Incidence of Pediatric Cancers in French Guiana: How Does It Compare to Global Estimates?

French Guiana is a French territory in South America. The exposome of persons living there is quite different from that in mainland France and the ethnic make-up of the population is also quite different. Poverty is also widespread with difficulties in accessing care magnified by the low medical-professional density. In this singular context, we aimed to measure the incidence of pediatric cancers and to compare it with other continents. We used French Guiana's certified cancer registry to study this between 2003 and 2017. Incidences were standardized using the world population with three strata: 0-4 years, 5-9 years, and 10-14 years. There were 164 solid tumors or hematologic malignancies diagnosed in children under the age of 15 (92 in boys and 72 in girls). Over the study period, the standardized incidence rate was 14.1 per 100,000 among children aged under 15 years. There was no significant trend during the study period. The three most common causes of cancer were leukemias-mostly lymphoblastic-CNS tumors, and sarcoma. The standardized incidence of pediatric cancers in French Guiana was similar to those in Western Europe and North America. As others have discovered, we found that males tended to be more likely to develop cancer, notably leukemia, CNS tumors, sarcoma, and retinoblastoma. As elsewhere, the predominant cancer types changed with age. Our initial assumption was that given the singular context of French Guiana, there may have been differences in pediatric cancer incidences. Here we showed that overall, contrary to our assumption and to trends in tropical countries, the incidence of pediatric cancers was in a range between Western Europe and North America with some apparent but non-significant differences in the main types of cancers observed in global statistics. Quality cancer registry data in this tropical region confirm the suspicion that lower incidences in tropical low- and middle-income countries are likely to result from incomplete diagnosis and data collection.

Chromoblastomycosis in French Guiana: Epidemiology and Practices, 1955-2023.

Chromoblastomycosis (CBM) is a chronic neglected fungal disease, usually met in tropical areas. French Guiana is a South American territory with limited epidemiological data. This retrospective study concerned all patients with CBM proven by at least one paraclinical examination and diagnosed in French Guiana between 1950 and 2023. In total, 23 patients were included, mostly males (87%) of Creole origin, living in the coastal region (87%) and involved in outdoor occupations (74%). Lesions were mostly observed on the lower limbs (78.3%), with a median time to diagnosis of four years. Laboratory tests included positive direct microscopic examinations (78.3%) and mycological cultures (69.6%), identifying 14 cases of Fonsecaea pedrosoi and one case of Exophiala janselmei. Various treatments were employed, including antifungals, surgery and combinations of both. In conclusion, CBM in French Guiana involves a different population than other subcutaneous mycoses such as Lobomycosis or Paracoccidioidomycosis, mostly found in the forest hinterland. Surgery should be recommended for recent and limited lesions. Itraconazole and terbinafine should systematically be proposed, either in monotherapy or in combination with surgery or cryotherapy.

Factors associated with chronic kidney disease in patients with diabetes in French Guiana.

Introduction: With over half of the population living under the poverty threshold, the social and health context in French Guiana is more difficult than in mainland France. The prevalence of diabetes is twice as great and end-stage renal failure is 45% higher than in mainland France. Objective: Our objective was to describe the profile of diabetic patients with chronic kidney disease in French Guiana and search for possible risk factors. Method: We conducted a multicenter cross-sectional observational study based on the CODIAM cohort (Cohort of Diabetes in French Amazonia). We analyzed 1,287 patients followed up between May 2019 and June 2021 at Cayenne Hospital, Saint Laurent Hospital, and delocalized health centers. Results: In our cohort, chronic kidney disease was present after an average of 12 years of diabetes. Compared with the French population, 41% of diabetic patients had chronic kidney disease (i.e., 12% more), and had an average age of 56 years (i.e., 10 years younger). Forty-eight per cent of these patients were obese (i.e., 7% more). Seventy-four per cent of patients were precarious and 45% were foreigners but neither was associated with chronic kidney disease, contrary to countries where the health system is not universal. Conclusion: Screening of patients with chronic kidney disease among diabetics in French Guiana remains a real challenge. Patients were younger and more obese than in other French territories. In this cohort, precariousness and immigration were not associated with the presence of chronic kidney disease. However, particular attention should be paid to hypertensive patients and those over 65 years of age, which are, with diabetes itself, the two most obvious risk factors for developing chronic kidney disease among diabetic patients in our territory.

