Risk of depression and anxiety in 7.302 patients with sarcoidosis: a nationwide cohort study.

BACKGROUND AND AIM: The aim was to investigate the association between sarcoidosis and anxiety and/or depression (A/D) in patients with sarcoidosis and comparators matched on age, gender, residency, and cohabitation status. METHODS: Patients with newly diagnosed sarcoidosis between 2001 and 2015 were identified in the Danish National Patient Register. Cases were matched 1:4 with non-sarcoidosis comparators. We estimated the cumulative incidence of A/D using the Cumulative Incidence Function and the subdistribution hazard ratio (sHR) for A/D using the Fine-Gray subdistribution hazard model. Estimates were adjusted for socio-economic status and Deyo-Charlson Comorbidity Index. RESULTS: We identified 7.302 cases and 26.145 matched comparators. The cumulative incidence of A/D after five years was 6.0% (95%CI 5.5-6.4) for cases and 4.2% (95%CI 4.0-4.4) for matched comparators. The cumulative incidence was higher among cases for both males and females and in all age-groups compared with the matched comparators. The adjusted-sHR for A/D was 1.38 (95%CI 1.24-1.53). The adjusted-sHR for A/D was 1.51 (95%CI 1.30-1.75) for male cases and 1.25 (95%CI 1.08-1.45) for female cases compared with the matched comparators. The adjusted-sHR for A/D was higher for cases in all age-groups compared with the matched comparators, although not statistically significant among cases aged 30-39 years (a-sHR 1.15; 95%CI 0.92-1.44). CONCLUSIONS: Sarcoidosis cases had a higher risk of A/D compared with matched comparators during 18 years of follow-up. The risk of developing A/D was greater for male and female cases and within all age-groups compared with the matched comparators.

Pulmonary infections with nontuberculous mycobacteria.

This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications, antibiotic choice, resistance and side effects. Treatment of nontuberculous pulmonary disease is complex, lengthy, and fraught with side effects. Increased attention on this disease is needed in order to alleviate the severe consequences of this growing disease. Cooperation between pulmonologists and infectious disease specialists is needed to ensure uniform treatment, and to account for the heterogeneity seen in patients and mycobacteria alike.

Description of an activity-based enzyme biosensor for lung cancer detection.

BACKGROUND: Lung cancer is associated with the greatest cancer mortality as it typically presents with incurable distributed disease. Biomarkers relevant to risk assessment for the detection of lung cancer continue to be a challenge because they are often not detectable during the asymptomatic curable stage of the disease. A solution to population-scale testing for lung cancer will require a combination of performance, scalability, cost-effectiveness, and simplicity. METHODS: One solution is to measure the activity of serum available enzymes that contribute to the transformation process rather than counting biomarkers. Protease enzymes modify the environment during tumor growth and present an attractive target for detection. An activity based sensor platform sensitive to active protease enzymes is presented. A panel of 18 sensors was used to measure 750 sera samples from participants at increased risk for lung cancer with or without the disease. RESULTS: A machine learning approach is applied to generate algorithms that detect 90% of cancer patients overall with a specificity of 82% including 90% sensitivity in Stage I when disease intervention is most effective and detection more challenging. CONCLUSION: This approach is promising as a scalable, clinically useful platform to help detect patients who have lung cancer using a simple blood sample. The performance and cost profile is being pursued in studies as a platform for population wide screening.

Lung cancer is responsible for more deaths worldwide than all other cancers. It is often detected with the appearance of symptoms when treatment is limited and outcomes for the patient are much worse. While imaging chest scans can detect disease, they are poorly used even in the United States where it is an approved screening method. When cancer is present, protease enzymes are responsible for making space and modifying the lung tissue for the growing tumor. This report describes a panel of 18 sensors that release a fluorescent signal when these enzymes are present in a blood sample. The signal acts like a fingerprint of activity that can be used to identify people with lung cancer. This sensor platform can detect patients with curable lung cancer and could provide a platform for screening very large populations of at-risk individuals.

