BACKGROUND Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients' quality of life. AIM This study investigates potential novel therapeutic options that could ameliorate symptoms of DN. METHODOLOGY Research and review papers from the last 10 years were taken into consideration. RESULTS There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy. CONCLUSION Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs.

BACKGROUND Previously, we assessed the impact of restrictive diets, including caloric restriction (CR), intermittent fasting (IF), or fasting-mimicking diet (FMD), on a healthy gastrointestinal tract. We revealed that each of the diets shows anti-inflammatory outcomes. OBJECTIVE The current study aimed to verify the diets' applicability in treating colitis. METHODS We exposed a mouse model with mild chronic DSS colitis to ad libitum control feeding, CR, IF, or FMD. The collected samples were analyzed for markers of inflammation. RESULTS The diets reduced DSS-triggered increases in spleen weight and myeloperoxidase (MPO) activity. Diet intervention also influenced occludin levels, small intestine morphology, as well as cytokine and inflammatory gene expression, mainly in the mucosa of the proximal colon. The diets did not reverse DSS-enhanced gut permeability and thickening of the colon muscularis externa. Concerning inflammatory gene expression, the impact of DSS and the dietary intervention was limited to the colon as we did not measure major changes in the jejunum mucosa, Peyer's patches, and mesenteric lymph nodes. Further, rather modest changes in the concentration of intestinal bile acids were observed in response to the diets, while taurine and its conjugates levels were strongly affected. CONCLUSIONS Despite the differences in the dietary protocol, the tested diets showed very similar impacts and, therefore, may be interchangeable when aiming to reduce inflammation in the colon. However, FMD showed the most consistent beneficial impact.

African swine fever virus (ASFV) is a complex DNA virus causing severe hemorrhagic disease in domestic pigs and wild boar. The disease has spread worldwide, with important socio-economic consequences. Early virus detection and control measures are crucial as there are no effective vaccines nor antivirals on the market. While the diagnosis of ASFV is fast and based primarily on qPCR, the detection of infectious ASFV is a labor-intensive process requiring susceptible macrophages and subsequent antibody-based staining or hemadsorption. The latter cannot detect ASFV isolates devoid of functional CD2v (EP402R) expression. Here, we report the development of a plasmid-based reporter assay (RA) for the sensitive detection and titration of infectious ASFV. To this end, we constructed a plasmid for secreted NanoLuc® luciferase (secNluc) expression driven by the ASFV DNA polymerase gene G1211R promoter. Infection of plasmid-transfected immortalized porcine kidney macrophages (IPKM) followed by measurement of secNluc from cell culture supernatants allowed reliable automated quantification of infectious ASFV. The RA-based titers matched the titers determined by conventional p72-staining or hemadsorption protocols. The novel assay is specific for ASFV as it does not detect classical swine fever virus nor porcine reproductive and respiratory syndrome virus. It is applicable to ASFV of different genotypes, virulence, and sources, including ASFV from sera and whole blood from infected pigs as well as non-hemadsorbing ASFV.

Urban logistics implementation causes environmental pollution; therefore, it is necessary to consider the impact on the environment when carrying out such logistics. Electric vehicles are alternative vehicles that reduce the impact on the environment. For this reason, this study investigated which electric vehicle has the best indicators for urban logistics. An innovative approach when selecting such vehicles is the application of a fuzzy–rough method based on expert decision making, whereby the decision-making process is adapted to the decision makers. In this case, two methods of multi-criteria decision making (MCDM) were used: SWARA (stepwise weight assessment ratio analysis) and MARCOS (measurement alternatives and ranking according to compromise solution). By applying the fuzzy–rough approach, uncertainty is included when making a decision, and it is possible to use linguistic values. The results obtained by the fuzzy–rough SWARA method showed that the range and price of electric vehicles have the greatest influence on the selection of an electric delivery vehicle. The results of applying the fuzzy–rough MARCOS method indicated that the Kangoo E-Tech Electric vehicle has the best characteristics according to experts’ estimates. These results were confirmed by validation and the application of sensitivity analysis. In urban logistics, the selection of an electric delivery vehicle helps to reduce the impact on the environment. By applying the fuzzy–rough approach, the decision-making problem is adjusted to the preferences of the decision makers who play a major role in purchasing a vehicle.

