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To describe the real-world clinical impact of a commercially available plasma cell-free DNA metagenomic next-generation sequencing assay, the Karius test (KT).
Methods:
We retrospectively evaluated the clinical impact of KT by clinical panel adjudication. Descriptive statistics were used to study associations of diagnostic indications, host characteristics, and KT-generated microbiologic patterns with the clinical impact of KT. Multivariable logistic regression modeling was used to further characterize predictors of higher positive clinical impact.
Results:
We evaluated 1000 unique clinical cases of KT from 941 patients between January 1, 2017–August 31, 2023. The cohort included adult (70%) and pediatric (30%) patients. The overall clinical impact of KT was positive in 16%, negative in 2%, and no clinical impact in 82% of the cases. Among adult patients, multivariable logistic regression modeling showed that culture-negative endocarditis (OR 2.3; 95% CI, 1.11–4.53; P .022) and concern for fastidious/zoonotic/vector-borne pathogens (OR 2.1; 95% CI, 1.11–3.76; P .019) were associated with positive clinical impact of KT. Host immunocompromised status was not reliably associated with a positive clinical impact of KT (OR 1.03; 95% CI, 0.83–1.29; P .7806). No significant predictors of KT clinical impact were found in pediatric patients. Microbiologic result pattern was also a significant predictor of impact.
Conclusions:
Our study highlights that despite the positive clinical impact of KT in select situations, most testing results had no clinical impact. We also confirm diagnostic indications where KT may have the highest yield, thereby generating tools for diagnostic stewardship.
Literature on the necessity for reform of Australia‘s federal division of government continues to blossom, reflecting the assessment of a leading expert in the area that the system is now at a ‘cross-road’ between delivering a vibrant and beneficial federalism to the Australian public or ‘merely a mask for the effective centralisation of power’. Although the solutions advanced by many commentators towards ensuring the first of these outcomes over the second are many and various, it is notable that none looks exclusively to constitutional amendment as the silver bullet of reform. The notorious difficulty of attaining a successful referendum result – particularly on federal issues which have traditionally been amongst the most contentious proposals –as well as the difficulty of encapsulating all that might be done in the way of federal reform within a single suite of proposed amendments, has ensured that sub-constitutional institutions and mechanisms have been looked to as a simpler, more effective way to achieve change.
Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.
Although atypical antipsychotics have lowered the prevalence and severity of extrapyramidal symptoms (EPS), they still contribute to the overall side-effect burden of approved antipsychotics. Drugs with novel mechanisms without D2 dopamine receptor blocking activity have shown promise in treating schizophrenia without the side effects of currently available treatments. KarXT (xanomeline–trospium chloride) represents a possible alternative that targets muscarinic receptors. KarXT demonstrated efficacy compared with placebo in 3 out of 3 short-term acute studies and has not been associated with many of the side effects of D2 dopamine receptor antagonists. Here, we further characterize EPS rates with KarXT in these trials.
Methods
EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) were 5-week, randomized, double-blind, placebo-controlled, inpatient trials in people with schizophrenia experiencing acute psychosis. Data from the safety populations, defined as all participants who received ³1 dose of trial medication, were pooled. For this analysis, we used a broader definition of EPS-related adverse events (AEs) to encompass any new onset of dystonia, dyskinesia, akathisia, or extrapyramidal disorder reported any time after the first dose of medication. Additionally, EPS were assessed by examining change from baseline to week 5 on the Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS).
Results
A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the analyses. The rate of treatment-emergent AEs (TEAEs) associated with EPS was 3.2% in the KarXT group vs 0.9% in the placebo group. The most commonly reported TEAE was akathisia (KarXT, 2.4%; placebo 0.9%); half of possible akathisia cases in the KarXT group (4/8 TEAEs) were from a single US site, considered by the investigator to be unrelated to trial drug, and resolved without treatment. Overall rates of akathisia TEAEs deemed related to trial drug were low (KarXT, 0.6%; placebo 0.3%). Dystonia, dyskinesia, and extrapyramidal disorder TEAEs were reported by only a single subject each (0.3%) in the KarXT arm. All reported TEAEs were mild to moderate in severity. KarXT was associated with no clinically meaningful mean±SD changes from baseline to week 5 on the SAS (-0.1±0.6), BARS (-0.1±0.9), or AIMS (0.0±0.7).
Conclusions
The incidence of EPS-related TEAEs with KarXT was low in comparison to those observed in similar trials of antipsychotics (D2 dopamine receptor antagonists), although head-to-head studies have not been completed. Moreover, KarXT was not associated with increased scores on EPS scales (SAS, BARS, AIMS) across 5 weeks of treatment. These results, combined with the robust efficacy of KarXT in trials to date, suggest that KarXT’s novel mechanism of action may provide therapeutic benefit in the absence of EPS frequently associated with currently available antipsychotics.
