Revisiting column selectivity choices in ultra-high performance liquid chromatography-Using multidimensional analytical Design Spaces to identify column equivalency.

Current guides and column selection system (CSS) platforms can provide some helpful insights with regard to the selection of alternative phases. Their practical reliability however, can also turn out to be questionable, especially considering the lack of detailed specifics, such as a clear definition of points of equivalence-appropriate running conditions under which the given analytical mixture can be satisfactorily resolved on various stationary phases. In this context, the use of multivariate modeling tools can be highly beneficial. These tools, when applied systematically, are ideal for uniquely characterizing complex LC-separation systems, a fact supported by numerous peer-reviewed papers. Revisiting our earlier work [1] and the applied systematic workflow [2], we used a Design Space modeling software (DryLab), with the main focus on building and comparing 3-dimensional separation models of amlodipine and its related impurities to identify shared method conditions under which columns are conveniently interchangeable. Our study comprised 5, C18-modified ultra-high performance liquid chromatography (UHPLC) columns in total, in some cases with surprising results. We identified several equivalences between the Design Spaces (DSs) of markedly different columns. Conversely, there were cases where, despite the predicted similarities in column data, the modeled DSs demonstrated clear differences between the selected stationary phases.

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging.

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

Challenges and opportunities for improvement in the management and financing system of Health Promotion Offices in Hungary.

Background: One hundred ten Health Promotion Offices (HPOs) have started operating in Hungary in response to public health challenges. Many of them have been active for almost 10 years, yet their operational experience has not been evaluated. The specific objectives of our study were: (1) to describe the current operational and funding system of HPOs, (2) to identify challenges related to the current management and funding practices, and (3) to formulate recommendations for improvement based on gathered experience and international experience. Design: In order to gain a deeper insight into the operational experience of HPOs, an online survey was conducted with the professional or economic managers of HPOs. A scoping review was carried out to gather international experiences about best practices to formulate recommendations for improvement in developing the operational and financing scheme for HPOs. Results: We found that current HPO network in Hungary faces three main challenges: a deficient management system, inflexible financing scheme, and unequal ability to purchase or provide services for the population. Conclusions: Based on the survey complemented by international experiences, we propose the overhaul of the professional management system and switching toa combination of fixed and performance-based financing scheme for the HPOs in Hungary.

International practices in health technology assessment and public financing of digital health technologies: recommendations for Hungary.

Background: Evaluating and integrating digital health technologies is a critical component of a national healthcare ecosystem in the 2020s and is expected to even increase in significance. Design: The paper gives an overview of international practices on public financing and health technology assessment of digital health technologies (DHTs) in five European Union (EU) countries and outlines recommendations for country-level action that relevant stakeholders can consider in order to support uptake of digital health solutions in Hungary. A scoping review was carried out to identify and gather country-specific classifications and international practices on the financing DHTs in five pioneering EU countries: Germany, France, Belgium, the United Kingdom and Finland. Results: Several frameworks have been developed for DHTs, however there is no single, unified framework or method for classification, evaluation, and financing of digital health technologies in European context. European countries apply different taxonomy, use different assessment domains and regulations for the reimbursement of DHTs. The Working Group of the Hungarian Health Economic Society recommends eight specific points for stakeholders, importantly taking active role in shaping common clinical evidence standards and technical quality criteria across in order for common standards to be developed in the European Union single market. Conclusion: Specificities of national healthcare contexts must be taken into account in decisions to allocate public funds to certain therapies rather than others.

The Effectiveness of Supplementation with Key Vitamins, Minerals, Antioxidants and Specific Nutritional Supplements in COPD-A Review.

