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Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

The European Prospective Investigation into Cancer and Nutrition (EPIC) is a multicentre prospective study conducted in 23 centres in 10 European countries. Here we review the findings from EPIC on the relationship between diet-related exposures and incidence or mortality from the four most frequent cancers in the European population: colorectal, breast, lung, and prostate cancer. We conducted a systematic review following PRISMA guidelines and identified 110 high-quality studies based on the EPIC cohort. Fruit and vegetable consumption had a protective effect against colorectal, breast, and lung cancer, whereas only fruit had a protective effect against prostate cancer. A higher consumption of fish and lower consumption of red and processed meat were related with a lower risk of colorectal cancer; and higher consumption of fatty fish with lower risk of breast cancer. Calcium and yogurt intake were found to protect against colorectal and prostate cancer. Alcohol consumption increased the risk for colorectal and breast cancer. Finally, adherence to the Mediterranean diet emerged as a protective factor for colorectal and breast cancer. The EPIC study results are in agreement with the latest evidence from leading authorities on cancer prevention and help to inform public prevention policies and strategies.

Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the gene, suggesting its implication in the association between depression and obesity. To confirm these findings by investigating the polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis. The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT. In the replication cohorts, we observed a significant interaction between , BMI and depression with fixed effects meta-analysis (β = 0.12, = 2.7 × 10 ) and with the Han/Eskin random effects method ( = 1.4 × 10 ) but not with traditional random effects (β = 0.1, = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, = 0.027) being highly significant based on the Han/Eskin model ( = 6.9 × 10 ). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of This meta-analysis provides additional support for a significant interaction between , depression and BMI, indicating that depression increases the effect of on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

Longer time intervals to diagnosis and treatment are associated with worse survival for various types of cancer. The patient, diagnostic, and treatment intervals are considered core indicators for early diagnosis and treatment. This review estimated the median duration of these intervals for various types of cancer and compared it across high- and lower-income countries. We conducted a systematic review with meta-analysis (prospectively registered protocol CRD42020200752). Three databases (MEDLINE, Embase, and Web of Science) and information sources including grey literature (Google Scholar, OpenGrey, EThOS, ProQuest Dissertations & Theses) were searched. Eligible articles were published during 2009 to 2022 and reported the duration of the following intervals in adult patients diagnosed with primary symptomatic cancer: patient interval (from the onset of symptoms to first presentation to a healthcare professional), diagnostic interval (from first presentation to diagnosis), and treatment interval (from diagnosis to treatment start). Interval duration was recorded in days and study medians were combined in a pooled estimate with 95% confidence intervals (CIs). The methodological quality of studies was assessed using the Aarhus checklist. A total of 410 articles representing 68 countries and reporting on 5,537,594 patients were included. The majority of articles reported data from high-income countries (n = 294, 72%), with 116 (28%) reporting data from lower-income countries. Pooled meta-analytic estimates were possible for 38 types of cancer. The majority of studies were conducted on patients with breast, lung, colorectal, and head and neck cancer. In studies from high-income countries, pooled median patient intervals generally did not exceed a month for most cancers. However, in studies from lower-income countries, patient intervals were consistently 1.5 to 4 times longer for almost all cancer sites. The majority of data on the diagnostic and treatment intervals came from high-income countries. Across both high- and lower-income countries, the longest diagnostic intervals were observed for hematological (71 days [95% CI 52 to 85], e.g., myelomas (83 days [47 to 145])), genitourinary (58 days [50 to 77], e.g., prostate (85 days [57 to 112])), and digestive/gastrointestinal (57 days [45 to 67], e.g., colorectal (63 days [48 to 78])) cancers. Similarly, the longest treatment intervals were observed for genitourinary (57 days [45 to 66], e.g., prostate (75 days [61 to 87])) and gynecological (46 days [38 to 54], e.g., cervical (69 days [45 to 108]) cancers. In studies from high-income countries, the implementation of cancer-directed policies was associated with shorter patient and diagnostic intervals for several cancers. This review included a large number of studies conducted worldwide but is limited by survivor bias and the inherent complexity and many possible biases in the measurement of time points and intervals in the cancer treatment pathway. In addition, the subintervals that compose the diagnostic interval (e.g., primary care interval, referral to diagnosis interval) were not considered. These results identify the cancers where diagnosis and treatment initiation may take the longest and reveal the extent of global disparities in early diagnosis and treatment. Efforts should be made to reduce help-seeking times for cancer symptoms in lower-income countries. Estimates for the diagnostic and treatment intervals came mostly from high-income countries that have powerful health information systems in place to record such information.

