Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial.

Background: Treatment resistance is a significant problem among young people experiencing moderate-to-severe anxiety, affecting nearly half of all patients. This study investigated the safety and efficacy of cannabidiol (CBD), a non-intoxicating component of Cannabis sativa, for anxiety disorders in young people who previously failed to respond to standard treatment.Methods: In this open-label trial, 31 young people aged 12-25 years with a DSM-5 anxiety disorder and no clinical improvement despite treatment with cognitive-behavioral therapy and/or antidepressant medication were enrolled between May 16, 2018, and June 28, 2019. All participants received add-on CBD for 12 weeks on a fixed-flexible schedule titrated up to 800 mg/d. The primary outcome was improvement in anxiety severity, measured with the Overall Anxiety Severity and Impairment Scale (OASIS), at week 12. Secondary outcomes included comorbid depressive symptoms, Clinical Global Impressions scale (CGI) score, and social and occupational functioning.Results: Mean (SD) OASIS scores decreased from 10.8 (3.8) at baseline to 6.3 (4.5) at week 12, corresponding to a -42.6% reduction (P < .0001). Depressive symptoms (P < .0001), CGI-Severity scale scores (P = .0008), and functioning (P = .04) improved significantly. Adverse events were reported in 25 (80.6%) of 31 participants and included fatigue, low mood, and hot flushes or cold chills. There were no serious and/or unexpected adverse events.Conclusions: These findings suggest that CBD can reduce anxiety severity and has an adequate safety profile in young people with treatment-resistant anxiety disorders. Randomized controlled trials are needed to confirm the efficacy and longer-term safety of this compound.Trial Registration: New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12617000825358.

Kidney Complications and Hospitalization in Patients With Chronic Hypoparathyroidism: A Cohort Study in Sweden.

CONTEXT: Kidney complications may be considerably higher in patients with chronic hypoparathyroidism (hypoPT) treated with activated vitamin D and calcium supplementation. OBJECTIVE: We aimed to investigate the risk of chronic kidney disease (CKD), urolithiasis, and hospitalization in patients with chronic hypoPT. METHODS: In this population-based cohort study in Sweden, national registries (Swedish National Patient Register, Swedish Prescribed Drug Register, and Total Population Register, 1997-2018) were used to identify patients with chronic hypoPT and controls matched by sex, age, and county of residence. We determined time to CKD and urolithiasis diagnosis, and incidence rates of hospitalization. RESULTS: A total of 1562 patients with chronic hypoPT without preexisting CKD and 15 620 controls were included. The risk of developing CKD was higher in patients with chronic hypoPT compared with controls (hazard ratio [HR] 4.45; 95% CI, 3.66-5.41). In people without prior urolithiasis (n = 1810 chronic hypoPT and n = 18 100 controls), the risk of developing urolithiasis was higher in patients with chronic hypoPT (HR 3.55; 95% CI, 2.84-4.44) compared with controls. Patients with chronic hypoPT had higher incidence rates for all-cause hospitalization (49.59; 95% CI, 48.50-50.70, per 100 person-years vs 28.43; 95% CI, 28.15-28.71, respectively) and for CKD (3.46; 95% CI, 3.18-3.76, per 100 person-years vs 0.72; 95% CI, 0.68-0.77, respectively), compared with controls. Men with hypoPT appear to have a higher risk of CKD than women. CONCLUSION: Patients with chronic hypoPT had an increased risk of CKD, urolithiasis, and hospitalization compared with controls.

Treatment of tungiasis using a tea tree oil-based gel formulation: protocol for a randomised controlled proof-of-principle trial.

