Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova.

The projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDR M. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDR Mtb have found that Mtb strains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. Using Mtb genome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR Ural Mtb has been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.

Identifying local foci of tuberculosis transmission in Moldova using a spatial multinomial logistic regression model.

BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) represents a major public health concern in the Republic of Moldova, with an estimated 31% of new and 56% of previously treated TB cases having MDR disease in 2022. A recent genomic epidemiology study of incident TB occurring in 2018 and 2019 found that 92% of MDR-TB was the result of transmission. The MDR phenotype was concentrated among two M. tuberculosis (Mtb) lineages: L2.2.1 (Beijing) and L4.2.1 (Ural). METHODS: We developed and applied a hierarchical Bayesian multinominal logistic regression model to Mtb genomic, spatial, and epidemiological data collected from all individuals with diagnosed TB in Moldova in 2018 and 2019 to identify locations in which specific Mtb strains are being transmitted. We then used a logistic regression model to estimate locality-level factors associated with local transmission. FINDINGS: We found differences in the spatial distribution and degree of local concentration of disease due to specific strains of Beijing and Ural lineage Mtb. Foci of transmission for four strains of Beijing lineage Mtb, predominantly of the MDR-TB phenotype, were located in several regions, but largely concentrated in Transnistria. In contrast, transmission of Ural lineage Mtb had less marked patterns of spatial aggregation, with a single strain (also of the MDR phenotype) spatially clustered in southern Transnistria. We found a 30% (95% credible interval 2%-80%) increase in odds of a locality being a transmission cluster for each increase of 100 persons per square kilometer, while higher local tuberculosis incidence and poverty were not associated with a locality being a transmission focus. INTERPRETATION: Our results identified localities where specific Mtb transmission networks were concentrated and quantified the association between locality-level factors and focal transmission. This analysis revealed Transnistria as the primary area where specific Mtb strains (predominantly of the MDR-TB phenotype) were locally transmitted and suggests that targeted intensified case finding in this region may be an attractive policy option. FUNDING: Funding for this work was provided by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health.

Drug-Resistant Tuberculosis, Georgia, Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, 2017-2022.

In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).

Effects of the COVID-19 Pandemic on the Wellbeing of LGBTQ+ Individuals in Moldova: A Mixed Methods Analysis.

Research on the effects of the COVID-19 pandemic for LGBTQ+ people is limited, particularly in eastern Europe. This mixed methods study explored the direct and indirect effects of the pandemic on the mental and physical wellbeing of LGBTQ+ individuals in Moldova. From June to the end of July 2022, 86 surveys and 12 interviews were completed by self-identified LGBTQ+ adults in Moldova. Survey data were analyzed with descriptive statistics and interviews were coded and analyzed using the grounded theory methodology. The two data sets were interpreted concurrently to identify emergent themes. Overall, data suggest LGBTQ+ people experienced both negative and positive effects on their mental wellbeing due to the pandemic. Participants expressed feelings of anxiety, loneliness, and depression, and an inability to be their authentic selves. Conversely, participants had more capacity to explore their identities and they demonstrated social support within the LGBTQ+ community. Regarding physical impacts, there were interruptions to transgender medical care and concerns about housing affordability. Findings highlight the unique impacts of the pandemic on LGBTQ+ people and stress the importance of further research in this area and policies and plans to address the needs of LGBTQ+ people in response to the pandemic and future health crises.

Family-focused intervention to promote adolescent mental health and well-being in Moldova and North Macedonia (FLOURISH): feasibility study protocol.

