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Background. Despite the availability of antimicrobial therapies, gram-negative bacteremia remains a significant cause of morbidity and mortality on a global level. Recent randomized controlled trials support shorter antibiotic treatment duration for individuals with uncomplicated gram-negative bacteremia. The target trial framework using the cloning approach utilizes real-world data but eliminates the issue of immortal time bias seen in observational studies by emulating the analysis of randomized trials with full adherence. Method. A hypothetical target trial allocating individuals with gram-negative bacteremia to either short antibiotic treatment duration (5–7 days) or longer antibiotic treatment duration (8–14 days) was specified and emulated using the cloning, censoring, and weighting approach. The primary outcome was 90-day all-cause mortality. Secondary outcome was a composite endpoint of clinical and microbiological relapse. The emulated trial included individuals from four hospitals in Copenhagen from 2018 through 2021. Results. In sum, 1040 individuals were included. The median age of the cohort was 76 years, the majority were male (54%), had community-acquired gram-negative bacteremia (86%), urinary tract infection as the source of the infection (78%), and Escherichia coli as the pathogen of the infection (73%). The adjusted 90-day risk difference in all-cause mortality was 1.3% (95% confidence interval [CI]: -.7, 3.3), and the risk ratio was 1.12 (95% CI: .89, 1.37). The adjusted 90-day risk difference in relapse was 0.7% (95% CI: -2.3, 3.8), and the risk ratio was 1.07 (95% CI: .71, 1.45). Conclusions. We found comparative outcomes for shorter treatment duration compared to longer treatment duration in patients with gram-negative bacteremia.

Background We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence. Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73–1.58; 30-day mortality: 1.08, 0.62–1.91). Relapse (1.00, 0.50–1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80–1.22); and infection complications (local: 1.62 0.76–3.47; distant: 2.00, 0.18–22.08), were without significant difference, and so were adverse events or resistance emergence. No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation For patients hemodynamica

Background We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence. Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73–1.58; 30-day mortality: 1.08, 0.62–1.91). Relapse (1.00, 0.50–1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80–1.22); and infection complications (local: 1.62 0.76–3.47; distant: 2.00, 0.18–22.08), were without significant difference, and so were adverse events or resistance emergence. No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation For patients hemodynamica

[Background] We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups., [Methods] Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence. Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment., [Findings] Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73–1.58; 30-day mortality: 1.08, 0.62–1.91). Relapse (1.00, 0.50–1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80–1.22); and infection complications (local: 1.62 0.76–3.47; distant: 2.00, 0.18–22.08), were without significant difference, and so were adverse events or resistance emergence. No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection., [Interpretation] For patients hemodynamically stable and afebrile at 48 h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation.

Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.

Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.

Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.

Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.

BACKGROUND: One year of adjuvant durvalumab following concurrent chemoradiotherapy significantly improves progression-free survival (PFS) and overall survival (OS) for patients with stage III non-small cell lung cancer (NSCLC). However, the optimal length of adjuvant therapy has not been determined. METHODS: We identified patients with stage III NSCLC treated with definitive chemoradiation and adjuvant durvalumab from November 2017 to April 2021 from the United States Veterans Affairs system. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of durvalumab treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model and time-dependent Cox modelling. RESULTS: We included 1006 patients with stage III non-small cell lung cancer who received concurrent chemoradiotherapy and at least one dose of adjuvant durvalumab. The median duration of durvalumab treatment was 7 months (interquartile range 2.8-11.5) and 31% completed the intended durvalumab course. The most common reasons for early discontinuation were tumour progression (22%), immune-related adverse events (15%), and non-immune-related toxicity (6.0%), Marginal structural models suggested similar PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months. CONCLUSIONS: A substantial proportion of patients undergoing adjuvant durvalumab discontinue therapy early due to toxicity, and shorter durvalumab treatment durations may provide similar disease control to 12 months of therapy. Prospective randomised controlled studies are needed to characterise the optimal durvalumab treatment duration in locally advanced NSCLC patients.

[Objective] To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes., [Methods] A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis., [Results] 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments., [Conclusions] 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.

Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens. METHOD(S): Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2. RESULT(S): Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44-327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC. CONCLUSION(S): Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenstrom macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ++1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P 5 .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ++3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.Copyright © 2020 American Society of Hematology. All rights reserved.

