Descriptive complexity provides intrinsic, i.e. machine-independent, characterizations of the main complexity classes. On the other hand, logic can be useful for designing programs in a natural ...declarative way. This is especially important for parallel computation models such as cellular automata, since designing parallel programs is considered a difficult task.
This paper establishes three logical characterizations of the three classical complexity classes modeling minimal time, called real-time, of one-dimensional cellular automata according to their canonical variations: unidirectional or bidirectional communication, input word given in a parallel or sequential way.
Our three logics are natural restrictions of existential second-order Horn logic with built-in successor and predecessor functions. These logics correspond exactly to the three ways of deciding a language on a square grid circuit of side n according to one of the three natural locations of an input word of length n: along a side of the grid, on the diagonal that contains the output cell – placed on the vertex (n,n) of the square grid–, or on the diagonal opposite to the output cell.
The key ingredient to our results is a normalization method that transforms a formula from one of our three logics into an equivalent normalized formula that closely mimics a grid circuit.
Then, we extend our logics by allowing a limited use of negation on hypotheses like in Stratified Datalog. By revisiting in detail a number of representative classical problems - recognition of the set of primes by Fisher's algorithm, Dyck language recognition, Firing Squad Synchronization problem, etc. - we show that this extension makes easier programming and we prove that it does not change the real-time complexity of our logics.
Finally, based on our experience in expressing these representative problems in logic, we argue that our logics are high-level programming languages: they make it possible to express in a natural, complete and synthetic way the algorithms of the literature, based on signals – and even to design new inductive algorithms –, and to translate them automatically into cellular automata of the same complexity.
Lithium use in mental diseases has changed over the years but remains a cornerstone of treatment in bipolar disorders. In two companion papers, we have reviewed existing (and especially recent) data ...on lithium efficacy and updated basic knowledge regarding the practical fundamentals of lithium therapy. The present paper reviews safety data on lithium available to date. Gastrointestinal pain or discomfort, diarrhoea, tremor, polyuria, nocturnal urination, weight gain, oedema, flattening of affect and exacerbation of psoriasis are typical complaints of patients receiving long-term lithium therapy. Renal involvement results in a reduced urinary concentrating capacity, expressed as obligate polyuria, with secondary thirst. With long-term therapy, this may result in nephrogenic diabetes insipidus. In addition, glomerular filtration rate falls slightly in about 20% of patients. The view that only a few patients receiving long-term lithium are at increased risk of glomerular impairment and progressive renal insufficiency should be regarded with caution. The risk is increased in case of concomitant diseases or medications. Lithium treatment may inhibit thyroid hormone release and induce goitre. Consequently, the prevalence of both overt and subclinical hypothyroidism is increased, with circulating thyroid auto-antibodies frequently being found. Much less commonly, thyrotoxicosis may also develop in association with lithium therapy. Long-term lithium treatment may also be associated with persistent hyperparathyroidism and hypercalcaemia, as well as with hypermagnesaemia. Overweight of up to 4-10 kg is found in approximately 30% of lithium-treated patients. Most neurological manifestations are benign, for example, the fine postural and/or action tremor present in 4-20% of patients. This is increased by high caffeine consumption and concomitant use of other psychotropic agents. A number of rare, potentially serious neurological adverse effects have been reported, including extrapyramidal symptoms, 'pseudotumour cerebri' or occasionally cerebellar symptoms. Severe neurological sequelae are exceptional. Cognitive disturbances are often mentioned as a lithium-related adverse effect. The few controlled studies do show a statistically significant negative effect of lithium on memory, vigilance, reaction time and tracking. There are frequent reports of mild effects of lithium on cognition at therapeutic serum concentrations. A number of deaths associated with lithium treatment have been reported. The most serious issue is that of non-accidental overdose, i.e. either long-term overdosage or acute overdose on long-term treatment. Progressive renal insufficiency, an exceptional complication of long-term lithium therapy, may also have a fatal outcome. In relation to pregnancy, lithium salts are rated as category D (positive evidence of risk). Therefore, prescription of lithium should be avoided during the first trimester of pregnancy unless the benefit to the mother exceeds the risk to the fetus. Although lithium transfer into breast milk is well established, the long-term fate of babies breast-fed by mothers receiving lithium therapy is unknown. Whether lithium therapy is safe in breast-feeding women is controversial. Although there is no absolute contraindication, it is known that the kidney is particularly sensitive to lithium just after birth. Intoxication in patients on long-term treatment with lithium in the absence of history of acute ingestion is not rare. Contributing factors include change in daily dose, long-term high dosage, kidney disease or drug interaction. In suspected cases, serum concentrations should be obtained early and repeatedly. In addition to supportive measures, haemodialysis is the treatment of choice for severe cases. Thorough knowledge of the limitations and drawbacks of lithium therapy is mandatory for its optimal use, especially at a time when its risk/benefit profile needs to be compared accurately with that of antiepileptic drugs and other mood stabilizing medications.