Fungal Density in Lobomycosis in French Guiana: A Proposal for a New Clinico-Histological and Therapeutic Classification.

BACKGROUND: Lobomycosis is a rare cutaneous tropical neglected disease caused by the fungal agent Lacazia loboi, recently renamed Paracoccidioides lobogeorgii. Our objectives were to present all cases of lobomycosis diagnosed in French Guiana, to offer a precise description of their histopathological features and to propose a new clinico-histological prognostic classification. METHODS: All cases of lobomycosis diagnosed in French Guiana between 1959 and 2022 were included. We looked for associations between the occurrence of relapses and the clinic-histological form. RESULTS: 31 patients diagnosed with lobomycosis were included. An epidemiological shift was observed in the 2000s as Brazilian patients became the most important ethnic group. Gold mining, forestry and fishing/sailing were reported as professional exposures. New histological features, such as inflammatory "rosettes" formations were described. We describe two clinic-histological patterns: a major form (high fungal density and/or multifocal lesions) and a minor form (low fungal density, unifocal lesions, association with fewer relapses). CONCLUSIONS: The changing epidemiology of lobomycosis in French Guiana is characterized by a shift towards Brazilian patients, mostly gold miners. Minor forms should be treated with surgery, major forms with a combination of surgery followed by nultiple drug therapy (MDT) or posaconazole.

Pulmonary Histoplasmosis in People Living with Human Immunodeficiency Virus in French Guiana: Clinical Epidemiology, Medical Imaging and Prognostic.

BACKGROUND: Histoplasmosis is mainly described as a disseminated disease in people living with HIV (PLHIV). Compared to historical descriptions in immunocompetent individuals, knowledge is lacking on the detailed clinical and radiological findings and outcomes of pulmonary histoplasmosis (PH). Overlooked or misdiagnosed with other AIDS-defining condition, prognostic of PLHIV may be at risk because of inappropriate care. METHODS: A retrospective multicentric study was conducted in PLHIV from French Guiana between January 1988 and October 2019. Proven PH were documented through mycological direct examination, culture, or histology. Patients with concomitant respiratory infections were excluded. RESULTS: Among 65 patients, sex ratio M:F was 2.4 with a median age of 39 years [IQR 25-75%: 34-44]. Median CD4 count was 24 cells/mm3 [11-71], with histoplasmosis as the AIDS-defining condition in 88% and concomitant AIDS-defining conditions in 29%. Clinical findings were fever (89%), cough (58%), dyspnea (35%), expectoration (14%), and hemoptysis (5%). Sixty-one X-rays and 24 CT-scans were performed. On X-rays, an interstitial lung disease was mainly found (77%). On CT-scans, a nodular pattern was predominant (83%): mostly miliary disease (63%), but also excavated nodules (35%). Consolidations were present in 46%, associated with miliary disease in 21%. Thoracic lymphadenopathies were found in 58%, mainly hilar and symmetric (33%). Despite antifungal treatment, case-fatality rate at one month was 22%. CONCLUSION: When faced with an interstitial lung disease on X-rays or a miliary pattern on CT-scans in advanced PLHIV, physicians in endemic areas, apart from tuberculosis or pneumocystosis, should include histoplasmosis as part of their differential diagnoses.

Diagnostic and Management of Emphysematous Hepatitis with Emphasis on Biopathology.

Emphysematous hepatitis is a rare infectious disease, which corresponds to the presence of gas in the liver, without collection and after exclusion of vascular origin. This entity belongs to the group of emphysematous infections, whose physiopathology seems to be linked to the presence of unbalanced diabetes and to bacterial fermentation, leading to the production of gas within the liver parenchyma. Very few cases of emphysematous hepatitis have been described in the literature, and most of them had a rapidly fatal course. In this manuscript, we report the case of a 59-year-old man with emphysematous hepatitis due to wild-type Klebsiella pneumoniae that was successfully managed by surgery, and we perform a review of the literature to describe the clinical and biopathological aspects of this rare hepatic disease. Our manuscript underlines the need to perform biological and histopathological sampling to better understand the pathophysiology of this rare entity. The causes and mechanisms of emphysematous hepatitis, which seem to be multiple, lead us to believe that it is a syndrome rather than a simple infectious disease.

