GlaxoSmithKline (Poland)

PURPOSE: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III or IV NSCLC, performance status < or = 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m2/d on days 1 to 5 or IV docetaxel 75 mg/m2 day 1 every 21 days. RESULTS: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.

Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Augmented reality (AR) may be capable of shaping the competitive advantage of companies by providing various benefits for the consumers. The aim of this article is to assess if AR is attractive to consumers and in which areas it can create the most value. Hence, we have sought to identify the most useful areas of AR applications, as well as factors influencing AR’s attractiveness. Our study finds that consumers regard AR as the most useful in the areas of education, medicine and tourism. Furthermore, we found a gap between the supply and needs of customers in terms of types of AR application offered on the market. We identified advantages and disadvantages of AR applications over their traditional counterparts impacting its adoption. Our research confirms that both hedonic and utilitarian aspects of the user experience are important for AR’s adoption.

BACKGROUND: Although acute otitis media (AOM) remains a major public health problem worldwide and brings economic burden on health care system and caregivers, little information is available about its epidemiology in Eastern Europe. METHODS: We conducted an epidemiological, prospective, observational, multi-centre cohort study (NCT01365390) in five East European countries (Estonia, Lithuania, Poland, Romania and Slovenia) between June 2011 and January 2013 to determine the incidence and clinical characteristics of AOM among children aged < 6 years during 1 year. RESULTS: AOM incidence was 160.7 cases (95 % confidence interval [CI]: 144.7-177.9) per 1000 person-years (PY) being the lowest in the < 1 year age group (92.3 cases [95 % CI: 59.7-136.2] per 1000 PY) and the highest in the 3- < 4 years age group (208.9 cases [95 % CI: 165.1-260.7] per 1000 PY). AOM incidence was similar across the countries, with the exception of Slovenia (340.3 cases [95 % CI: 278.3-412.0] per 1000 PY). There was a lower risk in breastfed children and a higher risk in those attending school/childcare or with allergies. AOM required 521 visits to the doctor. Antibiotics were prescribed for 276 (74.8 %) episodes with the lowest prescription rate in Estonia (51.4 %) and the highest in Romania (83.7 %). Complications were rare and hospitalisations occurred in 2 % of the cases. CONCLUSIONS: The disease burden of AOM in Eastern Europe is relevant and public health initiatives to reduce it should be considered. TRIAL REGISTRATION: ClinicalTrial.gov NCT01365390 .

BACKGROUND: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. METHODS: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. RESULTS: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. CONCLUSIONS: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

INTRODUCTION: -agonist (SABA) reliever overuse is common in asthma, despite availability of inhaled corticosteroid (ICS)-based maintenance therapies, and may be associated with increased risk of adverse events (AEs). This systematic literature review (SLR) and meta-analysis aimed to investigate the safety and tolerability of SABA reliever monotherapy for adults and adolescents with asthma, through analysis of randomized controlled trials (RCTs) and real-world evidence. METHODS: An SLR of English-language publications between January 1996 and December 2021 included RCTs and observational studies of patients aged ≥ 12 years treated with inhaled SABA reliever monotherapy (fixed dose or as needed) for ≥ 4 weeks. Studies of terbutaline and fenoterol were excluded. Meta-analysis feasibility was dependent on cross-trial data comparability. A random-effects model estimated rates of mortality, serious AEs (SAEs), and discontinuation due to AEs (DAEs) for as-needed and fixed-dose SABA treatment groups. ICS monotherapy and SABA therapy were compared using a fixed-effects model. RESULTS: Forty-two studies were identified by the SLR for assessment of feasibility. Final meta-analysis included 24 RCTs. Too few observational studies (n = 2) were available for inclusion in the meta-analysis. One death unrelated to treatment was reported in each of the ICS, ICS + LABA, and fixed-dose SABA groups. No other treatment-related deaths were reported. SAE and DAE rates were < 4%. DAEs were reported more frequently in the SABA treatment groups than with ICS, potentially owing to worsening asthma symptoms being classified as an AE. SAE risk was comparable between SABA and ICS treatments. CONCLUSIONS: Meta-analysis of data from RCTs showed that deaths were rare with SABA reliever monotherapy, and rates of SAEs and DAEs were comparable between SABA reliever and ICS treatment groups. When used appropriately within prescribed limits as reliever therapy, SABA does not contribute to excess rates of mortality, SAEs, or DAEs.

