The smallest worthwhile effect on pain intensity of exercise therapy for people with chronic low back pain: a discrete choice experiment study.

OBJECTIVE: To identify the smallest worthwhile effect (SWE) of exercise therapy for people with non-specific chronic low back pain (CLBP). DESIGN: Discrete choice experiment. METHODS: The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email obtained from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS: Two-hundred and thirteen participants completed the survey. The mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. In the sensitivity analyses, the SWE varied with different levels of certainty calibration; from 0% without certainty calibration to 60% with more extreme certainty calibration. CONCLUSION: This patient-informed threshold of clinical importance could guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise.

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials: A Systematic Review.

Importance: Observational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence to policy and practice. Objective: To assess the reporting of observational studies that explicitly aimed to emulate a target trial. Evidence Review: We searched Medline, Embase, PsycINFO, and Web of Science for observational studies published between March 2012 and October 2022 that explicitly aimed to emulate a target trial of a health or medical intervention. Two reviewers double-screened and -extracted data on study characteristics, key predefined components of the target trial protocol and its emulation (eligibility criteria, treatment strategies, treatment assignment, outcome[s], follow-up, causal contrast[s], and analysis plan), and other items related to the target trial emulation. Findings: A total of 200 studies that explicitly aimed to emulate a target trial were included. These studies included 26 subfields of medicine, and 168 (84%) were published from January 2020 to October 2022. The aim to emulate a target trial was explicit in 70 study titles (35%). Forty-three studies (22%) reported use of a published reporting guideline (eg, Strengthening the Reporting of Observational Studies in Epidemiology). Eighty-five studies (43%) did not describe all key items of how the target trial was emulated and 113 (57%) did not describe the protocol of the target trial and its emulation. Conclusion and Relevance: In this systematic review of 200 studies that explicitly aimed to emulate a target trial, reporting of how the target trial was emulated was inconsistent. A reporting guideline for studies explicitly aiming to emulate a target trial may improve the reporting of the target trial protocols and other aspects of these emulation attempts.

The smallest worthwhile effect on pain intensity of nonsteroidal anti-inflammatory drugs and exercise therapy for acute and chronic low back pain: a benefit-harm trade-off study.

QUESTION: What are the smallest worthwhile effects of nonsteroidal anti-inflammatory drugs (NSAIDs) for people with acute and chronic low back pain (LBP)? What is the smallest worthwhile effect of individualised exercise for people with chronic LBP compared with no intervention? DESIGN: Benefit-harm trade-off study. PARTICIPANTS: Participants were recruited by advertisement on social media and included if they were English-speaking adults in Australia who had non-specific LBP. OUTCOME MEASURE: Pain intensity. RESULTS: A total of 116 people with acute LBP and 230 people with chronic LBP were recruited. For acute LBP, the smallest worthwhile effect of NSAIDs additional to no intervention was a 30% (IQR 10 to 40%) reduction in pain intensity. For chronic LBP, the smallest worthwhile effect of NSAIDs additional to no intervention was a 27.5% (IQR 10 to 50%) reduction in pain intensity. For chronic LBP, the smallest worthwhile effect of exercise additional to no intervention was a 20% (IQR 10 to 40%) reduction in pain intensity. There were small associations between baseline pain, duration of pain and level of exercise and the smallest worthwhile effect of NSAIDs for acute LBP. There were no other clear associations. CONCLUSIONS: For people with LBP, the smallest worthwhile effect of exercise and NSAIDs additional to no intervention is approximately a 20 to 30% reduction in pain. These results can inform the interpretation of the effects of NSAIDs and exercise in randomised trials and meta-analyses, incorporating consumers' perspectives. Further research on comparisons between different interventions and on other core LBP outcomes may inform decision-making. REGISTRATION: OSF osf.io/3erjx/.

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication.