Currently, an increasing amount of evidence supports the notion that vitamins C, D and E, carotenoids, and omega-3 fatty acids may protect against the progression of chronic respiratory diseases. Although chronic obstructive pulmonary disease (COPD) primarily affects the lung, it is often accompanied by extrapulmonary manifestations such as weight loss and malnutrition, skeletal muscle dysfunction, and an excess of harmful oxidants, which can lead to a decline in quality of life and possible death. Recently, the role of various vitamins, minerals, and antioxidants in mitigating the effects of environmental pollution and smoking has received significant attention. Therefore, this review evaluates the most relevant and up-to-date evidence on this topic. We conducted a literature review between 15 May 2018 and 15 May 2023, using the electronic database PubMed. Our search keywords included COPD, chronic obstructive pulmonary disease, FEV1, supplementation: vitamin A, vitamin D, vitamin E, vitamin C, vitamin B, omega-3, minerals, antioxidants, specific nutrient supplementations, clinical trials, and randomized controlled trials (RCTs). We focused on studies that measured the serum levels of vitamins, as these are a more objective measure than patient self-reports. Our findings suggest that the role of appropriate dietary supplements needs to be reconsidered for individuals who are predisposed to or at risk of these conditions.

Effect of time-invariant pressure gradients on peak formation and efficiency in ultrahigh-pressure liquid chromatography.

In chromatography, pressure can affect the retention factors of compounds significantly. In liquid chromatography, this effect is primarily related to the change in the molecular volume of solute during adsorption that is remarkably high for large biomolecules such as peptides and proteins. As a result, the migration velocities of chromatographic bands vary spatially through the column affecting the degree of band broadening. In this work, based on theoretical considerations, chromatographic efficiencies are studied under pressure-induced gradient conditions. The retention factor and migration velocity of different components are examined, and it is shown that components with the same retention time can have different migration patterns. The width of the initial band after injection is affected by the pressure gradient, providing significantly thinner initial bands for compounds with higher pressure sensitivity. In addition to classical band broadening phenomena, the influence of pressure gradients on band broadening is remarkable. The positive velocity gradient leads to extra band broadening. Our results clearly demonstrate that the zones are significantly wider at the end of the column if the change of molar volume of solute during adsorption is large. If the pressure drop is increasing, this effect becomes more significant. In the same time, the high release velocity of the bands somewhat counteracts the extra band broadening effect, however, it can not offset it perfectly. As a result, the separation efficiency of large biomolecules is decreased significantly due to the chromatographic pressure gradient. Under UHPLC conditions, the extent of apparent efficiency loss can reach up to 50% compared to the intrinsic efficiency of the column.

Unbiased Determination of Adsorption Isotherms by Inverse Method in Liquid Chromatography.

The Inverse Method is a widely used technique for the determination of adsorption isotherms in liquid chromatography. In this method, isotherm is determined from the overloaded peak profile of the component by the iterative solution of the mass balance equation of liquid chromatography. Successful use of this method requires a prior assumption of equation of isotherm (Langmuir, BET etc.). In this work, we have developed an inverse method that gives results of similar accuracy to the frontal analysis without assuming the equation of the isotherm. The oversaturated peaks were calculated using a spline fitted to data points instead of the derivative of the isotherm. The distribution of the isotherm points were optimized for minimizing the difference between the measured and calculated overloaded peaks. The accuracy of the developed method was verified with synthetic benchmark peaks and by the determination of isotherm of buthyl-benzoate under real conditions. The results confirmed that the accuracy of the developed method is similar to that of Frontal Analysis.

Fluorescence Quenching of Tyrosine-Ag Nanoclusters by Metal Ions: Analytical and Physicochemical Assessment.

A new synthesis method is described for the first time to produce silver nanoclusters (AgNCs) by using the tyrosine (Tyr) amino acid. Several important parameters (e.g., molar ratios, initial pH, reaction time etc.) were optimized to reach the highest yield. The formed Tyr-AgNCs show characteristic blue emission at λem = 410 nm, and two dominant fluorescence lifetime components were deconvoluted (τ1 ~ 3.7 and τ2 ~ 4.9 ns). The NCs contained metallic cores stabilized by dityrosine. For possible application, the interactions with several metal ions from the tap water and wastewater were investigated. Among the studied cations, four different ions (Cu2+, Ni2+, Fe3+, and Rh3+) had a dominant effect on the fluorescence of NCs. Based on the detected quenching processes, the limit of detection of the metal ions was determined. Static quenching (formation of a non-luminescent complex) was observed in all cases by temperature-dependent measurements. The calculated thermodynamic parameters showed that the interactions are spontaneous ranked in the following order of strength: Cu2+ > Fe3+ > Rh3+ > Ni2+. Based on the sign and relations of the standard enthalpy (ΔH°) and entropy changes (ΔS°), the dominant forces were also identified.

