Enhanced joint hybrid deep neural network explainable artificial intelligence model for 1-hr ahead solar ultraviolet index prediction.

BACKGROUND AND OBJECTIVE: Exposure to solar ultraviolet (UV) radiation can cause malignant keratinocyte cancer and eye disease. Developing a user-friendly, portable, real-time solar UV alert system especially or wearable electronic mobile devices can help reduce the exposure to UV as a key measure for personal and occupational management of the UV risks. This research aims to design artificial intelligence-inspired early warning tool tailored for short-term forecasting of UV index (UVI) integrating satellite-derived and ground-based predictors for Australian hotspots receiving high UV exposures. The study further improves the trustworthiness of the newly designed tool using an explainable artificial intelligence approach. METHODS: An enhanced joint hybrid explainable deep neural network model (called EJH-X-DNN) is constructed involving two phases of feature selection and hyperparameter tuning using Bayesian optimization. A comprehensive assessment of EJH-X- DNN is conducted with six other competing benchmarked models. The proposed model is explained locally and globally using robust model-agnostic explainable artificial intelligence frameworks such as Local Interpretable Model-Agnostic Explanations (LIME), Shapley additive explanations (SHAP), and permutation feature importance (PFI). RESULTS: The newly proposed model outperformed all benchmarked models for forecasting hourly horizons UVI, with correlation coefficients of 0.900, 0.960, 0.897, and 0.913, respectively, for Darwin, Alice Springs, Townsville, and Emerald hotspots. According to the combined local and global explainable model outcomes, the site-based results indicate that antecedent lagged memory of UVI and solar zenith angle are influential features. Predictions made by EJH-X-DNN model are strongly influenced by factors such as ozone effect, cloud conditions, and precipitation. CONCLUSION: With its superiority and skillful interpretation, the UVI prediction system reaffirms its benefits for providing real-time UV alerts to mitigate risks of skin and eye health complications, reducing healthcare costs and contributing to outdoor exposure policy.

Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study.

OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.

[Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNFalpha agents failed are associated with response to rituximab in rheumatoid arthritis]. / La presenza del fattore reumatoide, la disabilità ed il numero di precedenti anti-TNFalpha falliti predicono la risposta clinica a rituximab nell'artrite reumatoide.

OBJECTIVE: Predictors of response to biologics in rheumatoid arthritis (RA) is an important issue in the current era. Rituximab (RTX) has been demonstrated effective and safe in active RA, resistant to traditional or biologic DMARDs. METHODS: Fifty-seven patients with active longstanding RA were treated with RTX after traditional DMARD or anti-TNF alpha therapy failure. RESULTS: Number of anti-TNF treatment previously failed (p=0.005), HAQ (p=0.013), rheumatoid factor (RF) (p=0.0002) and anti-CCP (p=0.006) were associated with an ACR response > or =50 at the end of 6th month by univariate analysis. Multivariate analysis confirmed that the number of anti-TNF previously failed, baseline HAQ and RF, but not anti-CCP were associated with an ACR response > or =50. EULAR moderate/good response was associated with ESR value (p=0.036), HAQ (p=0.032), and RF (p=0.01) by univariate analysis, while only RF positivity was associated with EULAR moderate/good response by multivariate analysis. CONCLUSIONS: RF positivity rather than anti-CCP positivity is a predictor of response to RTX, suggesting that RF-positive patients with low disability may obtain a clinical response when treated to RTX after the first anti-TNF agent failure or after traditional DMARD therapies. Larger studies are required to confirm these results.

[Fibronectin gene polymorphisms and clinical manifestations of mixed cryoglobulinemic syndrome: increased risk of lymphoma associated to MspI DD and HaeIII AA genotypes]. / Polimorfismi del gene della fibronectina e manifestazioni cliniche della sindrome crioglobulinemica: aumentato rischio di linfoma legato ai genotipi MspI DD e HaeIII AA.