The Danish lung cancer registry: A nationwide validation study.

BACKGROUND: This study evaluates the validity of the information in the Danish Lung Cancer Registry (DLCR). Since 2000, the DLCR has been a tool for monitoring interventions and outcome of all Danish lung cancer patients with the intent to streamline and improve treatment and survival. The DLCR receives information from the Danish Patient Registries in addition to clinical information from the treating physicians. In the year 2022, more than 50 papers have been published using DLCR as a data source. However, the DLCR has not previously been validated. METHODS: A random sample of 1000 patients diagnosed with non-small cell lung cancer from 2014 to 2016 and recorded in the DLCR were included for validation. Medical records were reviewed and were considered as the "gold standard" to which data listed in the DLCR were compared. RESULTS: Information was retrieved from medical charts for all patients. Agreement on stage at diagnosis was 90.1 % (95 % CI 88.0-91.9) and on date of diagnoses was 93.8 (95 % CI 92.1-93.2). Agreement on smoking status in pack years (+/- 10 pack years) was 91.2 % (95 % CI 88.6-93.2). The positive predictive value of treatment intent was 87.4 (95 % CI 85.1-89.6). CONCLUSION: The data in the DLCR are complete, detailed and accurate. The comparison of data from the DLCR with the medical records revealed overall high validity of the data in the registry.

Nationwide Increasing Incidence of Nontuberculous Mycobacterial Diseases Among Adults in Denmark: Eighteen Years of Follow-Up.

BACKGROUND: The epidemiology of nontuberculous mycobacteria (NTM) infections is not well described. In this study, we determine the incidence and prevalence of NTM infections and focus on social risk factors. In addition, we describe people with pulmonary and extrapulmonary NTM. RESEARCH QUESTION: What are the incidence and prevalence of NTM, and what are the characteristics of the affected patients? STUDY DESIGN AND METHODS: This is a nationwide retrospective register-based cohort study in Denmark. Adult patients in the Danish national registers who received a diagnosis of NTM disease from 2000 to 2017 were classified as having either pulmonary or extrapulmonary NTM disease. RESULTS: We identified 1,146 adults with an NTM diagnosis. Of these, 661 patients had pulmonary NTM, of whom 50.4% were male, whereas 485 had extrapulmonary NTM, of whom 59.6% were male. The median age (interquartile range) was 66 (18) years and 57 (32) years, respectively. The yearly incidence rate per 100,000 increased between 2000 and 2017 for both pulmonary NTM (0.4 to 1.3) and extrapulmonary NTM (0.3 to 0.6). The annual prevalence per 100,000 increased from 0.4 to 3.5 for pulmonary NTM and from 0.3 to 1.0 for extrapulmonary NTM. The incidence rate increased with age. The incidence of pulmonary NTM was highest among those who were 70 years of age or older (19.3 per 100,000). Compared with patients with pulmonary NTM, patients with extrapulmonary NTM were more likely to be employed and had a higher educational level. INTERPRETATION: The prevalence of NTM disease in Denmark increased between 2000 and 2017. Patients with pulmonary NTM and patients with extrapulmonary NTM represent two distinct groups that differ in age, sex, education, and employment status. Increased suspicion of pulmonary NTM disease is warranted in the elderly after exclusion of more common lung infections.

Prevalence estimates of tuberculosis infection in adults in Denmark: a retrospective nationwide register-based cross-sectional study, 2010 to 2018.

