Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Identification of members of the Wnt signaling pathway in the embryonic pituitary gland

Prop1 is one of several transcription factors important for the development of the pituitary gland. Downstream targets of PROP1 and other critical pituitary transcription factors remain largely unknown. We have generated a partial expression profile of the developing pituitary gland containing over 350 transcripts, using cDNA subtractive hybridization between Prop1 df/df and wild-type embryonic pituitary gland primordia. Numerous classes of genes including transcription factors, membrane associated molecules, and cell cycle regulators were identified in this study. Of the transcripts, 34% do not have sequence similarity to known genes, but are similar to ESTs, and 4% represent novel sequences. Pituitary gland expression of a number of clones was verified using in situ hybridization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42122/1/335-12-11-843_10120843.pd

Improving Practice for Urinary Continence Care on Adult Acute Medical and Rehabilitation Wards: A Multi-Site, Co-Created Implementation Study

Many adult inpatients experience urinary continence issues; however, we lack evidence on effective interventions for inpatient continence care. We conducted a before and after implementation study. We implemented our guideline-based intervention using strategies targeting identified barriers and evaluated the impact on urinary continence care provided by inpatient clinicians. Fifteen wards (acute = 3, rehabilitation = 7, acute and rehabilitation = 5) at 12 hospitals (metropolitan = 4, regional = 8) participated. We screened 2298 consecutive adult medical records for evidence of urinary continence symptoms over three 3-month periods: before implementation (T0: n = 849), after the 6-month implementation period (T1: n = 740), and after a 6-month maintenance period (T2: n = 709). The records of symptomatic inpatients were audited for continence assessment, diagnosis, and management plans. All wards contributed data at T0, and 11/15 wards contributed at T1 and T2 (dropouts due to COVID-19). Approximately 26% of stroke, 33% acute medical, and 50% of rehabilitation inpatients were symptomatic. The proportions of symptomatic patients (T0: n = 283, T1: n = 241, T2: n = 256) receiving recommended care were: assessment T0 = 38%, T1 = 63%, T2 = 68%; diagnosis T0 = 30%, T1 = 70%, T2 = 71%; management plan T0 = 7%, T1 = 24%, T2 = 24%. Overall, there were 4-fold increased odds for receiving assessments and management plans and 6-fold greater odds for diagnosis. These improvements were sustained at T2. This intervention has improved inpatient continence care

Improving Assessment, Diagnosis, and Management of Urinary Incontinence and Lower Urinary Tract Symptoms on Acute and Rehabilitation Wards That Admit Adult Patients: Protocol for a Before-and-After Implementation Study

Background: Urinary incontinence (UI) and lower urinary tract symptoms (LUTS) are commonly experienced by adult patients in hospitals (inpatients). Although peak bodies recommend that health services have systems for optimal UI and LUTS care, they are often not delivered. For example, results from the 2017 Australian National Stroke Audit Acute Services indicated that of the one-third of acute stroke inpatients with UI, only 18% received a management plan. In the 2018 Australian National Stroke Audit Rehabilitation Services, half of the 41% of patients with UI received a management plan. There is little reporting of effective inpatient interventions to systematically deliver optimal UI/LUTS care.Objective: This study aims to determine whether our UI/LUTS practice-change package is feasible and effective for delivering optimal UI/LUTS care in an inpatient setting. The package includes our intervention that has been synthesized from the best-available evidence on UI/LUTS care and a theoretically informed implementation strategy targeting identified barriers and enablers. The package is targeted at clinicians working in the participating wards.Methods: This is a pragmatic, real-world, before- and after-implementation study conducted at 12 hospitals (15 wards: 7/15, 47% metropolitan, 8/15, 53% regional) in Australia. Data will be collected at 3 time points: before implementation (T0), immediately after the 6-month implementation period (T1), and again after a 6-month maintenance period (T2). We will undertake medical record audits to determine any change in the proportion of inpatients receiving optimal UI/LUTS care, including assessment, diagnosis, and management plans. Potential economic implications (cost and consequences) for hospitals implementing our intervention will be determined.Results: This study was approved by the Hunter New England Human Research Ethics Committee (HNEHREC Reference No. 18/10/17/4.02). Preimplementation data collection (T0) was completed in March 2020. As of November 2020, 87% (13/15) wards have completed implementation and are undertaking postimplementation data collection (T1).Conclusions: Our practice-change package is designed to reduce the current inpatient UI/LUTS evidence-based practice gap, such as those identified through national stroke audits. This study has been designed to provide clinicians, managers, and policy makers with the evidence needed to assess the potential benefit of further wide-scale implementation of our practice-change package