INTRODUCTION: Tungiasis (sand flea disease or jigger infestation) is a neglected tropical disease caused by penetration of female sand fleas, Tunga penetrans, in the skin. The disease inflicts immense pain and suffering on millions of people, particularly children, in Latin America, the Caribbean and sub-Saharan Africa. Currently, there is no standard treatment for tungiasis, and a simple, safe and effective tungiasis treatment option is required. Tea tree oil (TTO) has long been used as a parasiticidal agent against ectoparasites such as headlice, mites and fleas with proven safety and efficacy data. However, current data are insufficient to warrant a recommendation for its use in tungiasis. This trial aims to generate these data by comparing the safety and efficacy of a 5% (v/w) TTO proprietary gel formulation with 0.05% (w/v) potassium permanganate (KMnO4) solution for tungiasis treatment. METHODS AND ANALYSIS: This trial is a randomised controlled trial (RCT) in primary schools (n=8) in South-Western Kenya. The study will include school children (n=88) aged 6-15 years with a confirmed diagnosis of tungiasis. The participants will be randomised in a 1:1 ratio to receive a 3-day two times a day treatment of either 5% TTO gel or 0.05% KMnO4 solution. Two viable embedded sandflea lesions per participant will be targeted and the viability of these lesions will be followed throughout the study using a digital handheld microscope. The primary outcome is the proportion of observed viable embedded sand fleas that have lost viability (non-viable lesions) by day 10 (9 days after first treatment). Secondary outcomes include improvement in acute tungiasis morbidities assessed using a validated severity score for tungiasis, safety assessed through adverse events and product acceptability assessed by interviewing the participants to rate the treatment in terms of effectiveness, side effects, convenience, suitability and overall satisfaction. ETHICS AND DISSEMINATION: The trial protocol has been reviewed and approved by the University of Canberra Human Research Ethics Committee (HREC-2019-2114). The findings of the study will be presented at scientific conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12619001610123); PACTR202003651095100 and U1111-1243-2294.

Estimates of the global reduction in liver disease-related mortality with increased coffee consumption: an analysis of the Global Burden of Disease Dataset.

BACKGROUND: Epidemiological data suggest that coffee has a dose-dependent protective effect on liver-related mortality. AIM: To estimate the potential impact of increased per capita coffee consumption on global liver-related mortality. METHODS: Using the Global Burden of Disease 2016 dataset (adults > 15 years), we modelled the impact of increased per capita coffee consumption on liver-related mortality in 2016 for 194 countries using published risk ratios for >2 cups coffee/ day (RR 0.54, 95% CI 0.42-0.69) and ≥4 cups/ day (RR 0.29, 95% CI 0.17-0.50), adjusted for confounders and tested model assumptions using sensitivity analyses. RESULTS: Worldwide, there were an estimated 1,240,201 (95% CI 118 4300-1 354 410) adult liver-related deaths in 2016. Median global liver mortality rate in 2016 was 15 deaths/ 100 000 population/ year (all ages, both genders; IQR 11-21 deaths per 100 000). If all countries with per capita coffee intake ≤2 cups/ day increased to >2 cups/ day, the predicted total number of liver-related deaths would have been 630 947 in 2016 (95% CI 629 693-631 861) with 452 861 (95% CI 451 948-454 116) deaths averted (PPR 7.8 liver-related deaths/ 100 000/ year). If per capita consumption was ≥ 4 cups/ day, the predicted number of liver-related deaths in 2016 would have been 360 523 (95% CI 359 825-361 992) with 723 287 (95% CI 721 817-723 984) deaths averted (PPR 12.1 liver-related deaths/100 000/year). CONCLUSION: Increasing per capita coffee consumption to > 2 cups per day on a population level has the potential to avert hundreds of thousands of liver-related deaths annually if the impact of coffee on liver-related mortality is confirmed in clinical trials.

Gaps in the HIV diagnosis and care cascade for migrants in Australia, 2013-2017: A cross-sectional study.