Psilocybin is being investigated as a treatment in adults with treatment-resistant depression (TRD). Withdrawal from serotonergic antidepressant drugs is a common prerequisite for taking part in trials of psilocybin due to the possibility of ongoing antidepressant drugs altering the psychedelic effect. This phase II, exploratory, international, fixed-dose, open-label study explored the safety, tolerability, and efficacy of a synthetic form of psilocybin (investigational drug COMP360) adjunct to a selective serotonin reuptake inhibitor in participants with TRD. Participants received a single 25 mg dose of psilocybin alongside psychological support and were followed-up for 3 weeks. The primary efficacy end point was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from Baseline at Week 3. Secondary end points were safety, including treatment-emergent adverse events (TEAEs), the proportion of responders and remitters at Week 3, and the change from Baseline to Week 3 in Clinical Global Impression-Severity (CGI-S) score. Nineteen participants were dosed and the mean Baseline MADRS total score was 31.7 (SD = 5.77). Twelve (63.2%) participants had a TEAE, most of which were mild and resolved on the day of onset. There were no serious TEAEs or indication of increased suicidal ideation or behavior. At Week 3, mean change from Baseline in MADRS total score was -14.9 (95% CI, -20.7 to -9.2), and -1.3 (SD = 1.29) in the CGI-S. Both response and remission were evident in 8 (42.1%) participants. Larger, comparator-controlled trials are necessary to understand if this paradigm can optimize treatment-outcome where antidepressant drug withdrawal would be problematic.

Movement behavior of swordfish provisions connectivity between the temperate and tropical southwest Pacific Ocean.

Swordfish (Xiphias gladius) are a widely distributed (45°N-45°S) large pelagic fish targeted by fisheries worldwide. Swordfish that occur at high latitudes tend to disproportionately be large adults, so their movements have implications for population dynamics and fisheries management. In the southwest Pacific, little is known about this subset of the stock and existing evidence suggests limited movement from the subtropics into cooler high latitude waters. Here, we capitalize on the recent emergence of a recreational swordfish fishery off temperate southeast Australia to characterize movements of swordfish caught in the fishery with pop-up satellite archival transmitting tags. Data were recovered from tags deployed for 56-250 days on 11 swordfish (50-350 kg) tagged between 38 and 43°S in the western Tasman Sea. Five swordfish entered the Coral Sea (< 30°S), with four reaching north to 11-24°S, up to 3275 km away from location of capture. Behavior modelling suggests these four individuals rapidly transited north until encountering 23-27 °C water, at which point they lingered in the area for several months, consistent with spawning-related partial migration. One migrating swordfish still carrying a tag after the spawning season returned to ~ 120 km of its release location, suggesting site fidelity. Movements toward the central south Pacific were confined to two individuals crossing 165°E. Swordfish predominantly underwent normal diel vertical migration, descending into the mesopelagic zone at dawn (median daytime depth 494.9 m, 95% CI 460.4-529.5 m). Light attenuation predicted daytime depth, with swordfish rising by up to 195 m in turbid water. At night, swordfish were deeper during the full moon, median night-time depth 45.8 m (37.8-55.5) m versus 18.0 m (14.9-21.8) m at new moon. Modelling fine-scale (10 min-1) swordfish depth revealed dynamic effects of moon phase varying predictably across time of night with implications for fisheries interactions. Studying highly migratory fishes near distribution limits allows characterization of the full range of movement phenotypes within a population, a key consideration for important fish stocks in changing oceans.

Interrogation of an Enzyme Library Reveals the Catalytic Plasticity of Naturally Evolved [4+2] Cyclases.

Stereoselective carbon-carbon bond forming reactions are quintessential transformations in organic synthesis. One example is the Diels-Alder reaction, a [4+2] cycloaddition between a conjugated diene and a dienophile to form cyclohexenes. The development of biocatalysts for this reaction is paramount for unlocking sustainable routes to a plethora of important molecules. To obtain a comprehensive understanding of naturally evolved [4+2] cyclases, and to identify hitherto uncharacterised biocatalysts for this reaction, we constructed a library comprising forty-five enzymes with reported or predicted [4+2] cycloaddition activity. Thirty-one library members were successfully produced in recombinant form. In vitro assays employing a synthetic substrate incorporating a diene and a dienophile revealed broad-ranging cycloaddition activity amongst these polypeptides. The hypothetical protein Cyc15 was found to catalyse an intramolecular cycloaddition to generate a novel spirotetronate. The crystal structure of this enzyme, along with docking studies, establishes the basis for stereoselectivity in Cyc15, as compared to other spirotetronate cyclases.