Human T-cell leukemia virus type 1 is associated with dysthyroidism in the French Amazon.

Background: Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus known to cause two major diseases: adult T-cell leukemia/lymphoma and a progressive neuromyelopathy-tropical spastic paraparesis. Many viruses may be involved in the pathogenesis of thyroiditis; however, few studies have focused on the role of HTLV-1. We aimed to investigate the association between HTLV-1 and biological thyroid dysfunction. Methods: We included 357 patients with a positive HTLV-1 serology and thyroid-stimulating hormone assay data between 2012 and 2021 in a hospital in French Guiana; we compared the prevalence of hypothyroidism and hyperthyroidism in this group with that in an HTLV-1-negative control group (722 persons) matched for sex and age. Results: The prevalence of hypothyroidism and hyperthyroidism in patients with HTLV-1 infection was significantly higher than that in the control group (11% versus 3.2% and 11.3% versus 2.3%, respectively; p < 0.001). Conclusion: Our study shows, for the first time, the association between HTLV-1 and dysthyroidism in a large sample, suggesting that thyroid function exploration should be systematically implemented in this population as this may have an impact on therapeutic management.

Leprosy in French Guiana, 2015 to 2021: Dynamics of a Persistent Public Health Problem.

A resurgence of leprosy as a public health problem in French Guiana was reported over the period 2007 to 2014, particularly among Brazilians gold miners. Prolonged multidrug therapy and reversal reactions represent a therapeutic challenge. The objective of this study was to assess the evolution of leprosy in this European overseas territory. All patients with leprosy confirmed in histopathology between 1 January 2015 and 31 December 2021 were included. A total of 86 patients were included, including 64 new cases and 22 previously diagnosed cases. Sixty patients (70%) were male, 6 cases were paediatric. Brazilian gold miners represented 44.1% of reported occupations (15/34). Maroons represented the second community (13 patients, 15%). Multibacillary and paucibacillary forms were found in 53 (71%) and 22 (29%) patients, respectively. The annual prevalence never exceeded the threshold of 1/10,000. The mean incidence and prevalence were significantly lower than during the period 2007 to 2014 (p < 0.0001). Reversal reactions were found in 29 patients and almost always required a long course of steroids. Infliximab allowed a reduction in the length of treatment with steroids in 2/2 cases. In conclusion, the prevalence of leprosy has decreased significantly in French Guiana, but remains driven by the population of illegal gold miners. Anti-tumour necrosis factor (anti-TNF) drugs represent a promising option in the management of reversal reactions.

The Epidemiologic Transition in French Guiana: Secular Trends and Setbacks, and Comparisons with Continental France and South American Countries.

There are great variations between population subgroups, notably in poorer countries, leading to substantial inconsistencies with those predicted by the classical epidemiologic transition theory. In this context, using public data, we aimed to determine how the singular case of French Guiana fit and transitioned in the epidemiologic transition framework. The data show a gradual decline in infant mortality to values above 8 per 1000 live births. Premature mortality rates were greater but declined more rapidly in French Guiana than in mainland France until 2017 when they reascended in a context of political turmoil followed by the COVID-19 pandemic and strong reluctance to get vaccinated. Although infections were a more frequent cause of death in French Guiana, there is a marked decline and circulatory and metabolic causes are major causes of premature death. Fertility rates remain high (>3 live births per woman), and the age structure of the population is still pyramid-shaped. The singularities of French Guiana (rich country, universal health system, widespread poverty) explain why its transition does not fit neatly within the usual stages of transition. Beyond gradual improvements in secular trends, the data also suggest that political turmoil and fake news may have detrimentally affected mortality in French Guiana and reversed improving trends.

The Singular Epidemiology of Plasmacytoma and Multiple Myeloma in French Guiana.

BACKGROUND: The objective was to review a decade of plasmacytoma (PC) and multiple myeloma (MM) data from French Guiana, and to study its spatial and temporal trends. METHODS: This was a retrospective study of MM and PC between January 2005 and December 2014 using cancer registry data, including age-standardized incidence and mortality rates. RESULTS: There were 110 cases of PC and MM (62 women and 48 men), representing the eighth most frequent malignancy in French Guiana. PC and MM were much more common in females. In men, 79% of cases occurred at ≥55 years, and in women, 90% of cases occurred at ≥50 years. The median age at diagnosis was 60 years for men and 66 years for women, while it was 72 years for men and 75 years for women in mainland France. The incidence rate standardized to the world population was 5.9 patients of PC and MM per 100,000 men/year and 7.8 per 100,000 women/year. CONCLUSIONS: In our territory, the incidence of PC and MM was higher and patients were diagnosed at a substantially younger age than in mainland France. Women had a greater incidence than men, and there was an increasing temporal trend of incidence among women. African ancestry and the frequency of obesity, notably among women, could have contributed to this observation.