Objective: To assess the procedural and clinical outcomes associated with the introduction of minimally invasive surfactant therapy (MIST) into standard care at 2 tertiary Australian neonatal intensive care units. Study design: A prospective audit was designed before the introduction of MIST in 2018, with data collected over a period of 18 months. Procedural data were completed by the clinical team performing MIST, including clinical observations, medication use, and adverse events. The audit team collected demographic data and subsequent clinical outcomes from medical records. Result(s): There were 135 MIST procedures recorded in 122 infants. For the included infants, the median gestation was 302/7 weeks (IQR, 276/7 to 322/7 weeks) and birth weight was 1439 g (IQR, 982-1958 g). During the MIST procedure, desaturation to a peripheral oxygen saturation of <80% was common, occurring in 75.2% of procedures. Other adverse events included need for positive pressure ventilation (10.6%) and bradycardia <100 beats per minute (13.3%). The use of atropine premedication was associated with a significantly lower incidence of bradycardia: 8.6% vs 52.9% (P < .01). Senior clinicians demonstrated higher rates of procedural success. The majority of infants (63.9%) treated with MIST did not require subsequent intubation and mechanical ventilation. Conclusion(s): MIST can be successfully introduced in neonatal units with limited experience of this technique. The use of atropine premedication decreases the incidence of bradycardia during the procedure. Success rates can be optimized by limiting MIST to clinicians with greater competence in endotracheal intubation.Copyright © 2020 Elsevier Inc.

Aim: To determine predictors and outcomes of extubation failure in extremely preterm (EP) infants born <28 weeks' gestational age (GA). Method(s): Retrospective clinical audit across two tertiary-level neonatal intensive care units in Melbourne, Australia. Two-hundred and four EP infants who survived to their first extubation from mechanical ventilation. Extubation failure (re-intubation) within 7 days after the first extubation. Result(s): Lower GA (odds ratio [OR] 0.71, 95% confidence interval (CI), 0.61-0.89, P < 0.001) and higher pre-extubation measured mean airway pressure (MAP) on the mechanical ventilator (OR 1.9 [95% CI 1.41-2.51], P < 0.001) predicted extubation failure. The area under a receiver operating characteristic curve for GA and MAP was 0.77 (95% CI 0.70-0.82). After adjustment for GA, infants who experienced extubation failure had higher rates of bronchopulmonary dysplasia (P < 0.001), post-natal systemic corticosteroid treatment (P < 0.001), airway trauma (P < 0.003), longer durations of treatment with mechanical ventilation (P < 0.001), non-invasive respiratory support (P < 0.001), supplemental oxygen therapy (P = 0.05) and longer hospitalisation (P = 0.025). Conclusion(s): Lower GA and higher pre-extubation measured MAP were predictive of extubation failure within 7 days in extremely preterm infants. Extubation failure was associated with increased morbidity and extended periods of respiratory support and hospitalisation.Copyright © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Background and objectives: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). Material(s) and Method(s): The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. Result(s): Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. Conclusion(s): This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.Copyright © 2020 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion

OBJECTIVES: In children, intravenous therapy (IVT) is generally administered via peripheral intravenous catheters (PIVCs) (2-6 cm in length). There is evidence that PIVCs are unreliable after 2 days. Long peripheral catheters (LPCs) (6-15 cm in length) could improve the delivery of IVT. The aim of this trial was to determine if LPCs could decrease catheter failure and the number of catheters in children receiving multiday IVT. METHOD(S): This was an open-label randomized controlled trial conducted at Monash Children's Hospital in Melbourne, Australia. Participants were from the ages of 1 to 17 years, undergoing surgery and requiring.48 hours of postoperative IVT. Participants were randomly assigned to a 2.5-cm 22G PIVC or an 8-cm 22G LPC. RESULT(S): Seventy-two children were randomly assigned, 36 received PIVCs, and 36 received LPCs. The median duration of IVT was 5.1 days and was similar between groups (P =.9). Catheter failure was higher for PIVCs than LPCs (66.7% vs 19.4%; relative risk [RR]: 3.4; P =.0001 or 187.9 vs 41.0 failures per 1000 catheter-days). Infiltration was the most common reason for PIVC failure (33.3% vs 2.8%; RR: 12.0; P =.001). LPCs exhibited superior life span (4.7 vs 3.5 days [median]; P =.01). Children with LPCs were twice as likely to complete therapy with a single catheter (80.6% vs 38.9%; RR: 2.1; P =.0006). CONCLUSION(S): LPCs reduce catheter failure and total catheters in children. They should be considered as the first-line device for peripheral access in any child receiving prolonged IVT.Copyright © 2021 by the American Academy of Pediatrics