Exclusive semileptonic b hadron decays (b → uℓν) serve as a sandbox for probing strong and electroweak interactions and for extracting the CKM element Vub. Instead, this work investigates their underexplored potential to reveal new short-distance physics. Utilizing SMEFT as a conduit to chart territory beyond the SM, we demonstrate that substantive new physics contributions in b → uℓν are necessarily linked to correlated effects in rare neutral-current b decays, neutral B meson mixing or high-mass Drell-Yan tails. We find that measurements of the latter processes strongly restrict the allowed deviations in the former. A complete set of tree-level mediators, originating from a perturbative ultraviolet model and matching at dimension 6, is thoroughly explored to support this assertion. As a showcase application, we examine the feasibility of a new physics interpretation of the recent tension in exclusive |Vub| extraction from B → Vℓν where V = (ρ, ω).

Objective: Ruptured abdominal aortic aneurysm (rAAA) is a critical condition with a high mortality rate. Over the years, endovascular aortic repair (EVAR) has evolved as a viable treatment option in addition to open repair (OR). The primary objective of this study was to compare the safety and efficacy of EVAR and OR for the treatment of rAAA based on a comprehensive analysis of our single-centre 30-year experience. Methods: Patients treated for rAAA at the Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Germany from 1 January 1993 to 31 December 2022 were included. Relevant information was retrieved from archived medical records. Patient survival and surgery-related complications were analysed. Results: None of the patient-specific markers, emergency department-associated parameters, and co-morbidities were associated with patient survival. The 30-day and in-hospital mortality was higher in the OR group vs. in the EVAR group (50% vs. 8.7% and 57.1% vs. 13%, respectively). OR was associated with more frequent occurrence of more severe complications when compared to EVAR. Overall patient survival was 56 ± 5% at 12 months post-surgery (52 ± 6% for OR vs. 73 ± 11% for EVAR, respectively) (p < 0.05). Patients ≥70 years of age showed poorer survival in the OR group, with a 12-month survival of 42 ± 7% vs. 70 ± 10% for patients <70 years of age (p < 0.05). In the EVAR group, this age-related survival advantage was not found (12-month survival: ≥70 years: 67 ± 14%, <70 years: 86 ± 13%). Gender-specific survival was similar regardless of the applied method of care. Conclusion: OR was associated with more severe complications in our study. EVAR initially outperformed OR for rAAA regarding patient survival while re-interventions following EVAR negatively affect survival in the long-term. Elderly patients should be treated with EVAR. Gender does not seem to have a significant impact on survival.

Additive manufacturing has undergone a significant transformation, evolving from a mere prototyping technique to a reliable and proven manufacturing technology that can produce products of varying sizes and materials. The incorporation of fibers in additive manufacturing processes has the potential to improve a range of material properties, including mechanical, thermal, and electrical properties. However, this improvement is largely dependent on the orientation of the fibers within the material, with the properties being enhanced primarily in the direction of fiber orientation. As a result, accurately predicting and controlling the fiber orientation during the extrusion or deposition process is critical. Various methods are available to control fiber orientation, such as manipulating the nozzle shape, extrusion and nozzle speed, the gap between the nozzle and substrate, as well as fiber features like aspect ratio and volume fraction. At the same time, the presence and orientation of fibers can significantly impact the flow pattern and extrusion pressure conditions, ultimately affecting the formation of printed strands in a manner distinct from those without fibers. For that reason, our study utilizes computational fluid dynamics to anticipate and comprehend the printing conditions that would result in favorable fiber orientations and strand shapes, incl. corner printing. Our findings may be utilized to determine optimal toolpaths for 3D printing composites, as well as printing conditions that will facilitate the achievement of the desired fiber orientation within individual strands.

