The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

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

Mecccanismi molecolari coinvolti nella guarigione di cervicite uterina sperimentale in ratto in seguito a somministrazione topica di Sucralfato

Introduzione - Il Sucralfato (a-D-glucopiranodide, b-D fructofuranosil, octachis (ac.sulfidrico) complesso di alluminio) ¨¨ un agente citoprotettivo impiegato nel trattamento delle ulcere gastroduodenali. Il sucralfato agisce sul processo riparativo e nella guarigione delle lesioni, formando una barriera fisica per la mucosa e proteggendo alcuni fattori di crescita (Epidermal Growth Factor, basic Fibroblastic Growth Factor, Transforming Growth Factor a) dalla degradazione proteolitica in ambiente acido. Nei processi di rimodellamento che accompagnano la guarigione delle ferite ¨¨ essenziale l¡¯espressione del recettore del fattore di crescita epidermico (EGFR) e dei propri ligandi a livello della lesione e del fattore di crescita fibroblastico basico (bFGF), implicato nei processi angiogenetici. Inoltre precedenti dati ottenuti del nostro gruppo mostrano che il Sucralfato ¨¨ in grado di modulare il sistema proteolitico del plasminogeno, in particolare l¡¯espressione del recettore dell¡¯attivatore del plasminogeno tipo-urochinasico (uPAR). Scopo della ricerca - Nel nostro studio abbiamo valutato l¡¯attivit¨¤ del Sucralfato nei processi di riparazione tissutale in un modello sperimentale di cervicite nel ratto in assenza dell¡¯apporto trofico ormonale. Lo scopo del nostro lavoro ¨¨ stato quello di valutare se nelle ratte ovariectomizzate si osservasse un comportamento analogo a quanto precedentemente rilevato nelle ratte non ovariectomizzate e se la modulazione dell¡¯attivit¨¤ dell¡¯uPAR sia EGFR-mediata. Per rilevare l¡¯attivit¨¤ del farmaco sono stati considerati i seguenti parametri: 1)Interleuchina 6, come marker flogistico; 2) fattore di crescita dei fibroblasti (b-FGF); 3) Recettore per l¡¯attivazione del plasminogeno (uPAR); 4) Recettore per il fattore di crescita epidermico (EGFR). Materiali e metodi - Sono stati utilizzati 60 ratti femmina Wistar, con un peso di circa gr.200¡À20 che sono stati divisi nei seguenti gruppi sperimentali: 1)Controlli sani; 2)Controlli ovariectomizzati; 3)Ratti ovariectomizzati con lesione cervicale, sacrificati al 4¡ã e 7¡ãgg; 4)Ratti ovariectomizzati, con lesione cervicale, trattati con Sucralfato, sacrificati al 4¡ã e 7¡ãgg. Una volta praticata la lesione, gli animali del gruppo trattato con il farmaco sono stati sottoposti ad una applicazione topica giornaliera di Sucralfato (50 ¦Ìl della preparazione in pomata al 12%), somministrato dal giorno successivo alla lesione fino al giorno del sacrificio; La lesione cervicale ¨¨ stata indotta, dopo anestesia con Cloralio Idrato (300 mg/kg p.c.) (Carlo Erba, Milano ¨C Italia), con un tampone imbevuto di Ac. Acetico glaciale (100 ¦Ìl) (Carlo Erba, Milano ¨C Italia) per 30 sec in modo da creare una lesione di tipo ulcerativo nella porzione intravaginale della cervice uterina. L¡¯ovariectomia ¨¨ stata effettuata, dopo anestesia con Cloralio Idrato, tramite un¡¯incisione longitudinale lungo la linea alba, accedendo alla cavit¨¤ addominale. Successivamente all¡¯individuazione delle corna dell¡¯utero, si applica una legatura con filo da sutura assorbibile, a livello delle estremit¨¤ superiori delle corna, recidendo la porzione superiore e asportando le ovaie. Gli animali operati sono tenuti in isolamento ed in terapia antibiotica per i successivi 4gg. La lesione ¨¨ effettuata dopo 21gg dall¡¯operazione. Sono