OBJECTIVE: To analyse FN gene polymorphisms in type II mixed cryoglobulinemic syndrome (MCsn), an immune-complex mediated systemic vasculitis linked to hepatitis C virus (HCV) infection and characterized by rheumatoid factor (RF) positive B-cell proliferation at high risk for the progression into non Hogkin's lymphoma (NHL). METHODS: Samples from eighty-one patients, with MCsn (type II serum cryoglobulins and clinical signs of vasculitis were studied. Sixty-five (65/81, 80.3%) patients were HCV-positive. Twenty-one (25.9%) patients had developed a B-cell NHL during the course of MCsn. Seventy-two patients with HCV-negative and MC-unrelated NHL and 110 healthy blood donors (HBDs) were taken as controls. HaeIIIb and MspI FN gene polymorphisms were analysed by ELISA, whenever possible. RESULTS: HaeIIIb and MspI allele and genotypic frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI allele and genotype frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI (OR = 5.56; DI = 1.67-18.51, p = 0.0046) and the AA-HaeIIIb (OR = 5.54, CI = 1.64- 18.76, p = 0.0066) homozygosis appeared significantly and independently associated with the development of B-cell NHL in MCsn patients, with the HaeIIIbA allele possibly conferring an increased risk of NHL in the general population (OR = 1.72, CI = 1.128-2.635, p = 0.0133). In contrast, the major vasculitic manifestations, such as peripheral neuropathy, skin ulcers and glomerulonephritis tended to be associated with the counterpart MspI C allele. No association between FN plasma levels and FN genotypes was found. CONCLUSION: Genotyping for MspI and HaeIIIb FN gene polymorphisms may be clinically relevant to define the predisposition to the major clinical manifestations in MCsn.

Fibronectin gene polymorphisms are associated with the development of B-cell lymphoma in type II mixed cryoglobulinemia.

OBJECTIVE: To analyse fibronectin (FN) gene polymorphisms in type II mixed cryoglobulinemic syndrome (MCsn), an immune-complex mediated systemic vasculitis linked to hepatitis C virus (HCV) infection and characterised by rheumatoid factor (RF) positive B-cell proliferation at high risk for the progression into non-Hodgkin's lymphoma (NHL). METHODS: Samples from 74 patients with MCsn (type II serum cryoglobulins and clinical signs of vasculitis) were studied. In all, 58 (78.4%) patients were HCV-positive. In total, 21 (28.4%) patients developed a B-cell NHL during the course of MCsn. A total of 72 patients with HCV-negative and MC-unrelated NHL and 110 healthy blood donors (HBDs) were taken as controls. HaeIIIb and MspI FN gene polymorphisms were analysed by PCR and specific restriction enzyme digestions, following reported procedures. Plasma FN levels were analysed by ELISA, whenever possible. RESULTS: HaeIIIb and MspI allele and genotype frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI (OR = 5.99; CI 1.77-20.261, p = 0.0039) and the AA-HaeIIIb (OR = 4.82, CI 1.42-16.39, p = 0.0176) homozygosis appeared significantly associated with the development of B-cell NHL in MCsn patients, with the HaeIIIb A allele possibly conferring an increased risk of NHL in the general population (OR = 1.72, CI 1.128-2.635, p = 0.0133). None of the other MCsn-related clinical manifestations were significantly associated with a particular genetic pattern. No association between FN plasma levels and FN genotypes was found. CONCLUSION: Genotyping for MspI and HaeIIIb FN gene polymorphisms may be clinically relevant to define the risk of lymphoma development in MCsn.

Bone marrow B-cell clonal expansion in type II mixed cryoglobulinaemia: association with nephritis.

OBJECTIVES: To investigate the relationship between the pattern of bone marrow (BM) B-cell expansion and the clinical features of mixed cryoglobulinaemia (MC) syndrome. METHODS: Fifty-five patients with type II MC syndrome were analysed. Their median age was 64 yrs (range 24-82), the median disease duration was 6 yrs (range 1-26) and the mean follow-up after BM analysis was 2.65 yrs (s.d. = 1.33). Peripheral neuropathy was present in 33 patients (60%), nephritis in 14 (25.4%), skin ulcers in 14 (25.4%) and lymphoma or atypical lymphoproliferative disorder (LPD) in 17/55 (30.9%). Anti-HCV antibodies were found in 43/55 patients (78.2%). BM B-cell expansion was evaluated by a semi-nested PCR amplification of the V-D-J region of the IgH genes. RESULTS: A clonal B-cell expansion in the BM was found in 33/55 (60%) patients, while a polyclonal pattern in 22/55 (40%). A BM pattern of clonal B-cell expansion increased the risk of nephritis of about 10 times [odds ratio (OR) = 10.11, CI95%1.52-67.31], if compared to a polyclonal pattern. In contrast, the risk of skin ulcers was decreased in BM clonal cases (OR = 0.09, CI95%0.02-0.49). Overt lymphomas did not emerge from patients with BM monoclonal expansion (without clinical or histopathological features of lymphoproliferation; or with LPD) in a short-term, consistent with the finding that monoclonality was associated with nephritis and not with an underlying, not recognized lymphoma. CONCLUSION: BM clonal B-cell expansion is associated with nephritis in MC syndrome. Particular B-cell clones may be preferentially expanded and may play a pathogenic role in MC nephritis.

Evaluation of immunologic assays to determine the effects of differential housing on immune reactivity.