Riding the Pandemic Waves-Lessons to Be Learned from the COVID-19 Crisis Management in Romania.

In our analysis, we assessed how Romania dealt with the numerous challenges presented by the COVID-19 pandemic during 2021. In that year, the government had to deal with two waves of COVID-19 pandemics caused by the new variants, the low vaccination rate of the population, the overload of the healthcare system and political instability at the same time. Based on publicly available databases and international literature, we evaluated government measures aimed at reducing the spread of the pandemic and ensure the operation of the healthcare workforce and infrastructure. In addition, we evaluated measures to provide health services effectively and the government's pandemic responses regarding excess mortality in 2021. In the absence of a complex monitoring system, limited information was available on the spread of the pandemic or the various risk factors at play. Due to incomplete and inadequate management systems, the government was unable to implement timely and adequate measures. Our analysis concludes that the management of a pandemic can only be successful if data are collected and evaluated using complex systems in a timely manner, and if members of society adhere to clearly communicated government measures due to high levels of trust in the government.

Roadmap for large-scale implementation of point-of-care testing in primary care in Central and Eastern European countries: the Hungarian experience.

OBJECTIVE: The aim of this study is to give a broad overview of the international best practices regarding the implementation of point-of-care testing (POCT) in primary care (PC) setting and to highlight the facilitators and barriers for widespread national uptake. The study focuses on the managerial and organizational side of POCT, offering a roadmap for implementation as well as highlighting the most important requirements needed to unlock the clinical and economical potential of POCT in the Hungarian healthcare system. METHODS: We conducted an English language scoping literature review between January 2012 and June 2021 to assess the recent trends of POCT implementation in developed countries. Our research focuses on the recent publications of several European and Anglo-Saxon countries where POCT utilization is common. In parallel, we reviewed the Hungarian regulatory framework, ongoing governmental legislation, and strategies influencing the POCT dissemination in the Hungarian PC sector. RESULTS: Among the possible POCT usage in PC, we identified several clinically relevant devices and tests (C-reactive protein, urine, blood glucose, D-dimer, prothrombin time) important in screening and early detection of morbidities representing high disease burden. Based on international literature, general practitioners (GPs) are interested in the shortened diagnostic times, portable devices, and better doctor-patient relations made possible by POCT. There are several concerns, however, regarding initial and operational costs and reimbursement, limited scientific evidence about quality and safety, unclear regulations on quality validation of tests, as well as managerial aspects like PC staff training and IT integration at the GP level. CONCLUSION: As our review highlights, there is considerable interest among GPs to implement POCT as it has the potential to improve quality of care; however, there are many obstacles to overcome before widespread uptake. Further investigation is recommended to elaborate management and quality insurance background and to develop appropriate regulatory framework and financial scheme for GP practices. Preferably this work should involve the local practicing GPs to better tailor the implementation roadmap to country-specific details.

Significant Regional Differences in Lung Cancer Incidence in Hungary: Epidemiological Study Between 2011 and 2016.

Objective: Hungary has one of the highest incidences and mortality rates of lung cancer (LC), therefore the objective of this study was to analyse and compare LC incidence and mortality rates between the main Hungarian regions. Methods: This nationwide, retrospective study used data from the National Health Insurance Fund and included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between Jan 1, 2011 and Dec 31, 2016. Age-standardized incidence and mortality rates were calculated and compared for the main regions. Results: The highest incidence rate in males was recorded in Northern Hungary (146.8/100,000 person-years [PY]), while the lowest rate was found in Western Transdanubia (94.7/100,000 PY in 2011). All rates showed a declining trend between 2011 and 2016, with the largest decrease in the Northern Great Plain (-20.0%; p = 0.008). LC incidence and mortality rates in women both showed a rising tendency in all regions of Hungary, reaching the highest in Central Hungary (59.86/100,000 PY in 2016). Lung cancer incidence and mortality rates in males correlated with the level of education and smoking prevalence (p = 0.006 and p = 0.01, respectively) in the regions. A correlation with GDP per capita and Health Development Index (HDI) index could also be observed in the Hungarian regions, although these associations were not statistically significant. No correlations could be detected between these parameters among females. Conclusion: This analysis revealed considerable differences in the epidemiology of LC between the 7 main Hungarian regions. LC incidence and mortality rates significantly correlated with smoking and certain socioeconomic factors in men, but not in women. Further research is needed to explain the regional differences.