BACKGROUND: Globally, few studies compare progress toward the Joint United Nations Program on HIV/AIDS (UNAIDS) Fast-Track targets among migrant populations. Fast-Track targets are aligned to the HIV diagnosis and care cascade and entail achieving 90-90-90 (90% of people living with HIV [PLHIV] diagnosed, 90% of those diagnosed on treatment, and 90% of those on treatment with viral suppression [VS]) by 2020 and 95-95-95 by 2030. We compared cascades between migrant and nonmigrant populations in Australia. METHODS AND FINDINGS: We conducted a serial cross-sectional survey for HIV diagnosis and care cascades using modelling estimates for proportions diagnosed combined with a clinical database for proportions on treatment and VS between 2013-2017. We estimated the number of PLHIV and number diagnosed using New South Wales (NSW) and Victorian (VIC) data from the Australian National HIV Registry. Cascades were stratified by migration status, sex, HIV exposure, and eligibility for subsidised healthcare in Australia (reciprocal healthcare agreement [RHCA]). We found that in 2017, 17,760 PLHIV were estimated in NSW and VIC, and 90% of them were males. In total, 90% of estimated PLHIV were diagnosed. Of the 9,391 who were diagnosed and retained in care, most (85%; n = 8,015) were males. We excluded 38% of PLHIV with missing data for country of birth, and 41% (n = 2,408) of eligible retained PLHIV were migrants. Most migrants were from Southeast Asia (SEA; 28%), northern Europe (12%), and eastern Asia (11%). Most of the migrants and nonmigrants were males (72% and 83%, respectively). We found that among those retained in care, 90% were on antiretroviral therapy (ART), and 95% of those on ART had VS (i.e., 90-90-95). Migrants had larger gaps in their HIV diagnosis and care cascade (85-85-93) compared with nonmigrants (94-90-96). Similarly, there were larger gaps among migrants reporting male-to-male HIV exposure (84-83-93) compared with nonmigrants reporting male-to-male HIV exposure (96-92-96). Large gaps were also found among migrants from SEA (72-87-93) and sub-Saharan Africa (SSA; 89-93-91). Migrants from countries ineligible for RHCA had lower cascade estimates (83-85-92) than RHCA-eligible migrants (96-86-95). Trends in the HIV diagnosis and care cascades improved over time (2013 and 2017). However, there was no significant increase in ART coverage among migrant females (incidence rate ratio [IRR]: 1.03; 95% CI 0.99-1.08; p = 0.154), nonmigrant females (IRR: 1.01; 95% CI 0.95-1.07; p = 0.71), and migrants from SEA (IRR: 1.03; 95% CI 0.99-1.07; p = 0.06) and SSA (IRR: 1.03; 95% CI 0.99-1.08; p = 0.11). Additionally, there was no significant increase in VS among migrants reporting male-to-male HIV exposure (IRR: 1.02; 95% CI 0.99-1.04; p = 0.08). The major limitation of our study was a high proportion of individuals missing data for country of birth, thereby limiting migrant status categorisation. Additionally, we used a cross-sectional instead of a longitudinal study design to develop the cascades and used the number retained as opposed to using all individuals diagnosed to calculate the proportions on ART. CONCLUSIONS: HIV diagnosis and care cascades improved overall between 2013 and 2017 in NSW and VIC. Cascades for migrants had larger gaps compared with nonmigrants, particularly among key migrant populations. Tracking subpopulation cascades enables gaps to be identified and addressed early to facilitate achievement of Fast-Track targets.

The effect of mindfulness training prior to total joint arthroplasty on post-operative pain and physical function: A randomised controlled trial.