INTRODUCTION: Family-Focused Adolescent & Lifelong Health Promotion (FLOURISH) project will adapt, implement and evaluate a programme to support adolescent mental health and well-being through strategies, such as strengthening parenting practices, adolescent-caregiver relationships, adolescent and parent socioemotional skills, and social support. METHODS AND ANALYSIS: The project will focus on adolescents aged 10-14 years and their caregivers in North Macedonia and Moldova. The countries were selected based on implementation readiness of two organisations and a need for accessible evidence-informed services to help mitigate health risks due to economic, social and political challenges. Parenting for Lifelong Health (PLH) for Parents and Teens is a family-based programme developed for low-resource settings. PLH has been adapted with input from advisory groups. The programme includes additional components to strengthen impacts on adolescents: adolescent mental health tools, based on UNICEF's Helping Adolescents Thrive, adolescent peer support and participation booster. This pilot is first of three study phases. The pilot will be a feasibility testing of the adapted intervention and the assessment and implementation procedures to determine further refinements. The pilot will examine if the adapted programme is acceptable for adolescents, their families and providers, explore contextual factors relevant to embedding this programme into longer-term scale-up and investigate whether the programme can be delivered with fidelity and participation; whether the participants report changes in adolescent emotional and behavioural problems, well-being and other outcomes; and whether the study tools are feasible and appropriate. Pre-post adolescent and caregiver questionnaires will provide outcome data. Process evaluation will include attendance and fidelity data, and focus groups. We will examine delivery cost and resource requirements. ETHICS AND DISSEMINATION: The study was approved at the University of Klagenfurt (Austria), Medical Faculty at St. Cyril and Methodius University (North Macedonia) and National Committee of Ethical Expertise for Clinical Trials (Moldova). Through stakeholder engagement and dissemination, FLOURISH will advance scale-up of open-source family interventions. TRIAL REGISTRATION NUMBER: Trial registration: ID101095528; project page: https://www.flourish-study.org/about.html; https://www.linkedin.com/company/flourish-study/.

Modelling the dispersion of particulate matter (PM10) via wind erosion from opencast mining-Moldova Noua tailings ponds, Romania.

Historically, Romania is known as a mining site of mineral substances, including gold, silver, copper, lead, zin, uranium, manganese, salt, and coal, whereby their long periods of exploitation and extraction affected human health and the environment in various ways. In Moldova Noua southwest region of Romania, we investigated the environmental impacts of mining activities on air quality over 2021. We quantified PM10 emission rates through in situ monitoring, dispersion modelling, and horizontal and vertical fluxes. Statistical metrics, including the fraction within factor 2 (FAC2), mean bias (MB), mean gross error (MGE), normalized mean bias (NMB), normalized mean gross error (NMGE), coefficient of efficiency (COE), index of agreements (IOAs), and Taylor diagram signifying standards deviation (SD), root mean squared error (RMSE), and correlation coefficient (R), were used to evaluate the reliability of modelling results against observation. Results conclude that PM10 dispersion agrees with MB, MGE, NMB, NMGE, COE, IOA, and Taylor diagram and moderately with FAC2 metrics. PM10 hotspot was investigated in the vicinity of the tailings ponds of 115.5 µg m-3 annual mean, 563.7 µg m-3 daily mean, 63.3 µg m-2 s-1 annual horizontal flux, and 3.0 µg m-2 s-1 annual vertical flux. PM10 dispersion was identified to expand to Moldova Noua City and nearby country Serbia. Findings concluded that a windy air mass accumulation across the overburdened dumps and ponds causes the increase of PM10 in the air, resulting in the region's pollution. Therefore, results recommend adopting a strategic mitigation measure for residents, policymakers, stakeholders, and urban planners.

Does training on the WHO package of essential noncommunicable (PEN) disease interventions enhance consultation quality? A real-world assessment of adherence to PEN protocol in primary health centres in the Republic of Moldova.

BACKGROUND: Noncommunicable diseases (NCDs) pose a significant global health challenge. Primary health centres are pivotal in addressing this challenge by providing essential care to NCD patients. The WHO Package of Essential Noncommunicable (PEN) disease interventions has been designed to enhance the quality of NCD consultations and ensure adherence to the protocol. This study investigates the effects of PEN training in Moldova. OBJECTIVES: The primary objective of this study is to assess the effects of training on WHO PEN on the quality of NCD consultations and adherence to the PEN protocol in a real -world setting in primary health centres in Moldova. METHODS: An observational, cross-sectional study was conducted, comparing primary health centres where health personnel received PEN training, provided by the Healthy Life project, to those where such training was not provided. In total, 24 family doctors and 24 medical assistants were observed for 233 workdays and covering 2,166 NCD consultations. RESULTS: Intervention primary health centres (PHCs) showed longer NCD consultation durations, with family doctors and medical assistants spending an added 1 minute 43 seconds and 3 minutes 10 seconds, respectively. These PHCs also reported a higher proportion of primary NCD consultations, indicating better screening for new NCD patients. Medical assistants in the intervention group took on a more pronounced role in NCD care. However, the findings also highlight the necessity to refine aspects of the PEN training, especially concerning follow-up consultations, risk assessments, and task delegation. CONCLUSIONS: The findings suggest that the PEN training contributed to improvement of both the quality of NCD consultations and adherence to the PEN protocol. Yet, there is a need for enhancing the identified aspects of the PEN training. The findings highlight the potential of PEN training in primary healthcare settings for improved NCD management.