Precariousness, Diabetes Control and Complications in French Guiana.

Aims: The social parameters of an individual impact the incidence of cardiovascular diseases. French Guiana, an overseas French territory with a lower standard of living than France, has a prevalence of diabetes mellitus that is twice that of mainland France. In this context we aimed to study the relation between precariousness, diabetes complications and glycemic control. Methods: A multicenter prospective cohort was initiated since May 2019. 1243 patients were included and their outcomes and history were compared between the precarious and non-precarious based on their EPICES score, a score that measures social isolation and precariousness. Results: 73.3% of the sample was considered precarious. Retinopathy was significantly more frequent among the deprived. There were no significant differences for other macro or microvascular complications.There was a significant difference in Glycated Haemoglobin between the precarious and non-precarious groups (8.3% (67 mmol/l) vs 8.8% (73mmol/l)). After adjusting for potential confounders, precariousness was no longer associated with poor glycemic control; the independent factors significantly associated with poor glycemic control were: not being fluent in French, having creole or portugese as mother language, and not having any insurance. Conclusions: Precariousness is a risk factor for retinal complications in patients with diabetes mellitus in French Guiana. In this chronic disease, the universal healthcare system alleviates health inequalities for many, but not all, diabetic complications.Translation and cultural mediation may further reduce health inequalities in this multicultural territory where a substantial proportion of the population is not fluent in French.

Epidemiological, Clinical, Ultrasonographic and Cytological Characteristics of Thyroid Nodules in an Afro-Caribbean Population: A Series of 420 Patients.

The incidence of thyroid cancer is increasing worldwide. The aim of this study is to describe the epidemiological, clinical and ultrasound characteristics of malignancy in thyroid nodules and to evaluate the predictive value of the Bethesda system for thyroid cytology in the diagnosis of malignancy in an Afro-Caribbean population. We conducted a retrospective study in Martinique involving 420 patients with a diagnosis of thyroid nodules between 2011 and 2014. Of the 192/420 (45.7%) patients operated on for thyroid nodules, 9% had thyroid cancer. All patients with thyroid cancer were obese women with a mean age of 50 years. The final histological examination revealed papillary microcarcinomas in 61% of cases and papillary carcinomas in 39% of cases. Thyroid cytology alone had a low sensitivity (22.2%) and positive predictive value (15.4%) for the diagnosis of malignancy, with a good specificity (91.1%) and negative predictive value (94.2%). None of the standard ultrasound criteria of malignancy were significantly predictive of cancer, but hypoechogenicity and central vascularity were frequently found in malignant nodules. These epidemiological, clinical and ultrasound results could increase awareness and guide practitioners in their diagnostic approach and management of thyroid nodules in an Afro-Caribbean population. Bethesda system-based cytology revealed lower sensitivity in analyzing the risk of malignancy in this population. The high prevalence of papillary microcarcinomas may explain the inconclusive ultrasound and cytological results.

Nutritional and Socioeconomic Determinants of Overweight and Obesity in the French Amazon: The Health Barometer Study.

Objectives: French Guiana is a multicultural overseas territory where obesity is a major public health problem. This study aimed to highlight the nutritional and socioeconomic determinants of overweight and obesity in different populations in French Guiana. Methods: A two-stage random sample of 1390 individuals aged 15 to 75 years was surveyed by telephone, and the participants were initially screened for diabetes. Logistic regression was fitted on the sample to adjust for potential confounding factors. Results: Overweight and obesity were found in 54.7% of the respondents, a higher proportion than in mainland France. There was a significant body image discrepancy in our population, with a higher risk of obesity among single women, often immigrants from the non-French Caribbean and South America, unemployed or low education. Conclusions: The main factors associated with obesity were being a precariousness immigrant; there was often a mismatch between body image and overweight/obesity, which is a major obstacle to the improvement of dietary behaviors and lifestyle. This information provides operational clues as to where to act and the necessary adaptations to attempt to modify behaviors in a culturally-adapted manner.

