrimination for the hemostasis data was by CFB for FVII and PLG or end-of-treatment FVII level. CONCLUSIONS: DA identifies differences between CHCs and may provide information on the factors associated with thrombotic risk.

Metabolic profile of a continuous versus a cyclic low-dose combined oral contraceptive after one year of use.

OBJECTIVES: To compare the effects of a combined oral contraceptive (COC) taken continuously with those of one of similar composition taken cyclically on 30 variables related to haemostasis, lipids, carbohydrates, bone metabolism, and sex hormone-binding globulin (SHBG). METHODS: Randomised, open-label, multicentre, comparative substudy of a larger phase 3 trial involving 147 healthy women (age 18-49 years). Participants received the COC either continuously (levonorgestrel [LNG] 90 µg/ethinylestradiol [EE] 20 µg) or cyclically (21/7 days pattern; LNG 100 µg/EE 20 µg). RESULTS: After 13 pill packs, changes in total cholesterol (+0.23 vs. -0.06 mmol/l), low-density lipoprotein cholesterol (+0.25 vs. -0.12 mmol/l), and high-density lipoprotein cholesterol(3) (-0.06 vs. -0.15 mmol/l) differed significantly (p<0.05) between the continuous and cyclic regimens, respectively. Increases were significantly greater (p <0.05) for protein C antigen (+11.8% vs. +6.1%) and SHBG (+791 vs. +565 nmol/l), and significantly smaller (p <0.05, ranks) for D-dimer (+19 vs. +37 µg FE/l). CONCLUSIONS: Overall, the continuous and cyclic regimens affected metabolic variables similarly. The larger increase in SHBG with the continuous COC is consistent with a higher net oestrogenic effect due to a lower daily dose of LNG. Prospective studies are required to determine the long-term effects of this continuous COC regimen.

Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Several lines of evidence suggest a possible role of 5-HT(6) receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB-742457 is a potent 5-HT(6) antagonist and has shown efficacy in different animal models of cognitive impairment. It is currently in development as a cognitive enhancer. Risperidone, commonly used to control agitation and psychotic features in both schizophrenia and Alzheimer's disease, is a D(2)/5-HT(2A ) antagonist with low affinity for 5-HT(6) receptors and limited effects on cognitive parameters. WHAT THIS STUDY ADDS: • As the combination of risperidone and SB-742457 may constitute a reasonable combination in cognitively impaired patients, pharmacodynamic interaction effects were investigated in this study. The only significant drug-drug interaction was a small increase of electroencephalogram (EEG) alpha and beta bands, which might suggest mild arousing activity of SB-742457 on the central nervous system-depressant effects of risperidone. The clinical relevance of these findings in patients remains to be established. Additionally, this study provided an extensive multidimensional pharmacodynamic profile of risperidone in healthy volunteers, showing that this antipsychotic suppresses motor performance (eye-hand coordination, finger tapping and postural stability), alertness, memory and neurophysiological functions (saccadic eye movements and EEG power spectrum). AIM: Several lines of evidence suggest a possible role of 5-HT(6 ) receptor antagonists in cognitive dysfunction of schizophrenia. Atypical antipsychotics, such as risperidone, are currently used in these disorders. Therefore, the pharmacological interactions between the 5-HT(6) antagonist SB-742457 and risperidone were investigated in the light of possible co-medication. METHODS: A randomized, double-blind, two-way crossover design was used to study the interaction between multiple doses SB-742457 50 mg and a single dose risperidone 2 mg in 18 healthy subjects. RESULTS: Treatment was well tolerated. The most common adverse event was somnolence in 83% during the combination vs. 50% of subjects after risperidone, 32% after placebo and 11% after SB-742457. Combination treatment produced a statistically significant increase in the maximum plasma concentration of risperidone and had no effect on SB-742457 pharmacokinetics. Risperidone decreased saccadic peak velocity, finger tapping, adaptive tracking, subjective alertness, delayed word recognition and body sway and increased electroencephalogram (EEG) theta power and prolactin. The only pharmacodynamic interaction of risperidone and SB-742457 was an increase of absolute EEG alpha (ratio = 1.25, 95% CI = 1.11, 1.40, P= 0.0004) and beta power (ratio = 1.14, 95% CI = 1.03, 1.27, P= 0.016). No significant effects of SB-742457 alone were found. CONCLUSION: The pharmacokinetic interactions between SB-742457 and risperidone detected in this study were not clinically relevant. The increase in EEG alpha and beta power is incompatible with enhanced risperidone activity, but could point to mild arousing effects of the combination. Most pharmacodynamic changes of risperidone are consistent with previously reported data. The potential cognitive effects of SB-742457 remain to be established.

Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review.

