Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

People first: a participatory community approach on patient-reported outcomes in tuberculosis.

Patient-reported outcomes (PROs) play a crucial role in understanding the impact of tuberculosis (TB) on both individuals and communities. Despite advances in TB treatment, conventional outcome definitions often overlook essential components of people with TB's experiences, leading to disparities in treatment understanding. The incorporation of PROs in TB scientific research can help bridge the gap between the health system and people's needs and expectations. PROs can offer valuable insights into non-observable constructs like health literacy, self-efficacy and overall wellbeing, contributing to the comprehensive assessment of diagnosis, treatment and research end-points. Participatory community approaches, such as Community-Based Participatory, emphasise the engagement and involvement of relevant stakeholders in designing interventions tailored to their needs. Key stakeholders, including healthcare professionals, researchers, clinical trial investigators, public health officials, and community health workers, TB survivors and people with TB, can play a vital role in promoting patient-centred care and engaging directly with the TB-affected community. An increased and cross-collaborative effort for the inclusion of PROs in TB research can entail their potential role in developing effective treatment regimens and promoting adherence, while maximising community engagement and improving outcomes for those affected by TB.

Mechanistic insights into the spontaneous induction of bone formation.

The grand discovery of morphogens, or "form-generating substances", revealed that tissue morphogenesis is initiated by soluble molecular signals or morphogens primarily belonging to the transforming growth factor-ß (TGF-ß) supergene family. The regenerative potential of bone rests on its extracellular matrix, which is the repository of several morphogens that tightly control cellular differentiating pathways, cellular matrix deposition and remodeling. Alluringly, the matrix also contains specific factors transferred from the heterotopic implanted bone matrices initiating "Tissue Induction", as provocatively described in Nature in 1945. Later, it was found that selected genes and gene products of the TGF-ß supergene family singly, synchronously, and synergistically mastermind the induction of bone formation. This review describes the phenomenon of the spontaneous and/or intrinsic osteoinductivity of calcium phosphate-based biomaterials and titanium' constructs without the applications of soluble osteogenetic molecular signals. The review shows the spontaneous induction of bone formation initiated by Ca++ activating stem cell differentiation and up-regulation of bone morphogenetic proteins genes. Expressed gene products are embedded into the concavities of the calcium phosphate-based substrata, initiating bone formation as a secondary response. Pure titanium's substrata do not initiate the spontaneous induction of bone formation. The induction of bone is solely dependent on acid, alkali and heat treatments to form apatite layers on the treated titanium surfaces. The induction of bone formation is achieved exclusively by apatite-based biomaterial surfaces. The hydroxyapatite, in its various forms and geometric configurations, finely tunes the induction of bone formation in heterotopic sites. Cellular differentiation by fine-tuning of the cellular molecular machinery is initiated by specific geometric modularity of the hydroxyapatite substrata that push cellular buttons that start the ripple-like cascade of "Tissue Induction", generating newly formed ossicles with bone marrow in heterotopic extraskeletal sites. The highlighted mechanistic insights into the spontaneous induction of bone formation are a research platform invocating selected molecular elements to construct the induction of bone formation.

Investigating the role of symptom valorisation in tuberculosis patient delay in urban areas in Portugal.

BACKGROUND: Diagnosis delay contributes to increased tuberculosis (TB) transmission and morbimortality. TB incidence has been decreasing in Portugal, but median patient delay (PD) has risen. Symptom valorisation may determine PD by influencing help-seeking behaviour. We aimed to analyse the association between symptom valorisation and PD, while characterising individuals who disregarded their symptoms. METHODS: A cross-sectional study was conducted among TB patients in Lisbon and Oporto in 2019 - 2021. Subjects who delayed seeking care because they did not value their symptoms or thought these would go away on their own were considered to have disregarded their symptoms. PD was categorised using a 21-day cut-off, and a 30-day cut-off for sensitivity analysis. We estimated the effect of symptom valorisation on PD through a directed acyclic graph. Then, a multivariable regression analysis characterised patients that disregarded their symptoms, adjusting for relevant variables. We fitted Poisson regression models to estimate crude and adjusted prevalence ratios (PR). RESULTS: The study included 75 patients. Median PD was 25 days (IQR 11.5-63.5), and 56.0% of participants had PD exceeding 21 days. Symptom disregard was reported by 38.7% of patients. Patients who did not value their symptoms had higher prevalence of PD exceeding 21 days compared to those who valued their symptoms [PR 1.59 (95% CI 1.05-2.42)]. The sensitivity analysis showed consistent point estimates but wider confidence intervals [PR 1.39 (95% CI 0.77-2.55)]. Being a smoker was a risk factor for symptom disregard [PR 2.35 (95% CI 1.14-4.82)], while living in Oporto [PR 0.35 (95% CI 0.16-0.75)] and having higher household incomes [PR 0.39 (95% CI 0.17-0.94)] were protective factors. CONCLUSIONS: These findings emphasise the importance of symptom valorisation in timely TB diagnosis. Patients who did not value their symptoms had longer PD, indicating a need for interventions to improve symptom recognition. Our findings also corroborate the importance of the socioeconomic determinants of health, highlighting tobacco as a risk factor both for TB and for PD.