OBJECTIVE: To evaluate the efficacy of Mindfulness-Based Stress Reduction (MBSR) in improving pain and physical function following total joint arthroplasty (TJA). DESIGN: Two-group, parallel-group, randomised controlled trial, conducted between September 2012 and May 2017. SETTING: Single centre study conducted at a University-affiliated, tertiary hospital. INTERVENTION: People with arthritis scheduled for TJA, with a well-being score <40 (Short Form-12 Survey) were randomly allocated to a pre-surgery eight-week MBSR program or treatment as usual (TAU). OUTCOME MEASURES: Self-reported joint pain and function at 12 months post-surgery, assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes were knee stiffness and global improvement (WOMAC); physical and psychological well-being (Veterans RAND 12-item Health Survey); self-efficacy (Arthritis Self-Efficacy Scale); and mindfulness (5-Factor Mindfulness Questionnaire). RESULTS: 127 participants were randomised; 65 to MBSR and 62 to TAU, of which 45 participants allocated to the intervention and 56 participants allocated to usual care proceeded to surgery and 100 (99%) completed primary outcome measures. Greater improvements in knee pain (mean difference, -10.3 points, 95% CI -19.0 to -1.6; P = 0.021) and function (mean difference, -10.2 points, 95% CI -19.2 to -1.3; P = 0.025) at 12 months post-surgery were observed in the MBSR group compared to the TAU group. A between group difference in global scores (-9.5 points, 95% CI -17.9 to -1.1; P = 0.027) was also observed. No other differences in secondary outcomes were observed. CONCLUSION: MBSR improves post-surgery pain and function in people with psychological distress undergoing TJA. Further research is required to examine potential barriers to broader implementation and uptake.

Treatment of scabies using a tea tree oil-based gel formulation in Australian Aboriginal children: protocol for a randomised controlled trial.

INTRODUCTION: In remote Aboriginal communities in Australia, scabies affects 7 out of 10 children before their first birthday. This is more than six times the rate seen in the rest of the developed world. Scabies infestation is frequently complicated by bacterial infection, leading to the development of skin sores and other more serious consequences, such as septicaemia and chronic heart and kidney diseases. Tea tree oil (TTO) has been used as an antimicrobial agent for several decades with proven clinical efficacy. Preclinical investigations have demonstrated superior scabicidal properties of TTO compared with widely used scabicidal agents, such as permethrin 5% cream and ivermectin. However, current data are insufficient to warrant a broad recommendation for its use for the management of scabies because previous studies were small or limited to in vitro observations. METHODS AND ANALYSIS: A pragmatic first trial will examine the clinical efficacy of a simple and low-cost TTO treatment against paediatric scabies and the prevention of associated secondary bacterial infections, with 1:1 randomisation of 200 participants (Aboriginal children, aged 5-16 years and living in remote Australia) into active control (permethrin 5% cream) and treatment (5% TTO gel) groups. The primary outcome for the study is clinical cure (complete resolution). Secondary outcome measures will include relief of symptoms, recurrence rate, adverse effects, adherence to treatment regimen and patient acceptability. ETHICS AND DISSEMINATION: The project has received approvals from the University of Canberra Human Research Ethics Committee (HREC 16-133), Wurli-Wurlinjang Health Service Indigenous subcommittee and the Aboriginal Medical Services Alliance Northern Territory reference group. The results of this study will be published in core scientific publications, with extensive knowledge exchange activities with non-academic audiences throughout the duration of the project. TRIAL REGISTRATION: ACTRN12617000902392; Pre-results.

Therapeutic Potential of Tea Tree Oil for Scabies.

Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted.

Comparison of oncological and health-related quality of life outcomes between open and robot-assisted radical prostatectomy for localised prostate cancer - findings from the population-based Victorian Prostate Cancer Registry.