OBJECTIVE: To review the effects of non-oral administration of postmenopausal hormone therapy (HT) on risk markers for atherosclerotic and venous thromboembolic disease.Non-oral postmenopausal HT appears not to increase venous thromboembolic risk, whereas the effect on coronary heart disease risk is less clear. DESIGN: Systematic review of literature obtained from MEDLINE, EMBASE, and CENTRAL databases from 1980 until and including April 2006. Terms for "postmenopausal hormone therapy" and for "non-oral administration" were combined in the search. SETTING: Randomized clinical trials. PATIENT(S): Postmenopausal women, both healthy and with established cardiovascular disease or specified cardiovascular risk factors INTERVENTION(S): Non-oral HT (e.g., transdermal or intranasal) compared with oral HT or no treatment/placebo. MAIN OUTCOME MEASURE(S): Lipoprotein(a), homocysteine, C-reactive protein (CRP), cell adhesion molecules, markers of endothelial dysfunction, coagulation, and fibrinolysis. RESULT(S): Seventy-two studies investigating either transdermal or intranasal administration were included. For non-oral HT, decreases in lipoprotein(a), cell adhesion molecules, and factor VII generally were significant, resistance to activated protein C (APCr) was slightly increased, and other markers including CRP and homocysteine did not change. Compared with oral HT, changes in CRP and APCr were smaller, changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller, whereas changes in other factors including lipoprotein(a) and homocysteine did not differ. CONCLUSION(S): Potentially unfavorable changes seen with oral HT on two important markers, CRP and APCr, are substantially smaller with non-oral HT. Non-oral HT has minor effects on the other cardiovascular risk markers studied. Therefore, compared with oral HT, non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk.

Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen.

OBJECTIVE: We evaluated the effects of a new combined hormonal contraceptive vaginal ring (CVR) delivering the nonandrogenic progestin Nestorone (NES) and ethinyl estradiol (EE) on several key estrogen-sensitive hepatic proteins that may be markers for the risk of arterial or venous disease events and on blood pressure (BP). Because the pharmacologic androgenicity of the progestin in these formulations influences the hepatic impact of EE, we selected an oral contraceptive (OC) delivering the androgenic progestin levonorgestrel (LNG) and EE as the comparator. We also investigated the effect of delivery route, which is known to modify the hepatic effects of estradiol, but has not been widely studied with EE. STUDY METHODS: Women, aged 18-34 years, with no contraindications to the use of combined OCs, were randomized to three cycles of treatment with a CVR delivering NES/EE (150/15 microg/day) or a combined OC providing LNG and EE (150/30 microg per tablet). Each cycle consisted of 21 days of active treatment, followed by 7 days without treatment. During the last weeks of the pretreatment and third treatment cycles, blood samples were obtained for determinations of plasma concentrations of angiotensinogen, an estrogen-sensitive hepatic protein, and serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and estrogen- and androgen-sensitive proteins. BP was also measured. RESULTS: Of 47 women randomized, 45 completed the study (CVR: 23; OC: 22). Within-group comparisons over time by repeated-measure analysis of variance demonstrated statistically significant changes over time with both treatments for all hepatic proteins (p < .02) but not for TC. The within-group effects, presented as relative percent difference [95% confidence interval (CI)], were greatest for angiotensinogen [CVR: 227% (195-262%); OC: 251.3% (218-288%)] and SHBG [CVR: 306% (237-389%); OC: 55% (30-86)]. Both treatments were associated with small changes in systolic BP and diastolic BP (DBP), but only the within-group change in DBP for the OC group was statistically significant (p = .04). Between-treatment comparisons of third treatment cycle mean values were performed by analysis of covariance (baseline values as covariate). No statistically significant between-treatment differences were found for angiotensinogen, sensitive only to estrogen, or BP. Statistically significant treatment differences were found for all estrogen- and androgen-sensitive proteins (p < or = .002) but not for TC. When presented as relative percent difference between the effects of treatment (CVR-OC/OC; 95% CI of percent difference), the difference was largest for SHBG (159% [117-210%]); smaller relative percent differences were found for HDL-C [31.9% (18.5-46.8%)], LDL-C [23.6% (33.4% to -2.4%)] and TG [39.0% (14.0-69.4%)], but not TC. CONCLUSION: Vaginal delivery of a combined hormonal contraceptive did not reduce the EE-associated changes in estrogen-sensitive hepatic proteins observed after use of a combined OC. Significant treatment differences between the NES/EE CVR and the LNG/EE OC were found for SHBG, HDL-C, LDL-C, and TG, proteins sensitive to androgen as well as estrogen. No treatment difference was observed for angiotensinogen, which is sensitive only to estrogen. The observed treatment differences were therefore most likely due to the difference in androgenicity between NES and LNG.

Comparative effects of a contraceptive vaginal ring delivering a nonandrogenic progestin and continuous ethinyl estradiol and a combined oral contraceptive containing levonorgestrel on hemostasis variables.

OBJECTIVE: This study aimed to compare the effects on hemostasis variables of a contraceptive vaginal ring with those of an oral contraceptive. STUDY DESIGN: Twenty-three and 22 healthy premenopausal women were randomized to the contraceptive vaginal ring (150 microg Nestorone and 15 microg ethinyl estradiol) or Stediril 30 during 3 cycles. Analysis of covariance was performed with baseline values as covariate. RESULTS: The contraceptive vaginal ring changed most hemostasis variables similarly but raised (95% confidence intervals of percent treatment differences) Factor VIIt (28% to 49%), extrinsic activated protein C resistance (14% to 65%), and sex hormone-binding globulin (117% to 210%) and lowered Protein S (-32% to -16%) and the global activated partial thromboplastin time-based activated protein C resistance (-12% to -2%) more than the oral contraceptive. CONCLUSION: The contraceptive vaginal ring affected some measured hemostasis variables and sex hormone-binding globulin differently from the oral contraceptive, most likely because of difference in androgenicity of the progestins. The results suggest that the contraindications for oral contraceptive use would also apply to the tested contraceptive vaginal ring.