PURPOSE: Although the World Health Organization recommends universal rotavirus immunization, uptake of the vaccine is low in Poland and Hungary, where it is not covered by the National Immunization Program. This study aimed to quantify mothers' preferences for vaccines preventing children's diarrheal illness and to examine whether willingness to vaccinate varies with working status. METHODS: Mothers of children aged <3 years living in Poland and Hungary completed an online discrete-choice experiment survey. In each of 9 choice questions, respondents indicated whether they preferred no vaccination or one of two hypothetical vaccine profiles described in terms of 6 features. Vaccine preference parameters were estimated for working and non-working mothers using a random-parameter logit model and were used to calculate the relative importance of changes in vaccine features. RESULTS: 350 mothers in Poland and 350 mothers in Hungary were surveyed. Of the attributes evaluated, changes in vaccine cost were most important in both countries, followed by changes in severity of illness prevented, vaccine effectiveness, mode of administration, duration of illness prevented, and number of doses. Mothers in both countries had a strong preference for vaccination versus no vaccination, which was more pronounced among working mothers. In Poland, working mothers placed less weight on effectiveness, illness severity, and cost than non-working mothers and were more likely to rate disruptions in work, child care, and routines as important reasons to vaccinate. In Hungary, working mothers were statistically significantly less likely to opt out of vaccination than non-working mothers. Preference for vaccination itself, relative to improving vaccine effectiveness (from 50% to 90% effective), was 7 times greater among working than among non-working mothers in Poland but was not considerably different between working and non-working mothers in Hungary. CONCLUSIONS: Polish and Hungarian working mothers are more likely to vaccinate children against diarrheal illness than non-working mothers.

INTRODUCTION: Adherence to therapy is one of the basic preconditions of successful treatment of asthma and COPD. Unfortunately, many patients take their medication incorrectly. The aim of this study was to assess doctors' knowledge of this phenomenon, including interventions able to improve patient adherence. MATERIAL AND METHODS: It was a questionnaire-based survey conducted among convenience sample of Polish physicians treating asthma and COPD. RESULTS: One hundred and sixty one physicians, mainly specialists in allergology (44.1%) and pulmonology (37.3%) took part in the study. According to participants, asthma patients took on average 65.4 ± 17.1% of doses of prescribed drugs, whereas COPD patients - 61.6 ± 24.2%. Over half of respondents claimed that during the first year of treatment, no more than 20% of asthma and COPD patients discontinue their therapy. Survey participants pointed at patients discourage (41.6%) and lack of knowledge about disease (19.3%) as the main reasons for discontinuation of therapy. Almost 2/3 of participants (65.8%) claimed that they could recognize non-adherence in their patients. Prescribing combination inhaled drugs (72.7%), drugs with infrequent dosing (63.4%), and affordable ones (53.4%) were the most common interventions aimed at improving adherence provided by respondents. CONCLUSIONS: Survey participants were aware of the phenomenon of non-adherence in patients with asthma and COPD, but underestimated the real prevalence and seriousness of it. They also overestimated their ability to recognise non-adherence in their patients. Therefore, not necessarily they may obtain better adherence in their asthma and COPD patients. These results point at the issues which should be addressed in pre- and postgraduate education of physicians treating chronic airways conditions.

While Internet of Things (IoT) systems/applications/ platforms/devices materialize with increasing speed, software engineering "reflection" does not follow "fast enough". The situation is particularly "unbalanced" when one considers integration of independently developed IoT artifacts. To address this problem, we attempt at cataloging software design patterns that materialize in the context of interoperability of/within IoT ecosystems. The aim of this contribution is to briefly describe most common patterns (based on results of the INTER-IoT project), including analysis of common issues, and elaboration of a need for the creation of new (or extending existing) patterns in order to achieve solutions applicable for IoT artifact integration.