Age and Gender Specific Lung Cancer Incidence and Mortality in Hungary: Trends from 2011 Through 2016.

Objective: No assessment was conducted describing the age and gender specific epidemiology of lung cancer (LC) prior to 2018 in Hungary, thus the objective of this study was to appraise the detailed epidemiology of lung cancer (ICD-10 C34) in Hungary based on a retrospective analysis of the National Health Insurance Fund database. Methods: This longitudinal study included patients aged ≥20 years with LC diagnosis (ICD-10 C34) between January 1, 2011 and December 31, 2016. Patients with different cancer-related codes 6 months before or 12 months after LC diagnosis or having any cancer treatment other than lung cancer protocols were excluded. Results: Lung cancer incidence and mortality increased with age, peaking in the 70-79 age group (375.0/100,000 person-years) among males, while at 60-69 age group for females (148.1/100,000 person-years). The male-to-female incidence rate ratio reached 2.46-3.01 (p < 0.0001) among the 70-79 age group. We found 2-11% decrease in male incidence rate at most age groups, while a significant 1-3% increase was observed in older females (>60) annually during the study period. Conclusion: This nationwide epidemiology study demonstrated that LC incidence and mortality in Hungary decreased in younger male and female population, however we found significant increase of incidence in older female population, similar to international trends. Incidence rates peaked in younger age-groups compared to Western countries, most likely due to higher smoking prevalence in these cohorts, while lower age LC incidence could be attributed to higher competing cardiovascular risk resulting in earlier mortality in smoking population.

Improvement in Lung Cancer Survival: 6-Year Trends of Overall Survival at Hungarian Patients Diagnosed in 2011-2016.

Objective: Lung cancer is one of the most common cancers worldwide and its survival is still poor. The objective of our study was to estimate long-term survival of Hungarian lung cancer patients at first time based on a nationwide review of the National Health Insurance Fund database. Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between January 1, 2011 and December 31, 2016. Survival rates were evaluated by year of diagnosis, patient gender and age, and morphology of lung cancer. Results: 41,854 newly diagnosed lung cancer patients were recorded. Mean age at diagnosis varied between 64.7 and 65.9 years during study period. One- and 5-year overall survival rates for the total population were 42.2 and 17.9%, respectively. Survival was statistically associated with gender, age and type of lung cancer. Female patients (n = 16,362) had 23% better survival (HR: 0.77, 95% confidence interval (CI): 0.75-0.79; p < 0.001) than males (n = 25,492). The highest survival rates were found in the 20-49 age cohort (5Y = 31.3%) and if the cancer type was adenocarcinoma (5Y = 20.5%). We measured 5.3% improvement (9.2% adjusted) in lung cancer survival comparing the period 2015-2016 to 2011-2012 (HR: 0.95 95% CI: 0.92-0.97; p = 0.003), the highest at females <60 year (0.86 (adjusted HR was 0.79), interaction analysis was significant for age and histology types. Conclusion: Our study provided long-term Lung cancer survival data in Hungary for the first time. We found a 5.3% improvement in 5-year survival in 4 years. Women and young patients had better survival. Survival rates were comparable to-and at the higher end of-rates registered in other East-Central European countries (7.7%-15.7%).

Development of a Fast and Robust UHPLC Method for Apixaban In-Process Control Analysis.