COVID-19 in Portugal: A Pandemic Redesigned by the Media.

The news media in Portugal played an important role during the COVID-19 pandemic by providing people with important and up-to-date health information. However, the number of news reports did not always correspond to the severity of the pandemic. There was significant media attention at the beginning of the pandemic (in early 2020), but media coverage soon declined, and the Portuguese media began to report on a greater diversity of topics. The present study assessed the evolution of news reports in Portugal during the period of the COVID-19 pandemic by analysis of epidemiological data (cases, deaths, and hospitalizations) and television news lineups from the three major generalist television channels, RTP1, SIC, TVI. The study period was from March 2020 (when the first lockdown was instituted) to March 2021 (when there was the second gradual withdrawal of restrictions). Our results indicated that there was intense media coverage of COVID-19 during the first phase of the pandemic, even though epidemiological data showed there was not a severe health crisis at that time. However, the number of news stories about the pandemic soon declined, and this number was much lower during the worst period of the pandemic. Hence, the intensity of coverage of the COVID-19 pandemic in the Portuguese media provided a distorted image of the actual pandemic. All things considered, we strongly advise for the inclusion of a communication plan that would help address future health emergency crisis. All things considered, we recommend that in future health crisis there is a planned communication strategy that takes into account media relations.

Tuberculosis incidence in foreign-born people residing in European countries in 2020.

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Treatment-shortening regimens for tuberculosis: updates and future priorities.

In the past 2 years, remarkable advances have been made in shortening tuberculosis (TB) treatment. In particular, four clinical trials (Study 31/A5349, Nix-TB, ZeNix and TB-PRACTECAL) have provided evidence of the efficacy of regimens based on new and repurposed drugs: the 4-month regimen for drug-susceptible TB, and the 6-month bedaquiline-pretomanid-linezolid regimen with or without moxifloxacin for multidrug-resistant/rifampicin-resistant TB. Even if the evidence at the basis of these new regimens is compelling, several questions remain open, particularly concerning linezolid dose finding, the upsurging threat of bedaquiline-resistant Mycobacterium tuberculosis and the feasibility of applying these results to the paediatric population. Several ongoing trials may fill the remaining gaps and produce further reliable evidence to address the outstanding questions in TB treatment shortening.

FGFR2 genetic variants in women with breast cancer.

Black African populations are more genetically diverse than others, but genetic variants have been studied primarily in European populations. The present study examined the association of four single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2, associated with breast cancer in non­African populations, with breast cancer in Black, southern African women. Genomic DNA was extracted from whole blood samples of 1,001 patients with breast cancer and 1,006 controls (without breast cancer), and the rs2981582, rs35054928, rs2981578, and rs11200014 polymorphisms were analyzed using allele­specific Kompetitive allele­specific PCR™, and the χ2 or Fisher's exact tests were used to compare the genotype frequencies. There was no association between those SNPs and breast cancer in the studied cohort, although an association was identified between the C/C homozygote genotype for rs2981578 and invasive lobular carcinoma. These results show that genetic biomarkers of breast cancer risk in European populations are not necessarily associated with risk in sub­Saharan African populations. African populations are more heterogenous than other populations, and the information from this population can help focus genetic risks of cancer in this understudied population.

Building bridges: multidisciplinary teams in tuberculosis prevention and care.