Although there has been a decrease in lithium use over several years, it is still recommended as a first-line mood stabilizer in all recent guidelines. It has been argued that many studies of lithium ...were conducted at a time when study design, assessment standards and the diagnostic criteria for patient selection were not as established as they presently are. However, recent placebo-controlled data from three-arm trials have demonstrated a definite efficacy of lithium in bipolar disorder. Regarding mania, recent trials of novel antimanic treatments (such as second-generation antipsychotics) that have included both placebo and lithium control groups have confirmed that lithium is effective in the treatment of moderate to severe manic episodes. The efficacy of lithium as monotherapy for acute bipolar depression is still controversial, but this therapy is recognized as a therapeutic option. For maintenance therapy, lithium is superior to placebo for the prevention of relapse or recurrence of mood episodes in bipolar I disorder patients with recent manic or hypomanic episodes. Lithium is more effective in preventing episodes of the manic/hypomanic type, including mixed episodes, than preventing depressive episodes. In rapid cycling patients, lithium improves clinical symptoms as efficiently as in nonrapid cycling persons, but is not likely to prevent recurrences. Finally, data from a number of studies suggest that lithium reduces the high suicide rates associated with mood disorders. A well designed cohort study and two independent meta-analyses are in agreement with this finding. In conclusion, most experts, and the most recent guidelines, continue to consider lithium as a keystone therapy of bipolar disorders.
After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its ...bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged <40 years; 20-25 mmol (740-925 mg) for those aged 40-60 years; and 15-20 mmol (550-740 mg) for patients aged >60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.
Descriptive complexity provides intrinsic, that is,machine-independent, characterizations of the major complexity classes. On the other hand, logic can be useful for designing programs in a natural ...declarative way. This is particularly important for parallel computation models such as cellular automata, because designing parallel programs is considered a difficult task.This paper establishes three logical characterizations of the three classical complexity classes modeling minimal time, called real-time, of one-dimensional cellular automata according to their canonical variants: unidirectional or bidirectional communication, input word given in a parallel or sequential way.Our three logics are natural restrictions of existential second-order Horn logic with built-in successor and predecessor functions. These logics correspond exactly to the three ways of deciding a language on a square grid circuit of side n according to one of the three canonical locations of an input word of length n: along a side of the grid, on the diagonal that contains the output cell, or on the diagonal opposite to the output cell.The key ingredient of our results is a normalization method that transforms a formula from one of our three logics into an equivalent normalized formula that faithfully mimics a grid circuit.Then, we extend our logics by allowing a limited use of negation on hypotheses like in Stratified Datalog. By revisiting in detail a number of representative classical problems - recognition of the set of primes by Fisher’s algorithm, Dyck language recognition, Firing Squad Synchronization problem,etc. - we show that this extension makes easier programming and we prove that it does not change the complexity of our logics in real-time.Finally, starting from our experience in expressing those representative problems in logic, we argue that our logics are high-level programming languages: they allow to express in a natural,precise and synthetic way the algorithms of literature, based on signals, and to translate them automatically into cellular automata of the same complexity.
Objective:
To analyze the course of p16/Ki-67-positive abnormal cytological cervical findings and high risk (hr)-HPV- and p16/Ki-67-clearances in women treated with a vaginal gel.
Methods:
172 women ...with a histological diagnosis of CIN2 or p16-positive CIN1 lesions were selected based on a positive cytological p16/Ki-67 test. For 3 months, 75 patients in the active arm (AA) daily administered 5 ml of a vaginal gel. Ninety seven patients in the control arm (CA) underwent no treatment (“watchful waiting”). Endpoints were cytological evolution, p16/Ki-67- and hr-HPV-clearances.
Results:
At 3 months, cytological regression was observed in 76% (57/75) of patients in the AA compared with 25% (24/97) in the CA. Progression occurred in 5% (4/75) of the AA compared with 15% (15/97) of the CA. The p16/Ki-67 status change was statistically significantly (
p
< 0.001) in favor of the AA: 77% (58/75) became negative compared to 21% (20/97) in the CA. hr-HPV prevalence decreased significantly (
p
< 0.001) in the AA from 87 to 44%, while increasing in the CA from 78 to 84%. Cytological regression and p16/Ki-67 changes persisted in the AA at 6 months.
Conclusions:
The vaginal gel significantly cleared hr-HPV and p16/Ki-67 and was associated with improved cytological findings, thereby potentially offering an effective option against oncogenic risk.
Clinical Trial Registration:
Identifier: ISRCTN11009040.
This meta-analysis was performed to assess the possible prophylactic benefit of prolonged treatment with oral
N-acetylcysteine (NAC) in chronic bronchitis (CB) based on qualifying clinical trials. ...Treatment of acute exacerbations with NAC was not investigated.
Prolonged treatment with oral NAC has been investigated in a number of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB in some but not all trials.
