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Background: This study analyzes the effect of frailty and Post-Operative Delirium (POD) on the functional status at hospital discharge and at 4-month follow-up in patients with hip fracture (HF). Methods: Multicenter prospective observational study of older patients with HF admitted to 12 Italian Orthogeriatric centers (July 2019-August 2022). POD was assessed using the 4AT. A 26-item Frailty Index (FI) was created using data collected on admission. The outcome measures were Cumulated Ambulation Score (CAS) ≤ 2 at discharge and a telephone-administered CAS ≤ 2 after 4 months. Poisson regression models were used to assess the effect of frailty and POD on outcomes. Results: 984 patients (median age 84 years, IQR = 79–89) were recruited: 480 (48.7%) were frail at admission, 311 (31.6%) developed POD, and 158 (15.6%) had both frailty and POD. In a robust Poisson regression, frailty alone (Relative Risk, RR = 1.56, 95% Confidence Intervals, CI 1.19–2.04, p = 0.001) and its combination with POD (RR = 2.57, 95% CI 2.02–3.26, p < 0.001) were associated with poor functional status at discharge. At 4-month follow-up, the combination of frailty with POD (RR 3.65, 95% CI 1.85–7.2, p < 0.001) increased the risk of poor outcome more than frailty alone (RR 2.38, 95% CI 1.21–4.66, p < 0.001). Conclusions: POD development exacerbates the negative effect that frailty exerts on functional outcomes in HF patients. [ABSTRACT FROM AUTHOR]

Background: First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report here the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups. Methods: Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported. Results: 25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016–2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group. Conclusions: Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup. Highlights: Medulloblastoma relapse occurs in 30% of patients and no standard therapeutic strategy exists. Surgical treatment of relapse may improve prognosis. Reirradiation can prolong survival, however field extension, doses and fractionation have not yet been determined. Relapsing patients with SHH subgroup medulloblastoma have a worse prognosis and may be preferentially treated with hypofractionated schedules. [ABSTRACT FROM AUTHOR]

Objective: The GCS-Pupils (GCS-P) score is a recently described scoring system to aid outcome prediction in patients with traumatic brain injury (TBI). The aim of this study was to provide the first external validation of the GCS-P score by identifying independent predictors of outcome in TBI patients. Methods: Review of prospective adult (≥ 16 years) TBI database at a tertiary neurosurgical center with a catchment population of 1.5 million over a 12-month period commencing October 2016. Multivariate logistic regression was used to identify predictors of discharge destination and 30-day mortality. Results: Three hundred and fifty-eight patients were included. The median age was 60 years with a male predominance of 64%. The median GCS-P was 14 (interquartile range 12–15) and the commonest GCS-P category was mild (13–15; 238/358, 66%). Discharge destination was home in 69% of patients and rehab services or equivalent in 31%. Multivariate analysis identified age (p = 0.01), CT findings of an acute subdural hematoma (p = 0.01) or diffuse axonal injury (p = 0.02), and a neurosurgical operation (p = 0.02) as independent predictors of discharge destination. The 30-day mortality rate was 11%. Within the category of severe TBI (GCS-P ≤ 8), GCS-P was able to identify patients with a very high likelihood of 30-day mortality (GCS-P ≤ 4; 16/31, 52%). Multivariate analysis revealed the Charlson comorbidity score (p = 0.01), GCS-P (p = 0.02), and traumatic subarachnoid hemorrhage (p = 0.05) as independent predictors of mortality. Conclusion: The GCS-P is a useful predictor of 30-day mortality, although its usefulness for other clinical outcomes remains to be proven. [ABSTRACT FROM AUTHOR]

Purpose: Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches. Methods: We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010–2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed. Results: Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6–16.2 months)/6.9 months (0.6–17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P < 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081). Conclusions: This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial. [ABSTRACT FROM AUTHOR]

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has caused a worldwide epidemic of enormous proportions, which resulted in different mortality rates in different countries for unknown reasons. We analyzed factors associated with mortality using data from the Italian national database of more than 4 million SARS-CoV-2-positive cases diagnosed between January 2020 and July 2021, including > 415 thousand hospitalized for coronavirus disease-19 (COVID-19) and > 127 thousand deceased. For patients for whom age, sex and date of infection detection were available, we determined the impact of these variables on mortality 30 days after the date of diagnosis or hospitalization. Multivariable weighted Cox analysis showed that each of the analyzed variables independently affected COVID-19 mortality. Specifically, in the overall series, age was the main risk factor for mortality, with HR > 100 in the age groups older than 65 years compared with a reference group of 15–44 years. Male sex presented a two-fold higher risk of death than female sex. Patients infected after the first pandemic wave (i.e. after 30 June 2020) had an approximately threefold lower risk of death than those infected during the first wave. Thus, in a series of all confirmed SARS-CoV-2-infected cases in an entire European nation, elderly age was by far the most significant risk factor for COVID-19 mortality, confirming that protecting the elderly should be a priority in pandemic management. Male sex and being infected during the first wave were additional risk factors associated with COVID-19 mortality. [ABSTRACT FROM AUTHOR]

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. [ABSTRACT FROM AUTHOR]