Major depressive disorder (MDD) is a serious, and common psychiatric disorder worldwide. By the year 2020, MDD will be the second cause of disability in the world. The GranadΣp study is the first, to the best of our knowledge, epidemiological study of mental disorders carried out in Andalusia (South Spain), being one of its main objectives to identify genetic and environmental risk factors for MDD and other major psychiatric disorders. In this study, we focused on the possible association of 91 candidate single nucleotide polymorphisms (SNPs) with MDD. A total of 711 community-based individuals participated in the GranadΣp study. All individuals were extensively assessed for clinical, psychological, sociodemographic, life style, and other environmental variables. A biological sample was also collected for subsequent genetic analyses in 91 candidate SNPs for MDD. DSM-IV diagnosis of MDD was used as the outcome variable. Logistic regression analysis assuming an additive genetic model was performed to test the association between MDD and the genetic data. The experiment-wide significance threshold adjusted with the SNP spectral decomposition method provided a maximum P-value (8×10(-3)) required to identify an association. Haplotype analyses were also performed. One SNP (rs623580) located in the tryptophan hydroxylase 1 gene (TPH1; chromosome 11), one intergenic variant (rs9526236) upstream of the 5-hydroxytryptamine receptor 2A gene (HTR2A; chromosome 13), and five polymorphisms (rs17689966, rs173365, rs7209436, rs110402, and rs242924) located in the corticotropin-releasing hormone receptor 1 gene (CRHR1; chromosome 17), all showed suggestive trends for association with MDD (P<0.05). Within CRHR1 gene, the TATGA haplotype combination was found to increase significantly the risk for MDD with an odds ratio =1.68 (95% CI: 1.16-2.42, P=0.006). Although limited, perhaps due to insufficient sample size power, our results seem to support the notion that the hypothalamic-pituitary-adrenal and serotonergic systems are likely to be involved in the genetic susceptibility for MDD. Future studies, including larger samples, should be addressed for further validation and replication of the present findings.

Background Longer time intervals to diagnosis and treatment are associated with worse survival for various types of cancer. The patient, diagnostic, and treatment intervals are considered core indicators for early diagnosis and treatment. This review estimated the median duration of these intervals for various types of cancer and compared it across high- and lower-income countries. Methods and findings We conducted a systematic review with meta-analysis (prospectively registered protocol CRD42020200752). Three databases (MEDLINE, Embase, and Web of Science) and information sources including grey literature (Google Scholar, OpenGrey, EThOS, ProQuest Dissertations & Theses) were searched. Eligible articles were published during 2009 to 2022 and reported the duration of the following intervals in adult patients diagnosed with primary symptomatic cancer: patient interval (from the onset of symptoms to first presentation to a healthcare professional), diagnostic interval (from first presentation to diagnosis), and treatment interval (from diagnosis to treatment start). Interval duration was recorded in days and study medians were combined in a pooled estimate with 95% confidence intervals (CIs). The methodological quality of studies was assessed using the Aarhus checklist. A total of 410 articles representing 68 countries and reporting on 5,537,594 patients were included. The majority of articles reported data from high-income countries (n = 294, 72%), with 116 (28%) reporting data from lower-income countries. Pooled meta-analytic estimates were possible for 38 types of cancer. The majority of studies were conducted on patients with breast, lung, colorectal, and head and neck cancer. In studies from high-income countries, pooled median patient intervals generally did not exceed a month for most cancers. However, in studies from lower-income countries, patient intervals were consistently 1.5 to 4 times longer for almost all cancer sites. The majority of data on the diagnostic and treatment intervals came from high-income countries. Across both high- and lower-income countries, the longest diagnostic intervals were observed for hematological (71 days [95% CI 52 to 85], e.g., myelomas (83 days [47 to 145])), genitourinary (58 days [50 to 77], e.g., prostate (85 days [57 to 112])), and digestive/gastrointestinal (57 days [45 to 67], e.g., colorectal (63 days [48 to 78])) cancers. Similarly, the longest treatment intervals were observed for genitourinary (57 days [45 to 66], e.g., prostate (75 days [61 to 87])) and gynecological (46 days [38 to 54], e.g., cervical (69 days [45 to 108]) cancers. In studies from high-income countries, the implementation of cancer-directed policies was associated with shorter patient and diagnostic intervals for several cancers. This review included a large number of studies conducted worldwide but is limited by survivor bias and the inherent complexity and many possible biases in the measurement of time points and intervals in the cancer treatment pathway. In addition, the subintervals that compose the diagnostic interval (e.g., primary care interval, referral to diagnosis interval) were not considered. Conclusions These results identify the cancers where diagnosis and treatment initiation may take the longest and reveal the extent of global disparities in early diagnosis and treatment. Efforts should be made to reduce help-seeking times for cancer symptoms in lower-income countries. Estimates for the diagnostic and treatment intervals came mostly from high-income countries that have powerful health information systems in place to record such information. Dafina Petrova and colleagues review the median duration of patient, diagnostic, and treatment intervals in adult patients with various types of cancer across high and lower-income countries. Author summary Why was this study done? Cancer is a leading cause of death globally and timely diagnosis and treatment are considered essential for improving cancer outcomes. Three main intervals describe the time patients spend in the pathway to treatment of cancer: the patient interval (from symptom start to first presentation to a healthcare professional), the diagnostic interval (from first presentation to diagnosis), and the treatment interval (from diagnosis to the start of treatment). The duration of these intervals could vary greatly depending on the type of cancer and the socioeconomic level of the country. What did the researchers do and find? We conducted a systematic review with meta-analysis of the duration of the patient, diagnostic, and treatment intervals in adult patients with diverse types of cancer. We included 410 articles representing 68 countries and reporting on 5,537,594 patients; the majority of articles reported data from high-income countries (72%), with only 28% reporting data from lower-income countries. Patient intervals in studies from lower-income countries were consistently 1.5 to 4 times longer that patient intervals from studies from high-income countries for almost all cancer sites. The majority of data on the diagnostic and treatment intervals came from high-income countries, and there was large variation according to the type of cancer. What do these findings mean? These results identify the cancers where diagnosis and treatment initiation may take the longest and reveal important global disparities in early diagnosis and treatment. Efforts should be made to reduce help-seeking times for cancer symptoms in lower-income countries and conduct more research in lower-income contexts, especially on the intervals to diagnosis and treatment. This review summarized a large number of studies conducted worldwide but is limited by biases that could arise due to patient selection (e.g., only patients who survived a certain amount of time) and the difficulty of accurately measuring time intervals for past events.