OBJECTIVE: To compare the short-term oncological and health-related quality of life (HRQOL) outcomes between open (ORP) and robot-assisted (RARP) radical prostatectomy in the population-based Victorian Prostate Cancer Registry. PATIENTS AND METHODS: This is a prospective cohort of patients with prostate cancer who had RP (1117 ORP and 885 RARP) between January 2009 and June 2012. The oncological outcomes of interest were: positive surgical margin (PSM) and biochemical recurrence (BCR), defined as postoperative PSA level of >0.2 ng/mL. The HRQOL outcomes were: sexual and urinary bother, assessed using the Expanded Prostate Cancer Index Composite at 1- and 2-years after diagnosis. For univariate comparison of continuous variables the Student's t-test or Mann-Whitney U-test were used, and the Pearson's chi-squared test was used for categorical variables. Bonferroni correction was applied to account for multiple testing, with a threshold for significance of P < 0.003 for univariate analyses. The inverse-probability-treatment-weighting (IPTW) approach was used to adjust for differences in baseline characteristics between ORP and RARP patients [including age, National Comprehensive Cancer Network (NCCN) risk categories, hospitals, and year of RP] in all multivariate analyses. Logistic regressions were used to analyse for PSM, Cox regressions for BCR, and ordinal logistic regressions for HRQOL outcomes. All multivariate analyses also adjusted for surgeons' average annual caseload, and employed the robust standard errors for clustering by surgeon. RESULTS: ORP and RARP patients were followed for a median of 19 and 17 months, respectively. The proportion of patients with NCCN low-risk prostate cancer was significantly higher among RARP patients (21% vs 26%; P = 0.002). Most RPs was done in private hospitals (77% ORP, and 85% RARP, P < 0.001). A higher proportion of RARP patients were operated by surgeons with higher annual caseloads (65% RARP and 53% ORP operated by surgeons with >20 case/year; P < 0.001). In the IPTW-adjusted multivariate analyses, RARP patients had a lower risk of PSM (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.38-0.81), and BCR (hazard ratio [HR] 0.73, 95% CI 0.55-0.99). In the sensitivity analyses (excluding public hospital patients), the lower PSM risk with RARP remained (OR 0.63, 95% CI 0.38-0.81), but the lower BCR risk with RARP was no longer statistically significant (HR 0.79, 95% CI 0.57-1.12). At 1-year follow-up, 61% of ORP and 59% of RARP patients reported 'moderate-big' sexual bother (P = 0.2), while 14% of ORP and 11% of RARP patients reported 'moderate-big' urinary bother (P = 0.08). The sexual and urinary bothers at 2 years were similar between ORP and RARP. In multivariate analyses, there were no statistically significant differences in the HRQOL outcomes between ORP and RARP. CONCLUSIONS: We report on a large population-based comparative study of ORP and RARP with better short-term oncological outcomes favouring RARP, but no significant differences in HRQOL outcomes. The results have to be interpreted taking into account significant surgeon heterogeneity in a population-based study.

Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.

BACKGROUND: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART). METHODS: Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients. RESULTS: Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART. CONCLUSION: Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.

Similar mortality and reduced loss to follow-up in integrated compared with vertical programs providing antiretroviral treatment in sub-saharan Africa.

BACKGROUND: Vertical HIV programs have achieved good results but may not be feasible or appropriate in many resource-limited settings. Médecins sans Frontières has treated HIV in vertical programs since 2000 and over time integrated HIV treatment into general health care services using simplified protocols. We analyzed the survival probability among patients receiving antiretroviral therapy (ART) from 2003 to 2010 in integrated versus vertical programs in 9 countries in sub-Saharan Africa. METHODS AND FINDINGS: Cox regression assessed mortality and program design association, adjusting for baseline age, body mass index, clinical WHO stage, tuberculosis, program age and setting. The analysis included 15,403 HIV-positive adults on ART in 7 vertical (14,124 patients) and 10 integrated (1279 patients) programs. Cox regression including 14,523 patients followed for up to 30 months ART showed similar outcomes for mortality (adjusted hazard ratio (aHR) 1.02; 95% confidence interval (CI): 0.83 to 1.24) and lower risk of loss to follow-up (aHR: 0.71; 95% CI: 0.61 to 0.83) in integrated compared with vertical programs. The greatest risk of death was from initiating ART at WHO stage 4 (aHR 1.99, 95% CI: 1.74 to 2.29), although greater program experience was protective (aHR: 0.77, 95% CI: 0.66 to 0.89). Risk of loss to follow-up was greater in experienced programs (aHR: 3.33; 95% CI: 2.92 to 3.79) and rural settings (aHR: 3.82; 95% CI: 3.49 to 4.20). CONCLUSIONS: ART delivery in integrated general health care programs results in good outcomes. Compared with vertical HIV programs, patients initiated ART in integrated programs at more advanced stages of clinical immunosuppression yet had similar risk of death and lower risk of loss to follow-up.