How many human pathogens are there in Laos? An estimate of national human pathogen diversity and analysis of historical trends.

OBJECTIVE: The emergence of infectious diseases pose major global health threats. Estimates of total in-country human pathogen diversity, and insights as to how and when species were described through history, could be used to estimate the probability of new pathogen discoveries. Data from the Lao People's Democratic Republic (Laos) were used in this proof-of-concept study to estimate national human pathogen diversity and to examine historical discovery rate drivers. METHODS: A systematic survey of the French and English scientific and grey literature of pathogen description in Laos between 1874 and 2017 was conducted. The first descriptions of each known human pathogen in Laos were coded according to the diagnostic evidence available. Cumulative frequency of discovery across time informed the rate of discovery. Four distinct periods of health systems development in Laos were identified prospectively and juxtaposed to the unmodelled rate of discovery. A model with a time-varying rate of discovery was fitted to these data using a Markov-Chain- Monte-Carlo technique. RESULTS: From 6456 pathogen descriptions, 245 discoveries of known human pathogens in Laos, including repeat discoveries using different grades of evidence, were identified. The models estimate that the Laos human pathogen species diversity in 2017 is between 169 and 206. During the last decade, there has been a 33-fold increase in the discovery rate coinciding with the strengthening of medical research and microbiology. CONCLUSION: Discovery curves can be used to model and estimate country-level human pathogen diversity present in a territory. Combining this with historical assessment improves the understanding of the factors affecting local pathogen discovery. PROSPERO REGISTRATION NUMBER: A protocol of this work was registered on PROSPERO (ID:CRD42016046728).

Seroprevalence and risk factors of hepatitis B and C virus infections in female workers of Lao garment factories.

The prevalence of hepatitis B and C virus infections may be higher in vulnerable populations or in individuals likely to be exposed through risk behaviors such as female garment factory workers in Lao People's Democratic Republic. A cross-sectional study was performed on 400 female garment workers in Vientiane Capital. Women were tested for hepatitis B virus surface antigen and antibodies against hepatitis B core, surface antigen and hepatitis C virus using commercial Enzyme-linked immuno-absorbent assays. Participants completed a standardized questionnaire about potential risk factors for both infections. Sixteen women (4±1.9%) were HBsAg carriers, 187 (47%) had anti-HBc, 116 (29%) anti-HBs and 7 (1.8±1.3%) anti-HCV antibodies. Three factors were significantly associated with the presence of anti-HBc (indicating previous exposure to HBV): (i) residence in dormitories, (ii) more than one sexual partner, (iii) history of abortion. Despite a high risk of exposure, the prevalence of anti HBV and anti HCV infection markers in this sample of female workers was not higher than in the Lao general population. Our data suggest that exposure to HBV happens later during life and was significantly associated with sexual risk behavior. Thus, this study highlights the vulnerability of these women who were mostly young, uneducated, unvaccinated, of rural origin and were not aware of the risk of infections. An occupational health program targeting the female factory workers should be implemented in Lao PDR.

The detection of cryptic Plasmodium infection among villagers in Attapeu province, Lao PDR.

BACKGROUND: Although the malaria burden in the Lao PDR has gradually decreased, the elimination of malaria by 2030 presents many challenges. Microscopy and malaria rapid diagnostic tests (RDTs) are used to diagnose malaria in the Lao PDR; however, some studies have reported the prevalence of sub-microscopic Plasmodium infections or asymptomatic Plasmodium carriers in endemic areas. Thus, highly sensitive detection methods are needed to understand the precise malaria situation in these areas. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional malaria field survey was conducted in 3 highly endemic malaria districts (Xaysetha, Sanamxay, Phouvong) in Attapeu province, Lao PDR in 2015, to investigate the precise malaria endemicity in the area; 719 volunteers from these villages participated in the survey. Microscopy, RDTs and a real-time nested PCR were used to detect Plasmodium infections and their results were compared. A questionnaire survey of all participants was also conducted to estimate risk factors of Plasmodium infection. Numbers of infections detected by the three methods were microscopy: P. falciparum (n = 1), P. vivax (n = 2); RDTs: P. falciparum (n = 2), P. vivax (n = 3); PCR: Plasmodium (n = 47; P. falciparum [n = 4], P. vivax [n = 41], mixed infection [n = 2]; 6.5%, 47/719). Using PCR as a reference, the sensitivity and specificity of microscopy were 33.3% and 100.0%, respectively, for detecting P. falciparum infection, and 7.0% and 100.0%, for detecting P. vivax infection. Among the 47 participants with parasitemia, only one had a fever (≥37.5°C) and 31 (66.0%) were adult males. Risk factors of Plasmodium infection were males and soldiers, whereas a risk factor of asymptomatic Plasmodium infection was a history of ≥3 malaria episodes. CONCLUSIONS/SIGNIFICANCE: There were many asymptomatic Plasmodium carriers in the study areas of Attapeu province in 2015. Adult males, probably soldiers, were at high risk for malaria infection. P. vivax, the dominant species, accounted for 87.2% of the Plasmodium infections among the participants. To achieve malaria elimination in the Lao PDR, highly sensitive diagnostic tests, including PCR-based diagnostic methods should be used, and plans targeting high-risk populations and elimination of P. vivax should be designed and implemented.