Kaposi Sarcoma with Mucocutaneous Involvement in French Guiana: An Epidemiological Study between 1969 and 2019.

Data on Kaposi sarcoma in French Guiana are scarce and out of date. This territory presents unique epidemiological features. The objectives of this retrospective study were to analyse the clinical features, outcome and incidence of the different forms of Kaposi sarcoma in patients diagnosed between 1969 and 2019. The study population comprised a total of 52 patients. Clinical forms included epidemic Kaposi sarcoma (n=30), endemic (n=18), iatrogenic (n=2), classic (n=1) and unclassified Kaposi sarcoma (n=1). The mean annual incidence rate of epidemic Kaposi reached a peak in the 1990s (0.93/100,000) then decreased in the 2000s (0.33/100,000), while the incidence of endemic Kaposi sarcoma reached a peak in the 1980s (0.82/100,000) before decreasing in the 2000s (0.12/100,000). Factors associated with the epidemic form were: sexual intercourse between men (p=0.0054) and Haitian origin (p=0.035). The presence of nodules and/or tumour, lesions limited to the lower limbs, and age >65 years were associated with the endemic form. While Creole populations seem to be as affected by endemic Kaposi sarcoma as their African counterparts, the dynamics of Kaposi sarcoma in French Guiana are now dominated by the epidemic form.

Pathological Significance of GLUT-1 Expression in Breast Cancer Cells in Diabetic and Obese Patients: The French Guiana Study.

The prevalence of obesity and type 2 diabetes is higher in French Guiana compared to mainland France. These metabolic disorders are associated with an increased risk of cancer. One of the factors involved is hyperinsulinemia that promotes the action of glucose transporter 1 (GLUT-1). The objective of this study is to characterize the expression of GLUT-1 in breast cancers cells in diabetic and obese patients compared to those who are not and to describe the clinical and histological prognostic factors of breast cancer in this population. We conducted a monocentric study including patients with breast cancer diagnosed between 2014 and 2020. Patients were classified into three groups: diabetes, obesity, and control group. The GLUT-1 expression was assessed by immunohistochemistry. In total, 199 patients were included in this study. The median age was 53.5 years, and the median tumor size was 2.8 cm. Luminal A was the most frequent molecular type (58.1%), followed by the triple-negative type (19.9%). The breast cancer in our population was characterized by a younger age at diagnosis, more aggressive molecular types, and larger tumor size. Thus, we suggest the advancement of the age of breast cancer screening in this territory. A total of 144 patients (31 diabetes, 22 obese, and 91 control group) were included for the study of GLUT-1 expression. Overexpression of GLUT-1 was observed in 60.4% of cases and in all carcinoma in situ lesions. GLUT-1 overexpression was associated with more aggressive cancers. This overexpression is correlated with high histological grade, high proliferation index, and aggressive molecular types. Our study found no difference in GLUT-1 expression between the diabetic or obese patients and the control group. These results highlight the potential role of GLUT-1 as a tumor metabolic prognostic marker and also as an interesting target therapy, independently of patient metabolic disorder.

Vitamin D Deficiency in Patients with Diabetes in French Guiana: Epidemiology and Relation with Microvascular and Macrovascular Complications.

Vitamin D (VD) insufficiency is common among patients with diabetes in French Guiana. The study aimed to evaluate the prevalence of VD deficiency in the different type of diabetes encountered and to analyze the relationship between VD deficiency and diabetes complications. METHODS: An observational study was conducted between May 2019 and May 2020 in French Guiana, based on data from the CODIAM study (Diabetes Cohort in French Amazonia), describing the characteristics of patients with diabetes mellitus. Among 600 patients enrolled with diabetes, 361 had an available VD assay. RESULTS: The mean 25(OH)VD (hydroxycalciferol) level was 27.9 ng/mL. The level of VD was inversely proportional to the HbA1c (glycated hemoglobin) level. Patients with angina pectoris had a greater proportion of deficiencies VD < 20 ng/mL than those without angina. By contrast, patients with retinopathy had higher vitamin D concentrations than those without retinopathy. There was no association between vitamin D and arteriopathy, stroke, nephropathy and polyneuropathy. VD deficiency was more frequent in women, and in patients with a high school education. CONCLUSION: The prevalence of VD deficiency was high in patients with diabetes in French Guiana, emphasizing the importance of VD supplementation.