BackgroundTuberculosis (TB) elimination requires identifying and treating persons with TB infection (TBI).AimWe estimate the prevalence of positive interferon gamma release assay (IGRA) tests (including TB) and TBI (excluding TB) in Denmark based on TBI screening data from patients with inflammatory bowel disease (IBD) or inflammatory rheumatic disease (IRD).MethodsUsing nationwide Danish registries, we included all patients with IBD or IRD with an IGRA test performed between 2010 and 2018. We estimated the prevalence of TBI and positive IGRA with 95% confidence intervals (CI) in adolescents and adults aged 15-64 years after sample weighting adjusting for distortions in the sample from the background population of Denmark for sex, age group and TB incidence rates (IR) in country of birth.ResultsIn 13,574 patients with IBD or IRD, 12,892 IGRA tests (95.0%) were negative, 461 (3.4%) were positive and 221 (1.6%) were indeterminate, resulting in a weighted TBI prevalence of 3.2% (95% CI: 2.9-3.5) and weighted positive IGRA prevalence of 3.8% (95% CI: 3.5-4.2) among adults aged 15-64 years in the background population of Denmark. Unweighted TBI prevalence increased with age and birthplace in countries with a TB IR higher than 10/100,000 population.ConclusionEstimated TBI prevalence is low in Denmark. We estimate that 200,000 persons have TBI and thus are at risk of developing TB. Screening for TBI and preventive treatment, especially in persons born in high TB incidence countries or immunosuppressed, are crucial to reduce the risk of and eliminate TB.

Introduction of the Danish Lung Nodule Registry: A part of the Danish Lung Cancer Registry.

BACKGROUND: The majority of lung cancer cases are diagnosed late, resulting in poor prognosis and high mortality rates. Early detection and management of lung cancer can improve patient outcomes and reduce mortality rates. Pulmonary nodules are key factors in the early detection of lung cancer, they are common in high-risk populations and require correct classification to determine whether they are benign or malignant. Over the last decade a steep increase in the number of thoracic CT scans has been seen in Denmark, resulting in substantial resources allocated to CT follow-up of incidentally detected pulmonary nodules. The implementation of a nationwide Danish prospective pulmonary nodule registry is to methodically record pulmonary nodules and thereby evaluate the scope of pulmonary nodule follow-up, the nature of the nodules, and the clinical progression of patients with pulmonary nodules. METHODS: A prospective pulmonary nodule registry (Danish Lung Nodule Registry) will be a natural appendix to the Danish Lung Cancer Registry. Three new ICD-10 classification codes will be introduced, defining the type of nodule: /DR91.1/ Solid nodule /DR91.2/ Part-solid nodule; /DR91.3/ Non-solid nodule. Furthermore, an additional letter will describe whether the imaging exam is performed on suspicion of lung cancer (A), or the finding is incidental (B). Registration of the nodules will be performed by the departments of respiratory medicine who manage follow-up of pulmonary nodules. It is estimated that around 7000 nodules will be registered annually. DISCUSSION: The registration of patients in the lung nodule registry complies with current Danish legislation. The registry will be seamlessly integrated with other nationwide Danish registries, including the Danish Lung Cancer Registry, to collect additional patient data and improve the quality and scope of the data acquired. The results from these comprehensive epidemiological studies will be of significant interest and offer valuable research opportunities.

Methylated Cell-Free Tumor DNA in Sputum as a Tool for Diagnosing Lung Cancer-A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related mortality worldwide. Early diagnosis is pivotal for the prognosis. There is a notable overlap between lung cancer and chronic bronchitis, and the potential use of methylated tumor DNA in sputum as a biomarker for lung cancer detection is appealing. This systematic review and meta-analysis followed the PRISMA 2020 statement. A comprehensive search was conducted in Embase, Medline, Web of Science, and the Cochrane Library, using these search strings: Lung cancer, sputum, and methylated tumor DNA. A total of 15 studies met the eligibility criteria. Studies predominantly utilized a case-control design, with sensitivity ranging from 10 to 93% and specificity from 8 to 100%. A meta-analysis of all genes across studies resulted in a summary sensitivity of 54.3% (95% CI 49.4-59.2%) and specificity of 79.7% (95% CI 75.0-83.7%). Notably, two less explored genes (TAC1, SOX17) demonstrated sensitivity levels surpassing 85%. The study's findings highlight substantial variations in the sensitivity and specificity of methylated tumor DNA in sputum for lung cancer detection. Challenges in reproducibility could stem from differences in tumor site, sample acquisition, extraction methods, and methylation measurement techniques. This meta-analysis provides a foundation for prioritizing high-performing genes, calling for a standardization and refinement of methodologies before potential application in clinical trials.