Discovery and biosynthetic assessment of 'Streptomyces ortus' sp. nov. isolated from a deep-sea sponge.

The deep sea is known to host novel bacteria with the potential to produce a diverse array of undiscovered natural products. Thus, understanding these bacteria is of broad interest in ecology and could also underpin applied drug discovery, specifically in the area of antimicrobials. Here, we isolate a new strain of Streptomyces from the tissue of the deep-sea sponge Polymastia corticata collected at a depth of 1869 m from the Gramberg Seamount in the Atlantic Ocean. This strain, which was given the initial designation A15ISP2-DRY2T, has a genome size of 9.29 Mb with a G+C content of 70.83 mol%. Phylogenomics determined that A15ISP2-DRY2T represents a novel species within the genus Streptomyces as part of the Streptomyces aurantiacus clade. The biosynthetic potential of A15ISP2-DRY2T was assessed relative to other members of the S. aurantiacus clade via comparative gene cluster family (GCF) analysis. This revealed a clear congruent relationship between phylogeny and GCF content. A15ISP2-DRY2T contains six unique GCFs absent elsewhere in the clade. Culture-based assays were used to demonstrate the antibacterial activity of A15ISP2-DRY2T against two drug-resistant human pathogens. Thus, we determine A15ISP2-DRY2T to be a novel bacterial species with considerable biosynthetic potential and propose the systematic name 'Streptomyces ortus' sp. nov.

The Efficacy of Graded Motor Imagery and Its Components on Phantom Limb Pain and Disability: A Systematic Review and Meta-Analysis.

Introduction: Graded Motor Imagery (GMI) is a non-invasive and inexpensive therapy used to treat Phantom Limb Pain (PLP) by sequentially activating motor networks in such a way that movement and pain are unpaired. The objective of this systematic review was to critically appraise relevant data on the efficacy of GMI and its components for reducing PLP and disability in amputees. Methods: We searched 11 electronic databases for controlled trials investigating GMI and its components in amputees with PLP from inception until February 2023. Two reviewers independently screened studies and extracted relevant data. Study-level data were entered using the inverse variance function of the Review Manager 5 and pooled with the random effects model. Results: Eleven studies with varying risk of bias were eligible. No eligible study considered left/right judgement tasks in isolation. Studies showed no effect for imagined movements, but positive effects were seen for GMI [weighted mean difference: -21.29 (95%CI: -31.55, -11.02), I2= 0%] and mirror therapy [weighted mean difference: -8.55 (95%CI: -14.74, -2.35, I2= 61%]. A comparison of mirror therapy versus sham showed no difference [weighted mean difference: -4.43 (95%CI: -16.03, 7.16), I2= 51%]. Conclusion: Our findings suggest that GMI and mirror therapy may be effective for reducing PLP. However, this conclusion was drawn from a limited body of evidence, and the certainty of the evidence was very low. Therefore, rigorous, high-quality trials are needed to address the gap in the literature and inform practice.

Contexte: L'imagerie motrice graduelle (IMG) est un traitement non invasif et peu coûteux utilisé pour traiter la douleur du membre fantôme par activation séquentielle des réseaux moteurs de manière à ce que le mouvement et la douleur soient dissociés. L'objectif de cette revue systématique était d'évaluer de manière critique les données sur l'efficacité de l'IMG et de ses composantes pour réduire la douleur du membre fantôme et l'invalidité chez les amputés.Méthodes: Nous avons effectué des recherches dans 11 bases de données électroniques afin d'y repérer des essais contrôlés portant sur l'utilisation de l'IMG et de ses composantes auprès des amputés atteints de douleur du membre fantôme depuis le début jusqu'en février 2023. Deux évaluateurs indépendants ont examiné les études et extrait les données pertinentes Les données au niveau de l'étude ont été saisies à l'aide de la fonction de variation inverse de Review Manager 5 et regroupées selon un modèle à effets aléatoires.Résultats: Onze études présentant un risque de biais variable ont été retenues. Aucune étude admissible ne se penchait sur les tâches de jugement gauche/droite de manière isolée. Les études n'ont montré aucun effet pour les mouvements imaginés, mais des effets positifs ont été observés pour l'IMG [différence moyenne pondérée : -21,29 (IC à 95 % : -31,55, -11,02), I2 = 0 %] et la thérapie miroir [différence moyenne pondérée: -8,55 (IC 95% : -14,74, -2,35, I2 = 61%]. La comparaison de la thérapie miroir à une thérapie factice n'a montré aucune différence [différence moyenne pondérée : -4,43 (IC à 95 % : -16,03, 7.16), I2 = 51 %].Conclusion: Nos résultats indiquent que l'IMG et la thérapie miroir peuvent être efficaces pour réduire la douleur du membre fantôme. Cependant, cette conclusion a été tirée à partir d'un ensemble limité de données probantes, et la certitude de ces dernières était très faible. Par conséquent, des essais rigoureux et de haute qualité sont nécessaires pour combler les lacunes dans la littérature et éclairer la pratique.