stati allestiti preparati istologici colorati con ematossilina-eosina per valutare l¡¯aspetto morfologico della lesione e l¡¯effetto del Sucralfato nel processo di riparazione tissutale. Inoltre con l¡¯impiego di metodiche quali l¡¯analisi Western Blot ed immunoistochimica sono state valutate le variazioni dei livelli bFGF e EGFR, utilizzando specifici anticorpi (rabbit polyclonal IgG anti-EGFR, anti-bFGF) (Santa Cruz, California, USA). Per le valutazioni semiquantitative del Western Blot, le immagini sono state acquisite al computer ed analizzate con un apposito software (Kodak 1D 3.6). La valutazione della concentrazione dell¡¯interleuchina 6 (IL-6) nell¡¯omogenato di cervice, ¨¨ stata effettuata utilizzando specifici kit ELISA (Bender Medsystem). Risultati ¨C L¡¯analisi istologica e quella microscopica mettono in evidenzia che la lesione prodotta con Ac. Acetico determina un danneggiamento del tessuto cervicale evidente al giorno 4; l¡¯entit¨¤ della lesione risulta apprezzabile anche al giorno 7. Negli animali con cervicite e trattati con Sucralfato si osserva un sensibile miglioramento al giorno 4, ed al giorno 7 il tessuto sembra ormai avviato ad una completa guarigione. L¡¯analisi mediante test ELISA di IL-6 degli omogenati tissutali evidenzia una riduzione della flogosi, con una diminuzione (non significativa) a 4 (804.255¡À215.372 pg/mg di proteine) e 7gg (661.477¡À183.369 pg/mg di proteine) nel gruppo ovariectomizzato trattato con Sucralfato, rispetto al relativo gruppo ovariectomizzato non trattato (401.3099¡À64.199 pg/mg di proteine) e (364.328¡À52.506 pg/mg di proteine). Dai dati ottenuti con il Western Blot si evidenzia una variazione significativamente maggiore dei livelli di EGFR, nel gruppo con cervicite trattato con Sucralfato al giorno 4, rispetto al controllo operato (2.157¡À0.726 ua vs 1.00¡À0.105 ua p<0.05) e nel gruppo lesionato sacrificato a 7gg rispetto al relativo gruppo trattato con Sucralfato (2.878¡À0.545 ua vs 1.555¡À0.652 ua p<0.05). I livelli di bFGF sono significativamente maggiori nel gruppo ovariectomizzato con cervicite a 4gg rispetto al controllo operato (2.126¡À0.627 ua vs 0.961¡À0.272 ua p<0.05) e nel gruppo ovariectomizzato con cervicite a 7gg rispetto sia al controllo sano (2.627¡À0.797 ua vs 1.283¡À0.318 ua p<0.05), che al controllo ovariectomizzato (2.627¡À0.797 ua vs 0.961¡À0.272 ua p<0.05). Valori di bFGF significativamente maggiori si osservano ulteriormente nel gruppo ovariectomizzato con cervicite trattato con Sucralfato a 4gg rispetto sia al controllo sano (3.054¡À0.726 ua vs 1,283¡À0,318 ua p<0.05) che al controllo con ovariectomia (3.054¡À0.726 ua vs 0.961¡À0.272 ua p<0.05) e nel gruppo ovariectomizzato trattato con Sucralfato a 7gg rispetto al controllo ovariectomizzato (1.956¡À0.872 ua vs 0.961¡À0.272 ua p<0.05). La valutazione tramite metodiche immunoistochimiche per la valutazione dell¡¯espressione dei recettori EGFR e uPAR ha evidenziato una analoga distribuzione al giorno 4 sia nel gruppo con cervicite (a livello sottoepiteliale) che nel gruppo trattato con Sucralfato (a livello epiteliale) Conclusioni - Dai risultati sperimentali ottenuti possiamo concludere che nel nostro modello sperimentale di cervicite nel ratto l¡¯applicazione topica di Sucralfato si ¨¨ dimostrata in grado di accelerare il processo di riparazione della lesione; come ipotizzato nel nostro precedente lavoro, tale effetto potrebbe essere imputato all¡¯effetto anti-flogistico del Sucralfato, alla modulazione sia di fattori di crescita (bFGF) che dei recettori EGFR ed uPAR ed al loro possibile cofunzionamento