Complete genomes of two clinical Staphylococcus aureus strains: Evidence for the rapid evolution of virulence and drug resistance

Staphylococcus aureus is an important nosocomial and community-acquired pathogen. Its genetic plasticity has facilitated the evolution of many virulent and drug-resistant strains, presenting a major and constantly changing clinical challenge. We sequenced the ≈2.8-Mbp genomes of two disease-causing S. aureus strains isolated from distinct clinical settings: a recent hospital-acquired representative of the epidemic methicillin-resistant S. aureus EMRSA-16 clone (MRSA252), a clinically important and globally prevalent lineage; and a representative of an invasive community-acquired methicillin-susceptible S. aureus clone (MSSA476). A comparative-genomics approach was used to explore the mechanisms of evolution of clinically important S. aureus genomes and to identify regions affecting virulence and drug resistance. The genome sequences of MRSA252 and MSSA476 have a well conserved core region but differ markedly in their accessory genetic elements. MRSA252 is the most genetically diverse S. aureus strain sequenced to date: ≈6% of the genome is novel compared with other published genomes, and it contains several unique genetic elements. MSSA476 is methicillin-susceptible, but it contains a novel Staphylococcal chromosomal cassette (SCC) mec-like element (designated SCC(476)), which is integrated at the same site on the chromosome as SCCmec elements in MRSA strains but encodes a putative fusidic acid resistance protein. The crucial role that accessory elements play in the rapid evolution of S. aureus is clearly illustrated by comparing the MSSA476 genome with that of an extremely closely related MRSA community-acquired strain; the differential distribution of large mobile elements carrying virulence and drug-resistance determinants may be responsible for the clinically important phenotypic differences in these strains

The genome of the protist parasite Entamoeba histolytica.

Entamoeba histolytica is an intestinal parasite and the causative agent of amoebiasis, which is a significant source of morbidity and mortality in developing countries. Here we present the genome of E. histolytica, which reveals a variety of metabolic adaptations shared with two other amitochondrial protist pathogens: Giardia lamblia and Trichomonas vaginalis. These adaptations include reduction or elimination of most mitochondrial metabolic pathways and the use of oxidative stress enzymes generally associated with anaerobic prokaryotes. Phylogenomic analysis identifies evidence for lateral gene transfer of bacterial genes into the E. histolytica genome, the effects of which centre on expanding aspects of E. histolytica's metabolic repertoire. The presence of these genes and the potential for novel metabolic pathways in E. histolytica may allow for the development of new chemotherapeutic agents. The genome encodes a large number of novel receptor kinases and contains expansions of a variety of gene families, including those associated with virulence. Additional genome features include an abundance of tandemly repeated transfer-RNA-containing arrays, which may have a structural function in the genome. Analysis of the genome provides new insights into the workings and genome evolution of a major human pathogen

Comparative genomic analysis of three Leishmania species that cause diverse human disease

Leishmania parasites cause a broad spectrum of clinical disease. Here we report the sequencing of the genomes of two species of Leishmania: Leishmania infantum and Leishmania braziliensis. The comparison of these sequences with the published genome of Leishmania major reveals marked conservation of synteny and identifies only 200 genes with a differential distribution between the three species. L. braziliensis, contrary to Leishmania species examined so far, possesses components of a putative RNA-mediated interference pathway, telomere-associated transposable elements and spliced leader–associated SLACS retrotransposons. We show that pseudogene formation and gene loss are the principal forces shaping the different genomes. Genes that are differentially distributed between the species encode proteins implicated in host-pathogen interactions and parasite survival in the macrophage

The genome of the African trypanosome Trypanosoma brucei

African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of &lt;i&gt;Trypanosoma brucei&lt;/i&gt;. The 26-megabase genome contains 9068 predicted genes, including ~900 pseudogenes and ~1700 &lt;i&gt;T. brucei&lt;/i&gt;–specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of &lt;i&gt;T. brucei&lt;/i&gt;, &lt;i&gt;T. cruzi&lt;/i&gt;, and &lt;i&gt;Leishmania major&lt;/i&gt; reveals the least overall metabolic capability in &lt;i&gt;T. brucei&lt;/i&gt; and the greatest in &lt;i&gt;L. major&lt;/i&gt;. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified