Synthesising Programs with Non-trivial Constants.

Program synthesis is the mechanised construction of software. One of the main difficulties is the efficient exploration of the very large solution space, and tools often require a user-provided syntactic restriction of the search space. While useful in general, such syntactic restrictions provide little help for the generation of programs that contain non-trivial constants, unless the user is able to provide the constants in advance. This is a fundamentally difficult task for state-of-the-art synthesisers. We propose a new approach to the synthesis of programs with non-trivial constants that combines the strengths of a counterexample-guided inductive synthesiser with those of a theory solver, exploring the solution space more efficiently without relying on user guidance. We call this approach CEGIS(T), where T is a first-order theory. We present two exemplars, one based on Fourier-Motzkin (FM) variable elimination and one based on first-order satisfiability. We demonstrate the practical value of CEGIS(T) by automatically synthesising programs for a set of intricate benchmarks. Additionally, we present a case study where we integrate CEGIS(T) within the mature synthesiser CVC4 and show that CEGIS(T) improves CVC4's results.

Clinical management of a granulomatous tubulointerstitial nephritis associated with a bilateral granulomatous anterior uveitis: A challenging case report and review of the literature.

Acute granulomatous tubulointerstitial nephritis (GTIN) is a rare finding in renal biopsy. Differential diagnosis is facilitated when GTIN is associated with granulomatous bilateral anterior uveitis (GBAU). Nevertheless, differentiation between a rare form of granulomatous tubulointerstitial nephritis and uveitis syndrome (TINU) and sarcoidosis can be challenging. We report a case of biopsy-proven GTIN with concomitant GBAU, leading to a dead-end diagnosis. We discuss workup and propose a diagnostic algorithm based on a literature review. We also report a successful treatment of ophthalmologic and renal relapse using mycophenolate mofetil.

A Lower Global Lung Ultrasound Score Is Associated with Higher Likelihood of Successful Extubation in Invasively Ventilated COVID-19 Patients.

Lung ultrasound (LUS) can be used to assess loss of aeration, which is associated with outcome in patients with coronavirus disease 2019 (COVID-19) presenting to the emergency department. We hypothesized that LUS scores are associated with outcome in critically ill COVID-19 patients receiving invasive ventilation. This retrospective international multicenter study evaluated patients with COVID-19-related acute respiratory distress syndrome (ARDS) with at least one LUS study within 5 days after invasive mechanical ventilation initiation. The global LUS score was calculated by summing the 12 regional scores (range 0-36). Pleural line abnormalities and subpleural consolidations were also scored. The outcomes were successful liberation from the ventilator and intensive care mortality within 28 days, analyzed with multistate, competing risk proportional hazard models. One hundred thirty-seven patients with COVID-19-related ARDS were included in our study. The global LUS score was associated with successful liberation from mechanical ventilation (hazard ratio [HR]: 0.91 95% confidence interval [CI] 0.87-0.96; P = 0.0007) independently of the ARDS severity, but not with 28 days mortality (HR: 1.03; 95% CI 0.97-1.08; P = 0.36). Subpleural consolidation and pleural line abnormalities did not add to the prognostic value of the global LUS score. Examinations within 24 hours of intubation showed no prognostic value. To conclude, a lower global LUS score 24 hours after invasive ventilation initiation is associated with increased probability of liberation from the mechanical ventilator COVID-19 ARDS patients, independently of the ARDS severity.

In Search of an Efficient Complexing Agent for Oxalates and Phosphates: A Quantum Chemical Study.

Limiting gastrointestinal oxalate absorption is a promising approach to reduce urinary oxalate excretion in patients with idiopathic and enteric hyperoxaluria. Phosphate binders, that inhibit gastrointestinal absorption of dietary phosphate by the formation of easily excretable insoluble complexes, are commonly used as a treatment for hyperphosphatemia in patients with end-stage renal disease. Several of these commercially available phosphate binders also have affinity for oxalate. In this work, a series of metallic cations (Li+, Na+, Mg2+, Ca2+, Fe2+, Cu2+, Zn2+, Al3+, Fe3+ and La3+) is investigated on their binding affinity to phosphate and oxalate on one side and anionic species that could be used to administer the cationic species to the body on the other, e.g., acetate, carbonate, chloride, citrate, formate, hydroxide and sulphate. Through quantum chemical calculations, the aim is to understand the competition between the different complexes and propose possible new and more efficient phosphate and oxalate binders.

