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.

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.

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.

Traumatic head injuries in Moldova: a cross-sectional analysis of medical registry data.

AIM: The aims of this study were to evaluate the demographics and crash profiles of road traffic-related traumatic brain injury (TBI) patients treated at two emergency departments in the Republic of Moldova, and to identify areas for prevention.

SARS-CoV-2 from COVID-19 Patients in the Republic of Moldova: Whole-Genome Sequencing Results.

Since the onset of the COVID-19 pandemic, no viral genome sequences of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been documented from the Republic of Moldova, a developing country geographically located in Eastern Europe between Romania and Ukraine. Here, we report the analysis of 96 SARS-CoV-2 sequences from Delta and Omicron variants of the SARS-CoV-2 cases in the Republic of Moldova obtained between August and November 2021 and between January and May 2022. Comparison to global viral sequences showed that among the Delta variant of the SARS-CoV-2, AY.122 (n = 25), followed by AY.4.2.3 (n = 6), AY.4 (n = 5), AY.43 (n = 3), AY.98.1 (n = 3), B.1.617.2 (n = 1), AY.125 (n = 1), AY.54 (n = 1), AY.9 (n = 1), AY.126 (n = 1), and AY.33 (n = 1) were the most frequently found lineages. Furthermore, 10 lineages of the Omicron variant, namely, BA.2 (n = 14), followed by BA.2.9 (n = 10), BA.1 (n = 5), BA.1.1 (n = 5), BA.1.18 (n = 4), BA.1.15.1 (n = 3), BA.1.17.2 (n = 2), BA.1.17 (n = 2), BA.1.15 (n = 1), and BA.2.1 (n = 1) were detected. In addition, we also identified the impact of the military crisis between Russia and Ukraine, when the COVID-19 epidemiological rules collapsed, on the distribution of Delta and Omicron variants in the Republic of Moldova. Additional studies are warranted to characterize further the impact of the war between Russia and Ukraine on the genomic epidemiology of the SARS-CoV-2 in the Republic of Moldova and Eastern Europe.

Phylogeography and transmission of M. tuberculosis in Moldova: A prospective genomic analysis.

BACKGROUND: The incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible tuberculosis (TB), is the main driver of incident MDR-TB in these countries. METHODS AND FINDINGS: We conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of Mycobacterium tuberculosis. Of 2,236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. Moreover, 92% of multidrug-resistant M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified 3 large clades that were comprised nearly uniformly of MDR-TB: 2 of these clades were of Beijing lineage, and 1 of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity. Our study lasted for only 2 years, a relatively short duration compared with the natural history of TB, and, thus, the ability to infer the full extent of transmission is limited. CONCLUSIONS: The MDR-TB epidemic in Moldova is associated with the local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.

The impact of COVID-19 on fertility behaviour and intentions in a middle income country.

The COVID Pandemic may affect fertility behaviour and intentions in many ways. Restrictions on service provision reduce access to family planning services and increase fertility in the short term. By contrast, the economic uncertainty brought about by the pandemic and its impact on mental health and well-being may reduce fertility. These various pathways have been explored in the context of high income countries such as the United States and Western Europe, but little is known about middle income countries. In this paper we asses the impact of the COVID pandemic on fertility intentions and behaviour in the Republic of Moldova, a middle income country in Eastern Europe, using the Generations and Gender Survey. This survey was conducted partially before and partially after the onset of the pandemic in 2020, allowing for detailed comparisons of individual circumstances. The results indicate that the pandemic reduced the used of intrauterine devices, and increased the use of male condoms, but with no overall decrease in contraceptive use. Conversely individuals interviewed after the onset of the pandemic were 34.5% less likely to be trying to conceive, although medium term fertility intentions were unchanged. Indicators therefore suggest that in the medium term fertility intentions may not be affected by the pandemic but restricted access to contraception requiring medical consultation and a decrease in short-term fertility intentions could disrupt short term family planning.

Hepatitis B and C infections among lymphoma patients: a national study in the Republic of Moldova.

INTRODUCTION: Hepatitis B virus (HBV) and hepatitis C virus (HCV) represent common infections that are presumably associated with various types of lymphoma and specific clinical features. However, conclusive data are lacking and results from different regional studies are conflicting. Hence, a national study was performed in order to investigate potential associations between hepatitis infections and lymphoma in the Republic of Moldova. METHODOLOGY: Data were collected from newly diagnosed adult lymphoma patients from January 2020 to January 2022. Patients who were not tested for HBsAg and anti-HCV and those with an undetermined lymphoma subtype diagnosis were excluded from the study. Subjects with and without viral hepatitis were then evaluated on the basis of clinical and pathological characteristics. RESULTS: One hundred and twenty-nine lymphoma patients were included in the study; 15 (11.6%) patients were diagnosed with hepatitis B, 21 (16.3%) patients with hepatitis C, and 1 (0.78%) patient was positive for both. The majority of hepatitis patients were over 60 years old (62.2%), presented with stage III or IV (81%), had normal lactate dehydrogenase (58.3%) and 0 or 1 extranodal sites (78.4%). The most common lymphoma subtypes were diffuse large B-cell lymphoma (64.9%) and marginal zone lymphoma (8.1%). We did not find any statistically significant differences between infected and uninfected lymphoma patients in regards to clinical features, specific lymphoma subtypes, and presence and location of extranodal involvement. CONCLUSIONS: Presence of hepatitis B or C virus infections is not associated with specific clinical and pathological features in Moldovan lymphoma patients.

Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova.

The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Phlebotomine sand fly survey in the Republic of Moldova: species composition, distribution and host preferences.

