Reversión de sobrepeso y obesidad en población infantil de Vilafranca del Penedès: Programa ACTIVA’T (2012)

Objective

To assess a 6-month nutritional and physical activity intervention program on the nutritional status of overweight or obese and not very active 8-14 years old children by means of a controlled pre-post design (ACTIVA’T program).

Comprehensive Validation Study of Quality-of-Life Questionnaire Using Objective Clinical Measures: Breast Cancer Treatment Outcome Scale (BCTOS), Brazilian Portuguese Version

Introduction

When evaluating a quality-of-life questionnaire (QLQ), many validation studies do not correlate quality-of-life scores with objective measurements of complications associated with treatment.

Comparative Effectiveness of Bladder-preserving Tri-modality Therapy Versus Radical Cystectomy for Muscle-invasive Bladder Cancer

Introduction

There are limited randomized data comparing radical cystectomy (RC) with bladder-sparing tri-modality therapy (TMT) in the treatment of muscle-invasive bladder cancer (MIBC). Both strategies are thought to have similar survival outcomes with different morbidity profiles. We compare the effectiveness of TMT and RC using decision-analytic modeling and the endpoint of quality-adjusted life years (QALYs).

Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials

BackgroundAt ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses.MethodsParticipants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25.ResultsIn the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.ConclusionsVariation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT02417064","term_id":"NCT02417064"}}NCT02417064 and {"type":"clinical-trial","attrs":{"text":"NCT02418585","term_id":"NCT02418585"}}NCT02418585; www.clinicaltrials.gov     

Sex bias of females in survival from cancer and infections. Is X the answer?

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.Subject terms: Cancer epigenetics, Oncology

One of the striking features of the coronavirus disease 2019 (COVID-19) outbreak has been the higher death rates in men even though the infection rates seem similar between men and women.¹ Similar findings were reported from Wuhan where men had 2.4 times the death rate of women² and in New York where press releases stated twice the death rate of men compared with women.³ Although men had higher rates of comorbidities, these differences were not considered sufficient to explain the higher death rates and other explanations have been sort. Women are considered to have stronger immune responses against infective diseases and a higher rate of autoimmune diseases, so this has questioned whether the lower death rate may have an immune basis.A sex bias is not only seen in infections, but also in cancers where a strong sex bias in survival from cancer is well documented.^4,5 For example, women in Australia have approximately half the death rates from melanoma as males.⁶ A number of explanations have been proposed to account for these major differences in melanoma, such as higher sun exposure in males⁷ and higher mutation rates⁸ in melanoma from males. When stringent statistical analyses are carried out, however, female sex remains as the major contributor to longer survival.⁴Melanoma is not the only cancer to show improved survival in females and previous researchers have asked whether this may be due to differences in the sex chromosomes between male and females. In a mammoth study, Dunford and colleagues examined information in The Cancer Genome Atlas (TCGA) from 21 different tumour types from 4100 cancers.⁵ They found that 6 out of 783 X chromosome genes had loss-of-function mutations with tumour-suppressive function in males but not in females. There were no similar differences in 18,055 non-X autosomal genes. Importantly, four of the six genes were known epigenetic regulators, such as KDM6A (lysine-specific demethylase 6A), KDM5C (lysine-specific demethylase 5C), ATRX (Alpha thalassaemia/mental retardation syndrome X-linked) and DDX3X (DEAD-box helicase 3 X-linked).⁵These findings point to important differences in X chromosomes between the sexes. The Y chromosome codes mainly for genes that determine male sex, but X chromosomes are quite large and code for >800 genes many of which are involved in immune responses.⁹ To equalise the number of genes between the sexes, one of the X chromosomes in females undergoes inactivation (Xi) of its genes.¹⁰ The silencing process is, however, not perfect and between 10 and 20% of the genes on the X may be expressed in females depending on the tissue involved. It is probably of significance that failure to silence genes may be particularly high in activated lymphocytes.