Background: The COVID-19 pandemic has resulted in reduced cancer diagnoses. Impacts on existing cancer patients has not been well documented. We report the experience of a large metropolitan multisite cancer service that undertook proactive review of systemic anti-cancer therapy (SACT) of all patients to consider changes in response to the pandemic. The aim was to re-balance the risks and benefits of current treatment strategies in light of the pandemic. Method(s): From March-April 2020, all current SACT orders (excluding those related to clinical trials) were reviewed. Patients on curative therapy, or with large perceived benefit were reviewed but not included in further processing. For all other SACT orders, a documented recommendation regarding planned treatment was sent to the patient's individual clinician for consideration. A categorical assessment of the recommendations is presented. Result(s): 570 SACT orders were reviewed, pertaining to 317 patients. 730 individual recommendations were made. The population consisted of 130 males and 187 females, with an average age 60.6 years. Intentions of treatment were: Curative (n=16), Neoadjuvant (n=30), Adjuvant (n = 74), and Palliative (n = 197). Distribution by tumour types (number) was: Breast (93), Gastrointestinal (76), Thoracic (63), Gynaecological (31), Genitourinary (21), Head andNeck/Melanoma (19),CNS (8), andOther (6). The most commonrecommendations (number)were:NoChange (160), Change route of delivery (e.g. intravenous to subcutaneous) (67), Reduce duration of treatment (68), Consider treatment break (60), Reconsider benefit of current treatment (58), Cease treatment (53), and Refer to HITH (47). Conclusion(s): This is the only dataset known to date of the actual impact of COVID-19 on the recommendations for SACT for patients on treatment at the start of the pandemic in Australia.Most patients had some type of modification in their cancer therapymadein the context of competing risk to their health posed by

Patients with impaired kidney function have a significantly slower decrease of procalcitonin (PCT) levels during infection. Our aim was to study PCT-guided antibiotic stewardship and clinical outcomes in patients with impairments of kidney function as assessed by creatinine levels measured upon hospital admission. We pooled and analyzed individual data from 15 randomized controlled trials who were randomly assigned to receive antibiotic therapy based on a PCT-algorithms or based on standard of care. We stratified patients on the initial glomerular filtration rate (GFR, ml/min/1.73 m2) in three groups (GFR >90 [chronic kidney disease; CKD 1], GFR 15-89 [CKD 2-4] and GFR<15 [CKD 5]). The main efficacy and safety endpoints were duration of antibiotic treatment and 30-day mortality. Mean duration of antibiotic treatment was significantly shorter in PCT-guided (n=2,492) compared to control patients (n=2,510) (9.5-7.6 days; adjusted difference in days -2.01 [95% CI, -2.45 to -1.58]). CKD 5 patients had overall longer treatment durations, but a 2.5-day reduction in treatment duration was still found in patients receiving in PCT-guided care (11.3 vs. 8.6 days [95% CI -3.59 to -1.40]). There were 397 deaths in 2,492 PCT-group patients (15.9%) compared to 460 deaths in 2,510 control patients (18.3%) (adjusted odds ratio, 0.88 [95% CI 0.78 to 0.98)]. Effects of PCT-guidance on antibiotic treatment duration and mortality were similar in subgroups stratified by infection type and clinical setting (p interaction >0.05). This individual patient data meta-analysis confirms that the use of PCT in patients with impaired kidney function, as assessed by admission creatinine levels, is associated with shorter antibiotic courses and lower mortality rates.Copyright © 2020 Eva Heilmann et al., published by De Gruyter, Berlin/Boston.

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenstrom macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ++1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P 5 .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ++3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.Copyright © 2020 American Society of Hematology. All rights reserved.

