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Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
A significant portion of patients with Clostridium difficile infections (CDI) experience recurrence, and there is little consensus on its treatment. With the availability of newer agents for CDI and the added burdens of recurrent disease, a cost-effectiveness analysis may provide insight on the most efficient use of resources.
A decision-tree analysis was created to compare the cost-effectiveness of 3 possible treatments for patients with first CDI recurrence: oral vancomycin, fidaxomicin, or bezlotoxumab plus vancomycin. The model was performed from a payer’s perspective with direct cost inputs and a timeline of 1 year. A systematic review of literature was performed to identify clinical, utility, and cost data. Quality-adjusted life years (QALY) and incremental cost-effectiveness ratios were calculated. The willingness-to-pay (WTP) threshold was set at $100,000 per QALY gained. The robustness of the model was tested using one-way sensitivity analyses and probabilistic sensitivity analysis.
Vancomycin had the lowest cost ($15,692) and was associated with a QALY gain of 0.8019 years. Bezlotoxumab plus vancomycin was a dominated strategy. Fidaxomicin led to a higher QALY compared to vancomycin, at an incremental cost of $500,975 per QALY gained. Based on our WTP threshold, vancomycin alone was the most cost-effective regimen for treating the first recurrence of CDI. Sensitivity analyses demonstrated the model’s robustness.
Vancomycin alone appears to be the most cost-effective regimen for the treatment of first recurrence of CDI. Fidaxomicin alone led to the highest QALY gained, but at a cost beyond what is considered cost-effective.
In Hong Kong, universal varicella vaccination started in July 2014. Before this, children could receive varicella vaccine via the private market. We analysed the epidemiology of varicella and zoster before universal vaccination. We estimated varicella vaccination coverage through surveys in preschool children. We estimated the burden of varicella and zoster with varicella notifications from 1999/00 to 2013/14, Accident and Emergency Department (A&E) attendance and inpatient admissions to public hospitals from 2004/05 to 2013/14. We fitted a catalytic model to serological data on antibodies against varicella-zoster virus to estimate the force of infection. We found that varicella vaccination coverage gradually increased to about 50% before programme inception. In children younger than 5 years, the annual rate of varicella notifications, varicella admission and zoster A&E attendance generally declined. The annual notification, A&E attendance and hospitalisation rate of varicella and zoster generally increased for individuals between 10 and 59 years old. Varicella serology indicated an age shift during the study period towards a higher proportion of infections in slightly older individuals, but the change was most notable before vaccine licensure. In conclusion, we observed a shift in the burden of varicella to slightly older age groups with a corresponding increase in incidence but it cannot necessarily be attributed to private market vaccine coverage alone. Increasing varicella vaccination uptake in the private market might affect varicella transmission and epidemiology, but not to the level of interrupting transmission.
While the intersection of the Grassmannian Bruhat decompositions for all coordinate flags is an intractable mess, it turns out that the intersection of only the cyclic shifts of one Bruhat decomposition has many of the good properties of the Bruhat and Richardson decompositions. This decomposition coincides with the projection of the Richardson stratification of the flag manifold, studied by Lusztig, Rietsch, Brown–Goodearl–Yakimov and the present authors. However, its cyclic-invariance is hidden in this description. Postnikov gave many cyclic-invariant ways to index the strata, and we give a new one, by a subset of the affine Weyl group we call bounded juggling patterns. We call the strata positroid varieties. Applying results from [A. Knutson, T. Lam and D. Speyer, Projections of Richardson varieties, J. Reine Angew. Math., to appear, arXiv:1008.3939 [math.AG]], we show that positroid varieties are normal, Cohen–Macaulay, have rational singularities, and are defined as schemes by the vanishing of Plücker coordinates. We prove that their associated cohomology classes are represented by affine Stanley functions. This latter fact lets us connect Postnikov’s and Buch–Kresch–Tamvakis’ approaches to quantum Schubert calculus.
Brain serotonin2 (5-hydroxytryptamine2; 5-HT2) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT2 receptors in contrast to antidepressant medications, which down-regulate brain 5-HT2 receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT2 receptors, but the effects of ECT on these receptors in individuals with depression are unknown.
To determine if a course of ECT alters brain 5-HT2 receptors in individuals with depression and whether such changes correlate with improvement in symptoms.
Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT2 receptors with ECT and their relationship to therapeutic outcome.
Widespread reduction in brain 5-HT2 receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT2 receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms.
Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT2 receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.
We construct the Schubert basis of the torus-equivariant K-homology of the affine Grassmannian of a simple algebraic group G, using the K-theoretic NilHecke ring of Kostant and Kumar. This is the K-theoretic analogue of a construction of Peterson in equivariant homology. For the case where G=SLn, the K-homology of the affine Grassmannian is identified with a sub-Hopf algebra of the ring of symmetric functions. The Schubert basis is represented by inhomogeneous symmetric functions, calledK-k-Schur functions, whose highest-degree term is a k-Schur function. The dual basis in K-cohomology is given by the affine stable Grothendieck polynomials, verifying a conjecture of Lam. In addition, we give a Pieri rule in K-homology. Many of our constructions have geometric interpretations by means of Kashiwara’s thick affine flag manifold.
Although 5-hydroxytryptamine (5-HT) has been implicated in mania, the precise alterations in the 5-HT system remain elusive.
To assess brain 5-HT2 receptors in drug-free individuals experiencing a manic episode in comparison with healthy volunteers using positron emission tomography (PET).
Participants (n = 10) with DSM–IV bipolar I disorder – manic episode and healthy controls (n = 10) underwent [18F]- setoperone scans. The differences in 5-HT2 receptor binding potential between the two groups were determined using statistical parametric mapping (SPM) analysis.
Age was a significant correlate with 5-HT2 receptor binding potential with a similar magnitude of correlation in both groups. The SPM analysis with age as a covariate showed that the individuals with current mania had significantly lower 5-HT2 receptor binding potential in frontal, temporal, parietal and occipital cortical regions, with changes more prominent in the right cortical regions compared with controls.
This study suggests that brain 5-HT∗2 receptors are decreased in people with acute mania.
Dedicated to George Szekeres on his ninetieth birthday
In this paper we prove that a bipartite graph with parts of sizes M and N, having no cycles of even length less that or equal to 2(2k + 1), where k is a positive integer, has at most (NM)(k+1)/(2k+1) + Dk(N + M) edges, where Dk only depends on k.
In particular, we show that when k = 1, D1 = 1 is possible.
The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown.
To determine the effects of RTD on brain 5-HT2 receptors using positron emission tomography (PET) and 18F-labelled setoperone.
Ten healthy women underwent two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days.
The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT2 receptor binding in various cortical regions following the RTD session.
When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT2 receptors, these findings suggest that a decrease in 5-HT2 binding following RTD might be an adaptive response that provides protection against depressive symptoms.