National Development in the Use of Inhaled Corticosteroid Treatment in Chronic Obstructive Pulmonary Disease: Repeated Cross-Sectional Studies from 1998 to 2018.

Recommendations for the treatment of chronic obstructive pulmonary disease (COPD) have shifted towards a more restrictive use of inhaled corticosteroids (ICS). We aimed to identify the nationwide development over time in the use of ICS treatment in COPD. We conducted a register-based repeated cross-sectional study using Danish nationwide registers. On a yearly basis from 1998 to 2018, we included all patients in Denmark ≥ 40 years of age with an ICD-10 diagnosis of COPD (J44). Accumulated ICS use was calculated for each year based on redeemed prescriptions. Patients were divided into the following groups: No ICS, low-dose ICS, medium-dose ICS, or high-dose ICS. From 1998 to 2018, the yearly proportion of patients without ICS treatment increased (from 50.6% to 57.6%), the proportion of patients on low-dose ICS treatment increased (from 11.3% to 14.9%), and the proportion of patients on high-dose ICS treatment decreased (from 17.0% to 9.4%). We demonstrated a national reduction in the use of ICS treatment in COPD from 1998 to 2018, with an increase in the proportion of patients without ICS and on low-dose ICS treatment and a decrease in the proportion of patients on high-dose ICS treatment.

Consequences of Losing Incidental Pulmonary Nodules to Follow-Up: Unmonitored Nodules Progressing to Stage IV Lung Cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer-related death globally. Incidental pulmonary nodules represent a golden opportunity for early diagnosis, which is critical for improving survival rates. This study explores the impact of missed pulmonary nodules on the progression of lung cancer. METHODS: A total of 4,066 stage IV lung cancer cases from 2019 to 2021 in Danish hospitals were investigated to determine whether a chest computed tomography (CT) had been performed within 2 years before diagnosis. CT reports and images were reviewed to identify nodules that had been missed by radiologists or were not appropriately monitored, despite being mentioned by the radiologist, and to assess whether these nodules had progressed to stage IV lung cancer. RESULTS: Among stage IV lung cancer patients, 13.6% had undergone a chest CT scan before their diagnosis; of these, 44.4% had nodules mentioned. Radiologists missed a nodule in 7.6% of cases. In total, 45.3% of nodules were not appropriately monitored. An estimated 2.5% of stage IV cases could have been detected earlier with proper surveillance. CONCLUSION: This study underlines the significance of monitoring pulmonary nodules and proposes strategies for enhancing detection and surveillance. These strategies include centralized monitoring and the implementation of automated registries to prevent gaps in follow-up.

Trends in COPD mortality from 1983 to 2018: protocol for a population-based cohort study in Denmark.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide, which is partly contributed to the increasing prevalence of COPD owning to a demographic shift towards an older population. Conversely, recent studies on COPD mortality that take this demographic shift in age into account find decreasing overall age-standardised COPD mortality rates over time. This decrease in the age-standardised COPD mortality rate is contributed advances in COPD diagnostics and treatment, decreasing smoking prevalence and general advances in medical care particularly in western countries. However, it is unknown if patients with COPD have experienced a comparable relative increase in survival in line with the general population.Hence, there is a need for longitudinal studies comparing trends in mortality in patients with COPD compared with matched non-COPD individuals from the background population. METHODS AND ANALYSES: This is a cohort study with a matched non-COPD comparator cohort. Data are retrieved from the Danish national registers. Data from multiple registries from 1983 to 2018 will be merged on an individual level using the 10-digit Civil Registration numbers that are unique to each citizen in Denmark. Time trends in mortality in patients with COPD compared with the matched comparator cohort will be examined in three study periods: 1983-1993, 1994-2007 and 2008-2018. ETHICS AND DISSEMINATION: The study is entirely based on registry data and ethical approval is not required according to Danish Law and National Ethics Committee Guidelines. The results will be published in peer-reviewed journals and reported at appropriate national and international conferences.

Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies.

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. RESEARCH QUESTION: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? STUDY DESIGN AND METHODS: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment. RESULTS: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy.

COPD and Smoking Status - It Does Matter: Characteristics and Prognosis of COPD According to Smoking Status.

Background: Chronic obstructive pulmonary disease is a chronic, often progressive disease, which in most patients is caused by tobacco smoking. Our study focuses on differences in COPD-related outcomes between never smokers, former smokers, and current smokers. Methods: A nationwide, population-based cohort study utilizing Danish health registries. Clinical and socioeconomic variables including smoking status, comorbidities, and dyspnea were obtained. Poisson and Cox Regression were used to calculate the impact of these clinical parameters on the risk of moderate and severe exacerbations and mortality during 12 months of follow-up. Results: A total of 49,826 patients ≥40 years of age, with a hospital diagnosis of COPD in 2008-2017, were identified (mean age 69.2 years, 52% females). A total of 2127 (4%) were never smokers, 29,854 (60%) were former smokers and 17,845 (36%) current smokers. Compared to former and current smokers, never smokers reported a lower modified Medical Research Council score and had a milder COPD stage according to the Global Initiative for Chronic Obstructive Lung Disease classification. During follow-up, never smokers had a significantly lower risk of severe exacerbations (hazard ratio 0.87, 95% confidence interval [CI] 0.78-0.97) and a lower rate of death (mortality ratio 0.75, 95% CI 0.70-0.81) compared to patients with a smoking history. Discussion: Our nationwide study showed that COPD in never smokers is characterized by a lower level of dyspnea, milder lung function impairment, and a lower risk of exacerbations and death. At the same time, we found active smokers to have the highest risk. These findings highlight the need for campaigns to prevent smoking and may help general practitioners as well as other health care professionals to motivate patients with COPD to stop smoking.

Tobacco Exposure and Efficacy of Biologic Therapy in Patients With Severe Asthma: A Nationwide Study From the Danish Severe Asthma Register.

BACKGROUND: Randomized trials of biologics in severe, uncontrolled asthma have excluded patients with a cumulative tobacco exposure of more than 10 pack-years. Therefore, our knowledge of the impact of smoking exposure on the clinical effects of biologics in severe asthma remains incomplete. However, because many patients with asthma are current or former smokers, investigating the potential impacts of tobacco exposure on the effects of biologic treatment is clinically important. OBJECTIVE: To investigate the impact of smoking history and tobacco exposure on the effectiveness of biologic therapy in real-life patients with severe asthma. METHODS: We used data from a complete nationwide cohort of patients with severe asthma who were receiving biologics, the Danish Severe Asthma Register. We divided patients according to smoking history and cumulative tobacco exposure and analyzed data at baseline and after 12 months of biologic treatment. RESULTS: A total of 724 bio-naive patients were identified in the Danish Severe Asthma Register, 398 of whom had never been smokers (55%), 316 were previous smokers (44%), and 10 were current smokers (1%). Within the group of current and former smokers, 37% had 1 to 9 pack-years of tobacco exposure, 26% had 10 to 19 pack-years, and 37% had 20 or more pack-years of tobacco exposure. Patients with tobacco exposure had similar reductions in the number of exacerbations, reductions in maintenance oral corticosteroid use, and improvements in asthma symptoms compared with patients with 0 pack-years. CONCLUSION: Former smoking history and lifetime tobacco exposure do not have an impact on the efficacy of biologics in patients with severe asthma.

Pulmonary Mycobacterium abscessus infection treated in combination with inhaled tigecycline.

Pulmonary disease caused by Mycobacterium abscessus is difficult to treat, as there is currently no reliable evidence-based treatment. Treatment is long, complex and has many side effects. In this case, we report a patient with treatment-refractory pulmonary M abscessus disease, treated with inhaled tigecycline. Treatment with inhaled tigecycline lasted 15 months with comparably limited side effects. There were no positive mycobacterial cultures in the follow-up period of 2 years. Inhaled tigecycline is an option in the treatment of pulmonary M. abscessus when first-line treatment fails. Additional research should investigate this further.

