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Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Background: The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far. Methods: Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150mg/m2 every 2 weeks) and paclitaxel (225mg/m2 every 2 weeks) with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4). Results: Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. Trial registration: Current Controlled Trials ISRCTN38983527.
Early maternal care may counteract familial liability for psychopathology in the reward circuitry
(2018)
Reward processing is altered in various psychopathologies and has been shown to be susceptible to genetic and environmental influences. Here, we examined whether maternal care may buffer familial risk for psychiatric disorders in terms of reward processing. Functional magnetic resonance imaging during a monetary incentive delay task was acquired in participants of an epidemiological cohort study followed since birth (N = 172, 25 years). Early maternal stimulation was assessed during a standardized nursing/playing setting at the age of 3 months. Parental psychiatric disorders (familial risk) during childhood and the participants’ previous psychopathology were assessed by diagnostic interview. With high familial risk, higher maternal stimulation was related to increasing activation in the caudate head, the supplementary motor area, the cingulum and the middle frontal gyrus during reward anticipation, with the opposite pattern found in individuals with no familial risk. In contrast, higher maternal stimulation was associated with decreasing caudate head activity during reward delivery and reduced levels of attention deficit hyperactivity disorder (ADHD) in the high-risk group. Decreased caudate head activity during reward anticipation and increased activity during delivery were linked to ADHD. These findings provide evidence of a long-term association of early maternal stimulation on both adult neurobiological systems of reward underlying externalizing behavior and ADHD during development.
We present a higher-order call-by-need lambda calculus enriched with constructors, case-expressions, recursive letrec-expressions, a seq-operator for sequential evaluation and a non-deterministic operator amb that is locally bottom-avoiding. We use a small-step operational semantics in form of a single-step rewriting system that defines a (nondeterministic) normal order reduction. This strategy can be made fair by adding resources for bookkeeping. As equational theory we use contextual equivalence, i.e. terms are equal if plugged into any program context their termination behaviour is the same, where we use a combination of may- as well as must-convergence, which is appropriate for non-deterministic computations. We show that we can drop the fairness condition for equational reasoning, since the valid equations w.r.t. normal order reduction are the same as for fair normal order reduction. We evolve different proof tools for proving correctness of program transformations, in particular, a context lemma for may- as well as mustconvergence is proved, which restricts the number of contexts that need to be examined for proving contextual equivalence. In combination with so-called complete sets of commuting and forking diagrams we show that all the deterministic reduction rules and also some additional transformations preserve contextual equivalence.We also prove a standardisation theorem for fair normal order reduction. The structure of the ordering <=c a is also analysed: Ω is not a least element, and <=c already implies contextual equivalence w.r.t. may-convergence.
Motivated by the question of correctness of a specific implementation of concurrent buffers in the lambda calculus with futures underlying Alice ML, we prove that concurrent buffers and handled futures can correctly encode each other. Correctness means that our encodings preserve and reflect the observations of may- and must-convergence. This also shows correctness wrt. program semantics, since the encodings are adequate translations wrt. contextual semantics. While these translations encode blocking into queuing and waiting, we also provide an adequate encoding of buffers in a calculus without handles, which is more low-level and uses busy-waiting instead of blocking. Furthermore we demonstrate that our correctness concept applies to the whole compilation process from high-level to low-level concurrent languages, by translating the calculus with buffers, handled futures and data constructors into a small core language without those constructs.
The paper proposes a variation of simulation for checking and proving contextual equivalence in a non-deterministic call-by-need lambda-calculus with constructors, case, seq, and a letrec with cyclic dependencies. It also proposes a novel method to prove its correctness. The calculus’ semantics is based on a small-step rewrite semantics and on may-convergence. The cyclic nature of letrec bindings, as well as nondeterminism, makes known approaches to prove that simulation implies contextual equivalence, such as Howe’s proof technique, inapplicable in this setting. The basic technique for the simulation as well as the correctness proof is called pre-evaluation, which computes a set of answers for every closed expression. If simulation succeeds in finite computation depth, then it is guaranteed to show contextual preorder of expressions.
This paper proves several generic variants of context lemmas and thus contributes to improving the tools for observational semantics of deterministic and non-deterministic higher-order calculi that use a small-step reduction semantics. The generic (sharing) context lemmas are provided for may- as well as two variants of must-convergence, which hold in a broad class of extended process- and extended lambda calculi, if the calculi satisfy certain natural conditions. As a guide-line, the proofs of the context lemmas are valid in call-by-need calculi, in callby-value calculi if substitution is restricted to variable-by-variable and in process calculi like variants of the π-calculus. For calculi employing beta-reduction using a call-by-name or call-by-value strategy or similar reduction rules, some iu-variants of ciu-theorems are obtained from our context lemmas. Our results reestablish several context lemmas already proved in the literature, and also provide some new context lemmas as well as some new variants of the ciu-theorem. To make the results widely applicable, we use a higher-order abstract syntax that allows untyped calculi as well as certain simple typing schemes. The approach may lead to a unifying view of higher-order calculi, reduction, and observational equality.
We show on an abstract level that contextual equivalence in non-deterministic program calculi defined by may- and must-convergence is maximal in the following sense. Using also all the test predicates generated by the Boolean, forall- and existential closure of may- and must-convergence does not change the contextual equivalence. The situation is different if may- and total must-convergence is used, where an expression totally must-converges if all reductions are finite and terminate with a value: There is an infinite sequence of test-predicates generated by the Boolean, forall- and existential closure of may- and total must-convergence, which also leads to an infinite sequence of different contextual equalities.
Motivated by our experience in analyzing properties of translations between programming languages with observational semantics, this paper clarifies the notions, the relevant questions, and the methods, constructs a general framework, and provides several tools for proving various correctness properties of translations like adequacy and full abstractness. The presented framework can directly be applied to the observational equivalences derived from the operational semantics of programming calculi, and also to other situations, and thus has a wide range of applications.