People with or affected by tuberculosis (TB) experience complex social and cultural constraints that may affect treatment outcomes by impeding access to proper care or by hindering treatment adherence. Low levels of health literacy which leads to inadequate disease information; stigma, discrimination and other forms of prejudice that may result in marginalisation and ostracisation; and socioeconomic vulnerabilities that hamper one's capacity to access essential goods or increase the risk of exposure to the disease are some of the barriers highlighted. These complex hurdles are also disproportionately felt by people with or affected by TB due to gender-related inequalities that need to be properly addressed. Additionally, TB prevention and care should encompass interventions aimed at improving and promoting mental health, given that mental unhealth may further thwart treatment adherence and success. A multifaceted and multidisciplinary approach to TB is required to answer these complex barriers.

Altered microRNA expression in patients with sarcoidosis.

Background Sarcoidosis is a granulomatous multisystem disease of uncertain aetiology. The disease has major inflammatory and immune components; however, the immunopathogenesis is not well understood. Micro ribonucleic acids (microRNAs) are classes of miniature, single-stranded, non-coding RNAs. Their key recognised role includes mediating the silencing of target genes post-transcriptionally. Recently, the role of miRNAs has gained interest in numerous disorders, suggested as being involved in pathogenesis of those diseases and acting as disease markers. Very little is known about the role of miRNAs in sarcoidosis, with nothing known regarding miRNAs in South African patients. The main objective, therefore, was to investigate the serum expression of approximately 800 miRNAs in patients with sarcoidosis compared with race-, age- and gender-matched healthy controls. Methods A total of six patients and six matched controls participated in this study. Whole blood samples were collected in EDTA tubes, processed and the plasma retained. RNA was extracted from the stored plasma samples using the QIAGEN miRNeasy Mini Kit® and concentrated using a salt-ethanol precipitation. The extracted miRNA was profiled using an nCounter® miRNA human v3 expression assay and data analysed using the nSolver™ Analysis Software. Results After excluding one sample/control pair because of cellular RNA contamination, the remaining five patient and five matched control samples were analysed, and 145 miRNAs were found to be potentially differentially expressed. On applying a Bonferroni correction, the only miRNA that was significantly different was miRNA let-7a-5p, which was significantly overexpressed (141-fold change; p<0.0003) in patients compared with controls. Conclusion This is the first miRNA report of differentially expressed miRNAs in the serum of patients with sarcoidosis and matched healthy controls in South Africa. The results obtained suggest that miRNAs may play a role in sarcoidosis pathogenesis. Whether these molecules have diagnostic or prognostic implications, needs future studies recruiting larger patient cohorts.

Anxiety and Depression Symptoms During the COVID-19 Pandemic: A Cluster Analysis of Individuals Living in Portugal.

INTRODUCTION: The COVID-19 pandemic is an illustration of how a physical illness can damage people's minds. In this regard, the goal of this study was to see how different sociodemographic and behavioral factors were linked to anxiety and depression symptoms in a group of individuals living in Portugal. METHODS: Between November 2020 and February 2021, a cross-sectional, snowball online study was conducted. The study's target population was adults over the age of 18, residents of the country. For the statistical analysis, the clustering technique - K-means algorithm was applied. The chi-squared test was used to determine the relationships between clusters and sociodemographic and behavioral characteristics. Statistical analyses were conducted in R language, with a significance level of 0.05. A total of 453 participants were included. RESULTS: The majority were female (69.8%), under the age of 40 (60.8%), with a higher education degree (75.3%), and not married (54.4%). Furthermore, the majority were from the country's north region (66%). Cluster 1 (n = 194) was characterized by low or nonexistent levels of anxiety and depression symptoms, which means normal; cluster 2 by severe symptoms (n = 82), meaning case; and cluster 3 by mild symptoms (n = 177), which means borderline. Younger participants (p-value 0.024), female (p-value 0.041), with drinking habits (p-value 0.002), food insecurity (p-value < 0.001), food affordability exacerbation (p-value < 0.001), comorbidity (p-value < 0.001), use of anxiolytics (p-value < 0.001), insufficient household income (p-value 0.017) and income change (p-value < 0.001) were significantly associated with the anxiety-depression clusters. From the three clusters, cluster 2 was mainly represented by younger participants, with more persons stating that their household income was insufficient and that their income has changed as a result of COVID-19 and that they had the highest probability of food insecurity. CONCLUSION: The impacts of a crisis on mental health extend longer than the event itself. We were able to observe that younger women with insufficient household income who suffered a change in income due to COVID-19 and were classified as food insecure presented higher levels of anxiety and depression symptoms. These results highlight the presence of a social gradient where we saw that people who were less advantaged in terms of socioeconomic position presented worse mental health outcomes, stressing, in this sense, the need to bring the best public health responses for these specific groups of the population.