The Aetiologies and Impact of Fever in Pregnant Inpatients in Vientiane, Laos.

INTRODUCTION: Laos has the highest maternal mortality ratio in mainland Southeast Asia and a high incidence of infectious diseases. Globally, malaria has been the pathogen most intensively investigated in relation to impact on pregnancy, but there has been relatively little research on the aetiology and impact of other diseases. We therefore aimed to determine the causes and impact of fever in pregnant women admitted to two central hospitals in Vientiane City, Lao PDR (Laos). MATERIALS AND METHODS: This hospital-based prospective study was conducted in Mahosot Hospital and the Mother and Child Hospital, Vientiane, between 2006 and 2010, with the aim to recruit 250 consenting pregnant women admitted with tympanic temperature ≥37.5°C. Primary outcome was the cause of fever and secondary outcomes were pregnancy outcomes. Specific investigations (culture, antigen, molecular and serological tests) were performed to investigate causes of fever. After discharge, all pregnant women were asked to return for review and convalescence serum on day 10-14 and were monitored until delivery. PRINCIPLE FINDINGS: 250 pregnant women were recruited to this study between February 2006 and November 2010. Fifty percent were pregnant for the first time. Their median (range) gestational age on admission was 24 (4-43) weeks. The median (range) tympanic admission temperature was 38.5°C (37.5-40.5°C). Fifteen percent of patients stated that they had taken antibiotics before admission. Headache, myalgia, back pain and arthralgia were described by >60% of patients and 149 (60%) were given a laboratory diagnosis. Of those with confirmed diagnoses, 132 (53%) had a single disease and 17 (7%) had apparent mixed diseases. Among those who had a single disease, dengue fever was the most common diagnosis, followed by pyelonephritis, scrub typhus, murine typhus and typhoid. Patients were also diagnosed with tuberculosis, appendicitis, Staphylococcus aureus septicemia, leptospirosis, Japanese encephalitis virus infection and Plasmodium falciparum malaria. Severe consequences, including maternal death, miscarriage, stillbirth, low birth weight and preterm birth, were found among 28 (78%) mothers with dengue fever, rickettsioses and typhoid. CONCLUSION: Fevers other than malaria, such as dengue, pyelonephritis, rickettsioses and typhoid are common causes of fever during pregnancy in the Asian tropics. Further investigations of their impact in the community on maternal death, fetal loss, vertical transmission, low birth weight and preterm birth are needed.

Factors associated with the failure of first and second-line antiretroviral therapies therapy, a case control study in Cambodian HIV-1 infected children.

