Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype-genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions-MLRB2 in α1(I) and MLBR 3 in α2(I)-could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Chronic toxicity and long-term outcome in intraoperative electron radiotherapy as boost followed by whole-breast irradiation.

PURPOSE: The administration of a dose boost to the tumor bed after breast-conserving surgery has proven to reduce local recurrence. Intra-operative electron radiotherapy (IOERT) offers an alternative method to deliver a boost with several advantages, such as direct visualization of the tumor bed, less inter- and intrafraction motion and a reduction in the number of medical appointments. The objective of our study is to assess chronic toxicity and long-term outcome for our patients after IOERT boost. MATERIAL AND METHODS: Forty-six patients treated at our institution between July 2013 and June 2020 with IOERT boost during Breast-Conserving Surgery and consecutive whole breast irradiation were prospectively analyzed. A 10-12 Gy boost was prescribed to 42 patients and 4 patients received a 20 Gy boost. An analysis for overall survival, local relapse and distant progression was performed. Acute and chronic toxicity was assessed by CTCAE 4.0. RESULTS: The median age was 64.5 years (40-90). The median follow-up was 62 months (4-86). We had no local recurrences but 2 patients (4.3%) presented a distant recurrence. Mean pathological tumor size was 16 mm (6-52). 84.8% (39) of the patients had invasive ductal carcinoma. 52.2% (24) presented histological grade II. 52.2% (24) were Luminal A like, 21.7% (10) Luminal B like, 13% (6) HER2 positive, 13% (6) triple negative. No Grade 3-4 chronic toxicity was observed. Grade 1-2 fibrosis was evidenced in 13% (6) of the patients, 4.3% (2) patients presented fat necrosis, 6.5% (3) presented seroma, 4.3% (2) had localized pain, 2.2% (1) presented localized hematoma and 2.2% (1) presented localized edema. CONCLUSIONS: IOERT boost in breast cancer treatment during BCS is a safe option with low chronic toxicity. The recurrence rates are comparable to published data and emphasize that IOERT as boost is an effective treatment.

Role of boost radiotherapy for local control of pure ductal carcinoma in situ after breast-conserving surgery: a multicenter, retrospective study of 622 patients.

PURPOSE: To evaluate the effect of boost radiotherapy on ipsilateral breast tumor recurrence (IBTR) for ductal carcinoma in situ (DCIS) after breast-conserving surgery and whole breast radiotherapy (WBRT) with or without boost. METHODS AND MATERIALS: Retrospective, multicentre study of 622 patients (624 tumors) diagnosed with pure DCIS from 1993-2011. RESULTS: Most tumors (377/624; 60.4%) received a boost. At a median follow-up of 8.8 years, IBTR occurred in 64 cases (10.3%). A higher percentage of patients with risk factors for IBTR received a boost (p < 0.05). Boost was not associated with lower rates of IBTR than WBRT alone (HR 0.75, 95% CI 0.42-1.35). On the univariate analyses, IBTR was significantly associated with tumor size (11-20 mm, HR 2.32, 95% CI 1.27-4.24; and > 20 mm, HR 2.10, 95% CI 1.14-3.88), re-excision (HR 1.76, 95% CI 1.04-2.96), and tamoxifen (HR 2.03, 95% CI 1.12-3.70). Boost dose > 16 Gy had a protective effect (HR 0.39, 95% CI 0.187-0.824). Multivariate analyses confirmed the independent associations between IBTR and 11-20 mm (p = 0.02) and > 20 mm (p = 0.009) tumours, and re-excision (p = 0.006). On the margin-stratified multivariate analysis, tamoxifen was a poor prognostic factor in the close/positive margin subgroup (HR 4.28 95% CI 1.23-14.88), while the highest boost dose ( > 16 Gy) had a significant positive effect (HR 0.34, 95% CI 0.13-0.86) in the negative margin subgroup. CONCLUSIONS: Radiotherapy boost did not improve the risk of IBTR. Boost radiotherapy was more common in patients with high-risk disease. Tumor size and re-excision were significant independent prognostic factors.