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8513 Background: A combination of a 5-HT3 receptor antagonist (5-HT3 RA) + dex is standard for prevention of CINV due to HEC. However, NK-1 RAs are now also of interest. The current trial evaluated casopitant mesylate, a potent, oral, selective NK-1 RA, in a triple therapy regimen with a 5-HT3 RA and dex in pts receiving HEC. Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group study, pts receiving HEC were stratified by gender and randomized among six arms. HEC consisted of regimens including cisplatin ≥ 70 mg/m 2 IV over 1–4 hours (h) day 1 (D1). All pts received ond 32mg IV D1 and dex PO D1–4 with either placebo control, casopitant 50mg QD D1–3, casopitant 100mg QD D1–3, or casopitant 150mg QD D1–3. Pts on exploratory arms received ond/dex plus either casopitant 150 mg D1 only or aprepitant 125mg D1 and 80mg D2–3. The primary endpoint was complete response (CR) rate (no vomiting, retching, rescue medications or premature withdrawals) during the first 120 h following initiation of HEC. Target intent-to-treat (ITT) group enrollment was 82 pts per arm. Results: 493 enrolled patients comprised the ITT group. CR rate was 60% in the control arm; 76% for casopitant 50mg; 86% for 100mg; and 77% for 150mg (p=.0036, Cochran-Armitage trend test). CR rate was 75% with casopitant 150 mg D1 and 72% for 3-day aprepitant. CR rates at 24 h were similar in all groups (86%-96%). Casopitant prolonged time to emesis (p=.0029) and increased the proportion of pts without vomiting (p=.0122) relative to control. There were no differences in rates of nausea or use of rescue medication among groups. Adverse events were similar across all arms, with neutropenia, nausea, and hiccups (≤ 17%) as most common. All casopitant doses were generally well tolerated. Conclusions: The addition of casopitant to ond/dex at all doses tested and in 1- or 3-day administration regimens was well tolerated and significantly reduced CINV rates over a 5-day period in pts receiving HEC. The results of the exploratory 1-day regimen are of particular interest for future evaluation. [Table: see text]

This study was performed to assess attribution of high grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) to human papillomavirus (HPV) genotypes and secondarily to assess reproducibility of HG-CIN/ICC diagnosis obtained in Poland. Formaldehyde fixed, paraffin embedded blocks of HG-CIN/ICC from two distant institutions were sent to a central laboratory together with original histological diagnoses. Central/expert review of histopathological specimens was performed and agreement between local and central/expert diagnoses was calculated. HPV detection and genotyping in the samples was carried out with the use of SPF10-LiPA25 technology. Results were analyzed for 205 HG-CIN and 193 ICC cases with centrally confirmed diagnoses. Kappa coefficients and 95 % confidence intervals for HG-CIN and ICC diagnoses were: 0.13 (0.09;0.17) and 0.19 (0.11;0.26) respectively. Cohen's kappa coefficients for lesions with representative number of samples ranged from 0.01 for cervical intraepithelial neoplasia grade 2 to 0.75 for adenocarcinoma. HPV DNA was detected in 96.1 and 91.2 % of the confirmed HG-CIN and ICC specimens respectively. HPV positive HG-CIN was most commonly attributed to HPV types: 16 (62.8), 33 (7.8), 31 (6.6), 52 (3.7), 45 (2.6) and 58 (2.6 %). HPV positive ICC was most commonly attributed to HPV types: 16 (72.1), 18 (10.8), 33 (5.7), 45 (3.4) and 31 (1.7 %). Reproducibility of histological diagnosis of HG-CIN/ICC obtained in Poland generally increases with the severity of lesion and is lowest for cervical intraepithelial neoplasia grade 2 and highest for adenocarcinoma. Over 80 % of ICC cases are vaccine-preventable in Poland.

Background In China, the prevalence of severe asthma with eosinophilic phenotype is rising, yet treatment options are limited. Mepolizumab is the first targeted biologic therapy for eosinophilic-driven disease in China. This study (clinicaltrials.gov identifier NCT03562195 ) evaluated efficacy and safety of mepolizumab in Chinese patients with severe asthma. Methods The phase III, multicentre, randomised, placebo-controlled, double-blind, parallel-group study enrolled patients aged ≥12 years with severe asthma, with two or more exacerbations in the previous year, and on inhaled corticosteroids plus at least one controller medication. Following a 1–4-week run-in, patients were randomised 1:1 to mepolizumab 100 mg or placebo subcutaneously every 4 weeks for 52 weeks. The primary end-point was annualised rate of clinically significant exacerbations (CSEs) through week 52. Secondary end-points were time to first CSE, frequency of CSEs requiring hospitalisation/emergency department visits or hospitalisation over 52 weeks, mean change in St George's Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) at week 52; safety was evaluated. Results The modified intention-to-treat population included 300 patients. At week 52 with mepolizumab versus placebo, annualised rate of CSEs was 65% lower (0.45 versus 1.31 events per year; rate ratio 0.35, 95% CI 0.24–0.50; p&lt;0.001); time to first CSE longer (hazard ratio 0.38, 95% CI 0.26–0.56; p&lt;0.001) and number of CSEs requiring hospitalisation/emergency department visit lower (rate ratio 0.30, 95% CI 0.12–0.77; p=0.012). From baseline to week 52, SGRQ score improved (p=0.001) and pre-bronchodilator FEV 1 increased (p=0.006). Incidence of adverse events was similar between treatment groups. Conclusion Mepolizumab provided clinical benefits to patients with severe asthma in China and showed a favourable benefit–risk profile.