BACKGROUND: Little is known about the efficacy of first and and second-line antiretroviral therapies (ART) for HIV-1 infected children in resource limited Southeast Asian settings. Previous studies have shown that orphans are at a higher risk for virological failure (VF) in Cambodia. Consequently most of them required transfer to second-line ART. We assessed the factors associated with VF among HIV-1 infected children who were either under first-line (mostly 3TC + D4T + NVP) or under second-line (mostly ABC + DDI + LPV) therapies at a referral hospital in Cambodia. METHODS: A case-control study was conducted from February to July 2013 at the National Pediatric Hospital among HIV-1 infected children (aged 1-15 years) under second-line ART (cases) or first-line (matched controls at a ratio of 1:3) regimens. Children were included if a HIV-1 RNA plasma viral load (VL) result was available for the preceding 12 months. A standardized questionnaire explored family sociodemographics, HIV history, and adherence to ART. Associations between VF (HIV-1 RNA levels ≥1000 copies/ml) and the children's characteristics were assessed using bivariate and multivariate analyses. RESULTS: A total of 232 children, 175 (75.4 %) under first-line and 57 (24.6 %) under second-line ART, for a median of 72.0 (IQR: 68.0-76.0) months, were enrolled. Of them, 94 (40.5 %) were double orphans and 51 (22.0 %) single orphans, and 77 (33.2 %) were living in orphanages. A total of 222 children (95.6 %) were deemed adherent to ART. Overall, 18 (7.7 %; 95 % CI 4.6-11.9) showed a VF, 14 (8.6 %; 95 % CI 4.8-14.0) under first-line and 4 (7.0 %; 95 % CI 1.9-17.0) under second-line ART (p = 0.5). Their median CD4 percentage was 8 % (IQR 2.9-12.9) at ART initiation. Children under second-line ART were older; more often double orphans, and had lower CD4 cell counts at the last control. In the multivariate analysis, having the last CD4 percentage below 15 % was the only factor associated with VF for ART regimen separately or when combined (OR 40.4; 95 % CI 11-134). CONCLUSIONS: The pattern of risk factors for VF in children is changing in Cambodia. Improved adherence evaluation and intensified monitoring of children with low CD4 counts is needed to decrease the risk of VF.

[Management of sexually transmitted infections by private pharmacies in Hanoi]. / Prise en charge des infections sexuellement transmissibles dans les pharmacies privées à Hanoi.

AIM: This cross-sectional study comprising quantitative and qualitative analysis of clinical practices was designed to evaluate the quality and relevance of management of sexually transmitted infections (STI) based on a syndrome approach by private pharmacies in Hanoi in 2010 compared to a similar study conducted in 2000. METHODS: One investigator played the role of a customer presenting signs of STI. He visited 60 randomly selected private pharmacies in Hanoi and noted the treatments, questions and advice provided by pharmacists. RESULTS: The results show that pharmacists proposed a treatment for 87% of cases of urethral discharge and 30% of cases of genital ulcers. The patient was not asked any questions in 55% of cases. None of the prescriptions complied with national guidelines. Only 8.3% of pharmacists/shop assistants asked the "patient" questions concerning the spouse/partner and 20% provided advice (the use of condoms in 26.6% of cases and a screening test for HIV in only one case). Pharmacists/shop assistants recommended consulting a doctor in only 43.3% of cases or a specialized STI clinic in only 16.7% of cases. CONCLUSION: The behaviour of private pharmacists/shop assistants in Hanoi have not changed over the last ten years (2000-2010). They readily treat STI inappropriately and provide little advice concerning prevention, screening and treatment. In the age of the HIV pandemic and microbial resistance to antibiotics, patients with STI should be advised to seek management by competent public services.

Urine antibiotic activity in patients presenting to hospitals in Laos: implications for worsening antibiotic resistance.

Widespread use of antibiotics may be important in the spread of antimicrobial resistance. We estimated the proportion of Lao in- and outpatients who had taken antibiotics before medical consultation by detecting antibiotic activity in their urine added to lawns of Bacillus stearothermophilus, Escherichia coli, and Streptococcus pyogenes. In the retrospective (N = 2,058) and prospective studies (N = 1,153), 49.7% (95% confidence interval [CI] = 47.4-52.0) and 36.2% (95% CI = 33.4-38.9), respectively, of Vientiane patients had urinary antibiotic activity detected. The highest frequency of estimated antibiotic pre-treatment was found in patients recruited with suspected central nervous system infections and community-acquired septicemia (both 56.8%). In Vientiane, children had a higher frequency of estimated antibiotic pre-treatment than adults (60.0% versus 46.5%; P < 0.001). Antibiotic use based on patients histories was significantly less frequent than when estimated from urinary antibiotic activity (P < 0.0001).

Chromoblastomycosis after a leech bite complicated by myiasis: a case report.