Aim: Haemodialysis treatment prescription varies widely internationally. This study explored patient- and centre-level characteristics associated with weekly haemodialysis hours. Method(s): Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry data were analysed. Characteristics associated with weekly duration were evaluated using mixed-effects linear regression models with patient- and centre-level covariates as fixed effects, and dialysis centre and state as random effects using the 2017 prevalent in-centre haemodialysis (ICHD) and home haemodialysis (HHD) cohorts. Evaluation of patterns of weekly duration over time analysed the 2000 to 2017 incident ICHD and HHD cohorts. Result(s): Overall, 12 494 ICHD and 1493 HHD prevalent patients in 2017 were included. Median weekly treatment duration was 13.5 (interquartile range [IQR] 12-15) hours for ICHD and 16 (IQR 15-20) hours for HHD. Male sex, younger age, higher body mass index, arteriovenous fistula/graft use, Aboriginal and Torres Strait Islander ethnicity and longer dialysis vintage were associated with longer weekly duration for both ICHD and HHD. No centre characteristics were associated with duration. Variability in duration across centres was very limited in ICHD compared with HHD, with variation in HHD being associated with state. Duration did not vary significantly over time for ICHD, whereas longer weekly HHD treatments were reported between 2006 and 2012 compared with before and after this period. Conclusion(s): This study in the Australian and New Zealand haemodialysis population showed that weekly duration was primarily associated with patient characteristics. No centre effect was demonstrated. Practice patterns seemed to differ across states/countries, with more variability in HHD than ICHD.Copyright © 2020 Asian Pacific Society of Nephrology

Objective: To assess the procedural and clinical outcomes associated with the introduction of minimally invasive surfactant therapy (MIST) into standard care at 2 tertiary Australian neonatal intensive care units. Study design: A prospective audit was designed before the introduction of MIST in 2018, with data collected over a period of 18 months. Procedural data were completed by the clinical team performing MIST, including clinical observations, medication use, and adverse events. The audit team collected demographic data and subsequent clinical outcomes from medical records. Result(s): There were 135 MIST procedures recorded in 122 infants. For the included infants, the median gestation was 302/7 weeks (IQR, 276/7 to 322/7 weeks) and birth weight was 1439 g (IQR, 982-1958 g). During the MIST procedure, desaturation to a peripheral oxygen saturation of <80% was common, occurring in 75.2% of procedures. Other adverse events included need for positive pressure ventilation (10.6%) and bradycardia <100 beats per minute (13.3%). The use of atropine premedication was associated with a significantly lower incidence of bradycardia: 8.6% vs 52.9% (P < .01). Senior clinicians demonstrated higher rates of procedural success. The majority of infants (63.9%) treated with MIST did not require subsequent intubation and mechanical ventilation. Conclusion(s): MIST can be successfully introduced in neonatal units with limited experience of this technique. The use of atropine premedication decreases the incidence of bradycardia during the procedure. Success rates can be optimized by limiting MIST to clinicians with greater competence in endotracheal intubation.Copyright © 2020 Elsevier Inc.

Aim: To determine predictors and outcomes of extubation failure in extremely preterm (EP) infants born <28 weeks' gestational age (GA). Method(s): Retrospective clinical audit across two tertiary-level neonatal intensive care units in Melbourne, Australia. Two-hundred and four EP infants who survived to their first extubation from mechanical ventilation. Extubation failure (re-intubation) within 7 days after the first extubation. Result(s): Lower GA (odds ratio [OR] 0.71, 95% confidence interval (CI), 0.61-0.89, P < 0.001) and higher pre-extubation measured mean airway pressure (MAP) on the mechanical ventilator (OR 1.9 [95% CI 1.41-2.51], P < 0.001) predicted extubation failure. The area under a receiver operating characteristic curve for GA and MAP was 0.77 (95% CI 0.70-0.82). After adjustment for GA, infants who experienced extubation failure had higher rates of bronchopulmonary dysplasia (P < 0.001), post-natal systemic corticosteroid treatment (P < 0.001), airway trauma (P < 0.003), longer durations of treatment with mechanical ventilation (P < 0.001), non-invasive respiratory support (P < 0.001), supplemental oxygen therapy (P = 0.05) and longer hospitalisation (P = 0.025). Conclusion(s): Lower GA and higher pre-extubation measured MAP were predictive of extubation failure within 7 days in extremely preterm infants. Extubation failure was associated with increased morbidity and extended periods of respiratory support and hospitalisation.Copyright © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Background and objectives: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). Material(s) and Method(s): The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. Result(s): Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. Conclusion(s): This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.Copyright © 2020 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens. METHOD(S): Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2. RESULT(S): Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44-327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC. CONCLUSION(S): Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