The impact of the COVID-19 pandemic on primary health care practices and patient management in the Republic of Moldova - results from the PRICOV-19 survey.

BACKGROUND: The COVID-19 pandemic has had an enormous impact on health systems in Europe and has generated unprecedented challenges for tertiary care. Less is known about the effects on the activities of local family doctors (FDs), who have shifted tasks and adapted their practice to accommodate the new services brought by the pandemic. The PRICOV-19 study was a multi-country survey aiming to understand the challenges posed by the pandemic in primary health care (PHC) practices around Europe. Within the framework of this study, we assessed the impact of the pandemic on PHC facilities in urban, rural, and mixed urban/rural areas in the Republic of Moldova. METHODS: We present the results from the PRICOV-19 questionnaire designed at Ghent University (Belgium) and distributed between January and March 2021 to PHC facilities from the 35 districts of the Republic of Moldova. This analysis presents descriptive data on limitations to service delivery, staff role changes, implementation and acceptance of COVID-19 guidelines, and incidents reported on staff and patient safety during the pandemic. RESULTS: Results highlighted the differences between facilities located in urban, rural, and mixed areas in several dimensions of PHC. Nearly half of the surveyed facilities experienced limitations in the building or infrastructure when delivering services during the pandemic. 95% of respondents reported an increase in time spent giving information to patients by phone, and 88% reported an increase in responsibilities. Few practices reported errors in clinical assessments, though a slightly higher number of incidents were reported in urban areas. Half of the respondents reported difficulties delivering routine care to patients with chronic conditions and a delay in treatment-seeking. CONCLUSIONS: During the pandemic, the workload of PHC staff saw a significant increase, and practices met important structural and organizational limitations. Consequently, these limitations may have also affected care delivery for vulnerable patients with chronic conditions. Adjustments and bottlenecks need to be addressed, considering the different needs of PHC facilities in urban, rural, and mixed areas.

Hepatitis C Elimination in Moldova Is Feasible and Cost-Saving: A Modeling Study.

BACKGROUND: Moldova, an upper-middle-income country in Eastern Europe, is facing a high burden of hepatitis C virus (HCV). Our objective was to assist the National Agency of Public Health of Moldova in planning to achieve the World Health Organization's HCV elimination goals by 2030. METHODS: This study adapted a previously developed microsimulation model to simulate the HCV epidemic in Moldova from 2004 to 2050. Model outcomes included temporal trends in HCV infection, prevalence, mortality, and total cost of care, including screening and treatment. We evaluated scenarios that could eliminate HCV by 2030. RESULTS: Multiple strategies could lead to HCV elimination in Moldova by 2030. A realistic scenario of a 20% annual screening and 80% treatment rate would require 2.75 million individuals to be screened and 65 000 treated by 2030. Compared to 2015, this program will reduce HCV incidence by 98% and HCV-related deaths by 72% in 2030. Between 2022 and 2030, this strategy would cost $17.5 million for HCV screening and treatment. However, by 2050, the health system would save >$85 million compared to no investment in elimination efforts. CONCLUSIONS: HCV elimination in Moldova is feasible and can be cost saving, but requires resources to scale HCV screening and treatment.

Insights on aerosol properties using two decades-long ground-based remote sensing datasets in Moldova, Eastern Europe.

