Notes on the discovery of a new Eucalyptus

A few notes on the discovery of a new Eucalypt may be of some interest to the Fellows of the Royal Society, especially the introductory remarks, for whioh I am greatly indebted to our illustrious honorary member Baron von Mueller who thus forwards his determination on what he considers a most important botanical discovery. During a recent exploration, for the Government, of the country situated between the townships o£ New Norfolk and· Victoria, au Eucalypt which had never come under my observation during any of my numerous wanderings through the unexplored portions of Tasmania, and one which I could not find described in the Flora of the Colonies, was first observed on a saddle of the dividing range between the Huon and Derwent watersheds

Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance.

In this study, 132 patients with lymphadenopathy were investigated. Fifty-two (39.4%) were diagnosed with tuberculosis (TB). The microscopic observation drug susceptibility (MODS) assay provided rapid (13 days), accurate diagnosis (sensitivity, 65.4%) and reliable drug susceptibility testing (DST). Despite its lower sensitivity than that of other methods, its faster results and simultaneous DST are advantageous in resource-poor settings, supporting the incorporation of MODS into diagnostic algorithms for extrapulmonary TB

The effect of surgery on the outcome of treatment for multidrug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: In 2014 only 50 % of multidrug-resistant tuberculosis (MDR-TB) patients achieved a successful treatment outcome. With limited options for medical treatment, surgery has re-emerged as an adjuvant therapeutic strategy. We conducted a systematic review and meta-analysis to assess the evidence for the effect of surgery as an adjunct to chemotherapy on outcomes of adults treated for MDR-TB. METHODS: Databases and grey literature sources were searched using terms incorporating surgery and MDR-TB. No language or publication type limits were applied. Articles published pre-1990, without a comparator group, or reporting <10 surgical participants were excluded. Two-stage sifting in duplicate was employed. Data on WHO-defined treatment outcomes were abstracted into a standardised database. Study-level risk of bias was evaluated using standardised tools. Outcome-level evidence quality was assessed using GRADE. Forest plots were generated, random effects meta-analysis conducted, and heterogeneity assessed using the I(2) statistic. RESULTS: Of 1024 unique citations identified, 62 were selected for full-text review and 15 retained for inclusion. A further four articles were included after bibliography/citation searching, and one additional unpublished manuscript was identified, giving 20 articles for final inclusion. Six were meta-analyses/systematic reviews and 14 were primary research articles (observational studies). From the 14 primary research articles, a successful outcome (cured/treatment completed) was reported for 81.9 % (371/453) and 59.7 % (1197/2006) in the surgical and non-surgical group respectively, giving a summary odds ratio of 2.62 (95 % confidence interval 1.94-3.54). Loss to follow-up and treatment failure were lower in the surgery group (both p = 0.01). Overall GRADE quality of evidence for all outcomes considered was "very low". CONCLUSIONS: This meta-analysis suggests that surgery as an adjunct to chemotherapy is associated with improved treatment outcomes in MDR-TB patients. However, inherent limitations in observational study design, insufficient reporting, and lack of adjustment for confounders, led to grading of the evidence as very low quality. Data on rationale for surgical referral, subsequent outcomes and resource-limited settings are scarce, precluding evidence-based recommendations on the suitability of surgery by patient characteristics or setting. It is hoped that highlighted methodological and reporting gaps will encourage improved design and reporting of future surgical studies for MDR-TB

Experiencing sense of place in virtual and physical Avebury.

This paper discusses the findings from a project to construct a simulation of Avebury henge, a Late Neolithic/ Early Bronze Age monument in SW Britain, in a 3D, virtual world environment. The aims of the study were to explore the archaeological research and interpretation necessary to plan and construct such a simulation in an interactive, online environment, to identify which aspects of visualisation and soundscape design appear to have the greatest impact upon users’ sense of place in the virtual simulation and to explore the experiences of a small group of users in the virtual simulation and the effects of those experiences upon their sense of place at the physical site. The findings from this project demonstrated that in undertaking a simulation of an ancient site, a core set of sources need to be selected to create the main parts of the simulation. There is often much debate in archaeological literature regarding the way in which archaeological findings are interpreted, and a different virtual Avebury would be constructed if different interpretations had been chosen. Any simulation of an ancient site should therefore clearly recognise and state the basis upon which it has been designed. The evaluation showed that responses to virtual environments, and the resulting effect upon responses to physical environments, are complex and personal, resulting in a range of experiences and perceptions, suggesting that the range of users’ experiences might be a more significant issue than attempting to find any general consensus on user reactions to simulated ancient sites