Lanthanum carbonate to control plasma and urinary oxalate level in type 1 primary hyperoxaluria?

INTRODUCTION: The therapy to reduce urinary oxalate excretion in primary hyperoxaluria type 1 is still required. CASE PRESENTATION: A 37-year-old hemodialyzed man suffered from systemic oxalosis secondary to primary hyperoxaluria type 1 exhibited a drastic plasma oxalate decrease from 110 to 22 µmol/L two months after adjunction of lanthanum carbonate to classical treatment (intensive hemodialysis with pyridoxine). A 34-year-old woman with normal kidney function presented 10 years of bilateral kidney stones due to primary hyperoxaluria type 1 [hyperoxaluria (109.2 mg/24 h), plasma oxalate (56.0 µmol/L)]. The oxalate level remained uncontrolled despite of low oxalate-normal calcium diet, pyridoxine and increased water intake though the lanthanum carbonate adjunction resulted in significant decrease in plasma oxalate and oxaluria. CONCLUSION: We report the lanthanum efficacy in reducing circulating and urinary oxalate levels in type 1 primary hyperoxaluria. Possible mechanism of observed falls in oxalate concentration would be a decrease in the intestinal absorption of oxalate.

Automated formal synthesis of provably safe digital controllers for continuous plants.

We present a sound and automated approach to synthesizing safe, digital controllers for physical plants represented as time-invariant models. Models are linear differential equations with inputs, evolving over a continuous state space. The synthesis precisely accounts for the effects of finite-precision arithmetic introduced by the controller. The approach uses counterexample-guided inductive synthesis: an inductive generalization phase produces a controller that is known to stabilize the model but that may not be safe for all initial conditions of the model. Safety is then verified via bounded model checking: if the verification step fails, a counterexample is provided to the inductive generalization, and the process further iterates until a safe controller is obtained. We demonstrate the practical value of this approach by automatically synthesizing safe controllers for physical plant models from the digital control literature.

Validation of a biopsychosocial distress screening tool, "You, Your Family and COH Are a Team".

OBJECTIVE: We examined the psychometric properties of a biopsychosocial screening tool "You, Your Family and City of Hope are a Team" implemented via touchpad technology (YYFcore03) at a cancer center in newly diagnosed patients and patients on active treatment, with the primary objective to evaluate concurrent validity with screening criterion measures of depression and anxiety. METHODS: YYFcore03, Patient Health Questionnaire [PHQ-9], and Generalized Anxiety Disorder [GAD-7] were administered to 608 patients in out-patient clinics. A subset of 158 patients responding a second time to YYFcore03 at a subsequent visit were included for assessing reliability. Exploratory factor analysis followed by confirmatory factor analysis were conducted to identify underlying factors. The identified factor of psychological distress (PD) was then correlated with PHQ-9 and GAD-7 for concurrent validity and to estimate sensitivity-specificity. Demographic and clinical variables associated with the PD score were identified. Test-retest reliability of PD score was examined. RESULTS: Factor analysis suggested three factors, including PD. Correlations between PD score and PHQ-9 and GAD-7 were 0.63 and 0.67, respectively. Treating PHQ-9 and GAD-7 as criterion measures, PD score had a sensitivity of 0.77 for identifying depression and 0.86 for identifying anxiety. Younger age, lower household income, and cancer (vs noncancer) diagnosis were independently associated with worse PD score. Omega total for composite reliability was 0.88; intraclass correlation was 0.78. CONCLUSIONS: The YYFcore03 administered via touchpad is a valid instrument for identifying PD in newly diagnosed patients and patients undergoing active treatment.

Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management.