Correction: Back et al. A New Micromonospora Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge. Mar. Drugs 2021, 19, 105.

After publication of this article [...].

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

Adverse event reports of anaphylaxis after Comirnaty and Vaxzevria COVID-19 vaccinations, Western Australia, 22 February to 30 June 2021.

Within the first 4 months of the Western Australian COVID-19 immunisation programme, 49 suspected anaphylaxis cases were reported to the vaccine safety surveillance system. Twelve reports met Brighton Collaboration case definition, corresponding to rates of 15.9 and 17.7 per million doses of Vaxzevria and Comirnaty administered respectively.

Rescaling pain intensity measures for meta-analyses of analgesic medicines for low back pain appears justified: an empirical examination from randomised trials.

OBJECTIVE: Meta-analyses of analgesic medicines for low back pain often rescale measures of pain intensity to use mean difference (MD) instead of standardised mean difference for pooled estimates. Although this improves clinical interpretability, it is not clear whether this method is justified. Our study evaluated the justification for this method. METHODS: We identified randomised clinical trials of analgesic medicines for adults with low back pain that used two scales with different ranges to measure the same construct of pain intensity. We transformed all data to a 0-100 scale, then compared between-group estimates across pairs of scales with different ranges. RESULTS: Twelve trials were included. Overall, differences in means between pain intensity measures that were rescaled to a common 0-100 scale appeared to be small and randomly distributed. For one study that measured pain intensity on a 0-100 scale and a 0-10 scale; when rescaled to 0-100, the difference in MD between the scales was 0.8 points out of 100. For three studies that measured pain intensity on a 0-10 scale and 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.2 points out of 100 (range 5.5 points lower to 2.7 points higher). For two studies that measured pain intensity on a 0-100 scale and a 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points out of 100 (range 6.2 points lower to 12.1 points higher). Finally, for six studies that measured pain intensity on a 0-100 scale and a 0-4 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points (range 5.4 points lower to 8.3 points higher). CONCLUSION: Rescaling pain intensity measures may be justified in meta-analyses of analgesic medicines for low back pain. Systematic reviewers may consider this method to improve clinical interpretability and enable more data to be included. STUDY REGISTRATION/DATA AVAILABILITY: Open Science Framework (osf.io/8rq7f).

The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation.

BACKGROUND: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin's effects on cognitive function have not been widely or systematically studied. AIM: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. METHODS: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support - each participant having an assigned, dedicated therapist available throughout the session. RESULTS: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. CONCLUSIONS: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. CLINICAL TRIAL REGISTRATION: EudraCT (https://www.clinicaltrialsregister.eu/) number: 2018-000978-30.

Rare presentation of Fabry disease as 'burnt-out' hypertrophic cardiomyopathy.

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow-up, before presenting with end-stage heart failure. This was initially suspected as dilated cardiomyopathy and then 'burnt-out phase' of HCM but subsequently the underlying diagnosis was Fabry disease. Fabry disease is an uncommon lysosomal-storage disease due to reduced or absent activity of the alpha-galactosidase A enzyme. Cardiac involvement most frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabry can progress to a 'burnt out' phase, whereby initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle.

Leibovich score is the optimal clinico-pathological system associated with recurrence of non-metastatic clear cell renal cell carcinoma.