INTRODUCTION: Identifying individual characteristics or underlying conditions linked to adverse drug reactions (ADRs) can help optimise the benefit-risk ratio for individuals. A systematic evaluation of statistical methods to identify subgroups potentially at risk using spontaneous ADR report datasets is lacking. OBJECTIVES: In this study, we aimed to assess concordance between subgroup disproportionality scores and European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) discussions of potential subgroup risk. METHODS: The subgroup disproportionality method described by Sandberg et al., and variants, were applied to statistically screen for subgroups at potential increased risk of ADRs, using data from the US FDA Adverse Event Reporting System (FAERS) cumulative from 2004 to quarter 2 2021. The reference set used to assess concordance was manually extracted from PRAC minutes from 2015 to 2019. Mentions of subgroups presenting potential differentiated risk and overlapping with the Sandberg method were included. RESULTS: Twenty-seven PRAC subgroup examples representing 1719 subgroup drug-event combinations (DECs) in FAERS were included. Using the Sandberg methodology, 2 of the 27 could be detected (one for age and one for sex). No subgroup examples for pregnancy and underlying condition were detected. With a methodological variant, 14 of 27 examples could be detected. CONCLUSIONS: We observed low concordance between subgroup disproportionality scores and PRAC discussions of potential subgroup risk. Subgroup analyses performed better for age and sex, while for covariates not well-captured in FAERS, such as underlying condition and pregnancy, additional data sources should be considered.

BACKGROUND: In 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use updated its efficacy guideline for good clinical practice and introduced predefined quality tolerance limits (QTLs) as a quality control in clinical trials. QTLs are complementary to Quality by Design (QbD) principles (ICH-E8) and are one of the components of the risk-based clinical trial quality management system. METHODS: Currently the framework for QTLs process is well established, extensively describing the operational aspects of Defining, Monitoring and Reporting, but a single source of commonly used methods to establish QTLs and secondary limits is lacking. This paper will primarily focus on closing this gap and include applications of statistical process control and Bayesian methods on commonly used study level quality parameters such as premature treatment discontinuation, study discontinuation and significant protocol deviations as examples. CONCLUSIONS: Application of quality tolerance limits to parameters that correspond to critical to quality factors help identify systematic errors. Some situations pose special challenges to implementing QTLs and not all methods are optimal in every scenario. Early warning signals, in addition to QTL, are necessary to trigger actions to further minimize the possibility of an end-of-study excursion.

Large language models (LLMs) are useful tools with the capacity for performing specific types of knowledge work at an effective scale. However, LLM deployments in high-risk and safety-critical domains pose unique challenges, notably the issue of "hallucinations", where LLMs can generate fabricated information. This is particularly concerning in settings such as drug safety, where inaccuracies could lead to patient harm. To mitigate these risks, we have developed and demonstrated a proof of concept suite of guardrails specifically designed to mitigate certain types of hallucinations and errors for drug safety, with potential applicability to other medical safety-critical contexts. These guardrails include mechanisms to detect anomalous documents to prevent the ingestion of inappropriate data, identify incorrect drug names or adverse event terms, and convey uncertainty in generated content. We integrated these guardrails with an LLM fine-tuned for a text-to-text task, which involves converting both structured and unstructured data within adverse event reports into natural language. This method was applied to translate individual case safety reports, demonstrating effective application in a pharmacovigilance processing task. Our guardrail framework offers a set of tools with broad applicability across various domains, ensuring LLMs can be safely used in high-risk situations by eliminating the occurrence of key errors, including the generation of incorrect pharmacovigilance-related terms, thus adhering to stringent regulatory and quality standards in medical safety-critical environments.

PURPOSE: Community-acquired pneumonia (CAP) is a common infection with significant morbidity and mortality. In January 2017, Poland introduced pneumococcal conjugate vaccine (PCV) into their national immunisation programme to protect children against invasive pneumococcal disease. This study was designed to investigate pneumonia-related hospitalisation rates and trends from 2009 to 2016 prior to the introduction of nationally funded PCV vaccination. METHODS: Using national public statistic data available from the National Institute of Public Health - National Institute of Hygiene, annual hospitalisation rates for pneumonia were analysed, categorised by aetiology and age (<2, 2-3, 4-5, 6-19, 20-59, 60+ years). Trends over time were assessed, as well as in-hospital mortality. RESULTS: The overall hospitalisation rate due to pneumonia varied between 325.9 and 372.2/100,000 population. Higher rates of hospitalisation were seen in older adults and children ≤5 years. Trends were observed when analysing hospitalisations by pneumonia aetiology within age groups: between 2009 and 2016, Streptococcus pneumoniae hospitalisations significantly increased for children aged <2, 2-3, and 4-5 years, from 5.3 to 12.4, 5.2 to 8.2, and 1.9 to 4.6/100,000 population respectively. Whereas hospitalisations due to Haemophilus influenzae pneumonia decreased significantly from 7.8 to 1.8 and 4.8 to 1.9/100,000 children aged <2 and 2-3 years respectively. The numbers of in-hospital deaths increased from 5578 in 2009 to 8149 in 2016, with >85% of deaths in the 60+ age group. CONCLUSIONS: This is the first national study of pneumonia hospitalisations in Poland, providing the baseline data from which to investigate the impact of the change in vaccination policy on pneumonia hospitalisations in Poland.

