Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China

Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

Molecular Identification of Mycobacterium Strains Responsible of Bovine Tuberculosis Cases in Bobo-Dioulasso Slaughterhouse, Burkina Faso

Bovine tuberculosis (bTB) is an endemic zoonosis significantly affects animal health in Burkina Faso. The primary causative agent is Mycobacterium tuberculosis (M. tuberculosis) complex, mainly M. bovis. Cattle are considered as natural reservoir of M. bovis. However, in Burkina Faso, the circulation of these strains remains poorly understood and documented. This study aimed to identify and characterize Mycobacterium strains from suspected carcasses during routine meat inspection at Bobo-Dioulasso refrigerated slaughterhouse. A prospective cross-sectional study was conducted from January 2021 to December 2022 on cases of seizures linked to suspected bovine tuberculosis. Microbiological and molecular analyzes were used for mycobacterial strain isolation and characterization. Out of 50 samples, 24% tested positive by microscopy and 12% by culture. Molecular analysis identified 6 strains of Mycobacteria, exclusively Mycobacterium bovis specifically the subspecies bovis (Mycobacterium bovis subsp bovis). In conclusion, M. bovis subsp bovis is the primary agent responsible for bovine tuberculosis in Bobo-Dioulasso. Continuous monitoring of mycobacterial strains is therefore necessary for the effective control of this pathology in the local cattle population.

Tuberculosis in the Carcinal Environment in Chad Due to the Mycobacterium Tuberculosis Circulante Complex

Tuberculosis (TB) is a serious infectious disease and its control is considered a challenge, particularly among vulnerable populations such as prisoners. The prevalence of TB in prisons is an alarming public health problem in many countries. The aim of this study is to describe the epidemiology of tuberculosis and the strategies for controlling this disease in the Chadian prison population. During the course of our study, the prevalence of tuberculosis in prisons was 9.64%. The age group between 55 years and over (43.33%) was the most represented in this study, and all patients were men with a frequency of 62.66%. The cross-tabulation of Culture_7H9G and Culture_7H9P showed that out of our total positive sample, we found a total of 87 positive strains and 63 negative strains. Our study shows that it is essential to know the prevalence of tuberculosis in all the country’s prisons. Indeed, this can serve as an indication of the need for action in prisons to reduce TB rates, in particular by improving the structure of prison environments, diagnosing new cases quickly and accurately, identifying drug-resistant strains and implementing effective, direct treatment observed in people with tuberculosis.

Early Prosthetic Valve Endocarditis with Mycobacterium Tuberculosis after Mitral Valve Replacement: A Case Report

Background: Tuberculous endocarditis is a rare but serious complication of heart valve replacement surgery. We report the case of a 24-year-old patient, who presented with tuberculous endocarditis after mechanical mitral valve replacement, with a favorable clinical course following anti-tuberculosis treatment. Case Presentation: We report a 24-year-old male patient, admitted to the cardiac surgery department of the Fann Hospital (Dakar, Senegal), for the management of severe mixed (rheumatic and endocarditic) mitral insufficiency with associated tricuspid insufficiency. He had a history of recurrent angina and polyarthralgia in childhood, was hospitalized several times for refractory global cardiac decompensation, and for a suspected infective endocarditis a month before his admission. On admission, the clinical examination revealed signs suggestive of mitral and tricuspid insufficiency. Transthoracic echocardiography revealed severe post-endocarditic mitral insufficiency with A3 amputation, highly mobile 15 mm vegetations on the free edge of the large valve, moderate tricuspid insufficiency, and severe pulmonary artery hypertension. Mechanical mitral valve replacement and tricuspid valve annuloplasty using autologous pericardial strip were performed via median sternotomy. After ten days, the patient presented with global cardiac decompensation associated with a clinico-biological infectious syndrome, and tans-oesophageal echography revealed an abscess at the sinotubular junction, communicating with the aorta. A thoraco-abdomino-pelvic CT scan was done, which revealed a bilateral alveolar-interstitial syndrome with mediastinal lymphadenopathy. Anti-tuberculosis treatment with RHZE was initiated for 06 months. The clinical course was favorable. Conclusion: Tuberculous endocarditis in prostheses is a serious complication of heart valve replacement surgery, which may evolve favorably under medical treatment.

Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant Mycobacterium Tuberculosis Patients in Xinjiang

Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods:The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tuberculosis were amplified through fluorescence quantitative PCR,and the amplified products were sequenced and compared.Results:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51%(20/148),among which the inhA gene mutation rate among patients of Han,Uygur,and Kazakh ethnicity were 15.87%,13.21%,and 17.65%,respectively.There was no significant difference in the inhA mutation rate among nationalities(c^(2)=2.897,P>0.05).The mutation rate of the katG gene was 84.46%(125/148),among which the mutation rates of patients of Han,Uyghur,and Kazak ethnicities were 82.54%,84.91%,and 76.47%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There was no significant difference in the mutation rate of the katG gene among different ethnicities(c^(2)=3.772,P>0.05).The mutation rates of the inhA gene in southern Xinjiang,northern Xinjiang,and other provinces were 18.60%,9.28%,and 37.50%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)and between southern Xinjiang and other provinces(c^(2)=1.424,P>0.05).However,the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang(c^(2)=5.539,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.

Breaking barriers:The potential of nanosystems in antituberculosis therapy

Tuberculosis(TB),caused by Mycobacterium tuberculosis,continues to pose a significant threat to global health.The resilience of TB is amplified by a myriad of physical,biological,and biopharmaceutical barriers that challenge conventional therapeutic approaches.This review navigates the intricate landscape of TB treatment,from the stealth of latent infections and the strength of granuloma formations to the daunting specters of drug resistance and altered gene expression.Amidst these challenges,traditional therapies often fail,contending with inconsistent bioavailability,prolonged treatment regimens,and socioeconomic burdens.Nanoscale Drug Delivery Systems(NDDSs)emerge as a promising beacon,ready to overcome these barriers,offering better drug targeting and improved patient adherence.Through a critical approach,we evaluate a spectrum of nanosystems and their efficacy against MTB both in vitro and in vivo.This review advocates for the intensification of research in NDDSs,heralding their potential to reshape the contours of global TB treatment strategies.

Recognizing and addressing the challenges of gastrointestinal tuberculosis

In this editorial,we comment on the article by Ali et al published in the recent issue of the World Journal of Clinical Cases.This case report shed light on a particularly rare manifestation of this disease-primary gastrointestinal tuberculosis(GTB)presenting as gastric outlet obstruction.GTB presents diagnostic challenges due to its nonspecific symptoms and lack of highly accurate diagnostic algorithms.This editorial synthesizes epidemiological data,risk factors,pathogenesis,clinical presentations,diagnostic methods,and therapies to raise awareness about GTB.GTB constitutes 1%-3%of all tuberculosis cases globally,with 6%-38%of patients also having pulmonary tuberculosis.Pathogenesis involves various modes of Mycobacterium tuberculosis complex entry into the gastrointestinal system,with the terminal ileum and ileocecal valve commonly affected.Clinical presentation varies,often resembling other intra-abdominal pathologies,necessitating a high index of suspicion.Diagnostic tools include a combination of biochemical,microbiological,radiological,and endoscopic assessments.Antitubercular medication remains the cornerstone of treatment,supplemented by surgical intervention in severe cases.Multidisciplinary management involving gastroenterologists,surgeons,pulmonologists,and infectious disease specialists is crucial for optimal outcomes.Despite advancements,timely diagnosis and management challenges persist,underscoring the need for continued research and collaboration in addressing primary GTB.

Foregut tuberculosis:Too close but miles apart

The worldwide burden of tuberculosis(TB)has increased and it can involve virtually any organ of the body.Intestinal TB accounts for about 2%of the cases of TB worldwide.The ileocecal region is the most commonly affected site,and the foregut is rarely involved.The reported incidence is approximately 0.5%.Esophageal TB presents with dysphagia,weight loss,and hematemesis in rare cases.Gastroduodenal TB usually manifests with symptoms such as nausea,vomiting,weight loss,and sometimes with gastric outlet obstruction.Gastroscopy may reveal shallow ulcers in stomach and duodenal deformity when underlying TB is suspected,therefore histopathology plays pivotal role.On computed tomography,duodenal TB typically manifests as duodenal strictures predominantly,accompanied by extrinsic compression,and occasionally as intraluminal mass.But their diagnosis can easily be missed if proper biopsies are not taken and samples are not sent for GeneXpert testing,TB polymerase chain reaction investigation and histopathological analysis.Despite being in close proximity to the lungs,the esophagus and stomach are rare sites of TB.The reasons could be low gastric pH and acidity which does not let mycobacterium grow.But there are various case reports of TB involving the foregut.We have summarized the rare cases of foregut TB in different sections and highlighted the importance of esophagogastroduodenoscopy,histopathology and advanced techniques like endoscopic ultrasound in establishing the diagnosis.