Impact of age and gender on glioblastoma onset, progression, and management

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, while its frequency in pe-diatric patients is 10-15%. For this reason, age is considered one of the major risk factors for the development of GBM, as it correlates with cellular aging phenomena involving glial cells and favoring the process of tumor transformation. Gender differences have been also identified, as the incidence of GBM is higher in males than in females, coupled with a worse outcome. In this review, we analyze age-and gender-dependent differences in GBM onset, mutational landscape, clinical manifestations, and survival, according to the literature of the last 20 years, focusing on the major risk factors involved in tumor development and on the mutations and gene alter-ations most frequently found in adult vs young patients and in males vs females. We then highlight the impact of age and gender on clinical manifestations and tumor localization and their involvement in the time of diagnosis and in determining the tumor prognostic value

Outcome Comparison of Drug-Resistant Trigeminal Neuralgia Surgical Treatments—An Umbrella Review of Meta-Analyses and Systematic Reviews

Medical treatment for trigeminal neuralgia (TN) is not always a feasible option due to a lack of full response or adverse effects. Open surgery or percutaneous procedures are advocated in these cases. Several articles have compared the results among different techniques. Nevertheless, the findings of these studies are heterogeneous. Umbrella reviews are studies sitting at the peak of the evidence pyramid. With this umbrella review, we provided a systematic review of the outcomes of the surgical procedures used for TN treatment. Only systematic reviews and meta-analyses were included following the PRISMA guidelines. Ten articles were enrolled for qualitative and quantitative assessment. Level of evidence was quantified using a specific tool (AMSTAR-2). Results were heterogenous in terms of outcome and measurements. Microvascular decompression (MVD) appeared to be the most effective procedure both in the short-term (pain relief in 85–96.6% of cases) and long-term follow-up (pain relief in 64–79% of cases), although showed the highest rate of complications. The results of percutaneous techniques were similar but radiosurgery showed the highest variation in term of pain relief and a higher rate of delayed responses. The use of the AMSTAR-2 tool to quantify the evidence level scored three studies as critically low and seven studies as low-level, revealing a lack of good quality studies on this topic. Our umbrella review evidenced the need of well-designed comparative studies and the utilization of validated scales in order to provide more homogenous data for pooled-analyses and meta-analyses in the field of TN surgical treatment

Collagen VI Deficiency Impairs Tendon Fibroblasts Mechanoresponse in Ullrich Congenital Muscular Dystrophy

The pericellular matrix (PCM) is a specialized extracellular matrix that surrounds cells. Interactions with the PCM enable the cells to sense and respond to mechanical signals, triggering a proper adaptive response. Collagen VI is a component of muscle and tendon PCM. Mutations in collagen VI genes cause a distinctive group of inherited skeletal muscle diseases, and Ullrich congenital muscular dystrophy (UCMD) is the most severe form. In addition to muscle weakness, UCMD patients show structural and functional changes of the tendon PCM. In this study, we investigated whether PCM alterations due to collagen VI mutations affect the response of tendon fibroblasts to mechanical stimulation. By taking advantage of human tendon cultures obtained from unaffected donors and from UCMD patients, we analyzed the morphological and functional properties of cellular mechanosensors. We found that the length of the primary cilia of UCMD cells was longer than that of controls. Unlike controls, in UCMD cells, both cilia prevalence and length were not recovered after mechanical stimulation. Accordingly, under the same experimental conditions, the activation of the Hedgehog signaling pathway, which is related to cilia activity, was impaired in UCMD cells. Finally, UCMD tendon cells exposed to mechanical stimuli showed altered focal adhesions, as well as impaired activation of Akt, ERK1/2, p38MAPK, and mechanoresponsive genes downstream of YAP. By exploring the response to mechanical stimulation, for the first time, our findings uncover novel unreported mechanistic aspects of the physiopathology of UCMD-derived tendon fibroblasts and point at a role for collagen VI in the modulation of mechanotransduction in tendons