•Zuranolone is a novel, investigational treatment under development for MDD•Zuranolone showed greater benefit vs placebo and active comparators•Results showed a favorable NNT and NNH for zuranolone ...vs all comparators•MDD patients may benefit from an improved benefit-to-risk profile with zuranolone
Zuranolone (SAGE-217) is a novel, investigational positive allosteric modulator of GABAA receptors being investigated in major depressive disorder (MDD). This analysis of phase 2 data quantified the benefit and risk of zuranolone (30mg) versus placebo and antidepressants in terms of number needed to treat (NNT) and number needed to harm (NNH).
Rates of response, remission, and all-cause discontinuation for zuranolone and 11 antidepressant comparators were obtained from the zuranolone phase 2 clinical study (N=89) and a published network meta-analysis, respectively. An indirect treatment comparison was conducted using the Bucher method to compare zuranolone to standard-of-care.
Zuranolone demonstrated greater benefit compared to placebo on Day 3 (NNT range for response=4-5, NNT for remission=10) and at Day 15 (NNT=3 for response and remission). Compared to SSRIs and SNRIs, zuranolone at Day 15 showed improved treatment response (NNT=4 95% CI = 3; 16 and 5 95% CI = 3; 25, respectively) and remission (NNT=4 95% CI = 2; 13 and 4 95% CI = 2; 18, respectively). This was accompanied by a reduction in all-cause discontinuation, with negative NNH values (−57 and −28), respectively.
Variations in study design across the included trials may limit the generalizability of results.
With a small positive NNT as early as Day 3 indicating robust benefit and a negative NNH indicating reduced harm, this analysis based on a phase 2 study suggests that patients with MDD may benefit from the benefit-to-risk profile of zuranolone.
People with amyotrophic lateral sclerosis (pALS) require complex, multi-disciplinary care, resulting in extensive healthcare resource utilization (HCRU). To investigate the relationship between HCRU ...and ALS progression, the study objectives were (i) to characterize HCRU in pALS and (ii) to establish whether this varied according to disease stage, as defined using three different methodologies: neurologist-defined early/mid/late stage, the King's clinical staging system for ALS, and the Milan Torino Staging system for ALS (MiToS). Real-world data were drawn from the Adelphi ALS Disease-Specific Programme™, a point-in-time survey of neurologists in France, Germany, Italy, Spain, the UK, and the USA conducted July 2020–March 2021. The analysis included survey responses from 142 physicians with respect to 880 pALS. With advancing ALS stage, significant differences were observed in the number of healthcare professional consultations and X-rays per person (both p < 0.05 for all staging systems), and the proportion of pALS with emergency room admissions, intensive care unit admissions, and assisted ventilation (all p < 0.05 for all staging systems). Across stages, >55% of pALS received care from a general neurologist and a general/primary care practitioner. With increasing stage, there was a significant difference in the proportion receiving care from a physical therapist, pulmonologist/respiratory care practitioner, respiratory therapist, speech/language therapist, and palliative care team, and in the proportion receiving care only from professional caregivers (all p < 0.05 for all staging systems). This study confirmed the substantial HCRU required to support pALS through all stages of ALS and highlighted an increasing need for healthcare resources as the disease progresses.
•People with ALS require complex, multi-disciplinary care.•ALS stage may be defined by a neurologist subjectively or using a verified staging system.•Advancing ALS stage is associated with increased healthcare resource utilization.
Background
Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons ...living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King’s, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS).
Methods
Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States.
Results
Neurologists (
n
= 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden.
Conclusions
Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.
Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding ...their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine.
Understanding how human neonates respond to infection remains incomplete. Here, a system-level investigation of neonatal systemic responses to infection shows a surprisingly strong but unbalanced ...homeostatic immune response; developing an elevated set-point of myeloid regulatory signalling and sugar-lipid metabolism with concomitant inhibition of lymphoid responses. Innate immune-negative feedback opposes innate immune activation while suppression of T-cell co-stimulation is coincident with selective upregulation of CD85 co-inhibitory pathways. By deriving modules of co-expressed RNAs, we identify a limited set of networks associated with bacterial infection that exhibit high levels of inter-patient variability. Whereas, by integrating immune and metabolic pathways, we infer a patient-invariant 52-gene-classifier that predicts bacterial infection with high accuracy using a new independent patient population. This is further shown to have predictive value in identifying infection in suspected cases with blood culture-negative tests. Our results lay the foundation for future translation of host pathways in advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis.