BACKGROUND: Chromoblastomycosis is a chronic mycotic infection, most common in the tropics and subtropics, following traumatic fungal implantation. CASE PRESENTATION: A 72 year-old farmer was admitted to Luang Namtha Provincial Hospital, northern Laos, with a growth on the left lower leg which began 1 week after a forefoot leech bite 10 years previously. He presented with a cauliflower-like mass and plaque-like lesions on his lower leg/foot and cellulitis with a purulent tender swelling of his left heel. Twenty-two Chrysomya bezziana larvae were extracted from his heel. PCR of a biopsy of a left lower leg nodule demonstrated Fonsecaea pedrosoi, monophora, or F. nubica. He was successfully treated with long term terbinafin plus itraconazole pulse-therapy and local debridement. CONCLUSIONS: Chromoblastomycosis is reported for the first time from Laos. It carries the danger of bacterial and myiasis superinfection. Leech bites may facilitate infection.

Predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection in adults.

OBJECTIVE: To examine the accuracy of the admission tourniquet test in the diagnosis of dengue infection among Lao adults. METHODS: Prospective assessment of the predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection, as defined by IgM, IgG and NS1 ELISAs (Panbio Ltd, Australia), among Lao adult inpatients with clinically suspected dengue infection. RESULTS: Of 234 patients with clinically suspected dengue infection on admission, 73% were serologically confirmed to have dengue, while 64 patients with negative dengue serology were diagnosed as having scrub typhus (39%), murine typhus (11%), undetermined typhus (12%), Japanese encephalitis virus (5%), undetermined flavivirus (5%) and typhoid fever (3%); 25% had no identifiable aetiology. The tourniquet test was positive in 29.1% (95% CI = 23.2-34.9%) of all patients and in 34.1% (95% CI = 27.0-41.2%) of dengue-seropositive patients, in 32.7% (95% CI = 23.5-41.8) of those with dengue fever and in 36.4% (95% CI = 24.7-48.0) of those with dengue haemorrhagic fever. Interobserver agreement for the tourniquet test was 90.2% (95% CI = 86.4-94.0) (Kappa = 0.76). Using ELISAs as the diagnostic gold standard, the sensitivity of the tourniquet test was 33.5-34%; its specificity was 84-91%. The positive and negative predictive values were 85-90% and 32.5-34%, respectively. CONCLUSIONS: The admission tourniquet test has low sensitivity and adds relatively little value to the diagnosis of dengue among Lao adult inpatients with suspected dengue. Although a positive tourniquet test suggests dengue and that treatment of alternative diagnoses may not be needed, a negative test result does not exclude dengue.

Different chest radiographic findings of pulmonary paragonimiasis in two endemic countries.

We compared the chest radiographic findings of patients with pulmonary paragonimiasis in the Lao People's Democratic Republic (PDR) with a report from Korea. The clinical and radiological characteristics of 50 confirmed Laotian pleuropulmonary paragonimiasis patients were studied between March 2003 and June 2007. In 49 patients, the chest radiographs showed abnormal findings (98%). Pulmonary parenchymal abnormalities were found in all 49 patients, whereas pleural effusion was only found in 11 patients (22%). The three most common intraparenchymal findings were multiple small cysts (90%), irregular linear densities (68%), and nodular opacities (40%). The numbers of patients who had these three findings were significantly different from the Korean report (P < 0.001). In conclusion, radiographic findings of pulmonary paragonimiasis may vary among countries.

Survival and health status of DOTS tuberculosis patients in rural Lao PDR.

BACKGROUND: Contact tracing of tuberculosis (TB) patients is rarely performed in low-income countries. Our objective was to assess the outcome of and compliance with directly observed treatment (DOTS) of TB patients over a 3 year period in rural Lao PDR. METHODS: We performed a retrospective cohort study in which we enrolled TB patients who started DOTS treatment at Attapeu Provincial Hospital. We traced, through hospital records, all patients in their residential village. We conducted a standardized questionnaire with all TB patients and performed physical and anthropometric examinations as well as evaluations of compliance through counting of treatment pills at home and at the health facilities. RESULTS: Of 172 enrolled TB patients (sex ratio female/male: 0.52, mean age: 46.9 years ± 16.9), 26 (15.1%) died. These had a lower weight at the start (34.6 vs. 40.8 kg, p < 0.001) and were less compliant (91.6% vs. 19.2%, p < 0.001) than survivors. Low compliance was associated with poor accessibility to health care (p = 0.01) and symptomatic improvement (p = 0.02). Survivors had persistently poor health status. They were underweight (54.7%), and still had clinical symptoms (53.5%), including dyspnoea (28.8%) and haemoptysis (9.5%). CONCLUSION: Our study suggests a lower rate of survival than expected from official statistics. Additionally, it showed that follow-up of TB patients is feasible although the patients lived in very remote area of Laos. Follow-up should be strengthened as it can improve patient compliance, and allow contact tracing, detection of new cases and collection of accurate treatment outcome information.