¹¹ As a result of this phenomenon, females have double expression of many genes involved in immune responses compared with males. Biologists have speculated that this is an evolutionary mechanism to protect the species by enhancing immune responses in females against harmful infections.Analysis of data in the TCGA on 458 melanoma patients revealed that KDM6A expression was strongly related to improved survival from melanoma in female patients. ATRX had prognostic significance in both sexes. Analysis of another series of 678 patients with earlier melanoma referred to as the Leeds Melanoma Cohort confirmed the association with KDM6A expression and also identified KDM5C and DDX3X as being related to improved survival.¹² Immune responses are known to be critical in survival from melanoma and the TCGA analysis allowed us to link high KDM6A to components of the immune system considered important in killing of melanoma. This was particularly so in the production of interferon γ in female patients which is a key cytokine needed by the immune system to kill cancer cells. Gene set analysis also showed downregulation of Myc and other oncogenic pathways that may have contributed to the improvement in survival.¹²These data add to a number of studies implicating KDM6A in immune responses against viral infections and in autoimmune diseases.¹³ At a molecular level, KDM6A is known to have an opposing role to EZH2 (enhancer of Zeste homologue 2) in the PRC2 complex in methylation of Lys 27 on H3 histone. This role may explain some of the effects of KDM6A on the immune system in that we previously reported that EZH2 was associated with the repression of several genes associated with antigen presentation and chemokines involved in T cell responses.¹⁴Although these studies are compelling in linking KDM6A to immune responses, it is still questionable whether it has a role in immune responses against COVID-19. If this was the case, we would expect that women being treated for severe COVID-19 infections in intensive care would have lower KDM6A expression than those with infections not requiring such care.¹⁵ We examined the RNA-seq data from blood samples of 102 COVID-19 patients. This included 38 women and 64 men, where 17 women and 34 men were admitted to intensive care unit. The analysis of KDM6A levels in the women showed that treatment in intensive care unit was associated with higher KDM6A expression ({"type":"entrez-geo","attrs":{"text":"GSE157103","term_id":"157103"}}GSE157103,¹⁵ data not shown). Although this was unexpected, it may indicate that KDM6A expression was linked to stronger responses causing higher inflammation in organs such as the lungs. No differences in KDM6A levels were detected in men irrespective of whether they were admitted to intensive care or not.Female patients with bi-allelic expression of KDM6A may induce the expression of interferon γ pathways which enhance anti-tumour immunity by recruiting immune modulatory cells (Fig. 1). These results point to the need for a better understanding of the role of X-linked genes in immune responses and whether EZH2-mediated suppression of immune modulatory genes have a role in infections as well as in cancer. In cancers and infections that have worst outcomes in males versus females, one approach might be to target (inhibit) the EZH2 epigenetic regulator that opposes KDM6A (Fig. 1). Another option may be to increase levels of KDM6A by administration of oestrogens. Oestrogen α receptors are expressed in practically all lymphocytes and were shown to physically interact with KDM6A to create a permissive chromatin state on endoplasmic reticulum (ER) targets such as C-X-C chemokine motif receptor 4.¹⁶ It was transactivated by ER to form a feed-forward loop. Administration of 17β-oestradiol has been suggested by others as treatment for COVID-19 infections.¹⁷Open in a separate windowFig. 1Proposed model of sex-biased role of the X-linked KDM6A gene in promoting immunity.Males harbour one X chromosome with no functional Y chromosome homologue. Hence, mutation in the X-linked epigenetic modifier KDM6A with tumour-suppressive or immunomodulatory role will probably lead to cancer or infection in males. Immune-related genes will be repressed by EZH2-mediated H3K27me3 deposition resulting in low KDM6A protein and immune evasion in male patients. In females, with two X chromosome, [one active (Xa) and one inactive (Xi)], a single mutation (m) in KDM6A is less likely to develop cancer or infections since another functional allele escapes X inactivation. Cells with high KDM6A level would be expected to demethylate H3K27me3 resulting in activation of the interferon γ pathway resulting in inactivation of natural killer (NK), dendritic or cytotoxic T cells to induce anti-tumour immunity and adaptive immunity against virus-infected cells.These studies have therefore raised many questions that require more detailed study to identify how the powerful survival benefits of the X-linked epigenetic regulators might be used to improve the therapeutic outcome in patients.     