psk1 virulence gene-induced pulmonary and systemic tuberculosis in a young woman with normal immune function:A case report

BACKGROUND Tuberculosis is a chronic infectious disease and an important public health pro-blem.Despite progress in controlling tuberculosis,the incidence of tuberculosis in China is still very high,with 895000 new cases annually.This case report des-cribes the investigation of a case of severe disseminated tuberculosis in a young adult with normal immune function,conducted to ascertain why a Mycobacterium tuberculosis(M.tuberculosis)strain caused such severe disease.CASE SUMMARY A previously healthy 28-year-old woman presented to our hospital with a 1-mo-nth history of fever and fatigue.She was diagnosed with severe disseminated pulmonary tuberculosis,spinal tuberculosis with paravertebral abscesses,and tuberculous meningitis.M.tuberculosis was isolated from bronchoal-veolar lavage fluid.She was treated with standard antituberculous therapy and underwent debridement,bone graft,and internal fixation surgery for spinal tuberculosis.She responded to therapy and regained her ability to walk following the surgery.We analysed the whole-genome sequence of the strain and designated it BLM-A21.Additional M.tuberculosis genomes were selected from the Virulence Factor Database(http://www.mgc.ac.cn/cgi-bin/VFs/genus.cgi?Genus=Mycobacterium)for comparison.An evolutionary tree of the BLM-A21 strain was built using PhyML maximum likelihood software.Further gene analysis revealed that,except for the pks1 gene,BLM-A21 had similar virulence genes to the CDC 1551 and H37Rv strains,which have lower dissemination.CONCLUSION We speculate that the pks1 virulence gene in BLM-A21 may be the key virulence gene responsible for the wide-spread dissemination of M.tuberculosis infection in this previously healthy adult with normal immune function.

The Retrospective Diagnostic Potential of Gene Xpert MTB/RIF for the Analysis of Formalin-Fixed Paraffin-Embedded Tissue from Extrapulmonary Tuberculosis Patients

Tuberculosis(TB)is a chronic disease caused by infection with Mycobacterium tuberculosis.Laboratory confirmation of this infection is challenging due to the paucibacillary nature of extrapulmonary tuberculosis(EPTB).

Surgical Management of Mitral Valve Infective Endocarditis with Accidental Finding of Open Pulmonary Tuberculosis

Objective: This case report aimed to highlight intersections of TB and Cardiovasular diseases which carry high morbidity and mortality rates. Methods: We are reporting the surgical management of forty seven years female who had back ground history of IDDM (Insulin dependent diabetic Mellitus), ESRD (End stage renal disease) on HD (haemodialysis) also she had left subclavian artery stenosis, and paroxysmal atrial fibrillation. She was diagnosed with mitral valve infective endocarditis and found accidently to have an open pulmonary tuberculosis (TB) on the day before surgery. Results: She was started on first line anti-TB treatment. She was isolated in her private room and airborne precautions measures applied. The patient underwent a tissue Mitral Valve replacement and tricuspid valve repair annuloplasty. Special precautions were applied in Theatre and on cardiopulmonary bypass Machine guided by KAMC-J disinfection protocol. The patient made good recovery postoperatively. She was discharged well on day 7 post operatively. Conclusion: Intersections of TB and cardiovasular diseases carry high morbidity and mortality rates. Early diagnosis and early anti tuberculosis treatment can surely improve the patient prognosis. Our decontamination and disinfective procedures are recommended. Cases like this should be monitored long term for the development of further cardiovascular complication.

Perianal tuberculous ulcer with active pulmonary,intestinal and orificial tuberculosis:A case report

BACKGROUND Orificial tuberculosis is a rare type of tuberculosis,which is easy to be misdiagnosed,and can cause great damage to the perianal skin and mucosa.Early diagnosis can avoid further erosion of the perianal muscle tissue by tuberculosis bacteria.CASE SUMMARY Here,we report a case of disseminated tuberculosis in a 62-year-old male patient with a perianal tuberculous ulcer and active pulmonary tuberculosis,intestinal tuberculosis and orificial tuberculosis.This is an extremely rare case of cutaneous tuberculosis of the anus,which was misdiagnosed for nearly a year.The patient received conventional treatment in other medical institutions,but specific treatment was delayed.Ultimately,proper diagnosis and treatment with standard anti-tuberculosis drugs for one year led to complete cure.CONCLUSION For skin ulcers that do not heal with repeated conventional treatments,consider ulcers caused by rare bacteria,such as Mycobacterium tuberculosis.