Integrating Large Language Models (LLMs) to enhance complex business document retrieval represents an emerging field known as retrieval-augmented generation (RAG). In highly regulated domains like drug safety (pharmacovigilance), its application has remained largely unexplored. This technology brings numerous advantages, including expedited staff on-boarding, enhanced comprehension of contextual queries, and swift information retrieval through natural language inquiries, surpassing conventional keyword searches. This study delves into various operational tasks, such as locating regulatory process guidance, navigating intricate scenarios for advice, and ensuring the LLM's competence in recognizing uncertainties to prevent misinformation. LLMs empower users to engage with documentation using natural language, markedly improving search efficiency. The case study underscores LLM's effectiveness in delivering prompt guidance within pharmacovigilance and adverse event processing and reporting, offering a user-centric solution that streamlines the search for intricate business documentation.

Purpose The institutional context in which family firms operate influences their behaviour and performance, yet literature reviews seldom analyse family firms on a regional basis. To fill this gap, this review aims to present research on family entrepreneurship in the transition economies of the Visegrád countries (V4). In this particular group of European economies, the current formal institutions have largely evolved along Western European lines. However, the transformation of informal institutions appears to be still in its infancy. Design/methodology/approach In order to identify the most representative authors, the methodologies used, the main research topics and to establish a future research agenda, the authors selected, through a systematic process, 112 papers from the Web of Science up to the year 2022. The authors performed a bibliographic analysis using clustering algorithms, complemented by a traditional literature review. Findings The performance of family firms in transition economies has been the subject of very little research. The results allowed the authors to identify four main areas of research: governance, innovation, sustainability, competitive advantage and considering the influence of the region's characteristics on family business behaviour. Originality/value Studies from transition economies can contribute to a broader understanding of family firms in terms of the impact of the institutional environment (especially the influence of sociological changes and specific historical experiences of family members) on their long-term planning, socioemotional wealth (SEW) protection and ethics. In light of recent events, research from the region may also contribute to the understanding of how and to what extent “familiness” influences crisis management or socially responsible behaviour in family firms.

Abstract Genome-wide association studies (GWASs) have identified tens of thousands of disease associated variants and provided critical insights into developing effective treatments. However, limited sample sizes have hindered the discovery of variants for uncommon and rare diseases. Here, we introduce KGWAS, a novel geometric deep learning method that leverages a massive functional knowledge graph across variants and genes to improve detection power in small-cohort GWASs significantly. KGWAS assesses the strength of a variant’s association to disease based on the aggregate GWAS evidence across molecular elements interacting with the variant within the knowledge graph. Comprehensive simulations and replication experiments showed that, for small sample sizes ( N =1-10K), KGWAS identified up to 100% more statistically significant associations than state-of-the-art GWAS methods and achieved the same statistical power with up to 2.67× fewer samples. We applied KGWAS to 554 uncommon UK Biobank diseases ( N case &lt;5K) and identified 183 more associations (46.9% improvement) than the original GWAS, where the gain further increases to 79.8% for 141 rare diseases (N case &lt;300). The KGWAS-only discoveries are supported by abundant functional evidence, such as rs2155219 (on 11q13) associated with ulcerative colitis potentially via regulating LRRC32 expression in CD4+ regulatory T cells, and rs7312765 (on 12q12) associated with the rare disease myasthenia gravis potentially via regulating PPHLN1 expression in neuron-related cell types. Furthermore, KGWAS consistently improves downstream analyses such as identifying disease-specific network links for interpreting GWAS variants, identifying disease-associated genes, and identifying disease-relevant cell populations. Overall, KGWAS is a flexible and powerful AI model that integrates growing functional genomics data to discover novel variants, genes, cells, and networks, especially valuable for small cohort diseases.