Predicting Treatment Effects from Surrogate Endpoints in Historical Trials in First-Line Metastatic Castration-Resistant Prostate Cancer.

Surrogate endpoints are becoming increasingly important in health technology assessment, where decisions are based on complex cost-effectiveness models (CEMs) that require numerous input parameters. Daniels and Hughes Surrogate Model was used to predict missing effect estimates in randomized controlled trials (RCTs) evaluating first-line treatments in metastatic castration-resistant prostate cancer (mCRPC) patients. Network meta-analyses (NMAs) were conducted to assess the comparative efficacy of these treatments. Databases were searched (inception to October 2022) using Ovid®. Several grey literature searches were also conducted (PROSPERO: CRD42021283512). Available trial data for radiographic progression-free survival (rPFS) and overall survival (OS) were used to predict the unreported effect of rPFS or OS for relevant comparator treatments. Bayesian NMAs were conducted using observed and predicted treatment effects. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best (p-best) were obtained. Twenty-five RCTs met the eligibility criteria and of these, 8 reported jointly rPFS and OS; while rPFS was predicted for 12 RCTs and 10 comparators, and OS was predicted for 5 RCTs and 6 comparators. A nonstandard dose of docetaxel (docetaxel 50 mg/m2 every 2 weeks) had the highest probability of being the most effective for rPFS (p-best: 59%) and OS (p-best: 48%), followed by talazoparib plus enzalutamide (13% and 19%, respectively). Advanced surrogate modelling techniques allowed obtaining relevant parameter and indirect estimates of previously unavailable data and may be used to populate future CEMs requiring rPFS and OS in first-line mCRPC.

Host IP3R channels are dispensable for rotavirus Ca2+ signaling but critical for intercellular Ca2+ waves that prime uninfected cells for rapid virus spread.

IMPORTANCE: Many viruses exploit host Ca2+ signaling to facilitate their replication; however, little is known about how Ca2+ signals from different host and viral channels contribute to the overall dysregulation of Ca2+ signaling or promote virus replication. Using cells lacking IP3R, a host ER Ca2+ channel, we delineated intracellular Ca2+ signals within virus-infected cells and intercellular Ca2+ waves (ICWs), which increased Ca2+ signaling in neighboring, uninfected cells. In infected cells, IP3R was dispensable for rotavirus-induced Ca2+ signaling and replication, suggesting the rotavirus NSP4 viroporin supplies these signals. However, IP3R-mediated ICWs increase rotavirus replication kinetics and spread, indicating that the Ca2+ signals from the ICWs may prime nearby uninfected cells to better support virus replication upon eventual infection. This "pre-emptive priming" of uninfected cells by exploiting host intercellular pathways in the vicinity of virus-infected cells represents a novel mechanism for viral reprogramming of the host to gain a replication advantage.

The Inositol Trisphosphate Receptor (IP 3 R) is Dispensable for Rotavirus-induced Ca 2+ Signaling and Replication but Critical for Paracrine Ca 2+ Signals that Prime Uninfected Cells for Rapid Virus Spread.

Rotavirus is a leading cause of viral gastroenteritis. A hallmark of rotavirus infection is an increase in cytosolic Ca 2+ caused by the nonstructural protein 4 (NSP4). NSP4 is a viral ion channel that releases Ca 2+ from the endoplasmic reticulum (ER) and the increase in Ca 2+ signaling is critical for rotavirus replication. In addition to NSP4 itself, host inositol 1,4,5- trisphosphate receptor (IP 3 R) ER Ca 2+ channels may contribute to rotavirus-induced Ca 2+ signaling and by extension, virus replication. Thus, we set out to determine the role of IP 3 R Ca 2+ signaling during rotavirus infection using IP 3 R-knockout MA104-GCaMP6s cells (MA104- GCaMP6s-IP 3 R-KO), generated by CRISPR/Cas9 genome editing. Live Ca 2+ imaging showed that IP 3 R-KO did not reduce Ca 2+ signaling in infected cells but eliminated rotavirus-induced intercellular Ca 2+ waves (ICWs) and therefore the increased Ca 2+ signaling in surrounding, uninfected cells. Further, MA104-GCaMP6s-IP 3 R-TKO cells showed similar rotavirus susceptibility, single-cycle replication, and viral protein expression as parental MA104- GCaMP6s cells. However, MA104-GCaMP6s-IP 3 R-TKO cells exhibited significantly smaller rotavirus plaques, decreased multi-round replication kinetics, and delayed virus spread, suggesting that rotavirus-induced ICW Ca 2+ signaling stimulates virus replication and spread. Inhibition of ICWs by blocking the P2Y1 receptor also resulted in decreased rotavirus plaque size. Conversely, exogenous expression of P2Y1 in LLC-MK2-GCaMP6s cells, which natively lack P2Y1 and rotavirus ICWs, rescued the generation of rotavirus-induced ICWs and enabled plaque formation. In conclusion, this study shows that NSP4 Ca 2+ signals fully support rotavirus replication in individual cells; however, IP 3 R is critical for rotavirus-induced ICWs and virus spread by priming Ca 2+ -dependent pathways in surrounding cells. Importance: Many viruses exploit host Ca 2+ signaling to facilitate their replication; however, little is known about how distinct types of Ca 2+ signals contribute to the overall dysregulation of Ca 2+ signaling or promote virus replication. Using cells lacking IP 3 R, a host ER Ca 2+ channel, we could differentiate between intracellular Ca 2+ signals within virus-infected cells and intercellular Ca 2+ waves (ICWs), which increase Ca 2+ signaling in neighboring, uninfected cells. In infected cells, IP 3 R was dispensable for rotavirus-induced Ca 2+ signaling and replication, suggesting the rotavirus NSP4 viroporin supplies these signals. However, IP 3 R-mediated ICWs increase rotavirus replication kinetics and spread, indicating that the Ca 2+ signals from the ICWs may prime nearby uninfected cells to better support virus replication upon eventual infection. This "pre-emptive priming" of uninfected cells by exploiting host intercellular pathways in the vicinity of virus-infected cells represents a novel mechanism for viral reprogramming of the host to gain a replication advantage.

