The place of non-invasive brain stimulation in the RANZCP clinical practice guidelines for mood disorders.

Clinical practice guidelines are important documents as they have the capacity to significantly influence and shape clinical practice in important areas of therapeutics. As such, they need to be developed informed by comprehensive and quality-based systematic reviews, involve consensus deliberations representative of the appropriate experts in the field and be subject to thorough critical review. A revised clinical practice guideline for the management of patients with mood disorders was recently published under the auspices of the Royal Australian and New Zealand College of Psychiatrists. However, this clinical practice guideline was not developed in a manner that reflects the appropriate standards that should apply to clinical practice guideline development and it has critical flaws, especially as it pertains to the use of repetitive transcranial magnetic stimulation treatment for patients with depression. The revision of the college clinical practice guideline has explicitly removed clear and unequivocal evidence-based recommendations that were found in a previous version of the clinical practice guideline and replaced these with consensus-based recommendations. However, the consensus-based recommendations were developed without consultation of the appropriate expert body within the college and contradict the scientific literature. There is substantive and unequivocal evidence supporting the antidepressant use of repetitive transcranial magnetic stimulation in the treatment of patients with depression and its use after a patient with depression has failed a limited number (typically around two) of antidepressant medication trials. Readers should refer to the college Professional Practice Guidelines for repetitive transcranial magnetic stimulation published in 2018 for thorough information about the use of this important new treatment.

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients ≥60 years old (median age 70 years; range, 60-83) were randomized to receive tosedostat (120 mg on days 1-21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2 /d) or decitabine (20 mg/m2 /d) every 35 d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 11.2 months (range, 0.5-22.3), and median survival was 11.5 months (95% confidence interval, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.

A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low-dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high-risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment-related grade 3-4 non-haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18-50%] and 6.8 months overall and 38% [95% CI, 19-57%] and 7.2 months at the MTD. The median disease-free survival was 7.4 months. Fifty-two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.

Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome.

Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset.

Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design.

Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly-diagnosed AML or high-risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m(2) days 1-3), together with idarubicin (12 mg/m(2) days 1-2), might provide a complete response (CR) rate ≥40% with <30% grade 3-4 non-haematological toxicity. We treated 39 patients (34 AML; five MDS with >10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m(2) dose because of excess toxicity (two of three patients) and the 60 mg/m(2) dose because of low efficacy (CR rate 10/33), although no grade 3-4 non-haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.

Impacts of Covid-19 on mental health service provision in the Western Cape, South Africa: The MASC study.

In the context of an already large treatment gap in South Africa, this study aimed to examine how Covid-19 and the related lockdown measures affected the availability, accessibility, quality, and continuity of mental health services in the Western Cape province in South Africa. A mixed-methods design was employed, using narrative surveys, quantitative surveys, and qualitative semi-structured interviews, with 17 public mental health providers, and secondary data from the District Health Information System. We analysed and combined the data using descriptive statistics, template analysis and methodological triangulation. Results showed that Covid-19 and the lockdowns had negative impacts on mental health service provision at all levels of care, such as reduced access to services, increased stigma and discrimination, disrupted medication supply, increased workload and stress for providers, and the closure of psychosocial and therapeutic services. Innovations used by providers to mitigate these impacts included telehealth, online training, peer support groups, and community outreach. The study concludes that Covid-19 and the lockdowns exposed and exacerbated the existing gaps and challenges in mental health service provision in South Africa. Key recommendations for policy formation and response to future pandemics in the public mental health sector include: classifying psychological treatments as essential services, establishing an intersectoral mental health emergency response plan, involving mental health care users in the development of pandemic responses, creating policies for managing health emergencies in psychiatric facilities, and increasing resources for the mental health sector in South Africa. These recommendations are relevant for South Africa and other LMICs in ensuring adequate mental health care during public health emergencies.

Prostatic Artery Embolization Allows to Maintain Full Sexual Activity in Patients Suffering from Bothersome Lower Urinary Tracts Symptoms related to Benign Prostatic Hyperplasia.

INTRODUCTION: The effect of prostate artery embolization (PAE) on male sexual function is currently the subject of debate in the literature. The main purpose of this study was to define changes in all domains of sexual activity after PAE, using the international index of erectile function score (IIEF-15). METHODS: A single-center retrospective study was conducted on 129 patients (mean age of 65.5 ± 7 years), who underwent PAE from February 2014 to January 2017 for symptomatic benign prostatic hyperplasia (BPH). Fifty consecutive patients fulfilling the inclusion criteria were evaluated before and after PAE follow-up using the IIEF-15, IPSS, prostate volume (PV) and cardiovascular risk factor and BPH drugs. The IIEF-15 domains analyzed were: erectile function (EF) ejaculation and orgasm (Ej/O), sexual desire (SD), intercourse satisfaction (IS) and overall satisfaction (OS). A paired sample t test or Wilcoxon signed-rank test was used to compare IIEF-15 between baseline and follow-up. RESULTS: The study showed nonsignificant change in IIEF-15 total score (58.0 ± 13.8 SD; p = 0.71) and the five domains (EF 24.5 ± 7.0 SD, p = 0.82; EJ/O 8.2 ± 2.3 SD, p = 0.50; SD 7.2 ± 2.7 SD, p = 0.57; IS 10.3 ± 3.0 SD, p = 0.77; OS 8.2 ± 2.7 SD; p = 0.11) after PAE. We also found a significant improvement in IPSS score after PAE. CONCLUSION: Based on the IIEF-15 questionnaire, PAE was showed to allow good urinary symptoms results and no deterioration in sexual function.

Prevalence of Vitamin a Deficiency among Infants Participating in the Mama SASHA Proof of Concept Project in Western Kenya.

Objectives: Vitamin A (VA) deficiency (VAD) is a significant burden among children under-5- years-old and pregnant and lactating women in sub-Saharan Africa. We assessed the levels of VA and prevalence of VAD among children age 6-23 mo in 2 counties in western Kenya. Methods: Dry-Blood-Spot (DBS) samples were obtained from 1838 infants in a community-based cross-sectional survey. Laboratory analysis of retinol-binding protein (RBP) and C-reactive protein (CRP) was carried out using a rapid EIA to estimate VA and subclinical inflammation statuses, respectively. A validation of DBS as a matrix using 60 matching serum-DBS samples was carried out. Values were adjusted for influence of inflammation using CRP (CRP, >5 mg/L) and population prevalence of VAD (RBP<0.825 μmol/L, biologically equivalent to 0.70 μmol/L retinol) estimated. Results: Mean (geometric±SD) concentration of RBP was adequate (1.56±0.79 μmol/L) with inflammation-adjusted mean (±SE) prevalence of VAD being high (18.3±1.1%). The level of CRP was within normal range (1.06±4.95 mg/L) whilst 18.4±0.9% had subclinical inflammation (CRP>5 mg/L). VAD was not associated with child sex (Chi-squared, Χ2=0.42, P=0.51), child nutritional status (wasting (P=0.68) and stunting (P=0.91), reported child intake of VA capsule within the past 1 year (P=0.84), maternal VA nutritional knowledge (Χ2=0.10, P=0.80), or reported maternal intake of VA capsule within 2 months of delivery (P=0.27). Older children had a 10% increased risk of VAD. Conclusions: Prevalence of VAD in this sample of infants was high irrespective of intake of VA capsule or maternal VA nutrition knowledge. A sustainable food-based intervention in this area of western Kenya to combat VAD especially in pregnant women and infants is warranted.