Prevalence of Latent Tuberculosis Infection [LTBI] in Prison Officers: A Systematic Review and Meta-Analysis

This study aimed to perform a systematic review and meta-analysis to determine the LTBI prevalence in prison officers worldwide. A systematic search was performed in PubMed, WoS, Embase, and BVS, including all articles related to LTBI prevalence and risk factors. After critical evaluation and qualitative synthesis of the identified articles, a meta-analysis was used. Five studies carried out between 2012 and 2022 were included, with a total sample size of 1718 prison officers. The overall LTBI prevalence was 50% [95% confidence interval [CI]: 48% - 52%;n = 816], with high heterogeneity between studies. Smoking [OR = 1.76;CI 95% = 1.26 - 2.46] and males [OR = 2.08;CI 95% = 1.31 - 3.31] were positively related to a higher LTBI prevalence among prison officers. Thus, preventive measures and the rapid and accurate diagnosis of new cases should be emphasized to ensure tuberculosis control, especially among risk groups such as prison officers.

Characteristics of Mycobacterium tuberculosis serine protease Rv1043c in enzymology and pathogenicity in mice

The serine proteases of Mycobacteria tuberculosis(Mtb)are important contributors to the process of bacterial invasion and its pathogenesis.In the present study,we systematically characterized the role of the Rv1043c protein in Mycobacterium infection by purifying the Rv1043c protein in Escherichia coli and constructing a Mycobacterium smegmatis(Msg)strain overexpressing Rv1043c(Msg_Rv1043c).We found that Rv1043c had serine protease activity and localized to the surface of Mtb.We determined that the optimal pH and temperature for the Rv1043c serine protease were 9.0 and 45°C,respectively.Moreover,the serine protease activity of Rv1043c was enhanced by divalent metal ions of Ca^(2+)and Mg^(2+).Site-directed mutagenesis studies demonstrated that the serine 279 residue in Rv1043c plays a catalytic role.Additionally,mouse model studies confirmed that Rv1043c significantly enhanced the survival of Msg in vivo,induced pulmonary injury and lung cell apoptosis,and promoted the release of pro-inflammatory cytokines interleukin-1βand interleukin-6 in mice.This study presents novel insights into the relationship between mycobacterial serine protease and the pathogenesis of the disease.

Evaluation of Microsphere-based xMAP Test for gyrA Mutation Identification in Mycobacterium Tuberculosis

Drug-resistant(DR) tuberculosis(TB) is a growing threat to public health[1]. Fluoroquinolone(FQ) antibiotics have long been used as anti-tuberculosis drugs, and their widespread application has led to the development of resistance in clinical isolates of Mycobacterium tuberculosis complex(MTBC).

Characterization of Mutations in Genes Related to Rifampicin and Isoniazid Resistance in Multidrug-resistant Mycobacterium tuberculosis Strains from Hangzhou,China

Tuberculosis(TB),caused by the Mycobacterium tuberculosis complex(MTBC),is the 13^(th)leading cause of death and the second leading cause of infectious killer after COVID-19(above HIV and AIDS),according to the World Health Organization's 2022 Global TB Report.In 2021,10.6 million people were diagnosed with a new episode of TB and 1.6 million people died as a result.

Involvement of 2'-5'oligoadenylate synthetase-like proteinin the survivalof Mycobacterium tuberculosis avirulent strain in macrophages

Mycobacterium tuberculosis(M.tuberculosis)can replicate in the macrophage by interfering with many host protein functions.While it is far from known these host proteins for controlling M.tuberculosis infection.Herein,we infected macrophages including THP-1 and Raw264.7 cells with M.tuberculosis and identified the differentially expressed genes(DEGs)in the interferon signaling pathway.Among them,2'-5'oligoadenylate synthetase-like(OASL)underwent the greatest upregulation in M.tuberculosis-infected macrophages.Knockdown of the expression of OASL attenuated M.tuberculosis survival in macrophages.Further,bioinformatics analysis revealed the potential interaction axis of OASL-TAB3-RvO127,which was further validated by the yeast-two-hybrid(Y2H)assay and Co-IP.This interaction axis might regulate the M.tuberculosis survival and proliferation in macrophages.The study reveals a possible role of OASL during M.tuberculosis infection as a target to control its propagation.