In-process control (IPC) is an important task during chemical syntheses in pharmaceutical industry. Despite the fact that each chemical reaction is unique, the most common analytical technique used for IPC analysis is high performance liquid chromatography (HPLC). Today, the so-called "Quality by Design" (QbD) principle is often being applied rather than "Trial and Error" approach for HPLC method development. The QbD approach requires only for a very few experimental measurements to find the appropriate stationary phase and optimal chromatographic conditions such as the composition of mobile phase, gradient steepness or time (tG), temperature (T), and mobile phase pH. In this study, the applicability of a multifactorial liquid chromatographic optimization software was studied in an extended knowledge space. Using state-of-the-art ultra-high performance liquid chromatography (UHPLC), the analysis time can significantly be shortened. By using UHPLC, it is possible to analyse the composition of the reaction mixture within few minutes. In this work, a mixture of route of synthesis of apixaban was analysed on short narrow bore column (50 × 2.1 mm, packed with sub-2 µm particles) resulting in short analysis time. The aim of the study was to cover a relatively narrow range of method parameters (tG, T, pH) in order to find a robust working point (zone). The results of the virtual (modeled) robustness testing were systematically compared to experimental measurements and Design of Experiments (DoE) based predictions.

Theoretical study of the efficiency of liquid chromatography columns with particle size gradient.

Modern analytical applications of liquid chromatography require more and more efficient columns. In this work, the possibility of utilizing particle size gradient in the chromatographic column was studied by a theoretical approach. In the course of our work three different scenarios of particle size gradients were considered with different shapes (linear, convex and concave). The evolution of bandwidth inside the column was plotted for each scenario. As a reference point, the bandwidth of the uniform column was used, which had the same pressure drop as the non-uniform column. According to our calculations, in isocratic elution mode, the non-uniform column does not offer any advantage compared to the uniform column, regardless the type of the particle size gradient. In gradient elution mode, however, extra band compression occurs was found. For negative particle size gradients, the final physical bandwidth was found to be approximately 1-4 % smaller than for uniform columns. This slight gain in efficiency in terms of bandwidth compression can be expanded to 5-8 % by the optimization of the limiting particle sizes. These optimized results are obtained when the final particle size is approximately 40% of the initial particle diameter.

Increase in the Length of Lung Cancer Patient Pathway Before First-Line Therapy: A 6-Year Nationwide Analysis From Hungary.

Objective: This study aimed to examine the characteristics of the lung cancer (LC) patient pathway in Hungary during a 6-years period. Methods: This nationwide, retrospective study included patients newly diagnosed with LC (ICD-10 C34) between January 1, 2011, and December 31, 2016, using data from the National Health Insurance Fund (NHIF) of Hungary. The following patient pathway intervals were examined: system, diagnostic and treatment interval by age, gender, tumor type, study year and first-line LC therapy. Results: During the 6-years study period, 17,386 patients had at least one type of imaging (X-ray or CT/MRI) prior to diagnosis, and 12,063 had records of both X-ray and CT/MRI. The median system interval was 64.5 days, and it was 5 days longer among women, than in men (68.0 vs. 63.0 days). The median system interval was significantly longer in patients with adenocarcinoma compared to those with squamous cell carcinoma or small cell lung cancer (70.4 vs. 64.0 vs. 48.0 days, respectively). Patients who received surgery as first-line treatment had significantly longer median system intervals compared to those receiving chemotherapy (81.4 vs. 62.0 days). The median system interval significantly increased from 62.0 to 66.0 days during the 6-years study period. Conclusion: The LC patient pathway significantly increased in Hungary over the 6-years study period. There were no significant differences in the length of the whole LC patient pathway according to age, however, female sex, surgery as first-line treatment, and adenocarcinoma were associated with longer system intervals.

Impact of the column on effluent pH in cation exchange pH gradient chromatography, a practical study.