For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) gene and clinically characterized by the presence of pyogenic arthritis, pyoderma gangrenosum (PG), and acne (1,2). Due to the involvement of the PSTPIP1 gene in the regulation of innate immunity, mutations of this gene cause abnormal activation of inflammasomes, complexes of NLRP3/ASC/caspase-1 proteins. As a result, production of interleukin-1β, a key molecule that triggers synthesis of cytokines necessary for the recruitment of neutrophils, is significantly increased (2,3). Additionally, the levels of other pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin 17 (IL-7) are also elevated, which further disrupts inflammatory mechanisms in the microenvironment (4). Since hyperproduction of IL-1 and other involved cytokines is the predominant event in the pathogenesis, these molecules are promising targets in the treatment of PAPA syndrome. Corticosteroids and biologics are currently the most commonly used agents for inducing and hastening remission of symptoms (5). A substantial step forward in the treatment of PAPA syndrome has been the introduction of medications blocking the cytokines crucial in the pathogenesis of this disorder, with TNF-α and IL-1 inhibitors being the most frequent choice of such biological therapy (6). We report the case of a 22-year-old male patient with PAPA syndrome who was referred to our department 18 months ago due to exacerbation of skin changes. Initial presentation and subsequent evolution of disease in this patient matched the typical clinical pattern of PAPA syndrome. The first symptoms occurred at the age of two in the form of unspecific joint disease that was diagnosed as juvenile idiopathic arthritis. Subsequently, in the early adolescence the patient presented with new skin changes manifesting as severe acne and persistent pyoderma gangrenosum-like ulcers. At the same time, severity of joint involvement gradually decreased. After the characteristic phenotype of the disease had fully developed, suspicion of possible syndromic origin of symptoms arose. For this reason, genetic analysis was performed as requested by attending pediatricians at the University Clinical Center in Sarajevo, and E250Q mutation of the PSTPIP1 gene was detected. Thus, the diagnosis of PAPA syndrome was confirmed. Throughout the duration of the disease, several types of medication had been introduced in the treatment with varying success. Earliest joint symptoms were alleviated with non-steroidal anti-inflammatory drugs, while repeated courses of corticosteroids were the mainstay of the therapy during a decade-long period. As a consequence of prolonged steroid therapy, growth disorder, among various other side-effects, had been especially pronounced. Acting as a classic steroid-sparing immunosuppressive agent, methotrexate had also been part of the patient's treatment regimen. Lastly, biologics, including both TNF-α and IL-a inhibitors, had been separately administered as the remaining treatment options. However, adalimumab expressed a predominant effect on joint symptoms, whereas re-activation of previously undetected Hepatitis-B infection occurred during the subsequent therapy with anakinra. Due to this adverse reaction, anakinra treatment was discontinued. At the initial examination, the patient presented with multiple erythematous, partially excoriated papules and nodules, along with residual post-inflammatory hyperpigmented patches and scars on the skin of the whole back, chest, shoulders, and upper arms (Figure 1, Figure 2). The presence of postoperative scars on the elbows, resulting from previously performed surgical procedures of persistently affected joints with the goal of achieving pain relief and functional improvement, was also observed. Several smaller ulcers with undermined edges (Figure 3), as well as residual hyperpigmentation and cicatrices (Figure 4) were visible on the lower extremities. Additionally, the patient reported appearance of pustules and non-healing ulcers after minor trauma, which corresponds to the pathergy phenomenon, a common feature of PAPA syndrome. In contrast to the severity of cutaneous changes, the joint symptoms were mild. After thorough assessment of the patient's medical history and current condition, a multi-agent regimen was initiated, consisting of adalimumab, isotretinoin, and prednisone. Regular check-ups during the 12 months of treatment showed that the applied agents stabilized the patient's condition, alleviated more severe and acute skin changes, and slowed down further exacerbation of symptoms. Due to the rarity of PAPA syndrome, data on its treatment is scarce. Official guidelines are non-existing, and available information