In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.
Methods
The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression–Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.
Results
A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.
Conclusions
In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.
Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.
Methods
The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression–Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.
Results
The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen’s d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen’s d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen’s d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen’s d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen’s d, 0.63]).
Conclusions
In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.
Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.
Aims
To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.
Method
The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448).
Results
In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96).
Conclusion
Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.
A battery of 32 tests was administered to a sample including 144 Air Force Officer Candidates and 139 Air Cadets. The factor analysis, using Thurstone's complete centroid method and Zimmerman's graphic method of orthogonal rotations, revealed 12 interpretable factors. The non-reasoning factors were interpreted as verbal comprehension, numerical facility, perceptual speed, visualization, and spatial orientation. The factors derived from reasoning tests were identified as general reasoning, logical reasoning, education of perceptual relations, education of conceptual relations, education of conceptual patterns, education of correlates, and symbol substitution. The logical-reasoning factor corresponds to what has been called deduction, but eduction of correlates is perhaps closer to an ability actually to make deductions. The area called induction appears to resolve into three eduction-of-relations factors. Reasoning factors do not appear always to transcend the type of test material used.
Globally, financial system regulators are susceptible to deliberate and inadvertent influence by the industry that they oversee and, hence, are also susceptible to acting to benefit the industry rather than the public interest – a phenomenon known as ‘regulatory capture’. Australia, arguably, has an optimal model of financial system regulation (a ‘Twin Peaks’ model) comprising separate regulators for prudential soundness on the one hand, and market conduct and consumer protection on the other. However, the current design of the Twin Peaks model has not been sufficient to prevent and address prolonged and systemic misconduct that culminated in a public Royal Commission of Inquiry into misconduct in the industry. Subsequent to the Royal Commission and other inquiries, the Department of Treasury has proposed legislation to establish an Assessment Authority to assess the effectiveness of the Twin Peaks regulators. The proposal includes enquiries by an Assessment Authority into the regulators’ independence, so as to identify instances of, and thereby mitigate, their capture. As with all financial system regulators, the Assessment Authority itself may be susceptible to regulatory capture, either by the Twin Peaks regulators, or by the financial industry. Thus, this paper poses the question: how can the new Assessment Authority be optimally constituted by legislation, and operated, to effectively oversee the effectiveness of the regulators, but itself remain insulated from the influence of the regulators and industry? We analyse the primary sources of influence over financial system regulators that the Assessment Authority will likely face and recommend ways in which a robust design of the Assessment Authority can mitigate those sources of influence. In doing so, we adopt an inter-disciplinary approach, drawing upon not only regulatory theory but also for the first time in relation to this question, organisational psychology. Our findings address gaps in the proposed legislation currently before Federal Parliament and propose methods by which those gaps may be filled, in order to ensure that this important reform to Australia’s financial regulatory regime has the greatest chance of success.
The strategies of MNEs at the start of the twenty-first century were shaped by the turbulent international environment that redefined global competition in the closing decades of the twentieth century. It was during that turmoil that a number of different perspectives and prescriptions emerged about how companies could create strategic advantages in their worldwide businesses.
Historically, the strategic challenge for a company has been viewed primarily as one of protecting potential profits from erosion through either competition or bargaining. Such erosion of profits could be caused not only by the actions of competitors but also by the bargaining powers of customers, suppliers, and governments. The key challenge facing a company was assumed to be its ability to maintain its independence by maintaining strong control over its activities. Furthermore, this strategic approach emphasized the defensive value of making other entities depend on it by capturing critical resources, building switching costs, and exploiting other vulnerabilities.
This book focuses on the management challenges associated with developing the strategies, building the organizations, and managing the operations of companies whose activities stretch across national boundaries. Operating in an international rather than a domestic arena clearly presents managers with many new opportunities. Having worldwide operations not only gives a company access to new markets and low-cost resources, it also opens up new sources of information and knowledge and broadens the options for the strategic moves the company might make to compete with its domestic and international rivals. However, with all these new opportunities come the challenges of managing strategy, organization, and operations that are innately more complex, diverse, and uncertain.
As earlier chapters have made clear, the twenty-first century multinational enterprise (MNE) is markedly different from its twentieth century ancestors. It has been transformed by an environment in which multiple, often conflicting forces accelerate simultaneously. The globalization and deglobalization of markets, the acceleration of product and technology life cycles, the assertion of national governments’ demands, and, above all, the intensification of global competition have created an environment of complexity, diversity, and change for most of today’s MNEs.
In the preceding chapters, we described how changes in the international environment have forced MNEs to simultaneously respond to the strategic need for global efficiency, national responsiveness, and worldwide learning. Implementing a complex, three-pronged strategic objective would be difficult under any circumstances, but the very act of “going international” multiplies a company’s organizational complexity.