In ionexchange chromatography, the pH gradient mode becomes more and more popular today for the analysis of therapeutic proteins as this mode can provide higher or alternative selectivity to the commonly used salt gradient mode. Ideally, a linear pH response is expected when performing linear gradients. However up to now, only a very few buffer systems have been developed and are commercially available which can perform nearly linear pH responses when flowing through a given column. It is also known that a selected buffer system (mobile phase) can work well on one column but can fail on other column. The goal of this study was to practically evaluate the effects that ionexchange columns (weak and strong exchangers) might have on effluent pH, when performing linear pH gradient separations of therapeutic monoclonal antibodies. To attain this objective, the pH was monitored on-line at the column outlet using a specific setup. To make comprehensive observations of the phenomenon, four different mobile phase conditions and five cation exchange columns (weak and strong exchangers) were employed. The obtained pH responses were systematically compared to responses measured in the absence of the columns. From this work, it has become clear that both the column and mobile phase can have significant effects on pH gradient chromatography and that their combination must be considered when developing a new method. Phase systems (column + mobile phase) providing linear pH responses are indeed the most suitable for separating mAbs with different isoelectric points and, with them, it is possible to elute mAbs across wide retention time ranges and with high selectivity.

Development of retention mechanism for the separation of carboxylic acids and inorganic anions in cryptand-based ion chromatography.

The ion-exchange and complex forming equilibria were quantitatively described and demonstrated in order to understand major factors in the control of selectivity in the analytical separation of carboxylic acids and inorganic anions in cryptand based ion chromatography. A complex retention model has been developed for the separation on a non-conventional IC column. Changes in retention are treated both theoretically and experimentally. Retention mechanism is employed on a macrocycle-based (cryptand n-decyl-[2.2.2]) ion-exchange chromatographic phase to improve the selectivity for a mixture of model analytes. We introduced an alternative internal gradient method by mixed eluent (i.e. eluents formed by combination of two alkali hydroxide with different molar ratio). The effect of binary mixed eluent (Li/Na, Li/K) on the retention behavior and peak shape of carboxylic acids are also discussed in view of the proposed theory. It was shown that the effects of binary aqueous mobile phases, held isocratically behave very similar to the step gradient mode. The "internal gradient" separation system has advantages over traditional step gradient mode. Twenty-six anions of widely varying chemical character (mono-, di-, tri-valent inorganic anions, mono-, di-, tri-valent aliphatic carboxylic acids, aromatic- and haloacetic carboxylic acids) were investigated on the cryptand-based (D222) stationary phase using different methods by LiOH, NaOH and KOH eluent. The predicted vs measured retention data are in rather good agreement. High degree of linearity was obtained for inorganic anions, multivalent carboxylic acids, and for aromatic and haloacetic acids R2 = 0.992, 0.969, and 0.980, respectively.

Revising Incidence and Mortality of Lung Cancer in Central Europe: An Epidemiology Review From Hungary.

Objective: While Hungary is often reported to have the highest incidence and mortality rates of lung cancer, until 2018 no nationwide epidemiology study was conducted to confirm these trends. The objective of this study was to estimate the occurrence of lung cancer in Hungary based on a retrospective review of the National Health Insurance Fund (NHIF) database. Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between 1 Jan 2011 and 31 Dec 2016. Age-standardized incidence and mortality rates were calculated using both the 1976 and 2013 European Standard Populations (ESP). Results: Between 2011 and 2016, 6,996 - 7,158 new lung cancer cases were recorded in the NHIF database annually, and 6,045 - 6,465 all-cause deaths occurred per year. Age-adjusted incidence rates were 115.7-101.6/100,000 person-years among men (ESP 1976: 84.7-72.6), showing a mean annual change of - 2.26% (p = 0.008). Incidence rates among women increased from 48.3 to 50.3/100,000 person-years (ESP 1976: 36.9-38.0), corresponding to a mean annual change of 1.23% (p = 0.028). Age-standardized mortality rates varied between 103.8 and 97.2/100,000 person-years (ESP 1976: 72.8-69.7) in men and between 38.3 and 42.7/100,000 person-years (ESP 1976: 27.8-29.3) in women. Conclusion: Age-standardized incidence and mortality rates of lung cancer in Hungary were found to be high compared to Western-European countries, but lower than those reported by previous publications. The incidence of lung cancer decreased in men, while there was an increase in incidence and mortality among female lung cancer patients.