OBJECTIVES: In children, intravenous therapy (IVT) is generally administered via peripheral intravenous catheters (PIVCs) (2-6 cm in length). There is evidence that PIVCs are unreliable after 2 days. Long peripheral catheters (LPCs) (6-15 cm in length) could improve the delivery of IVT. The aim of this trial was to determine if LPCs could decrease catheter failure and the number of catheters in children receiving multiday IVT. METHOD(S): This was an open-label randomized controlled trial conducted at Monash Children's Hospital in Melbourne, Australia. Participants were from the ages of 1 to 17 years, undergoing surgery and requiring.48 hours of postoperative IVT. Participants were randomly assigned to a 2.5-cm 22G PIVC or an 8-cm 22G LPC. RESULT(S): Seventy-two children were randomly assigned, 36 received PIVCs, and 36 received LPCs. The median duration of IVT was 5.1 days and was similar between groups (P =.9). Catheter failure was higher for PIVCs than LPCs (66.7% vs 19.4%; relative risk [RR]: 3.4; P =.0001 or 187.9 vs 41.0 failures per 1000 catheter-days). Infiltration was the most common reason for PIVC failure (33.3% vs 2.8%; RR: 12.0; P =.001). LPCs exhibited superior life span (4.7 vs 3.5 days [median]; P =.01). Children with LPCs were twice as likely to complete therapy with a single catheter (80.6% vs 38.9%; RR: 2.1; P =.0006). CONCLUSION(S): LPCs reduce catheter failure and total catheters in children. They should be considered as the first-line device for peripheral access in any child receiving prolonged IVT.Copyright © 2021 by the American Academy of Pediatrics

Background: The COVID-19 pandemic has resulted in reduced cancer diagnoses. Impacts on existing cancer patients has not been well documented. We report the experience of a large metropolitan multisite cancer service that undertook proactive review of systemic anti-cancer therapy (SACT) of all patients to consider changes in response to the pandemic. The aim was to re-balance the risks and benefits of current treatment strategies in light of the pandemic. Method(s): From March-April 2020, all current SACT orders (excluding those related to clinical trials) were reviewed. Patients on curative therapy, or with large perceived benefit were reviewed but not included in further processing. For all other SACT orders, a documented recommendation regarding planned treatment was sent to the patient's individual clinician for consideration. A categorical assessment of the recommendations is presented. Result(s): 570 SACT orders were reviewed, pertaining to 317 patients. 730 individual recommendations were made. The population consisted of 130 males and 187 females, with an average age 60.6 years. Intentions of treatment were: Curative (n=16), Neoadjuvant (n=30), Adjuvant (n = 74), and Palliative (n = 197). Distribution by tumour types (number) was: Breast (93), Gastrointestinal (76), Thoracic (63), Gynaecological (31), Genitourinary (21), Head andNeck/Melanoma (19),CNS (8), andOther (6). The most commonrecommendations (number)were:NoChange (160), Change route of delivery (e.g. intravenous to subcutaneous) (67), Reduce duration of treatment (68), Consider treatment break (60), Reconsider benefit of current treatment (58), Cease treatment (53), and Refer to HITH (47). Conclusion(s): This is the only dataset known to date of the actual impact of COVID-19 on the recommendations for SACT for patients on treatment at the start of the pandemic in Australia.Most patients had some type of modification in their cancer therapymadein the context of competing risk to their health posed by

