Long-term auxological and endocrinological evaluation of patients with 9p trisomy: a focus on the growth hormone-insulin-like growth factor-I axis

BACKGROUND: Trisomy 9p is an uncommon anomaly characterised by mental retardation, head and facial abnormalities, congenital heart defects, kidney abnormalities, and skeletal malformations. Affected children may also show growth and puberty retardation with delayed bone age. Auxological and endocrinological data are lacking for this syndrome. METHODS: We describe three girls and one boy with 9p trisomy showing substantial growth failure, and we evaluate the main causes of their short stature. RESULTS: The target height was normal in all families, ranging from 0.1 and -1.2 standard deviation scores (SDS). The patients had a low birth-weight (from -1.2 to -2.4 SDS), birth length (from -1.1 to -3.2 SDS), and head circumference (from -0.5 to -1.6 SDS). All patients presented with substantial growth (height) retardation at the time of 9p trisomy diagnosis (from -3.0 to -3.8 SDS).The growth hormone stimulation test revealed a classic growth hormone (GH) deficiency (GHD) in patients 1, 3, and 4. In contrast, patient 2 was determined to have a GH neurosecretory dysfunction (GHNSD). The plasma concentrations of IGF-I and IGFBP-3 were low in all patients for their ages and sexes (from -2.0 to -3.4 SDS, and from -1.9 to -2.8 SDS, respectively).The auxological follow-up showed that those patients who underwent rhGH treatment exhibited a very good response to the GH therapy, whereas patients 3 and 4, whose families chose not to use rhGH treatment, did not experience any significant catch-up growth. CONCLUSIONS: GH deficiency appears to be a possible feature of patients with 9p trisomy syndrome. These patients, particularly those with growth delays, should be evaluated for GH secretion

Budget impact analysis of universal rotavirus vaccination in the Local Health Unit 11 Empoli, Tuscany, Italy

Background. Rotavirus (RV) infection is the first cause of acute viral gastroenteritis in children under five years of age all over the world; it mainly affects children between six and 24 months of age and can cause serious acute diarrhoea and dehydration. The aim of this study is to perform the budget impact analysis of universal rotavirus vaccination in the Local Health Unit (LHU) 11 Empoli, Tuscany, Italy.Methods. An ad hoc mathematical simulation model was developed to evaluate the budget impact analysis of 5-years universal rotavirus vaccination. Particularly, incidence of rotavirus gastroenteritis (RVGE), hospitalizations, nosocomial diarrhoea, medical consultations, prescriptions and accesses to emergency department were taken into account in the analysis. The direct medical costs due to RV diarrhoea and the costs of vaccination campaign were considered as the main outcome measures in the study.Results. The adoption of universal rotavirus vaccination campaign for five years in the LHU 11 Empoli results in relevant savings due to the health cares avoided. These savings would overlapped the costs of vaccination yet from the second year after the introduction of vaccination. The saving for the Health Service would be 1.5 million Euro after five years of campaign.Conclusions. Universal vaccination against rotavirus results clinically and economically favourable for both the Health Service and the Society perspectives

Molecular characterization of paediatric glioneuronal tumours with neuropil-like islands: a genome-wide copy number analysis.

Paediatric glioneuronal tumour with neuropil-like islands (GTNI) is a rare neoplasm of neuronal differentiation and diffusely infiltrating astroglial and oligodendrocyte-like components. The 2007 World Health Organization classification of central nervous system tumours considered it as a pattern variation of anaplastic astrocytoma. There are few data on paediatric GTNI probably both for their rarity and variable clinical aggressiveness. We studied by SNP/CGH array four tumour samples of GTNI from two males and two females (one new-born and three children aged from 4 to 8 years), in order to identify any possible common genomic alteration. All patients received chemo- and radiotherapy after their surgical treatment. No genomic instability nor recurrent alterations have been demonstrated in two of our GTNI cases. In the remaining two, we detected a mosaic trisomy 8 (15-20%) in one case, and an amplification at 5q14.1 involving DMGDH (partially), BHMT2 and BHMT genes, with the distal breakpoint falling at 23 Kbp from the 5’UTR of JMY, a p53 cofactor. Although the smallness of the sample impairs any clinical-histological correlation, GTNI appear different at the molecular level, with genomic imbalances playing a possible role in at least part of them. Our work gives an important contribution in knowledge and classification of this family of tumours

Assigning single clinical features to their disease-locus in large deletions: the example of chromosome 1q23-25 deletion syndrome

Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements. Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four malformations. Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly, short-hands/feet, and brachydactyly. Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its reliability

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Clinical Utility of a Structured Program to Reduce the Risk of Health-Related Quality of Life Impairment after Discharge from Intensive Care Unit: A Real-World Experience

Background. Postdischarge deterioration in health-related quality of life (HRQoL) is a major clinical issue for patients after an intensive care unit (ICU) hospitalization. A significant proportion of these patients is known to develop a progressive worsening of mental and physical performance—the so-called post-intensive care syndrome (PICS). Aim. We aimed at exploring the effects of a structured program for the management of ICU patients, aimed at improving postdischarge HRQoL and reducing the risk of PICS. Methods. A total of 159 patients hospitalized in our ICU with a length of stay >72 hours were enrolled in an institutional management protocol including specific recommendations: adequate sedation and analgesia protocols, to ensure a valid delirium prevention strategy, and to provide a planned midterm after discharge. The main endpoint was the occurrence of PICS at the 6-month follow-up visitation, defined as an abnormal physical or mental score in the SF-12 questionnaire in the presence of clinical evidence of new or worsening impairment in physical, cognitive, or mental health status. An additional questionnaire was administered, to assess the effects of ICU-related memories. Results. Most patients positively rated their health at the 6-month follow-up and had no significant impairment in physical or mental health status. The mean normalized values of the physical and mental component of the SF-12 score were 46 ± 11 and 48 ± 14, suggesting a normal physical and mental health status in most patients. Twenty-nine patients (18.2%) showed evidence of PICS. Similar good results were found by the questionnaire of memories. In multivariable analysis, no variable was found to predict the risk of PICS in our population. Conclusion. In this real-world analysis that lacks a control group, patients who used a program aimed at minimizing the risk of HRQoL deterioration and PICS reported a good perception of their state of health with a relatively low prevalence of PICS