The mechanism is being investigated to determine specifically how an environmental variation such as differential housing can influence the multiple components of the host defense mechanism. Male C3H/HeJ mice were housed either one or five per cage. Cells and sera from these mice were analyzed and compared by several immunologic techniques to determine in which cells or tissues the effect of differential housing was most pronounced. The individually housed mice (a) had a greater capacity to phagocytose dead cells of Candida albicans. (b) had spleens that produced more macrophage colony stimulating factor (M-CSF). (c) were more responsive to M-CSF, (d) had peritoneal macrophages that released greater quantities of interleukin-1 in vitro into the surrounding medium and that had a greater capacity to migrate toward a chemotactic stimulus, and (e) had higher titers of IgM hemagglutination antibody to sheep erythrocytes. Differential housing of mice may therefore be a highly important modulator and indicator of the nature and extent of an animal's immunologic response to an environmental stimulus.

Effect of differential housing and time on immune reactivity to sheep erythrocytes and Candida.

Male C3H/HeJ mice were housed 5 or 1 per cage for varying periods of time. Approximately 10-14 days after the animals were placed under the differential housing conditions, the reactivity of lymphocytes to concanavalin A and to intraperitoneal injection of sheep erythrocytes became greater in animals housed 1 per cage in comparison with those housed five per cage. By 3 weeks the immune reactivity was similar regardless of the number of animals housed per cage. Similarly, resistance to infection with Candida albicans was greater in animals housed one per cage at approximately 10-14 days after the animals had been isolated. By 3 weeks a difference in resistance to C. albicans was not apparent between animals housed 5 or 1 per cage. Thus, housing conditions can transiently alter immunologic reactivity, including susceptibility to an infectious agent in male C3H/HeJ mice. However, female C3H/HeJ mice and male C57BL/6J mice did not show an effect of housing conditions on immune reactions.

The effect of dietary zinc and prothymosin alpha on cellular immune responses of RF/J mice.

Mice of the RF/J strain on a normal diet are defective in some aspects of cellular immunity, as evidenced by their susceptibility to infection with Candida albicans, their failure to release detectable quantities of circulating migration inhibitory factor (MIF) in vivo, and the presence of a low rate of phagocytosis and killing by peritoneal macrophages. When the mice were fed a high-zinc diet (300 ppm) for 4 weeks and then treated daily with 160 ng prothymosin alpha, an increase occurred in resistance to infection with C. albicans, in the capacity to release MIF in vivo into the circulation and in the capacity of peritoneal macrophages to engulf (phagocytose) and kill cells of C. krusei. In addition, the number of spleen lymphocytes producing antibody to a T-dependent antigen was significantly increased in the mice fed a high-zinc diet and inoculated daily with prothymosin alpha.

Human prothymosin alpha: amino acid sequence and immunologic properties.

Prothymosin alpha has been purified from human thymus and its amino acid sequence determined, except for a 15 amino acid segment including 10 glutamyl residues near the middle of the molecule. Like prothymosin alpha from rat thymus [A. A. Haritos, R. Blacher, S. Stein, J. Caldarella, and B. L. Horecker (1985) Proc. Natl. Acad. Sci. USA 82, 343-346], human prothymosin contains the thymosin alpha 1 sequence at its NH2-terminus. It contains a total of 109-110 residues compared to 111-112 for rat prothymosin alpha, with deletions corresponding to positions Gln39 and Lys108 of the rat polypeptide. Human prothymosin alpha also differs from rat prothymosin alpha at positions corresponding to residues 87, 92, and 102 of the latter, with substitutions of alanine for proline, alanine for valine, and aspartic acid for glutamic acid, respectively. Human prothymosin is significantly less active than rat prothymosin in protecting mice against infection with Candida albicans and in stimulating release in vivo of migration inhibitory factor. Thus, the differences in amino acid sequences, present mainly the COOH-terminal half of the polypeptides, may determine species specificity in biological properties.

Parathymosin alpha: a peptide from rat tissues with structural homology to prothymosin alpha.

A peptide, parathymosin alpha, containing approximately equal to 105 amino acid residues, has been isolated from rat thymus, and the sequence of the first 30 residues at the NH2 terminus has been determined. In this region, it shows 43% structural identity with thymosin alpha 1 and prothymosin alpha. The common sequences do not include residues 2-9, which accounts for the poor reactivity of parathymosin alpha with an antibody directed against this epitope in thymosin alpha 1. Parathymosin alpha appears to modulate the action of prothymosin alpha in protecting sensitive strains of mice against opportunistic infection with Candida albicans.

Resistance and susceptibility to infection in inbred murine strains. IV. Effects of dietary zinc.

