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Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes.A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2.Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests.Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia.In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure.In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia.By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554.

We aimed to assess the tolerance of fentanyl pectin nasal spray (FPNS) when used to treat procedural pain caused by wound dressing or physiotherapy in patients older than 75 years with or without opioid background treatment.This is a prospective monocentric, noncontrolled, nonrandomized study conducted from December 2014 to October 2017 in 2 geriatric wards (rehabilitation and acute medicine).Fifty-seven patients were included and 314 procedures were monitored.For each patient, 6 procedures were monitored: the first 2 without specific treatment, then fentanyl was started at 100 μg with a titration over a few procedures up to 800 μg in non-opioid-naïve patients and 400 μg in opioid-naïve. Sedation and respiratory scale were monitored during the procedures. All adverse drug events occurring from inclusion to 5 days after the intervention were collected and their imputability was assessed separately by 2 pharmacovigilance experts.Overall, 14.4% of the sessions with FPNS administration resulted in adverse drug events. Main adverse drug events were nausea and vomiting, somnolence, and confusion. Most of them were of mild to moderate severity. Four severe adverse events were due to accidental overdoses. No unexpected adverse event occurred. Tolerance was similar for opioid-naïve and non-opioid-naïve patients (P value = .93).FPNS was overall well tolerated in geriatric patients. Given its interesting pharmacokinetics, fentanyl is a promising lead for procedural pain treatment in geriatric patients, even those who are opioid naïve.

The use of explicit definitions of potentially inappropriate prescriptions of antibiotics (antibiotic PIPs) might constitute an innovative means to fight against antimicrobial resistance. Explicit definitions of PIPs can reduce the rate of inappropriate prescriptions, but explicit definitions of antibiotic PIPs in geriatric medicine are currently lacking. The objective of the study was to develop explicit definitions of antibiotic PIPs for hospitalized older patients.We performed a qualitative study of focus groups involving geriatricians and infectious disease specialists. The study complied with the Consolidated Criteria for Reporting Qualitative Research. Transcripts of audio recordings were analyzed in a two-step independent reviewing process. The exact wording of the definitions was validated by a steering committee, an independent expert group, and the focus group participants.The four focus groups comprised 28 stakeholders. Our analysis identified 65 explicit definitions of antibiotic PIPs: 47 (73%) concerned misuse, 15 (23%) concerned overuse and three (5%) concerned underuse. Most definitions were related to critically important antibiotics: 11 (17%) for fluoroquinolones, eight (12%) for amoxicillin-clavulanic acid, eight (12%) for cephalosporins, seven (11%) for aminoglycosides, and five (8%) for carbapenems.To address the public health challenge of antimicrobial resistance, our study generated explicit definitions for antibiotic PIPs in older patients. We intend to refine and to validate these definitions through a national Delphi survey; the resulting consensus might provide key messages for prescribers and open up perspectives for reducing the incidence of antibiotic PIPs.

It is unclear whether invasive intraductal papillary mucinous neoplasm (IPMN) has different clinical and prognostic characteristics, beyond histological factors, when compared to pancreatic ductal adenocarcinoma (PDAC).compare prognostic features of resected PDAC and invasive IPMN METHODS: A retrospective study of patients resected for PDAC or invasive IPMN realized at Humanitas Cancer Center's Pancreatic Surgery Unit, Milan, Italy, between 2010 and 2016. Data recorded included patient demographics, onset symptoms, preoperative health status, tumor features, histology and surgical characteristics. Overall survival was estimated using Kaplan-Meier and prognostic factors for survival were assessed by multivariate Cox regression.A total of 332 patients were included (PDAC, n = 289; invasive IPMN, n = 43). Patients with invasive IPMN had better overall survival than PDAC patients (median: 76.6 versus 25.6 months; 5-year OS rate: 65.4% vs. 14.2%; p 0.001). PDAC histology was associated with a significantly higher risk of death than IPMN (hazard ratio 1.815, 95% CI: 1.02, 3.24; p = 0.044). Survival was also worse with PDAC in early-stage disease (IA-IB-IIA, N0). In multivariate analysis, independent predictors of worse survival included perineural invasion, preoperative ASA physical status ≥3 and pain at diagnosis.Patients with IPMN had a better prognosis than PDAC patients, regardless of disease stage.

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The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants’ gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity.

Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease. It has a substantial impact on patient quality of life and is a common cause of pain and mobility issues in older adults. The functional limitations, lack of curative treatments, and cost to society all demonstrate the need for translational and clinical research. The use of OA models in mice is important for achieving a better understanding of the disease. Models with clinical relevance are needed to achieve 2 main goals: to assess the impact of the OA disease (pain and function) and to study the efficacy of potential treatments. However, few OA models include practical strategies for functional assessment of the mice. OA signs in mice incorporate complex interrelations between pain and dysfunction. The current review provides a comprehensive compilation of mouse models of OA and animal evaluations that include static and dynamic clinical assessment of the mice, merging evaluation of pain and function by using automatic and noninvasive techniques. These new techniques allow simultaneous recording of spontaneous activity from thousands of home cages and also monitor environment conditions. Technologies such as videography and computational approaches can also be used to improve pain assessment in rodents but these new tools must first be validated experimentally. An example of a new tool is the digital ventilated cage, which is an automated home-cage monitor that records spontaneous activity in the cages.

Delayed gastric emptying (DGE) is a common complication in surgery, but incidence and relevance following multivisceral resection are unknown.Data from 100 consecutive patients treated for primary retroperitoneal sarcoma (RPS) were analyzed from our institutional prospectively maintained database from January 2019 to April 2020. DGE severity was graded according to the International Study Group of Pancreatic Surgery and classified as primary or secondary to other complications. The primary outcome was incidence and grade of clinically relevant DGE (grades B-C). Secondary outcomes were correlation with patient, tumor, and treatment characteristics, and non-DGE morbidity [Clavien-Dindo (CD) grade ≥ 3].Forty-two patients developed DGE and 28 had clinically relevant DGE. DGE was primary in 10 patients and secondary in 18 patients; the most common associated complications were: infections (11/18, 61.1%), pancreatic leak (7/18, 38.9%), bleeding (6/18, 33.3%), and bowel leak (6/18, 33.3%). DGE was related to longer length of hospital stay (P0.001), ICU admission (P = 0.004), ICU length of stay (P = 0.001), postoperative complications (CD [Formula: see text] 3 in 14/28 in DGE patients vs 11/72 in no-DGE; P = 0.04), and re-operation (P = 0.03). With multivariate analysis, the independent risk factors for DGE were patient comorbidities (OR 1.05; 95% CI 1.01-1.1; P = 0.04) and tumor size (OR 1.05; 95% CI 1.0-1.1; P = 0.02).Following multivisceral resection, DGE is a clinically relevant event that can be caused by an underlying complication. Prompt diagnosis and treatment of both DGE and any underlying complications led to full recovery in all cases.

Objective: Zoledronic acid (ZA) is an antiosteoporotic drug that has been proven to reduce mortality after a hip fracture (HF). ZA is however underused with older HF patients. One possible cause may be the high prevalence of severe renal failure and hypocalcemia which contraindicate ZA administration. The aim of this study was to assess the prevalence of these 2 contraindications in patients aged 75 years or older admitted into an orthogeriatric (OG) unit after a low-energy HF. The secondary objective was to assess the prevalence of situations in which ZA must be used with caution. Methods: Our retrospective descriptive monocentric study was performed in an OG unit on a cohort of elderly patients hospitalized for HF from August 2015 to August 2017. Prevalence of hypocalcemia lower than 2 mmol/L and Cockcroft creatinine clearance lower than 35 mL/min was recorded. Results: Among the 194 patients admitted for HF, 136 patients (mean age 86 ± 5.6 years; 101 women) were included. The mean length of hospital stay was 15 ± 9 days. 111 (81.5%) had no contraindications to ZA administration. More than 80% presented situations in which ZA had to be used with caution, including 25(OH)D deficiency (20%). Conclusion: The majority of subjects aged 75 years or older admitted to hospital after an HF seem to have no contraindication for ZA administration during their immediate postoperative hospital stay. The hospitalization period after HF repair gives the opportunity to give most of them this treatment to improve their prognosis, taking into account situations in which ZA must be used with caution.