Aerosol optical properties were studied over Chisinau in Moldova, one of the longest running AERONET sites in Eastern Europe. During two decades (September 1999-November 2018), the mean aerosol optical depth (AOD) and Angstrom exponent (AE) were observed as 0.21 ± 0.13 and 1.49 ± 0.29, respectively. The highest AOD (0.24 ± 0.13) and AE (1.60 ± 0.26) were observed during the summer. More than half (∼55%) of the share was occupied by clean continental aerosols with seasonal order of winter (74.8%) > autumn (62%) > spring (48.9%) > summer (44.8%) followed by mixed aerosols with a respective contribution of 30.7% (summer), 28.4% (spring), 22.5 (autumn) and 16.4% (winter). A clear dominance of volume size distribution in the fine mode indicated the stronger influence of anthropogenic activities resulting in fine aerosol load in the atmosphere. The peak in the fine mode was centered at 0.15 µm, whereas that of the coarse mode was centered either at 3.86 µm (summer and autumn) or 5.06 µm (spring and winter). 'Extreme' aerosol events were observed during 21 days with a mean AOD (AE) of 0.99 ± 0.32 (1.43 ± 0.43), whereas 'strong' events were observed during 123 days with a mean AOD (AE) of 0.57 ± 0.07 (1.44 ± 0.40), mainly influenced by anthropogenic aerosols (during 19 and 101 days of each event type) from urban/industrial and biomass burning indicated by high AE and fine mode fraction. During the whole period (excluding events days), the fine and coarse mode peaks were observed at the radius of 0.15 and 5.06 µm, which in the case of extreme (strong) events were at 0.19 (0.15) and 3.86 (2.24) µm respectively. The fine mode volume concentration was 4.78 and 3.32 times higher, whereas the coarse mode volume concentration was higher by a factor of 1.98 and 2.27 during extreme and strong events compared to the whole period.

[Ukrainian war and its consequences Module "Mother and Child" of the Swiss Humanitarian Aid in Moldova]. / La guerre en Ukraine et ses conséquences. Le module « Mère-Enfant ¼ de l'aide humanitaire suisse en Moldavie.

As a result of the Ukraine conflict, more than 6.3 million refugees had to flee to neighbouring countries, among them the Republic of Moldova (RoM), triggering a social and humanitarian crisis. From our assessment of the general health situation and upon request of the RoM Ministry of Health, Swiss Humanitarian Aid module "mother and child" has been deployed to refugee transit centres to deliver primary health care of mothers and children. Due to the specific refugee population consisting mainly of mothers and children, the module showed to be very beneficial, extremely flexible and was highly appreciated. Simultaneously, strategic hospitals were revisited for contingency planning, but also in view of logistical support. We organized a "train the trainer" course together with the National Centre of pre-hospital assistance.

En raison du conflit en Ukraine, plus de 6,3 millions de réfugiés ont dû fuir vers les pays voisins, dont la Moldavie, déclenchant une crise sociale et humanitaire. Sur la base de notre évaluation et à la demande du ministère de la Santé de Moldavie, le module « Mère-Enfant ¼ de l'Aide humanitaire suisse a été déployé dans les centres de transit pour réfugiés afin de fournir des soins de santé primaires aux mères et aux enfants. La population spécifique de réfugiés étant composée principalement de mères et d'enfants, le module s'est avéré très bénéfique, flexible et très apprécié. Dans le même temps, les hôpitaux stratégiques ont été revisités pour la planification d'urgence, mais aussi pour le soutien logistique. Nous avons organisé des « formations des formateurs ¼ en collaboration avec le Centre national d'assistance préhospitalière.

Whole genome sequencing and phylogenetic characterisation of rabies virus strains from Moldova and north-eastern Romania.

BACKGROUND: Rabies is the oldest fatal zoonotic disease recognised as a neglected tropical disease and is caused by an RNA virus belonging to the genus Lyssavirus, family Rhabdoviridae. METHODOLOGY/PRINCIPAL FINDINGS: A deep molecular analysis was conducted on full-length nucleoprotein (N) gene and whole genome sequences of rabies virus from 37 animal brain samples collected between 2012 and 2017 to study the circulation of rabies virus (RABV) variants. The overall aim was to better understand their distribution in Moldova and north-eastern Romania. Both Sanger and high throughput sequencing on Ion Torrent and Illumina platforms were performed. Phylogenetic analysis of the RABV sequences from both Moldova and Romania revealed that all the samples (irrespective of the year of isolation and the species) belonged to a single phylogenetic group: north-eastern Europe (NEE), clustering into three assigned lineages: RO#5, RO#6 and RO#7. CONCLUSIONS/SIGNIFICANCE: High throughput sequencing of RABV samples from domestic and wild animals was performed for the first time for both countries, providing new insights into virus evolution and epidemiology in this less studied region, expanding our understanding of the disease.