Exercise therapy for chronic low back pain.

BACKGROUND: Low back pain has been the leading cause of disability globally for at least the past three decades and results in enormous direct healthcare and lost productivity costs. OBJECTIVES: The primary objective of this systematic review is to assess the impact of exercise treatment on pain and functional limitations in adults with chronic non-specific low back pain compared to no treatment, usual care, placebo and other conservative treatments. SEARCH METHODS: We searched CENTRAL (which includes the Cochrane Back and Neck trials register), MEDLINE, Embase, CINAHL, PsycINFO, PEDro, SPORTDiscus, and trials registries (ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform), and conducted citation searching of relevant systematic reviews to identify additional studies. The review includes data for trials identified in searches up to 27 April 2018. All eligible trials have been identified through searches to 7 December 2020, but have not yet been extracted; these trials will be integrated in the next update. SELECTION CRITERIA: We included randomised controlled trials that assessed exercise treatment compared to no treatment, usual care, placebo or other conservative treatment on the outcomes of pain or functional limitations for a population of adult participants with chronic non-specific low back pain of more than 12 weeks' duration. DATA COLLECTION AND ANALYSIS: Two authors screened and assessed studies independently, with consensus. We extracted outcome data using electronic databases; pain and functional limitations outcomes were re-scaled to 0 to 100 points for meta-analyses where 0 is no pain or functional limitations. We assessed risk of bias using the Cochrane risk of bias (RoB) tool and used GRADE to evaluate the overall certainty of the evidence. When required, we contacted study authors to obtain missing data. To interpret meta-analysis results, we considered a 15-point difference in pain and a 10-point difference in functional limitations outcomes to be clinically important for the primary comparison of exercise versus no treatment, usual care or placebo. MAIN RESULTS: We included 249 trials of exercise treatment, including studies conducted in Europe (122 studies), Asia (38 studies), North America (33 studies), and the Middle East (24 studies). Sixty-one per cent of studies (151 trials) examined the effectiveness of two or more different types of exercise treatment, and 57% (142 trials) compared exercise treatment to a non-exercise comparison treatment. Study participants had a mean age of 43.7 years and, on average, 59% of study populations were female. Most of the trials were judged to be at risk of bias, including 79% at risk of performance bias due to difficulty blinding exercise treatments. We found moderate-certainty evidence that exercise treatment is more effective for treatment of chronic low back pain compared to no treatment, usual care or placebo comparisons for pain outcomes at earliest follow-up (MD -15.2, 95% CI -18.3 to -12.2), a clinically important difference. Certainty of evidence was downgraded mainly due to heterogeneity. For the same comparison, there was moderate-certainty evidence for functional limitations outcomes (MD -6.8 (95% CI -8.3 to -5.3); this finding did not meet our prespecified threshold for minimal clinically important difference. Certainty of evidence was downgraded mainly due to some evidence of publication bias.  Compared to all other investigated conservative treatments, exercise treatment was found to have improved pain (MD -9.1, 95% CI -12.6 to -5.6) and functional limitations outcomes (MD -4.1, 95% CI -6.0 to -2.2). These effects did not meet our prespecified threshold for clinically important difference. Subgroup analysis of pain outcomes suggested that exercise treatment is probably more effective than education alone (MD -12.2, 95% CI -19.4 to -5.0) or non-exercise physical therapy (MD -10.4, 95% CI -15.2 to -5.6), but with no differences observed for manual therapy (MD 1.0, 95% CI -3.1 to 5.1). In studies that reported adverse effects (86 studies), one or more adverse effects were reported in 37 of 112 exercise groups (33%) and 12 of 42 comparison groups (29%). Twelve included studies reported measuring adverse effects in a systematic way, with a median of 0.14 (IQR 0.01 to 0.57) per participant in the exercise groups (mostly minor harms, e.g. muscle soreness), and 0.12 (IQR 0.02 to 0.32) in comparison groups. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that exercise is probably effective for treatment of chronic low back pain compared to no treatment, usual care or placebo for pain. The observed treatment effect for the exercise compared to no treatment, usual care or placebo comparisons is small for functional limitations, not meeting our threshold for minimal clinically important difference. We also found exercise to have improved pain (low-certainty evidence) and functional limitations outcomes (moderate-certainty evidence) compared to other conservative treatments; however, these effects were small and not clinically important when considering all comparisons together. Subgroup analysis suggested that exercise treatment is probably more effective than advice or education alone, or electrotherapy, but with no differences observed for manual therapy treatments.