Rolling out new anti-tuberculosis drugs without diagnostic capacity.

Deaths from tuberculosis (TB) reached over 1.6 million in 2021 with 10.6 million people becoming ill. Multidrug-resistant TB, defined as the Mycobacterium tuberculosis organism having resistance to at least isoniazid and rifampicin, represented 3.9% of new TB cases and 18% of previously treated cases. While new drug regimens continue to be developed and introduced to improve treatment of drug-resistant forms of TB, diagnostic capability to identify drug resistance lags woefully behind. While significant mortality benefits exist for these newer drug regimens, implementing them without proper drug resistance diagnostic capacity could lead to development of more drug resistances and exhaust these new therapeutic tools. Moving forward, the roll-out of new TB drugs and regimens must be paired with implementation of diagnostics to ensure judicious use of resources and the best chance for improving TB worldwide.

PAM50 intrinsic subtypes, risk of recurrence score and breast cancer survival in HIV-positive and HIV-negative patients-a South African cohort study.

PURPOSE: Treatment decision making for patients with breast cancer increasingly depends on analysis of markers or systems for estimating risk of breast cancer recurrence. Breast cancer intrinsic subtypes and risk of recurrence (ROR) scores have been found to be valuable in predicting survival and determining optimal treatment for individual patients. We studied the association of breast cancer survival with the PAM50 gene expression assay in HIV-positive and HIV-negative patients. METHOD: RNA was extracted from formalin-fixed paraffin-embedded specimens of histologically confirmed invasive carcinoma and was purified using the AllPrep® DNA/RNA FFPE kit, Qiagen (Hilden, Germany). The NanoString RUO PAM50 algorithm was used to determine the molecular subtype and the risk of recurrence score of each sample. The overall and disease-free survival were determined with comparison made among HIV-positive and -negative patients. We then generated Kaplan-Meier survival curves, calculated p-values and estimated hazard ratios and their 95% confidence intervals using Cox regression models. RESULTS: Of the 384 RNA samples analysed, 98.4% met the required RNA quality standard and the specified QC threshold for the test. Luminal B was the most common PAM50 intrinsic subtype and 82.1% of patients were at high risk for disease recurrence based on ROR score. HIV infection, PAM50-based HER2-enriched and basal-like intrinsic subtypes, and high ROR were associated with poor overall and disease-free survival. HIV-positive patients with luminal A & B subtypes had significantly worse survival outcomes than HIV-negative luminal patents. CONCLUSION: Aggressive tumour biology was common in our cohort. HIV infection, PAM50 HER2-enriched,basal-like intrinsic subtypes and high ROR score were associated with poor overall and disease-free survival. HIV infection impacted survival in patients with luminal subtypes only.

Tuberculosis: current challenges and beyond.

Despite being a preventable and curable disease, tuberculosis (TB) is still a major global health threat and the second leading cause of death due to an infectious agent worldwide. All the efforts invested to end TB have resulted overall in rather slow decreases in TB incidence and mortality rates, which have been further negatively affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. While the majority of targets of the End TB Strategy remain off track, and we have not yet overcome the disruptions caused by the COVID-19 pandemic, recent conflicts such as the ongoing war in Ukraine are threatening the decrease of the burden of TB even further. To get back on track and get closer to ending TB, we need urgent, global, well-structured and committed multi-sectoral actions that go beyond national and global TB programmes with the support of deep investments in research and facilitation of equitable and rapid implementation of innovation worldwide.

Geographic patterns and hotspots of pediatric tuberculosis: the role of socioeconomic determinants.