BACKGROUND: Phlebotomine sand flies (Diptera: Psychodiae) in the Republic of Moldova have been understudied for decades. Our study provides a first update on their occurrence, species composition and bloodmeal sources after 50 years. METHODS: During 5 seasons (2013-2017), 58 localities from 20 regions were surveyed for presence of sand flies using CDC light traps and manual aspirators. Species identification was done by a combination of morphological and molecular approaches (DNA barcoding, MALDI-TOF MS protein profiling). In engorged females, host blood was identified by three molecular techniques (RFLP, cytb sequencing and MALDI-TOF peptide mass mapping). Population structure of most abundant species was studied by cox1 haplotyping; phylogenetic analyses of ITS2 and cox1 genetic markers were used to resolve relationships of other detected species. RESULTS: In total, 793 sand flies were collected at 30 (51.7%) localities from 12 regions of Moldova. Three species were identified by an integrative morphological and molecular approach: Phlebotomus papatasi, P. perfiliewi and Phlebotomus sp. (Adlerius), the first being the most abundant and widespread, markedly anthropophilic based on bloodmeal analyses, occurring also indoors and showing low population structure with only five haplotypes of cox1 detected. Distinct morphological and molecular characters of Phlebotomus sp. (Adlerius) specimens suggest the presence of a yet undescribed species. CONCLUSIONS: Our study revealed the presence of stable sand fly populations of three species in Moldova that represent a biting nuisance as well as a potential threat of pathogen transmission and shall be further studied.

Risk Factors for Cerebral Palsy in Moldova.

Background and Objectives: This is the first study assessing risk factors for cerebral palsy (CP) among children born in Moldova. The aim of this study was to identify and describe risk factors for cerebral palsy (CP) among children born in Moldova, which is one of the low-middle income countries in Europe. Materials and Methods: We identified 351 children with CP born during 2009 and 2010 in Moldova. Detailed information on 417 children without CP served as a reference group. Logistic regression analyses were applied to the calculate crude and adjusted odds ratios (OR) for CP with 95% confidence intervals (CI) in addition to attributable fraction (AF). Results: Among children with CP (40.5% girls), 26% had spastic unilateral, 54% bilateral, 13% dyskinetic, 5% ataxic and 2% unclassified CP. Significant risk factors for CP included maternal alcohol consumption during pregnancy (OR 1.7, p = 0.002), maternal hypertension (OR 2.0, p < 0.001), children born to mothers from the rural areas (OR 1.6, p < 0.001), maternal age ≥35 years (OR 0.6, p = 0.018), maternal epilepsy (OR 4.3, p < 0.001), breech delivery (OR 3.1, p = 0.001), home births (OR 6.3, p = 0.001), umbilical cord around neck (OR 2.2, p < 0.001), AVD (OR 3.1, p < 0.001), male gender (OR 1.3, p < 0.001), SGA (OR 1.3, p = 0.027), multiple gestations (OR 1.7, p < 0.001) and hyperbilirubinemia (OR 4.5, p < 0.001). Multivariable analyses showed that the AF of CP was 64% for rural residence (OR 2.8, p = 0.002), 87% for home birth (7.6, p = 0.005), 79% for pre-labor rupture of membrane (OR 4.9, p = 0.001), 66% for breech delivery (OR 2.9, p = 0.002) and 81% for hyperbilirubinemia (OR 5.4, p < 0.001). Conclusions: A combination of factors related to the mother, the delivery and the child were risk factors for CP in Moldova, many of them possibly avoidable. Improved pregnancy and maternity care would potentially reduce the risk of CP. A national CP registry in Moldova is suggested as an opportunity to follow up on these findings.

Do catastrophic costs impact treatment outcomes in people with rifampicin-resistant tuberculosis in the Republic of Moldova?

The Republic of Moldova is among the 30 Rifampicin-Resistant and/or Multidrug-Resistant (RR/MDR) Tuberculosis (TB) high burden countries in the world. Despite free TB diagnostics and treatment, TB patients face substantial economic losses and this may impact overall treatment outcomes. We assessed if there is an association between TB-related catastrophic costs and TB treatment outcomes. We conducted a cohort study using data from patient records and a survey that quantified catastrophic costs among RR/MDR-TB affected households in the Republic of Moldova in 2016. We included adult patients (age ≥18 years) with RR/MDR-TB who had been in inpatient (intensive phase) or outpatient (continuous phase) treatment for at least 2 months. Unfavourable treatment outcome, such as failure, death or lost to follow-up, was the primary outcome variable. The definition of catastrophic TB-related costs followed the World Health Organisation (WHO) guidelines: costs due to TB ≥20% of annual household income. Log-binomial regression was used to assess association between the outcome and catastrophic TB-related costs adjusting for other socio-demographic, behavioural and clinical covariates.  In total 287 RR/MDR-TB patients (78% males, mean age 42 years) were included. Of them, 30% experienced catastrophic TB-related costs. Overall, one in five patients (21%) had unfavourable treatment outcome, such as treatment failure (5%), death (8%) or lost to follow-up (8%). The experience of catastrophic TB-related costs was not associated with unfavourable treatment outcome [adjusted relative risk (aRR)=0.88, 95% CI: 0.50-1.50]. Major factors independently associated with unfavourable TB treatment outcomes were poverty (aRR=2.07; 95% CI: 1.06-4.07), urban residence (aRR=1.99; 95% CI: 1.12-3.52) and positive HIV (Human Immunodeficiency Virus) status (aRR=2.61; 95% CI: 1.31-4.89). As a result, we failed to find an association between catastrophic costs and treatment outcomes of RR/MDR-TB patients in the Republic of Moldova. However, we found that patients from poor households and urban areas were twice more likely to achieve unfavourable TB treatment outcomes disregarding whether they experienced catastrophic costs or not. Also, TB/HIV patients and urban residents were identified as the most vulnerable groups with higher risk of unfavourable treatment outcome and TB-related costs.