Climate aspects of dose inhalers in respitatory disorders.

Hydrofluorocarbons, the propellants used in metered dose inhalers, are powerful greenhouse gases. However, this review investigates the use of metered dose inhalers which continue to be on the rise in Denmark despite evidence that most patients are treated equally well with dry powder inhalers. If the use of metered dose inhalers in Denmark were reduced to approximately the level seen in Sweden it would lead to a reduction in CO2e comparable with the emissions from the electricity used in 16,500 typical Danish households.

Introduction of a systematic examination framework for chronic cough: a before-after cohort study in a clinical setting.

Cough is a condition that can be caused by several different mechanisms. There are numerous guidelines for diagnosing the cause of cough, yet the effect of a well-constructed examination framework has not been investigated. At the Department of Internal Medicine, Lillebaelt Hospital, Vejle, a systematic examination framework for diagnosing cough was introduced. Two hundred consecutive patients referred to the pulmonary outpatient clinic with cough were included. The first 100 patients (Group 1) were included before implementation of the examination framework and diagnosed as usual. The next 100 patients (Group 2) were examined using the systematic framework. The primary endpoint was the number of appointments required to establish a diagnosis. A multivariable Poisson regression was performed, adjusting for age, sex, body mass index, pulmonary function (FEV1/FVC), duration of cough, and smoking status. A diagnosis was established within 1-2 visits in 47% in Group 1 compared to 83% in Group 2. When adjusting for confounders, fewer appointments was required to establish a diagnosis in Group 2 (Incidence rate ratio = 0.713 (95% confidence interval: 0.592-0.859), P = 0.000). Using a systematic examination framework for diagnosing cough may reduce the number of appointments required to establish a diagnosis, seemingly without compromising the diagnostic outcome.

Burden of Disease and Productivity Loss in the European Economic Area in Patients Affected by Fibrosing Interstitial Lung Disease.

INTRODUCTION: Progression of fibrosis in interstitial lung diseases (ILD) has been associated with poor prognosis, lower quality of life for patients and caregivers, and higher healthcare costs. This study estimated the burden of disease and productivity loss of progressively fibrosing ILD, focusing on progressive pulmonary fibrosis other than idiopathic pulmonary fibrosis (non-IPF PPF) and systemic sclerosis-associated ILD (SSc-ILD) in the European Economic Area (EEA). METHODS: An economic model was built to estimate the clinical burden of SSc-ILD and non-IPF PPF. The model was based on published data on disease prevalence and disease burden (in terms of comorbidities, exacerbations, and deaths) as well as on productivity loss (in terms of sick days, early retirement, permanent disability, and job loss). Aggregate income loss was obtained by multiplying productivity loss by the median daily income in each country/area of investigation. A sensitivity analysis was performed to test the impact of the variability of the model assumptions. RESULTS: In the whole EEA, a total of 86,794 and 13,221 individuals were estimated to be affected by non-IPF PPF and SSc-ILD, respectively. Estimated annual sick days associated with the diseases were 3,952,604 and 672,172, early retirements were 23,174 and 5341, permanently disabled patients were 41,748 and 4037, and job losses were 19,789 and 2617 for non-IPF PPF and SSc-ILD, respectively. Annual exacerbations were estimated to be 22,401-31,181 and 1259-1753, while deaths were 5791-6171 and 572-638 in non-IPF PPF and SSc-ILD, respectively. The estimated annual aggregate income loss in EEA, accounting for losses due to annual sick days, early retirements, and permanently disabled patients, was €1433 million and €220 million in non-IPF PPF and SSc-ILD, respectively. The productivity loss due to job losses was €194 million and €26 million in non-IPF PPF and SSc-ILD, respectively. The main driver of aggregate income loss variability was the prevalence. CONCLUSION: The impact of non-IPF PPF and SSc-ILD on society is definitely non-negligible. Actions to reduce the burden on our societies are highly needed.