New vaccine adoption: qualitative study of national decision-making processes in seven low- and middle-income countries.

As more new and improved vaccines become available, decisions on which to adopt into routine programmes become more frequent and complex. This qualitative study aimed to explore processes of national decision-making around new vaccine adoption and to understand the factors affecting these decisions. Ninety-five key informant interviews were conducted in seven low- and middle-income countries: Bangladesh, Cameroon, Ethiopia, Guatemala, Kenya, Mali and South Africa. Framework analysis was used to explore issues both within and between countries. The underlying driver for adoption decisions in GAVI-eligible countries was the desire to seize GAVI windows of opportunity for funding. By contrast, in South Africa and Guatemala, non-GAVI-eligible countries, the decision-making process was more rooted in internal and political dynamics. Decisions to adopt new vaccines are, by nature, political. The main drivers influencing decisions were the availability of funding, political prioritization of vaccination or the vaccine-preventable disease and the burden of disease. Other factors, such as financial sustainability and feasibility of introduction, were not as influential. Although GAVI procedures have established more formality in decision-making, they did not always result in consideration of all relevant factors. As familiarity with GAVI procedures increased, questioning by decision-makers about whether a country should apply for funding appeared to have diminished. This is one of the first studies to empirically investigate national processes of new vaccine adoption decision-making using rigorous methods. Our findings show that previous decision-making frameworks (developed to guide or study national decision-making) bore little resemblance to real-life decisions, which were dominated by domestic politics. Understanding the realities of vaccine policy decision-making is critical for developing strategies to encourage improved evidence-informed decision-making about new vaccine adoptions. The potential for international initiatives to encourage evidence-informed decision-making should be realised, not assumed.

Impact of measles elimination activities on immunization services and health systems: findings from six countries.

BACKGROUND: One of the key concerns in determining the appropriateness of establishing a measles eradication goal is its potential impact on routine immunization services and the overall health system. The objective of this study was to evaluate the impact of accelerated measles elimination activities (AMEAs) on immunization services and health systems in 6 countries: Bangladesh, Brazil, Cameroon, Ethiopia, Tajikistan, and Vietnam. METHODS: Primary data were collected from key informant interviews and staff profiling surveys. Secondary data were collected from policy documents, studies, and reports. Data analysis used qualitative approaches. RESULTS: This study found that the impact of AMEAs varied, with positive and negative implications in specific immunization and health system functions. On balance, the impacts on immunization services were largely positive in Bangladesh, Brazil, Tajikistan, and Vietnam, while negative impacts were more significant in Cameroon and Ethiopia. CONCLUSIONS: We conclude that while weaker health systems may not be able to benefit sufficiently from AMEAs, in more developed health systems, disruptions to health service delivery are unlikely to occur. Opportunities to strengthen the routine immunization service and health system should be actively sought to address system bottlenecks in order to incur benefits to eradication program itself as well as other health priorities.

High dose cocaine use in Bolivia and Peru.

Drug-producing countries such as the Andean countries of South America where cocaine is manufactured are confronted by special difficulties associated with the widespread availability of drugs. There have been few detailed reports of patterns of use in relation to the type and severity of cocaine dependence problems within those countries. The present study looks at the patterns of cocaine use in relation to severity of dependence among a clinical sample of South American cocaine users. Information about patterns of cocaine use and severity of dependence was collected from a sample of 68 drug users who were receiving treatment for cocaine problems at treatment centres in Bolivia and Peru. Levels of cocaine consumption were extremely high. The mean daily dose was 16.4 grams. The majority of the users (87 per cent) smoked cocaine in the form of pasta, pitillo or basuco. More than half of the sample reported using cocaine at least 20 times a day. Severity-of-dependence scale scores were high and these are consistent with the frequent and compulsive pattern of use reported within the sample. It is suggested that the more severe cocaine problems reported in South America compared to some western countries may be due to the substantial differences in the amounts of cocaine which are typically ingested. In the Bolivian sample most of the users were taking cocaine in amounts which greatly exceed those usually seen in western countries.