Mice of several inbred strains have been fed diets containing either large amounts of zinc (300 ppm Zn), small amounts of zinc (5 ppm Zn), or routine laboratory mouse chow. When the mice are fed on a high-zinc diet, murine strains, such as C3H/HeJ, AKR/J, and CBA/CaJ, which are normally susceptible to infection with Candida albicans and which normally release low titers of migration-inhibition factor (MIF) in vivo into the circulation, become more resistant to infection with C. albicans and release higher titers of MIF in vivo into the circulation. In addition, their capacity to elicit delayed type hypersensitivity responses may be enhanced. When the mice are maintained on a low-zinc diet, murine strains, such as C57Bl/10SNJ, which are normally resistant to infection with C. albicans and which normally release high titers of MIF in vivo into the circulation on appropriate antigenic challenge, become more susceptible to infection and release lower titers of MIF into the circulation. Under these conditions of low-zinc concentrations in the diet, their capacity to elicit delayed type hypersensitivity may be reduced. Thus, the concentration of zinc in the diet may have a pronounced effect on some in vivo parameters of cell-mediated immunity.

Resistance and susceptibility to infection in inbred murine strains. III. Effect of thymosin on cellular immune responses of alloxan diabetic mice.

Three parameters of cell-mediated immunity, namely, (a) resistance to infection with Candida albicans, (b) in vivo release of migration inhibitory factor (MIF) into the circulation and (c) delayed hypersensitivity were markedly reduced when mice of such normally resistant high responder strains as C57B1/10SNJ and C57B1/KsJ became hyperglycaemic after treatment with alloxan. When the alloxan diabetic mice were inoculated daily intraperitoneally with thymosin fraction 5, beginning 3 days before infection, resistance to infection was greatly enhanced. When the mice were administered 5 micrograms thymosin fraction 5 for 3 days before sensitization and for 3 days before challenge, the amount of MIF released in vivo into the circulation after the antigenic challenge was much greater. When the mice were treated daily with 5 micrograms thymosin fraction 5, beginning on the day of sensitization, the capacity to develop delayed footpad reactions was increased. Thus, the treatment of alloxan diabetic mice with thymosin fraction 5 enhanced the three parameters of cell-mediated immunity that were under investigation.

Thymosin alpha 11: a peptide related to thymosin alpha 1 isolated from calf thymosin fraction 5.

Two peptides related to thymosin alpha 1 have been isolated from preparations of calf thymosin fraction 5. One, lacking four amino acid residues at the COOH terminus, is designated des-(25-28)-thymosin alpha 1. The other, named thymosin alpha 11, contains seven additional amino acid residues at the COOH terminus. The sequence of this peptide is: AcSer-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu- Lys-Glu-Lys- Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-Gly-Arg-Glu-Ala-Pro-Ala-AsnOH. Thymosin alpha 11, in doses of less than 300 ng per mouse, protects susceptible inbred murine strains against opportunistic infections with Candida albicans. It is approximately equal to 30 times as potent as thymosin fraction 5 and approximately equal in potency to thymosin alpha 1.

Resistance and susceptibility to infection in inbred murine strains. I. Variations in the response to thymic hormones in mice infected with Candida albicans.

Nine inbred murine strains were either highly resistant or highly susceptible to intravenous challenge with 4 X 10(4) to 1 X 10(5) cells of Candida albicans. The resistant strains had the capacity to develop delayed footpad reactions on appropriate sensitization and challenge; the susceptible strains did not have this innate capacity. Administration of thymosin fraction 5 beginning on the day of infection greatly increased the resistance of the susceptible strains to infection, but decreased the resistance of the resistant strains. In contrast, thymosin fraction 5 enhanced the delayed footpad responses of resistant-sensitized mice to specific antigen, but did not have a detectable effect on the delayed footpad reactions of the susceptible strains. Reinfection of the two types of strains had different effects, in that, depending on the strain, resistance could be increased, decreased, or not influenced at all.

Resistance and susceptibility to infection in inbred murine strains. II. Variations in the effect of treatment with thymosin fraction 5 on the release of lymphokines in vivo.

Of nine inbred murine strains sensitized intravenously with killed lyophilized Candida albicans and challenged 3 weeks later with a C. albicans filtrate, four strains were low responders and five were high responders in the in vivo release of migration inhibitory factor (MIF) and gamma interferon (IFN-gamma). An identical distribution of high- and low-responder strains occurred in response to sensitization with Mycobacterium bovis BCG and subsequent challenge with old tuberculin. Treatment of the murine strains with thymosin fraction 5 prior to sensitization and challenge had different effects: (a) the high-responder strains had a decrease in their release in vivo of the two lymphokines; (b) three of five of the low-responder strains had a striking increase in the in vivo release of MIF and IFN-gamma; and (c) one low-responder strain did not have its response altered. A parallelism existed between the capacity of a murine strain to release the two lymphokines in vivo on stimulation with C. albicans antigens and the capacity of that strain to resist intravenous infection with living C. albicans.