Rapid identification of paragonimiasis foci by lay informants in Lao People's Democratic Republic.

BACKGROUND: Paragonimiasis is a food-borne trematodiasis leading to lung disease. Worldwide, an estimated 21 million people are infected. Foci of ongoing transmission remain often unnoticed. We evaluated a simple questionnaire approach using lay-informants at the village level to identify paragonimiasis foci and suspected paragonimiasis cases. METHODOLOGY/PRINCIPAL FINDINGS: The study was carried out in an endemic area of Lao People's Democratic Republic. Leaders of 49 remote villages in northern Vientiane Province were asked to notify suspected paragonimiasis patients using a four-item questionnaire sent through administrative channels: persons responding positively for having chronic cough (more than 3 weeks) and/or blood in sputum with or without fever. We validated the village leaders' reports in ten representative villages with a door-to-door survey. We examined three sputa of suspected patients for the presence of Paragonimus eggs and acid fast bacilli. 91.8% of village leaders participated and notified a total of 220 suspected patients; 76.2% were eventually confirmed; an additional 138 suspected cases were found in the survey. Sensitivity of village leaders' notice for "chronic cough" and "blood in sputum" was 100%; "blood in sputum" alone reached a sensitivity of 85.7%. SIGNIFICANCE: Our approach led to the identification of three previously unknown foci of transmission. A rapid and simple lay-informant questionnaire approach is a promising low-cost community diagnostic tool of paragonimiasis control programs.

Morphological differences and molecular similarities between Paragonimus bangkokensis and P. harinasutai.

Paragonimus bangkokensis and Paragonimus harinasutai were found one after another in the same crab host, Potamon smithianus, in Thailand in 1967 and 1968. Both species were also recently found in China and Lao People's Democratic Republic (PDR). Those two Paragonimus spp. are distinguishable from each other by morphological features of metacercariae and adults. However, recently, the DNA sequences of second internal transcribed spacer region (ITS2) and cytochrome oxidase subunit 1 (CO1) genes of those two species in Thailand were reported to be highly similar to each other. In the present study, we collected P. bangkokensis in two provinces in Vietnam (the first record in Vietnam) and both P. bangkokensis and P. harinasutai in Lao PDR for the morphological and molecular phylogenetic analyses to clarify the mutual relationship between the two species. The results show that P. bangkokensis and P. harinasutai were distinguishable from each other by morphology such as the size of metacercariae and the arrangement of cuticular spines of adult worms. However, the molecular phylogenetic analyses of ITS2 and CO1 genes clearly indicate that P. bangkokensis and P. harinasutai make a monophyletic group.

Paragonimiasis: a common cause of persistent pleural effusion in Lao PDR.

Southeast Asia is the major endemic area for paragonimiasis. Diagnosis relies on identification of ova in the sputum, pleural fluid or tissue specimen, or serology. Low awareness, however, frequently results in the disease being overlooked. We report nine cases presenting as primary, massive and protracted pleural effusions. All patients had evidence of Paragonimus spp. in the pleural fluid; one discharged an adult worm through a chest tube during treatment with praziquantel. In three cases, resolution of symptoms and pleural effusions could not be achieved, despite repeated fluid evacuation procedures and courses of praziquantel, which contradicts the widely accepted statement of paragonimiasis being self-limited and easy to cure. The disease should be considered in any case of elusive pleural effusion occurring in endemic areas.

Three cases of intestinal capillariasis in Lao People's Democratic Republic.