Effects of cancer screening restart strategies after COVID-19 disruption

Background Many breast, cervical, and colorectal cancer screening programmes were disrupted due to the COVID-19 pandemic. This study aimed to estimate the effects of five restart strategies after the disruption on required screening capacity and cancer burden.Methods Microsimulation models simulated five restart strategies for breast, cervical, and colorectal cancer screening. The models estimated required screening capacity, cancer incidence, and cancer-specific mortality after a disruption of 6 months. The restart strategies varied in whether screens were caught up or not and, if so, immediately or delayed, and whether the upper age limit was increased.Results The disruption in screening programmes without catch-up of missed screens led to an increase of 2.0, 0.3, and 2.5 cancer deaths per 100 000 individuals in 10 years in breast, cervical, and colorectal cancer, respectively. Immediately catching-up missed screens minimised the impact of the disruption but required a surge in screening capacity. Delaying screening, but still offering all screening rounds gave the best balance between required capacity, incidence, and mortality.Conclusions Strategies with the smallest loss in health effects were also the most burdensome for the screening organisations. Which strategy is preferred depends on the organisation and available capacity in a country.Subject terms: Health policy, Population screening, Cancer screening, Cancer screening     

Tractography of the Cerebellar Peduncles in Second- and Third-Trimester Fetuses

BACKGROUND AND PURPOSE:Little is known about microstructural development of cerebellar white matter in vivo. This study aimed to investigate developmental changes of the cerebellar peduncles in second- and third-trimester healthy fetuses using motion-corrected DTI and tractography.MATERIALS AND METHODS:3T data of 81 healthy fetuses were reviewed. Structural imaging consisted of multiplanar T2-single-shot sequences; DTI consisted of a series of 12-direction diffusion. A robust motion-tracked section-to-volume registration algorithm reconstructed images. ROI-based deterministic tractography was performed using anatomic landmarks described in postnatal tractography. Asymmetry was evaluated qualitatively with a perceived difference of >25% between sides. Linear regression evaluated gestational age as a predictor of tract volume, ADC, and fractional anisotropy.RESULTS:Twenty-four cases were excluded due to low-quality reconstructions. Fifty-eight fetuses with a median gestational age of 30.6 weeks (interquartile range, 7 weeks) were analyzed. The superior cerebellar peduncle was identified in 39 subjects (69%), and it was symmetric in 15 (38%). The middle cerebellar peduncle was identified in all subjects and appeared symmetric; in 13 subjects (22%), two distinct subcomponents were identified. The inferior cerebellar peduncle was not found in any subject. There was a significant increase in volume for the superior cerebellar peduncle and middle cerebellar peduncle (both, P < .05), an increase in fractional anisotropy (both, P < .001), and a decrease in ADC (both, P < .001) with gestational age. The middle cerebellar peduncle had higher volume (P < .001) and fractional anisotropy (P = .002) and lower ADC (P < .001) than the superior cerebellar peduncle after controlling for gestational age.CONCLUSIONS:A robust motion-tracked section-to-volume registration algorithm enabled deterministic tractography of the superior cerebellar peduncle and middle cerebellar peduncle in vivo and allowed characterization of developmental changes.

In the second half of pregnancy, the cerebellum is growing rapidly and is extremely vulnerable.¹ Despite the increasingly recognized association of antenatal and perinatal cerebellar injury with adverse motor and neurologic outcomes later in life,^2-5 little is known about normal cerebellar developmental in the later part of gestation, in particular with regard to changes in microstructure. In fact, most existing fetal MR imaging data addresses primarily changes in cerebellar volume with gestational age (GA) or changes in volume and their association with specific diseases such as congenital heart disease.^6-8In vivo evaluation of cerebellar microstructure using fetal MR imaging has been limited by the technical challenges related to imaging the gravid abdomen, particularly patient motion. However, data from ex vivo MR imaging studies are promising. For instance, Takahashi et al^9,10 performed high-resolution ex vivo DTI of fetal specimens and demonstrated the feasibility of using tractography to outline the cerebellar peduncles prenatally. Even though tractography of the cerebellar peduncles has been sporadically reported in vivo in technical articles or general review articles on fetal DTI,¹¹ the GA-related microstructural changes that occur in the cerebellar peduncles in the second half of pregnancy remain largely unexplored.Recent advances in hardware and software have improved fetal MR imaging substantially. The use of 3T magnets, which have been shown to be safe, results in improvement of the SNR and spatial resolution, which is advantageous to image the small structures of the fetal brain.^12,13 In addition, postprocessing algorithms that enable reconstruction of motion-corrected fetal DTI data are increasingly available and have been used by several groups to characterize the development of the supratentorial white matter tracts in vivo.^14-16 We hypothesize that fetal DTI performed at 3T and processed with a robust section-to-volume motion-correction and registration¹⁴ algorithm will enable tractography of the cerebellar peduncles in fetuses in the second and third trimesters of pregnancy. We aimed to characterize fetal cerebellar tract microstructure and to investigate tract-specific developmental changes.     

Association of malnutrition with all-cause mortality in the elderly population: A 6-year cohort study

Background and aimsFew studies have explored the association between malnutrition, defined by the Geriatric Nutritional Risk Index (GNRI), and all-cause mortality, particularly in the Chinese population. This study aimed to investigate the association between the GNRI and all-cause mortality in the elderly population.Methods and resultsParticipants aged ≥60 years were eligible for this study and were divided into three groups by the GNRI: An adequate nutrition group, participants with a GNRI ≥98; mild malnutrition group, participants with a GNRI ≥82 but <98; and a severe malnutrition group, participants with a GNRI <82. The results implied that there was a positive association between severe malnutrition and all-cause mortality in the total population (hazard ratio (HR): 2.591 and 95% confidence interval (CI): 1.729–3.884), male subjects (HR: 2.903 and 95% CI: 1.718–4.906), and female subjects (HR: 2.081 and 95% CI: 1.071–4.046). Similar associations between severe malnutrition and all-cause mortality were observed in both the 60–69 and 70–79 years age groups (HR: 2.863 and 2.600, 95% CI: 1.444–5.678 and 1.394–4.849, respectively). However, no significant association was observed between mild malnutrition and all-cause mortality.ConclusionsSevere malnutrition could increase all-cause mortality in the 60- to 79-year-old population. However, there was no association of mild malnutrition with all-cause mortality.     

Rapid behavioral assessment of barriers and opportunities to improve vaccination coverage among displaced Rohingyas in Bangladesh,January 2018

Background

In November 2017, the World Health Organization received initial reports of suspected diphtheria cases in camps established for displaced Rohingyas in Cox’s Bazar district, Bangladesh. By January 11, 2018, over 4,000 suspected cases of diphtheria and 30 deaths were reported. The Bangladesh government and partners implemented a diphtheria vaccination campaign in December 2017. Outbreak response staff reported anecdotal evidence of vaccine hesitancy. Our assessment aimed to understand vaccination barriers and opportunities to enhance vaccine demand among displaced Rohingyas in Bangladesh.