Patients with impaired kidney function have a significantly slower decrease of procalcitonin (PCT) levels during infection. Our aim was to study PCT-guided antibiotic stewardship and clinical outcomes in patients with impairments of kidney function as assessed by creatinine levels measured upon hospital admission. We pooled and analyzed individual data from 15 randomized controlled trials who were randomly assigned to receive antibiotic therapy based on a PCT-algorithms or based on standard of care. We stratified patients on the initial glomerular filtration rate (GFR, ml/min/1.73 m2) in three groups (GFR >90 [chronic kidney disease; CKD 1], GFR 15-89 [CKD 2-4] and GFR<15 [CKD 5]). The main efficacy and safety endpoints were duration of antibiotic treatment and 30-day mortality. Mean duration of antibiotic treatment was significantly shorter in PCT-guided (n=2,492) compared to control patients (n=2,510) (9.5-7.6 days; adjusted difference in days -2.01 [95% CI, -2.45 to -1.58]). CKD 5 patients had overall longer treatment durations, but a 2.5-day reduction in treatment duration was still found in patients receiving in PCT-guided care (11.3 vs. 8.6 days [95% CI -3.59 to -1.40]). There were 397 deaths in 2,492 PCT-group patients (15.9%) compared to 460 deaths in 2,510 control patients (18.3%) (adjusted odds ratio, 0.88 [95% CI 0.78 to 0.98)]. Effects of PCT-guidance on antibiotic treatment duration and mortality were similar in subgroups stratified by infection type and clinical setting (p interaction >0.05). This individual patient data meta-analysis confirms that the use of PCT in patients with impaired kidney function, as assessed by admission creatinine levels, is associated with shorter antibiotic courses and lower mortality rates.Copyright © 2020 Eva Heilmann et al., published by De Gruyter, Berlin/Boston.

Background: Fear of cancer recurrence, depressive symptoms, and cancer-related fatigue are prevalent symptoms among cancer survivors, adversely affecting patients’ quality of life and daily functioning. Effect sizes of interventions targeting these symptoms are mostly small to medium. Personalizing treatment is assumed to improve efficacy. However, thus far the empirical support for this approach is lacking. The aim of this study is to investigate if systematically personalized cognitive behavioral therapy is more efficacious than standard cognitive behavioral therapy in cancer survivors with moderate to severe fear of cancer recurrence, depressive symptoms, and/or cancer-related fatigue. Methods: The study is designed as a non-blinded, multicenter randomized controlled trial with two treatment arms (ratio 1:1): (a) systematically personalized cognitive behavioral therapy and (b) standard cognitive behavioral therapy. In the standard treatment arm, patients receive an evidence-based diagnosis-specific treatment protocol for fear of cancer recurrence, depressive symptoms, or cancer-related fatigue. In the second arm, treatment is personalized on four dimensions: (a) the allocation of treatment modules based on ecological momentary assessments, (b) treatment delivery, (c) patients’ needs regarding the symptom for which they want to receive treatment, and (d) treatment duration. In total, 190 cancer survivors who experience one or more of the targeted symptoms and ended their medical treatment with curative intent at least 6 months to a maximum of 5 years ago will be included. Primary outcome is limitations in daily functioning. Secondary outcomes are level of fear of cancer recurrence, depressive symptoms, fatigue severity, quality of life, goal attainment, therapist time, and drop-out rates. Participants are assessed at baseline (T0), and after 6 months (T1) and 12 months (T2). Discussion: To our knowledge, this is the first rand

Background Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients. Methods This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis. Results We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39-0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16-2.45). The sensitivity analysis reinforced the results. Subgroups of age < 6

The work presented in this paper was dedicated to the investigation of the influence of the alkaline treatment parameters on the formation of mesopores in zeolite ZSM-5, SiO2/Al2O3=50. Concentration of NaOH, temperature and tretment duration were varied. The obtained samples were characterized using low temperature nitrogen adsorption, X ray diffraction and solid state 27Al MAS NMR spectroscopy. Formation of mesopores was found to be a process sensitive to changes of treatment parameters, which can lead to creation of hierarchical zeolites with different mesopore surfaces and distributions of pore size diameters. Also, treatment duration was found to have a lesser influence on the process, compared to other two investigated parameters. Mesopore introduction resulted in partial crystallinity reduction, in all modified samples. No significant buildup of extraframework Al was detected., U ovom radu prikazani su rezultati ispitivanja uticaja parametara alkalnog tretmana na formiranje mezopora u zeolitu ZSM-5, SiO2/Al2O3=50. Varirane su koncentracija natrijum hidroksida, temperatura i trajanje tratmana. Uzorci dobijenih hijerarhijskih formi zeolita ZSM-5 okarakterisani su metodama niskotemperaturske adsorpcije azota, rendgenskom difrakcionom analizom i 27Al MAS NMR sprektroskopijom čvrstog stanja. Utvrđeno je da je formiranje mezopora u zeolitu ZSM-5 proces osetljiv na promene ispitivanih parametara i da je moguće kreiranje hijerarhijskih ZSM-5 zeolita sa različitim veličinama mezoporoznih površina i raspodelama dijametara pora. Takođe, utvrđeno je da koncentracija NaOH i temperatura tretmana imaju značajniji uticaj na formiranje mezoporoznosti od trajanja tretmana. Dobijeni rezultati pokazuju da je formiranje mezopora ovim postupkom praćeno delimičnim smanjenjem kristaliniteta uzoraka zeolita. Na osnovu 27Al MAS NMR sprektroskopije zaključeno je da tretman nije doprineo stvaranju značajnih količina vanmrežnog aluminijuma.