Contribution to the Study of Resistance to Anti-Tuberculosis Drugs in the Mycobacterium tuberculosis Complex Isolated at the National Laboratory of Clinical Biology and Public Health in Bangui in the Central African Republic in 2022: Case of Rifampicin

Microscopy-positive and drug-resistant pulmonary tuberculosis (MPT+) is one of the most feared diseases due to the cost of its management and the associated mortality. The GeneXpert, a new molecular test, is in greater demand for the diagnosis of MPT+ resistance cases. The application of GeneXpert to new cases of MPT+ is not effective in the country’s TB screening centres. The objective of this study is to assess the contribution of GeneXpert to the determination of MPT+ resistance cases in Bangui. The study was cross-sectional and covered the period from February to July 2022. The diagnosis of tuberculosis was first performed by microscopy with Ziehl Neelsen hot stain. The GeneXpert was then used to test for resistance in the sputum of all patients with positive microscopy. The collected data was entered into Excel 2013 and analysed with Epi Info 3.3.7. We analysed data from 755 patients, 80 of whom had resistance. The 80 patients ranged in age from 6 to 68 years (mean age = 35 years). The prevalence of resistant TB was 10.60% (80/755). Primary resistance accounted for 73.75% and secondary resistance for 26.25%. The age group 20 - 39 years (57.50%), male (72.50%), 8th district (17.50%), people living in couples (53.75%), farmers (13.75%) were the socio-demographic characteristics most affected by resistance. Treatment failure (13.75%), relapses (13.75%), the notion of contagion (28.75%), a history of smoking (40%) and alcohol (61.25%) were the clinical antecedents reported by the patients. Treatment failure and relapse were the variables associated with the occurrence of resistant PMT+ (p 0.05). A considerable proportion of the overall Mycobacterium tuberculosis resistance to anti-tuberculosis drugs (10.60%) was identified by GeneXpert. Treatment failure and relapse were the factors associated with the risk of resistance.

Value of ultrasound guided biopsy combined with Xpert Mycobacterium tuberculosis/resistance to rifampin assay in the diagnosis of chest wall tuberculosis

BACKGROUND The thoracic wall lesions,particularly chest wall tuberculosis,and chest wall tumors and other pyogenic wall and actinomycetes infections,almost always present as a diagnostic challenge.AIM To explore the value of ultrasound-guided biopsy combined with the Xpert Mycobacterium tuberculosis/resistance to rifampin(MTB/RIF)assay to diagnose chest wall tuberculosis.METHODS We performed a retrospective study of patients with chest wall lesions from March 2018 to March 2021.All patients received the ultrasound-guided biopsy for pathology examination,acid-fast Bacillus staining,mycobacterial culture,and Xpert MTB/RIF analysis.The sensitivity,specificity,and area under the curve(AUC)were calculated for these diagnostic tests,either individually or combined.Rifampicin resistance results were compared between the mycobacterial culture and the Xpert MTB/RIF assay.RESULTS In 31 patients with the chest wall lesion biopsy,22 patients were diagnosed with chest wall tuberculosis.Of them,3,6,and 21 patients tested positive for mycobacterial culture,acid-fast stain,and Xpert MTB/RIF assay,respectively.The rifampicin resistance results of the 3 culture-positive patients were consistent with their Xpert MTB/RIF assay results.When considering the sensitivity,specificity,and AUC value,the Xpert MTB/RIF assay(95.5%,88.9%,and 0.92,respectively)was a better choice than the acid-fast Bacillus stain(27.3%,100.0%,and 0.64,respectively)and mycobacterial culture(13.6%,100.0%,0.57,respectively).No complications were reported during the procedure.CONCLUSION Ultrasound guided biopsy combined with Xpert MTB/RIF has high value in the diagnosis of chest wall tuberculosis,and can also detect rifampicin resistance.

Research progress on the drug action and resistance mechanism in Mycobacterium tuberculosis

Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium Tuberculosis(MTB).It is the second largest single cause of death besides novel coronavirus pneumonia.Along with the abuse of antibiotics and extensive use of anti-tuberculosis drugs,multidrug-resistant(MDR)TB,drug-resistant(XDR)TB and totally drug-resistant(TDR)TB became obstacles to the tuberculosis eradication worldwide.According to the World Health Organization(WHO)statistics,China is not only a high burden tuberculosis country in the world,but also a country with a serious epidemic of MDR.Traditional drugs fail to meet the needs of tuberculosis control.Therefore,it is urgent to find new targets of anti-tuberculosis drugs and develop new anti-tuberculosis drugs.Hence,this paper systematically summarizes the mechanism of traditional and newly developed anti-tuberculosis drugs,in which stressing the research progress of drug resistance mechanisms.This work provides us with new insights of new anti-tuberculosis drug developments,and may contribute to a reduction in the harm that tuberculosis brings to society.