Strengthening the strategy to sustain optimal iodine status in the Republic of Moldova: Assessing the use of iodized salt in industrially processed foods.

BACKGROUND: Although national legislation in the Republic of Moldova includes the use of iodized salt in processed food industry as well as household (cooking and table) salt, little is known of the actual use of iodized salt in the food industry and its contribution to the overall iodine intake of the population. This study has helped to address the gap in understanding about how much iodized salt is used in the production of different foods and to identify where more information is still required in order to more fully characterize the contribution of food industry salt to population iodine intake. METHODS: Using the available food consumption and production data, the assessment introduces a novel modelling technique, based on the methodology of the IGN Programme Guidance to assess the use of iodized salt in industrially produced foods (IPF). The method included the identification of key salt containing IPF and modelling of the salt and potential iodine intake in two groups of the population, non-pregnant adults and pregnant women. The findings were synthetized to develop a list of recommendations for adjustment or strengthening the existing salt iodization strategy. MAIN RESULTS: In RM, the salt used for industrially produced bread and household use provide almost 80% of all salt intake for adults. The intake from iodized salt at household level and the 8 key salt- containing IPF is estimated to currently meet 89% and 53% of the recommended nutrient for adults and pregnant women, respectively. If all salt used at household level and industrial bread baking would be iodized, then, potentially, it could ensure 181% and 109%, respectively, of the required iodine intake. CONCLUSIONS: Use of iodized salt in the processed food industry is of growing significance and universal use of iodized salt at household level and in bread production could result in a desirable increase in iodine intake. The national salt iodization strategy should include strengthened regulatory monitoring of iodized salt use in the bread baking industry.

Limited Nosocomial Transmission of Drug-Resistant Tuberculosis, Moldova.

Applying whole-genome-sequencing, we aimed to detect transmission events of multidrug-resistant/rifampin-resistant strains of Mycobacterium tuberculosis complex at a tuberculosis hospital in Chisinau, Moldova. We recorded ward, room, and bed information for each patient and monitored in-hospital transfers over 1 year. Detailed molecular and patient surveillance revealed only 2 nosocomial transmission events.

Key lessons learnt from COVID-19 intra-action reviews in the Republic of Moldova, Montenegro, Kosovo and North Macedonia 2020-2021: a qualitative study.

OBJECTIVES: Our study described how the WHO intra-action review (IAR) methodology was operationalised and customised in three Western Balkan countries and territories and the Republic of Moldova and analysed the common key findings to inform analyses of the lessons learnt from the pandemic response. DESIGN: We extracted data from the respective IAR reports and performed a qualitative thematic content analysis to identify common (between countries and territories) and cross-cutting (across the response pillars) themes on best practices, challenges and priority actions. The analysis involved three stages, namely: extraction of data, initial identification of emerging themes and review and definition of the themes. SETTING: IARs were conducted in the Republic of Moldova, Montenegro, Kosovo and the Republic of North Macedonia between December 2020 and November 2021. The IARs were conducted at different time points relative to the respective pandemic trajectories (14-day incidence rate ranging from 23 to 495 per 100 000). RESULTS: Case management was reviewed in all the IARs, while the infection prevention and control, surveillance and country-level coordination pillars were reviewed in three countries. The thematic content analysis identified four common and cross-cutting best practices, seven challenges and six priority recommendations. Recommendations included investing in sustainable human resources and technical capacities developed during the pandemic, providing continuous capacity-building and training (with regular simulation exercises), updating legislation, improving communication between healthcare providers at all levels of healthcare and enhancing digitalisation of health information systems. CONCLUSIONS: The IARs provided an opportunity for continuous collective reflection and learning with multisectoral engagement. They also offered an opportunity to review public health emergency preparedness and response functions in general, thereby contributing to generic health systems strengthening and resilience beyond COVID-19. However, success in strengthening the response and preparedness requires leadership and resource allocation, prioritisation and commitment by the countries and territories themselves.