PURPOSE: To determine the optimal post-operative risk stratification system associated with survival following surgery for clear cell renal cell carcinoma (ccRCC): tumour grade, tumour stage, Leibovich 2003, Leibovich 2018, Kattan, Stage, size, grade and necrosis (SSIGN) or UCLA Integrated Staging System (UISS) scores. METHODS: 542 patients with non-metastatic ccRCC who underwent nephrectomy 2008-2018 were reviewed. Primary outcome was recurrence-free survival (RFS), with secondary outcomes cancer-specific survival (CSS) and overall survival (OS). RESULTS: All systems were significantly associated with RFS, CSS and OS by Kaplan-Meier and unadjusted Cox-regression. ROC analysis identified that Leibovich 2003, Leibovich 2018A or B and SSIGN were optimally association with 5year RFS (AUC (Area under curve) 0.87, 0.86, 0.86 and 0.86), but Leibovich 2003 or 2018A offered additional information on adjusted regression analysis (HR 1.24, P = 0.02; HR 1.17, P = 0.04). ROC analysis identified that Leibovich 2018B, Leibovich 2003, SSIGN and UISS were equally associated with 5 year OS (AUC 0.76, 0.74, 0.73 and 0.72). UISS added additional explanation of the variance in OS on adjusted regression analysis (HR 1.96, P = 0.002). A novel combination of Leibovich 2003 score and Eastern Co-operative Oncology Group (ECOG) performance status improved 5 year OS association compared to the Leibovich 2003 alone (AUC 0.78, P = 0.001), without affecting association with 5year RFS (AUC 0.87, P = 0.75). CONCLUSIONS: All systems were robust tools associated with RFS, CSS and OS in ccRCC. In our cohort, the Leibovich 2003 and Leibovich 2018A scores may be better associated with RFS compared to other strategies. The UISS, Leibovich 2018B or Leibovich 2003 combined with ECOG performance status may stratify OS better than other modalities.

One vaccine for life: Lessons from immune ontogeny.

There remains a general misconception that the immune status of the fetus and neonate is immature or insufficient. However, emerging research in immune ontogeny prompts reconsideration of this orthodoxy, reframing this period instead as one of unique opportunity. Vaccine responses (qualitative and quantitative) vary between individuals, and across demographic cohorts. Elements of baseline immune status and function predict vaccine response - some of these factors are well described, others remain a subject of ongoing research, especially with the rapidly expanding field of 'omics' research, enabled by development of highly granular immune profiling techniques and increasing computational capacity. Age is one of the strongest predictive factors associated with variability in the response to vaccination; and predictable variation in response to vaccination is a key to identify the crucial underlying mechanisms. Specifically, circulating maternal antibody in the young infant can modulate immune response to vaccination, acting as an 'undercover adjuvant' that, counter to current dogma, may offer a pathway to longer lasting, higher quality immune response to vaccination. Exciting avenues for novel research in this area have the potential to dramatically alter how we protect the world's most vulnerable population - the very young.

A New Micromonospora Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge.

To tackle the growing problem of antibiotic resistance, it is essential to identify new bioactive compounds that are effective against resistant microbes and safe to use. Natural products and their derivatives are, and will continue to be, an important source of these molecules. Sea sponges harbour a diverse microbiome that co-exists with the sponge, and these bacterial communities produce a rich array of bioactive metabolites for protection and resource competition. For these reasons, the sponge microbiota constitutes a potential source of clinically relevant natural products. To date, efforts in bioprospecting for these compounds have focused predominantly on sponge specimens isolated from shallow water, with much still to be learned about samples from the deep sea. Here we report the isolation of a new Micromonospora strain, designated 28ISP2-46T, recovered from the microbiome of a mid-Atlantic deep-sea sponge. Whole-genome sequencing reveals the capacity of this bacterium to produce a diverse array of natural products, including kosinostatin and isoquinocycline B, which exhibit both antibiotic and antitumour properties. Both compounds were isolated from 28ISP2-46T fermentation broths and were found to be effective against a plethora of multidrug-resistant clinical isolates. This study suggests that the marine production of isoquinocyclines may be more widespread than previously supposed and demonstrates the value of targeting the deep-sea sponge microbiome as a source of novel microbial life with exploitable biosynthetic potential.