The discovery of circulating antibodies specific for native podocyte antigens has transformed the diagnostic workup and greatly improved management of idiopathic membranous nephropathy (iMN). In addition, their identification has clearly characterized iMN as a largely autoimmune disorder. Anti-PLA2R1 antibodies are detected in approximately 70% to 80% and anti-THSD7A antibodies in only 2% of adult patients with iMN. The presence of anti-THSD7A antibodies is associated with increased risk of malignancy. The assessment of PLA2R1 and THSD7A antigen expression in glomerular immune deposits has a better sensitivity than measurement of the corresponding autoantibodies. Therefore, in the presence of circulating anti-podocytes autoantibodies and/or enhanced expression of PLA2R1 and THSD7A antigens MN should be considered as primary MN (pMN). Anti-PLA2R1 or anti-THSD7A autoantibodies have been proposed as biomarkers of autoimmune disease activity and their blood levels should be regularly monitored in pMN to evaluate disease activity and predict outcomes. We propose a revised clinical workup flow for patients with MN that recommends assessment of kidney biopsy for PLA2R1 and THSD7A antigen expression, screening for circulating anti-podocytes antibodies, and assessment for secondary causes, especially cancer, in patients with THSD7A antibodies. Persistence of anti-podocyte antibodies for 6 months or their increase in association with nephrotic proteinuria should lead to the introduction of immunosuppressive therapies. Recent data have reported the efficacy and safety of new specific therapies targeting B cells (anti-CD20 antibodies, inhibitors of proteasome) in pMN which should lead to an update of currently outdated treatment guidelines.

Program synthesis: challenges and opportunities.

Program synthesis is the mechanized construction of software, dubbed 'self-writing code'. Synthesis tools relieve the programmer from thinking about how the problem is to be solved; instead, the programmer only provides a description of what is to be achieved. Given a specification of what the program should do, the synthesizer generates an implementation that provably satisfies this specification. From a logical point of view, a program synthesizer is a solver for second-order existential logic. Owing to the expressiveness of second-order logic, program synthesis has an extremely broad range of applications. We survey some of these applications as well as recent trends in the algorithms that solve the program synthesis problem. In particular, we focus on an approach that has raised the profile of program synthesis and ushered in a generation of new synthesis tools, namely counter-example-guided inductive synthesis (CEGIS). We provide a description of the CEGIS architecture, followed by recent algorithmic improvements. We conjecture that the capacity of program synthesis engines will see further step change, in a manner that is transparent to the applications, which will open up an even broader range of use-cases.This article is part of the themed issue 'Verified trustworthy software systems'.

The role of EEG brain mapping in quantification of brain damage in hypertensive disease associated with pregnancy.

UNLABELLED: The existence of a high blood pressure during the pregnancy represents a real danger for the mother and child, responsible for damage of the kidney, brain, liver, and placenta, cardiovascular and hormonal system. Nervous system changes can include blurred vision, seeing spots, severe headaches, convulsions, brain hemorrhage, and even occasionally blindness. AIM: To evaluate the spatial distribution of electroneuro-pathological aspects of brain activity at pregnant women with hypertensive disease by BEAM (Brain Electrical Activity Mapping). MATERIAL AND METHODS: Twenty pregnant women (week 20 to 39) with hypertensive disease were recruited. Healthy pregnant women were also recruited control group. Maternal monitoring included spectral multichannel EEG analysis (brain mapping), repeated clinical examinations and laboratory investigations. RESULTS: The major EEG changes observed were focal slowing of the background activity (14 patients)--occipital lobes especially, and intermittent spike and sharp wave transients (5 patients). CONCLUSIONS: Our finding's indicate that EEG brain mapping are probably sensitive in detecting the extent of the pathology in the brain in women with in hypertensive disease associated with pregnancy.

[Effectiveness of laparoscopic ovarian "drilling" in patients with polycystic ovarian syndrome and ovarian infertility]. / Eficienta "drilling"-ului ovarian percelioscopic la pacientele cu ovare polichistice si infertilitate ovariana.