OBJECTIVE: Children are an important demographic group for understanding overall tuberculosis epidemiology, and monitoring of childhood tuberculosis is essential for appropriate prevention. The present study sought to characterize the spatial distribution of childhood tuberculosis notification rates in continental Portugal; identify high-risk areas; and evaluate the association between childhood tuberculosis notification rates and socioeconomic deprivation. METHODS: Using hierarchical Bayesian spatial models, we analyzed the geographic distribution of pediatric tuberculosis notification rates across 278 municipalities between 2016 and 2020 and determined high-risk and low-risk areas. We used the Portuguese version of the European Deprivation Index to estimate the association between childhood tuberculosis and area-level socioeconomic deprivation. RESULTS: Notification rates ranged from 1.8 to 13.15 per 100,000 children under 5 years of age. We identified seven high-risk areas, the relative risk of which was significantly above the study area average. All seven high-risk areas were located in the metropolitan area of Porto or Lisbon. There was a significant relationship between socioeconomic deprivation and pediatric tuberculosis notification rates (relative risk = 1.16; Bayesian credible interval, 1.05-1.29). CONCLUSIONS: Identified high-risk and socioeconomically deprived areas should constitute target areas for tuberculosis control, and these data should be integrated with other risk factors to define more precise criteria for BCG vaccination.

Tuberculosis and COVID-19 Related Stigma: Portuguese Patients Experiences.

BACKGROUND: Tuberculosis (TB)-related stigma has been well-documented. Since the emergence of the coronavirus disease 2019 (COVID-19), different organizations have been alerted to the fact that stigma could arise again. Due to stigma's negative effects, this qualitative study aimed to explore the stigma felt by patients by evaluating the following: COVID-19 stigma and its temporal progression through the pandemic; stigma perceived by different patients with TB before and during COVID-19 pandemic; and difference perceived by individuals who contracted both diseases. METHODS: A semi-structured interview was developed according to the available literature on the theme. It was performed individually in 2022 upon receiving signed informed consent. Participants were recruited with a purposive sampling approach by searching medical records. Those who currently or previously had pulmonary TB and/ or COVID-19 were included. Data were subjected to thematic analysis. RESULTS: Nine patients were interviewed, including six (66.7%) females. The median age of patients was 51±14.7 years. Four participants (44.4%) had completed high school and four (44.4%) were never smokers. Three had both TB and COVID-19. Four only had TB and two only had COVID-19. Interviews identified eight main themes: knowledge and beliefs, with several misconceptions identified; attitudes towards the disease, varying from social support to exclusion; knowledge and education, assumed as of extreme importance; internalized stigma, with self-rejection; experienced stigma, with discrimination episodes; anticipated stigma, modifying actions for avoiding stigma; perceived stigma, with judgment by others prevailed; and temporal evolution of stigma. CONCLUSION: Individuals expressed strong stigma for both diseases. De-stigmatization of respiratory infectious diseases is crucial for limiting stigma's negative impact.

Discordance between PAM50 intrinsic subtyping and immunohistochemistry in South African women with breast cancer.

PURPOSE: Breast cancer is a heterogeneous disease with different gene expression profiles, treatment options and outcomes. In South Africa, tumors are classified using immunohistochemistry. In high-income countries multiparameter genomic assays are being utilized with implications for tumor classification and treatment. METHODS: In a cohort of 378 breast cancer patients from the SABCHO study, we investigated the concordance between tumor samples classified by IHC and the PAM50 gene assay. RESULTS: IHC classified patients as ER-positive (77.5%), PR-positive (70.6%), and HER2-positive (32.3%). These results, together with Ki67, were used as surrogates for intrinsic subtyping, and showed 6.9% IHC-A-clinical, 72.7% IHC-B-clinical, 5.3% IHC-HER2-clinical and 15.1% triple negative cancer (TNC). Typing using the PAM50 gave 19.3% luminal-A, 32.5% luminal-B, 23.5% HER2-enriched and 24.6% basal-like. The basal-like and TNC had the highest concordance, while the luminal-A and IHC-A group had the lowest concordance. By altering the cutoff for Ki67, and realigning the HER2/ER/PR-positive patients to IHC-HER2, we improved concordance with the intrinsic subtypes. CONCLUSION: We suggest that the Ki67 be changed to a cutoff of 20-25% in our population to better reflect the luminal subtype classifications. This change would inform treatment options for breast cancer patients in settings where genomic assays are unaffordable.