Case Report: Potential Role of Corticosteroids in the Management of Post-COVID-19 Pneumonia.

Certain patients who recover from severe pneumonia due to coronavirus disease 2019 (COVID-19) remain symptomatic in the post-infectious period, either clinically, radiologically, or respiratory. The post-COVID-19 period is characterized by clinical symptoms of varying duration from one subject to another and does not seem to depend on the severity of initial pneumonia. The persisting inflammatory and/or immune reactions in the post-COVID-19 period may play a role in the development of pulmonary lesions. Here, we report the case of a 61-year-old man with severe COVID-19 pneumonia, complicated by acute respiratory distress syndrome and pulmonary embolism, which required the patient's admission to the intensive care unit and high-flow oxygen therapy. The patient was hospitalized for 23 days for the management of his severe COVID-19 pneumonia. Afterwards, he was discharged home following a negative SARS-CoV-2 PCR test. The post-COVID-19 period was characterized by a complex respiratory symptomatology associating cough, resting dyspnea, and exertional dyspnea requiring oxygen therapy for several weeks. Surprisingly, the follow-up chest CT scan performed 4 weeks after discharge revealed bilateral interstitial lung lesions. After ruling out pulmonary superinfection, the patient was treated with oral corticosteroid for 3 months at a digressive dose. In our case, the use of corticosteroid therapy in the post-COVID19 phase had improved the outcome of the lung disease. These benefits are characterized by a rapid symptomatic improvement, accelerated repair of pulmonary images, rapid oxygen withdrawal, and rapid return to daily activities.

Cytological Spectrum of Pulmonary Histoplasmosis Diagnosed by Bronchoalveolar Lavage: 12 Years of Experience in French Guiana.

Disseminated histoplasmosis is a major cause of mortality in HIV-infected patients. Rapid and efficient diagnosis of Histoplasma capsulatum is crucial. Cytopathology is available in most hospitals and represents a rapid diagnostic alternative. In this study, we reviewed 12 years of experience to describe the cytology of histoplasmosis diagnosed by bronchoalveolar lavage (BAL) in relation to patient characteristics. BAL-diagnosed pulmonary histoplasmosis concerned 17 patients (14 HIV+). BAL cellularity ranged from 76,000 to 125,000 cells/mL in HIV patients, and 117,000 to 160,000 cells/mL in non-HIV patients. Macrophages predominated in all HIV patients (from 60% to 88%), lymphocytic infiltrates ranged from 5% to 15%, and neutrophils were very heterogeneous (from 2% to 32%). The number of H. capsulatum at hot spots seemed greater in HIV-infected than in immunocompetent patients (9 to 375 vs. 4 to 10) and were inversely proportional to the CD4 counts. Yeasts were both intracellular and extracellular in 85.7% of the HIV patients. This is the most comprehensive series detailing the cytological aspects of BAL in the diagnosis of H. capsulatum, focusing on the number of yeasts and their clustering pattern. The cytological examination of the Gomori-Grocott-stained BAL allows a reliable diagnosis of histoplasmosis.

SARS-CoV-2 and Mycobacterium tuberculosis coinfection: A case of unusual bronchoesophageal fistula.

Tuberculosis is a treatable and curable bacterial disease caused by Mycobacterium tuberculosis that most often affects the lung. Since 2018, it has become the leading cause of death from infectious diseases. Tuberculosis is a public health problem in French Guiana. The majority of reported cases are diagnosed among people coming from neighboring Latin American countries. Since March 2020, French Guiana has been affected, like the rest of the world, by the new infectious disease COVID19 linked to the SARS-CoV-2 coronavirus. We here report a case of COVID19 and pulmonary tuberculosis coinfection. COVID19 pneumonia was the mode of discovery of the tuberculosis. In the present case, the tuberculosis appeared as parenchymal and endobronchial pseudotumoral lesion, which has been complicated by a bronchoesophageal fistula. The evolution of the parenchymal, endobronchial lesion and bronchoesophageal fistula was favorable after two months of anti-tuberculosis treatment.