UNLABELLED: THE AIM of this study was to demonstrate the efficiency of laparoscopic ovarian drilling in the treatment of Polycystic Ovarian Syndrome (PCOS) associated with infertility. MATERIAL AND METHODS: We studied 54 patients with PCOS that also presented infertility and menorrhea. The PCOS was diagnosed by ultrasound in the 2nd Clinic of Obstetrics and Gynaecology in Iasi, using Bataglia and ASRM/ESHRE criteria. We selected 32 patients with PCOS and infertility, in which medical treatment with inductors of ovulation and Metformin failed and laparoscopy was indicated. In these patients we practiced bilateral laparoscopic ovarian drilling. RESULTS: In the next 3 months the menstrual cycle became regulated and 3 of the patients became pregnant. Other 10 patients became pregnant in the next 9 months after laparoscopic ovarian drilling. CONCLUSION: PCOS associated with infertility should be laparoscopy treated because the effect is faster and the fertility prognosis is better.

[Large ovarian cyst associated with pregnancy. Case report]. / Chist ovarian gigant asociat cu sarcina.

The incidence of adnexal masses in pregnancy is rather low. The diagnosis has become more common with the routine use of ultrasonography in prenatal care. The management of adnexal masses during pregnancy remains controversial. Ultrasonography can characterise correctly the adnexal mass and avoid antepartum surgery. We present the case of a 32 years old gravida, IV gesta, I para, with an ovarian cystic tumour that enlarged during pregnancy from 7 cm to 20 cm. The tumour was correctly characterised by ultrasound exam (Sassone 3) and surgery was not indicated. The pregnancy evoluated well and the patient delivered at term by c. section and ovariectomy was also performed. The postpartum evolution was good.

[Hysteroscopy in the diagnosis and treatment of tubal infertility]. / Histeroscopia în diagnosticul si tratamentul infertilitatii de cauza tubara.

The aim of this study is to present the authors' experience in the diagnosis and treatment of tubal proximal disease by means of hysteroscopy. The study includes 96 patients with tubal infertility to which hysteroscopy was performed in 1998-2003 in the 2nd Clinic of Obstetrics and Gynecology, Iasi. The average age was 32.5 +/- 1.2 years. The indication was proximal tubal obstruction diagnosed by hysterosalpingography or sono-hysterosalpingography. The hysteroscopy revealed lesions affecting fertility that were treated in the same operative sequence. Proximal tubal obstruction was present in 50 cases (52%): unilateral--41 cases, bilateral--9 cases. Tubal permeabilization was performed by tubal catheterization or by removing polyps, adhesion and was verified by chromo-tubation at the end of hysteroscopy and by sono-hysterosalpingography, 2 months after the intervention. When proximal tubal obstruction is suspected, hysteroscopy offers a solution by confirming the diagnosis and by efficiently treating the lesions, leading to an increased average of pregnancies.

[Specifics of therapy of tubal infertility in patients with endometriosis]. / Particularitatile tratamentului infertilitatii tubare la pacientele cu endometrioza.

Our purpose was to define the best way of treating tubal infertility caused by endometriosis. We have studied 24 patients with tubal infertility caused by endometriosis; the etiology has been laparoscopically established in the 2nd Clinic of Obstetrics and Gynecology Iasi. The endometriosis score (r-AFS) was used to establish the therapy. We performed laparoscopic treatment when endometriosis was visible. Postoperative medical therapy (Diphereline, 3 months) was indicated; patients with ,,unpigmented endometriosis" received the same medical therapy. The rate of pregnancies in patients that had benefit of combined therapy: surgical and medical (n=9) was superior (44.4%) to that obtained in patients that were only surgical treated (n=15): 26.6% (Spearman correlation--0.6595, p < 0.0012). Endometriosis is an important etiological factor in female infertility. The pathway is mechanic as well as chemical and it justifies the combined therapy. There are better results, as fertility prognosis in patients with endometriosis that receive both, surgical and medical therapy.

[Sono-hysterosalpingography in the assessment of tubal infertility]. / Sonohisterosalpingografia ca metoda de evaluare a infertilitatii tubare.

The assessment of the fallopian tubes patency is an important moment in the investigation for infertility. Vaginal sonographic hydrotubation was assessed in the evaluation of uterine configuration and tubal patency. In addition, technique using "agitated" saline during transvaginal sonography was evaluated. Ultrasound was more effective in detecting abnormalities of both interstitial and distal parts of the tube compared with hysterosalpingography. Sonohysterosalpingography is cheaper, may be performed in the office and also the pelvic irradiation is avoided.