Capillaria philippinensis is a rare zoonotic intestinal parasite that emerged in the 1960s. The outcome of intestinal capillariasis may be fatal if untreated in due time. We report three cases of intestinal capillariasis in Lao People's Democratic Republic (Lao PDR). The three patients were unrelated previously healthy young men (24, 26, and 27 years of age) with no underlying disease or immune depression. They had chronic diarrhea, abdominal pain, edema, and severe weight loss. Two of them acquired the infection in Thailand; the other patient had no travel history outside Lao PDR. All patients were seen several times in different hospitals before the diagnosis was made. All had concurrent parasite infections: Giardia lamblia, Entamoeba histolytica, Strongyloides stercoralis, Opisthorchis viverrini, and hookworm. The patients frequently consumed uncooked fish. After treatment with albendazole (400 mg/day for 21-30 days) all patients recovered. In Lao PDR, consumption of raw small freshwater fish is common. Therefore, the possibility of a capillariasis outbreak should be considered.

Noma in Laos: stigma of severe poverty in rural Asia.

Noma, or cancrum oris, is a debilitating necrotizing ulcerative stomatitis that destroys the mouth and face. It usually starts in early childhood and is associated with severe poverty, malnutrition, and infections. It is most frequently described from sub-Saharan Africa but is under-reported. There have been very few reports from Asia. We describe the clinical and social features of a series of 12 patients with noma from remote poor villages in rural Lao People's Democratic Republic (Laos). Noma is an ominous stigma of severe poverty and the description of this disease emphasizes the importance of poverty reduction and nutritional improvement in Lao development. In the meantime, more awareness of the problem and the importance of early therapy in acute noma by primary health care workers may reduce mortality and prevent progression to severe disfigurement.

A major trichinellosis outbreak suggesting a high endemicity of Trichinella infection in northern Laos.

Trichinellosis is an important and under-recognized food-borne zoonosis in Southeast Asia. After 30 years of no reports, a small outbreak was described in Central Lao PDR (Laos) in 2003. Here we report a large outbreak of at least 650 estimated patients in Udomxay (northern Laos) in June 2005. Trichinella ELISA assays on serum from 133 patients and Western blot assays on 16 patients were positive in 67.6% and 81.2%, respectively. No deaths were recorded. Consumption of uncooked or fermented pork at funeral and wedding ceremonies was the main source of infection. Larvae of Trichinella spiralis were found in 1 of 11 local pigs not involved in this outbreak. The results suggest that trichinellosis may be an under-recognized but important endemic disease in Laos and reinforces the need to urgently implement veterinary and educational programs.

Improving tuberculosis case detection rate with a lay informant questionnaire: an experience from the Lao People's Democratic Republic.

PROBLEM: In many countries, the tuberculosis (TB) annual case detection rate is below the target of 70%. In the Lao People's Democratic Republic in 2005, it did not exceed 55% APPROACH: The DOTS strategy promotes passive case detection of TB. In order to increase the detection rate, we validated a questionnaire targeting lay informants at village level to notify patients with chronic cough and assessed the relevance for TB case-finding. A three-item questionnaire was sent through the district health departments to all villages in six districts in six provinces. The village headmen were asked to notify chronic cough patients. Answers were validated in a door-to-door survey (20 villages/district). In a sub-sample (four villages/district) all confirmed patients were screened for TB and paragonimiasis. LOCAL SETTING: Attapeu, Luang Namtha, Luang Prabang, Saravane, Savanakhet and Vientiane provinces in the Lao People's Democratic Republic. RELEVANT CHANGES: Lay informant questionnaires sent from district health offices to villages are cost-effective and foster interaction between the health services and remote and underserved communities. Although the correct detection of patients is highly dependent on direct respondents, a substantial number of new TB and paragonimiasis cases were consistently diagnosed in chronic cough patients. LESSONS LEARNED: Out of 456 questionnaires, 295 were returned (65%). Return rates were highly variable between districts (48-87%), questionnaires' sensitivity (56-98%), positive predictive value (34-88%) and correlation between number of notified and confirmed patients (r: 0.26-0.78). In sub-sampled villages (13,541 population) 19 (5.1%) TB and 26 (7.0%) paragonimiasis cases were detected in 374 chronic cough patients. This quick questionnaire approach proved motivating for district authorities and village key informants, although no incentives were provided. The highly operator-dependent approach yielded a consistent detection rate of TB and paragonimiasis cases. This approach brings health services and populations in need in close contact, which is particularly crucial in remote and underserved areas.