Objective: To describe the organization, content and dosage of interdisciplinary pain rehabilitation, and the differences in degree of severity of problems of patients admitted to clinical units reporting to a Swedish national quality pain registry, grouped according to unit size and possible affiliation with a university hospital. Methods: Reports from 31 out of 39 clinical units in Sweden, on inclusion processes, organization, content and dosage of interdisciplinary pain rehabilitation, and patient-reported data from a Swedish national quality pain registry at assessment for interdisciplinary pain rehabilitation were analysed. Results: the number of patients treated annually at each unit ranged from 3 to 340. In 17 units, teams comprised 5 professionals. Dosage of interdisciplinary pain rehabilitation ranged from 20-180 h per patient in total. Patients at the university-hospital units scored the highest levels of symptoms and lowest levels of health related quality of life. Units used similar sets of inclusion criteria, and several treatments, such as education, self-training and psychological interventions, were used by most units. Conclusion: When interpreting outcome data from registries, aspects other than rehabilitation out-comes must be considered. The interpretation of outcomes from quality registries would be facilitated if data, in addition to assessments and patient reported outcomes, also includes standardized descriptions of the reporting clinical units.

Objectives: Primary Objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: * To determine the safety of the antiviral * To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale * To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms * To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation Trial design: This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. Participant(s): Inclusion Criteria: * Provision of informed consent by the participant * Age >=18 years * Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days * COVID-19 related symptom initiation within 5 days * Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. Exclusion criteria: * Known allergy to the study medication * Is on another clinical trial investigating an antiviral treatment for COVID-19 * Pregnancy * Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification * Patients with renal impairment requiring dialysis * Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. Intervention and comparator: The first candid

Background: Myelofibrosis is caused by constitutive activation of the JAK/STAT pathway. JAK inhibitors reduce spleen volume and improve symptoms, but disease progression through JAK inhibition underscores the need for therapies with distinct modes of action. Bomedemstat (IMG-7289) is an inhibitor of lysine-specific demethylase-1 (LSD1), an epigenetic regulator critical for self-renewal of malignant myeloid cells and for the differentiation of myeloid progenitors. LSD1 with GFI1b licenses maturation of progenitors to megakaryocytes and enables their normal function. In mouse models of MPNs (MplW515L, JAK2V617F), LSD1 inhibition improved peripheral cell counts, spleen volumes, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018). Aim(s): This multi-center, open-label Phase 2 study evaluated the safety and pharmacodynamics of bomedemstat administered orally once-daily in adult patients with high or intermediate-2 risk MF who were resistant to or intolerant of ruxolitinib. Method(s): The primary objectives were safety, PK and spleen volume (SV) reduction. Other endpoints included changes in total symptom scores (TSS), bone marrow (BM) fibrosis and inflammatory cytokines. Key inclusion criteria included platelet count >=100K/muL. Patients in the doserange finding study (N = 18) were treated daily for 12 weeks followed by a washout period of up to 28 days. Patients in the Phase 2b study (N = 16) were treated daily for 24 weeks. Abdominal imaging to measure SV was performed after every 12 weeks of treatment. The MPN10 responses were submitted at each clinic visit. Dosing was tailored using platelet count as a marker of bomedemstat activity on megakaryocyte function. Phase 2a patients started at the presumed sub-therapeutic dose of 0.25 mg/kg/d and were up-titrated weekly until the platelet count rested between 50 and 100K/muL. Phase 2b patients started at 0.5 mg/kg/d and were up-titrated until platelet counts rested between 50 and 75K

The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.Copyright © 2020 International Menopause Society.