The trials included in this analysis were selected from a MEDLINE
® search of the period from January 1, 1980, through June 30, 1995; references in the articles retrieved in the initial search; and consultation with 2 experts. Selection was based on the following criteria: published, double-blind, placebo-controlled, chronic bronchopulmonary disease, duration of therapy ≥ 2 months, and data sufficient to calculate an outcome variable permitting direct comparison of studies (effect size) for both NAC and placebo groups. The primary end point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for CB, with an additional criterion in some trials. For the meta-analysis, the end points of individual trials were transformed into an effect size as a common outcome.
Of 21 trials initially identified, 8 qualified for inclusion. References from the 8 papers and consultation with the experts produced 8 additional publications, 1 of which qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study), 600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times per week. The duration of treatment was 3 months (1 study), ≥ 5 months (2 studies), or 6 months (7 studies). The results of this meta-analysis showed a statistically significant effect size for NAC compared with placebo. The overall value of effect size was −1.37 (95% CI, −1.5 to −1.25). Sensitivity analyses did not significantly alter these results. In a subset analysis of trials with the number of acute exacerbations as a clinical end point, a mean difference of −0.32 clinical event (95% CI, −0.50 to −0.18) was found (ie, a 23% decrease in the number of acute exacerbations compared with placebo).
These findings suggest that a prolonged course of oral NAC prevents acute exacerbations of CB, thus possibly decreasing morbidity and health care costs.
A relational structure is
d
-degree-bounded, for some integer
d
, if each element of the domain belongs to at most
d
tuples. In this paper, we revisit the complexity of the evaluation problem of not ...necessarily Boolean first-order (
FO
) queries over
d
-degree-bounded structures. Query evaluation is considered here as a dynamical process. We prove that any
FO
query on
d
-degree-bounded structures belongs to the complexity class constant-Delay
lin
, that is, can be computed by an algorithm that has two separate parts: it has a precomputation step of time linear in the size of the structure and then, it outputs all solutions (i.e., tuples that satisfy the formula) one by one with a constant delay (i.e., depending on the size of the formula only) between each. Seen as a global process, this implies that queries on
d
-degree-bounded structures can be evaluated in total time
f
(|φ|).(|
S
| + |φ(
S
)|) and space
g
(|φ|).|
S
| where
S
is the structure, φ is the formula, φ(
S
) is the result of the query and
f
,
g
are some fixed functions.
Among other things, our results generalize a result of Seese on the data complexity of the model-checking problem for
d
-degree-bounded structures. Besides, the originality of our approach compared to related results is that it does not rely on the Hanf's model-theoretic technique and is simple and informative since it essentially rests on a quantifier elimination method.
Descriptive complexity may be useful to design programs in a natural declarative way. This is important for parallel computation models such as cellular automata, because designing parallel programs ...is considered difficult. Our paper establishes logical characterizations of the three classical complexity classes that model minimal time, called real-time, of one-dimensional cellular automata according to their canonical variants. Our logics are natural restrictions of the existential second-order Horn logic. They correspond to the three ways of deciding a language on a square grid circuit of side n according to the three canonical placements of an input word of length n on the grid. Our key tool is a normalization method that transforms a formula into an equivalent formula that faithfully mimics a grid circuit.
Purpose
The effect of SAM vaginal gel, a medical device containing adsorptive silicon dioxide and antioxidative sodium selenite and citric acid, on histologically-proven cervical intraepithelial ...neoplasia type 2 (CIN2) as well as p16 positive CIN1, and on the presence of the onco-marker p16 was investigated.
Methods
216 women aged 25–60 years were randomized to either receive an intravaginal daily dose of SAM gel for three 28-day periods, or be followed-up without intervention. The primary endpoint was efficacy, defined as a combined histological and cytological regression. At baseline and after 3 months participants had: a guided biopsy including p16 immunohistochemical (IHC) staining, only if a lesion was visible at colposcopy; a cervical smear for cytology, high-risk human papillomavirus (hr-HPV) and a p16/Ki-67 test. At 6 months a further cytology and p16/Ki-67 test was performed.
Results
Regression of CIN lesions was observed in 78 out of 108 patients (72.2%) in the SAM gel arm and in 27 out of 108 patients (25.0%) in the control arm. Similarly, the change in the p16/Ki-67 cytological test status was significantly in favor of the treatment arm. The prevalence of hr-HPV decreased significantly (
p
< 0.001) in the treatment arm, from 87.0% to 39.8%, while it slightly increased in the control arm, from 78.7% to 83.3%. At 6 months the cytological regression in the treatment group and the highly significant effect on p16/Ki-67 was still present.
Conclusion
SAM vaginal gel enhances the regression of cervical lesions and clears hr-HPV and p16/Ki-67 in smears significantly, thus offering an active non-destructive management to prevent cervical cancer.
Trial registration number
ISRCTN11009040, date of registration: 10/12/2019;
https://doi.org/10.1186/ISRCTN11009040
; retrospectively registered.
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