is based on case reports, case series, and a few smaller retrospective studies (5,7). In general, response to therapy remains inconsistent between patients, despite introduction of novel drugs. Furthermore, single treatment regimens are often not equally effective for all manifestations of the disease, which in a number of cases results in the administration of multi-agent treatment (2). As described in our case report, we opted for a multi-agent regimen not only due to specific individual role of each drug in the treatment of PAPA syndrome but also because of the possible augmented effect of combined therapy. Initially, a short course of systemic corticosteroid (prednisone 30 mg/day for 3 weeks) was introduced in order to alleviate acute symptoms until other agents started showing their effects. The initial dose of administered corticosteroid was gradually tapered by 5 mg every week and soon discontinued. Adalimumab (40 mg every 2 weeks for 12 months) was chosen since its previous administration was without significant adverse effects and with more acceptable end results, unlike therapy with anakinra (8). In addition, TNF-α inhibitors, such as adalimumab, etanercept, and infliximab, have been generally regarded as a more effective treatment option for cutaneous changes, while anakinra, an anti-IL-1 agent, has been more beneficial in alleviating joint symptoms (9-11). Since the skin of our patient was significantly more affected than the joints, adalimumab was a preferred option for biological treatment. Finally, isotretinoin (0.5 mg/kg/day for 6 months) also found a place in our multi-agent therapy plan as a specific, supportive treatment agent for acne (12). Due to the fact that our national health insurance system covered the costs of treatment with TNF-α inhibitors for only 12 months, adalimumab had to be discontinued after the end of this period. Episodes of acute exacerbation that the patient experienced after the cessation of multi-agent regimen were addressed with systemic corticosteroids and symptomatic therapy. Based on case reports, corticosteroids are usually one of the first agents to be administered in patients diagnosed with PAPA syndrome. They are frequently effective in alleviating joint symptoms, but, on the other hand, high doses of corticosteroids can worsen acne lesions (6). Moreover, due to the multiple side-effects of corticosteroids, such as electrolyte abnormalities, hypertension, hyperglycemia, osteoporosis, growth suppression, and adrenal insufficiency (13), a steroid-sparing agent is typically introduced into treatment together with or after corticosteroid therapy. A substantial step forward in the treatment of PAPA syndrome has been achieved with the introduction of medications targeting cytokines crucial in the pathogenesis of this disorder. The two most commonly used groups of such biological drugs have been those that block TNF-α and IL-1. A longer lasting improvement of symptoms has been achieved in a number of cases with both types of agents. Since other medications have often failed to establish long-term control of PAPA syndrome, such effects can be seen as a valuable accomplishment (6,14). Regardless of this observation, the response to treatment still differs between patients. More variable effects have been documented for IL-1 inhibitors, such as anakinra, while TNF-α inhibitors, such as adalimumab, infliximab, and etanercept, have been associated with more steady responses (4,6,10). The inconsistent effect of biologic therapies could be explained by the fact that PSTPIP1 protein is involved in various biochemical processes in different cells of the immune system. Thuse, none of the medications has an adequate spectrum of activity to control all involved immunological pathways (5,15). Overall, due to scarcity of valid information and guidelines, there is an increasing need for multicentric randomized controlled trials that would provide evidence-based data on effective treatment options for PAPA syndrome. Despite the rarity of this disorder, extensive research should be performed in order to discover therapies that could successfully manage all different manifestations of PAPA syndrome. Consequently, such efforts and breakthroughs would lead to decreased mortality and improved quality of life for patients suffering from this debilitating disease. The case described herein shows that PAPA syndrome can remain undiagnosed for longer periods of time, resulting in delayed treatment. Furthermore, the available therapeutic options are not sufficient to achieve long-term remission in many patients. Thus, continuous and comprehensive research is vital for ensuring adequate care of patients with PAPA syndrome.