Perioral ulcerative plaques have a broad list of differential diagnoses. We describe an unusual presentation of chronic progressive perioral ulceration due to herpes simplex type (HSV)-1 on a background of undiagnosed human immunodeficiency virus infection with acquired immunodeficiency syndrome. Whilst chronic mucocutaneous HSV is an AIDS-defining condition with both HSV-1 and HSV-2 implicated, typical reported cases describe vesicular eruptions rather than perioral ulcerative plaques. This case highlights that common infections may present atypically in immunocompromised individuals and may be a clue to underlying systemic illness.Copyright © 2019 The Australasian College of Dermatologists

Background: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. Method(s): A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. Result(s): There was no difference in mean change in musculoskeletal symptoms (- 0.6 +/- 1.7 vs - 0.4 +/- 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 +/- 8.8 vs placebo + 4.2 +/- 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. Conclusion(s): This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. Trial registration: ClinicalTrials.gov, NCT01504321. Registered 5 January 2012.Copyright © 2020 The Author(s).

Background: Hemodialysis treatment prescription varies widely around the world. This study explored patient- and center-level characteristics associated with weekly haemodialysis hours. Method(s): Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry data was analyzed. Characteristics associated with weekly duration were evaluated using mixed-effects linear regression models with patient- and center-level covariates as fixed effects, and dialysis center and state as random effects using the 2017 prevalent in-centre hemodialysis (ICHD) and home hemodialysis (HHD) cohorts. Evaluation of patterns of weekly duration over time analyzed the 2000 to 2017 incident ICHD and HHD cohorts. Result(s): Overall, 12,494 ICHD and 1,493 HHD prevalent patients in 2017 were included. Median weekly treatment duration was 13.5 (interquartile range (IQR) 12-15) hours for ICHD and 16 (IQR 15-20) hours for HHD. Male sex, younger age, higher body mass index, arteriovenous fistula/graft use, Aboriginal and Torres Strait Islander ethnicity and longer dialysis vintage were associated with longer weekly duration for both ICHD and HHD. No center characteristics were associated with weekly duration. Variability in duration across centers was very limited in ICHD compared to HHD, with variation in HHD being associated with state. Duration did not vary significantly over time for ICHD, whereas longer weekly HHD treatments were reported between 2006 and 2012 compared to before and after this period. Conclusion(s): This study in the Australian and New Zealand hemodialysis population showed that weekly treatment duration was primarily associated with patient characteristics. No center effect was demonstrated. Practice patterns seemed to differ across states/countries, with more variability in HHD than in ICHD. (Figure Presented).

Background: Elderly men (>/=75yo) comprise 25% of patients with prostate cancer. However, they are typically underrepresented in pivotal trials. Limited data suggest these patients receive less intensive treatment with greater toxicity, despite comparable response rates. Our retrospective study examined treatment patterns and outcomes in a real-world population with castration-resistant prostate cancer (CRPC). Method(s): Using the multi-centre electronic CRPC Australian Database (ePAD), we extracted clinicopathologic, treatment and outcome data. Descriptive statistics were used to report data in patients aged >/=75yo and <75yo. Comparisons between these groups were analysed using T-tests and Fisher's exact tests. Time-to-event analyses were performed using the Kaplan-Meier method. Result(s): We identified 753 men with CRPC, with 327 (43%) aged >/=75yo. Elderly patients had higher rates of ischemic heart disease (33% vs 16% in younger patients, p=0.004) and stroke (11% vs 5%, p=0.007). They were more likely to receive only one line of systemic therapy (67% vs 40%, p<0.001), and androgen receptor signalling inhibitors (ARSIs) were most commonly prescribed as initial therapy (78% vs 48%, p<0.001). Enrolment in clinical trials was less frequent (5% vs 15%, p<0.001). There was no statistical difference in treatment duration or PSA50 response rates with ARSIs or docetaxel (Table). Overall, serious adverse events (SAEs) leading to hospitalisation, dose delays or modifications occurred in more elderly men (24% vs 16%, p=0.003), with a trend towards greater SAEs in those receiving docetaxel or ARSIs. Elderly patients were more likely to stop docetaxel due to toxicity (39% vs 21%, p=0.02). [Formula presented]. Conclusion(s): In our real-world cohort, elderly men had greater comorbidities and received fewer lines of systemic therapy. Although there was no difference in treatment response or duration, elderly patients experienced higher SAE rates. Prospective studies are requir