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial

BACKGROUND: Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis. METHODS: This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete. FINDINGS: Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related. INTERPRETATION: The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis. FUNDING: Médecins Sans Frontières

Protection by the NDI1 Gene against Neurodegeneration in a Rotenone Rat Model of Parkinson's Disease

It is widely recognized that mitochondrial dysfunction, most notably defects in the NADH-quinone oxidoreductase (complex I), is closely related to the etiology of sporadic Parkinson's disease (PD). In fact, rotenone, a complex I inhibitor, has been used for establishing PD models both in vitro and in vivo. A rat model with chronic rotenone exposure seems to reproduce pathophysiological conditions of PD more closely than acute mouse models as manifested by neuronal cell death in the substantia nigra and Lewy body-like cytosolic aggregations. Using the rotenone rat model, we investigated the protective effects of alternative NADH dehydrogenase (Ndi1) which we previously demonstrated to act as a replacement for complex I both in vitro and in vivo. A single, unilateral injection of recombinant adeno-associated virus carrying the NDI1 gene into the vicinity of the substantia nigra resulted in expression of the Ndi1 protein in the entire substantia nigra of that side. It was clear that the introduction of the Ndi1 protein in the substantia nigra rendered resistance to the deleterious effects caused by rotenone exposure as assessed by the levels of tyrosine hydroxylase and dopamine. The presence of the Ndi1 protein also prevented cell death and oxidative damage to DNA in dopaminergic neurons observed in rotenone-treated rats. Unilateral protection also led to uni-directional rotation of the rotenone-exposed rats in the behavioral test. The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD

Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease, the most common adult neurodegenerative movement disorder, demonstrates a brain-wide pathology that begins pre-clinically with alpha-synuclein aggregates ("Lewy neurites") in processes of gut enteric and vagal motor neurons. Rostral progression into substantia nigra with death of dopamine neurons produces the motor impairment phenotype that yields a clinical diagnosis. The vast majority of Parkinson's disease occurs sporadically, and current models of sporadic Parkinson's disease (sPD) can utilize directly infused or systemic neurotoxins.</p> <p>Results</p> <p>We developed a differentiation protocol for human SH-SY5Y neuroblastoma that yielded non-dividing dopaminergic neural cells with long processes that we then exposed to 50 nM rotenone, a complex I inhibitor used in Parkinson's disease models. After 21 days of rotenone, ~60% of cells died. Their processes retracted and accumulated ASYN-(+) and UB-(+) aggregates that blocked organelle transport. Mitochondrial movement velocities were reduced by 8 days of rotenone and continued to decline over time. No cytoplasmic inclusions resembling Lewy bodies were observed. Gene microarray analyses showed that the majority of genes were under-expressed. qPCR analyses of 11 mtDNA-encoded and 10 nDNA-encoded mitochondrial electron transport chain RNAs' relative expressions revealed small increases in mtDNA-encoded genes and lesser regulation of nDNA-encoded ETC genes.</p> <p>Conclusion</p> <p>Subacute rotenone treatment of differentiated SH-SY5Y neuroblastoma cells causes process retraction and partial death over several weeks, slowed mitochondrial movement in processes and appears to reproduce the Lewy neuritic changes of early Parkinson's disease pathology but does not cause Lewy body inclusions. The overall pattern of transcriptional regulation is gene under-expression with minimal regulation of ETC genes in spite of rotenone's being a complex I toxin. This rotenone-SH-SY5Y model in a differentiated human neural cell mimics changes of early Parkinson's disease and may be useful for screening therapeutics for neuroprotection in that disease stage.</p