Introduction/BackgroundEndometrial cancer is a common malignancy affecting women worldwide, and in some cases, surgical resection may be challenging due to its advanced stage. Historically, these cases were managed palliatively but, even if there is still a paucity of literature about this topic, chemoradiotherapy has emerged as an effective treatment option lately. The aim of this case series is to provide clinicians and researchers with a comprehensive understanding of the role of this approach in the management of unresectable endometrial cancer.MethodologyWe retrospectively reviewed 5 patients diagnosed with FIGO stage IIIB-VA endometrial cancer in our institution, treated between 2020 and 2022. They completed treatment with Intensity-Modulated Radiation Therapy (IMRT) (dose 48.6 Gy in 1.8 Gy fractions given on 5 days per week) given with concurrent chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). They were then reevaluated with MRI and stratified to receive definite high dose rate (HDR) brachytherapy or surgery. Progression-free survival (PFS), local control (LC), overall survival (OS), and grade ≥3 toxicities were reported.ResultsMedian age was 51 (range: 42–78) with median follow-up being 11 months (range: 5–24). Four patients were downstaged and received surgery followed by intracavitary HDR brachytherapy, while 1 of them did not show any radiological response and received intrauterine HDR brachytherapy. The actuarial 1-year LC, PFS and OS were 90%, 80%, and 100%. There were no acute grade ≥3 toxicities. There were 2 late grade ≥3 toxicities due to urinary toxicity and gastrointestinal side effects.ConclusionThe combination of radiotherapy and chemotherapy is a safe treatment option for women with locally extensive unresectable endometrial cancer, with favorable local control and limited toxicity in 5 patients treated with this approach. Further studies are needed to optimize this treatment modality.DisclosuresThe authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.

Introduction/BackgroundPrimary tumors of the vulva and vagina are very rare and represent only a small percentage of all gynecological tumors. In both cases, the first consultation is usually late, which usually implies diagnoses in advanced stages that limit the surgical approach.Our objective was to analyse the local control and survival after radiochemotherapy and brachytherapy in locally advanced cancer of the vulva and vagina in a series of cases treated at our centre.MethodologyWe retrospectively reviewed 7 patients diagnosed with FIGO stage IVA vulvar cancer (5) and vaginal cancer (2) (figure 1), median age 58 years old, treated in our centre between 2020 and 2022. They completed treatment with Intensity-Modulated Radiation Therapy (IMRT) (dose 45 to 60 Gy, conventional fractionation) and concurrent chemotherapy, and 5 of them received complementary HDR intracavitary brachytherapy to achieve EQD2 85–90 Gy.ResultsThe 15-month overall survival was 85% (1 death cancer related), with locorregional and distant control in 6 patients. Only one patient with vulvar cancer had to stop treatment due to grade 3 (CTCAE v.5) radiation dermatitis, which was controlled in 2 weeks. After 24 months of follow-up, only two of them experienced significative vaginal stenosis.Abstract #194 Figure 1Before and after treatment with radical radio-chemotherapy of vaginal cancer in a 37-year-old patient which resulted in a complete response.[Figure omitted. See PDF]ConclusionRadical radiochemotherapy is an effective and safe treatment with high local control in patients with locally advanced primary vulvar and vaginal cancer.DisclosuresThe authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.