Abstract
Background
Aortitis is a heterogeneous rare condition causing aortic inflammation, often due to infectious or autoimmune aetiology. Its presentation, diagnosis and optimal management remain ...poorly understood, often requiring multidisciplinary input. With the advent of improved imaging techniques, an increasing number of radiology reports are identifying features of vasculitis necessitating clinical investigation. We investigated how cases identified on imaging with features of aortitis reflected clinical diagnosis and treatment. We further examined whether radiological detection of aortitis enables more rapid management decisions to improve outcomes.
Methods
A search was conducted of all radiology reports from St George’s Hospital between 2008 and 2018 for key words indicating “aortitis”, including ‘hyperintense vessel uptake’ and ‘periaortic inflammation.’ From 15,963 initial results, 80 reports were identified with radiological suspicion of aortitis.
Results
Of 80 cases, 36/80 were diagnosed with autoimmune or idiopathic inflammatory pathology: 9 retroperitoneal fibrosis, 8 idiopathic, 7 Takayasu’s, 4 giant cell arteritis, 2 inflammatory aneurysms, 2 Behçet's, 2 IgG4 disease, 1 lupus, 1 granulomatosis with polyangiitis. Diagnosis of autoimmune or idiopathic aortitis was based on symptomatology, imaging, serology, vessel biopsy, and treatment response. 14/80 had infective aortitis: 11 had positive microbiology and 3 demonstrated empirical antibiotic response. Table 1 shows demographics. 12/80 had atheromatous disease. 18/80 were not further investigated due to comorbidity, lack of correlation with symptoms, or absence of follow-up. Initial imaging modalities with the highest yield were computed tomography (CTs) with aorta protocols and CTs of thorax/abdomen/pelvis. The most useful radiology report terms included: aortitis, periaortic inflammation, Takayasu’s, and hyperintense vessel uptake.
Conclusion
Our study is the first retrospective case analysis, to our knowledge, of more than 15,000 radiology reports used as a starting point to evaluate for aortitis, identifying a large dataset with a broad case-mix. It contrasts with current literature identifying cases histologically and post-operatively. We found that radiology can be a useful early alert for possible diagnoses which require further assessment. Consequently, we developed an alerting system within our radiology department based on the search terms and imaging modalities identified. This links to a multidisciplinary meeting including vascular and rheumatology, so highlighted cases are discussed early.
Demographics of subjects with Infective Aortitis/Inflammatory Aortitis
Inflammatory
Infective
Total number
N = 36
N = 14
Mean age at diagnosis (standard deviation, SD)
60 (SD 16)
64 (SD 12)
Age range (years)
21-83
29-76
Gender - Female
19
1
Gender - Male
17
13
Current or Ex-Smoker
9
4
Mean number of comorbidities at time of diagnosis (SD)
3 (SD 2.2)
4(SD 2.6)
Comorbidities (% of total patients):
Hypertension
33.3%
50.0%
Ischaemic heart disease
25.0%
21.4%
Renal disease
13.9%
21.4%
Diabetes
13.9%
14.3%
Cardiomyopathy
13.9%
14.3%
Dyslipidaemia
11.1%
28.6%
Atrial fibrillation
11.1%
14.3%
Cerebro-vascular disease
8.3%
28.6%
Peripheral vascular disease
5.6%
14.3%
Legend: Total cases N = 80. Excluded from table N = 30: atheromatous disease =12; not followed up = 18
Disclosures
K. Townsend: None. G. Cattini: None. K. Moss: None. K. Stenson: None. P. Holt: None. R. Morgan: None. N. Sofat: None.
PDF