Some types of exercise are more effective than others in people with chronic low back pain: a network meta-analysis.

QUESTION: What are the effects of specific types of exercise treatments on pain intensity and functional limitation outcomes for adults with chronic low back pain? DESIGN: Systematic review with network meta-analysis of randomised controlled trials. PARTICIPANTS: Adults with non-specific low back pain for ≥ 12 weeks. INTERVENTION: Exercise treatments prescribed or planned by a health professional that involved conducting specific activities, postures and/or movements with a goal to improve low back pain outcomes. OUTCOME MEASURES: Pain intensity (eg, visual analogue scale or numerical rating scale) and back-related functional limitations (eg, Roland Morris Disability Questionnaire or Oswestry Disability Index), each standardised to range from 0 to 100. RESULTS: This review included 217 randomised controlled trials with 20,969 participants and 507 treatment groups. Most exercise types were more effective than minimal treatment for pain and functional limitation outcomes. Network meta-analysis results were compatible with moderate to clinically important treatment effects for Pilates, McKenzie therapy, and functional restoration (pain only) and flexibility exercises (function only) compared with minimal treatment, other effective treatments and other exercise types. The estimated mean differences for these exercise types compared with minimal treatment ranged from -15 to -19 for pain and from -10 to -12 for functional limitation. CONCLUSION: This review found evidence that Pilates, McKenzie therapy and functional restoration were more effective than other types of exercise treatment for reducing pain intensity and functional limitations. Nevertheless, people with chronic low back pain should be encouraged to perform the exercise that they enjoy to promote adherence. REGISTRATION: DOI:10.1002/14651858.CD009790.

Prolonged opioid use among opioid-naive individuals after prescription for nonspecific low back pain in the emergency department.

ABSTRACT: Low back pain is a leading cause of disability globally. It is a common reason for presentation to the emergency department where opioids are commonly prescribed. This is a retrospective cohort study of opioid-naive adults with low back pain presenting to 1 of 4 emergency departments in Nova Scotia. We use routinely collected administrative clinical and drug-use data (July 2010-November 2017) to investigate the prevalence of prolonged opioid use and associated individual and prescription characteristics. In total, 23,559 eligible individuals presented with nonspecific low back pain, with 84.4% being opioid-naive. Our study population included 4023 opioid-naive individuals who filled a new opioid prescription within 7 days after their index emergency department visit (24.4%). The prevalence of prolonged opioid use after a new opioid prescription for low back pain (filling an opioid prescription 8-90 days after the emergency department visit and filling a subsequent prescription ±30 days of 6 months) was 4.6% (185 individuals). Older age and female sex were associated with clinically important increased odds of prolonged opioid use. First prescription average >90 morphine milligram equivalents/day (odds ratio 1.6, 95% confidence interval 1.0-2.6) and greater than 7-day supply (1.9, 1.1-3.1) were associated with prolonged opioid use in adjusted models. We found evidence of declining opioid prescriptions over the study period, but that 24.3% of first opioid prescriptions in 2016 would not have aligned with current guideline recommendations. Our study provides evidence to support a cautious approach to prescribing in opioid-naive populations.

Nisin Z and lacticin 3147 improve efficacy of antibiotics against clinically significant bacteria.

Aim: To determine if bacteriocins improve antibiotic efficacy. Materials & methods: Deferred antagonism assays identified bacteriocins with activity. Growth curves and time kill assays demonstrated bactericidal activity of antimicrobial combinations, and checkerboard assays confirmed synergy. Methicillin-resistant Staphylococcus aureus-infected porcine skin model determined ex vivo efficacy. Results: Subinhibitory concentrations of lacticin with penicillin or vancomycin resulted in complete growth inhibition of strains and the improved inhibitory effect was apparent after 1 h. Nisin with methicillin proved more effective against methicillin-resistant Staphylococcus aureus than either antimicrobial alone, revealing partial synergy and significantly reduced pathogen numbers on porcine skin after 3 h compared with minimal inhibition for either antimicrobial alone. Conclusion: Nisin Z and lacticin 3147 may support the use of certain antibiotics and revive ineffective antibiotics.