BACKGROUND & AIMS Mediterranean diet may be beneficial for inflammatory bowel disease (IBD). The aim of this study was to evaluate the level of adherence to MD in Italian patients with IBD. METHODS Eighty consecutive outpatients with IBD, 62 with Crohn's Disease (CD) and 18 with Ulcerative Colitis (UC) were included in the study. Demographic and clinical data, previous and current medical history, nutritional status and Quality of Life (QoL) assessed with the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) were assessed. Adherence to MD was studied with the Medi-Lite questionnaire. RESULTS IBD patients reported a mean Medi-Lite score of 10.4 with no significant differences between CD and UC patients (p = 0.543). Among CD patients, adherence to MD was higher in patients with inactive disease (p

Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging abnormalities in young children with delayed developmental milestones. As the scientific community begins to better understand and research the mechanisms underlying leukodystrophies, clinical trials and approved therapies for specific disorders are becoming available. These interventions, ranging from repurposing of existing small molecules to recently approved gene therapies, are highly dependent on early diagnosis. It is essential for pediatricians to identify affected individuals promptly, but they face challenges including lack of awareness of the disorders and nonspecific symptom presentation (e.g., cognitive or motor developmental delay). This review provides five hypothetical clinical presentations and describes the disease mechanisms, typical symptoms, and treatments currently available for common leukodystrophies: Krabbe Disease, Aicardi Goutières Syndrome (AGS), Metachromatic leukodystrophy (MLD), Alexander Disease (AxD), Pelizaeus-Merzbacher Disease (PMD), and X-Linked Adrenoleukodystrophy (X-ALD.) This review educates pediatricians to recognize the presentation of leukodystrophies in affected children. These clinical vignettes can serve as a framework for pediatricians to identify potentially treatable rare disorders among their patients.

The purpose of this survey is to explore changes in the management of COVID-19 during the first versus the second wave, with particular emphasis on therapies, antibiotic prescriptions, and elderly care. An internet-based questionnaire survey was distributed to European Society of Clinical Microbiology and Infectious Diseases (ESCMID) members. Therapeutic approach to patients with mild-to-moderate (PiO2/FiO2 200–350) and severe (PiO2/FiO2

Background Patients with cognitive deficits are 3 times more likely to suffer a hip fracture than geriatric patients of the same age group without cognitive deficits. The persistence of perioperative pain following hip fracture is a risk factor for the occurrence of delirium, poor functional prognosis, and the development of secondary chronic pain. Patients with cognitive deficits receive 20 to 60% less analgesics than those without cognitive deficits. Our retrospective descriptive monocentric study was performed in an orthogeriatric unit on a cohort of elderly patients hospitalized for hip fracture. The aim of the study was to compare the quantity of strong opioids delivered in a morphine sulfate equivalent daily during the preoperative period after a hip fracture between cognitively intact patients and those with cognitive deficits. Results Our total population of 69 patients had a median age of 90 years old, and 46% of these patients had moderate or severe cognitive deficits. During the preoperative period, the same quantity of strong opioids was administered to both groups of patients (13.1 mg/d versus 10.8 mg/d (p = 0.38)). Patients with moderate to severe cognitive deficits more often experienced delirium during their hospitalization (p p = 0.025). Conclusions We reported that with standardized pain management in an orthogeriatric unit, patients aged 75 years and older received the same daily average quantity of strong opioids during the preoperative period regardless of the presence of cognitive deficits.

Background Older patients have a less pronounced immune response to infection, which may also influence infection biomarkers. There is currently insufficient data regarding clinical effects of procalcitonin (PCT) to guide antibiotic treatment in older patients. Objective and design We performed an individual patient data meta-analysis to investigate the association of age on effects of PCT-guided antibiotic stewardship regarding antibiotic use and outcome. Subjects and methods We had access to 9,421 individual infection patients from 28 randomized controlled trials comparing PCT-guided antibiotic therapy (intervention group) or standard care. We stratified patients according to age in four groups (85 years [n = 505]). The primary endpoint was the duration of antibiotic treatment and the secondary endpoints were 30-day mortality and length of stay. Results Compared to control patients, mean duration of antibiotic therapy in PCT-guided patients was significantly reduced by 24, 22, 26 and 24% in the four age groups corresponding to adjusted differences in antibiotic days of −1.99 (95% confidence interval [CI] −2.36 to −1.62), −1.98 (95% CI −2.94 to −1.02), −2.20 (95% CI −3.15 to −1.25) and − 2.10 (95% CI −3.29 to −0.91) with no differences among age groups. There was no increase in the risk for mortality in any of the age groups. Effects were similar in subgroups by infection type, blood culture result and clinical setting (P interaction >0.05). Conclusions This large individual patient data meta-analysis confirms that, similar to younger patients, PCT-guided antibiotic treatment in older patients is associated with significantly reduced antibiotic exposures and no increase in mortality.

Ampullary carcinoma (AC) is histologically classified as intestinal (In-AC), pancreaticobiliary (Pb-AC) or mixed-AC. The prognostic role of AC subtypes has been debated and remains unclear. The aims of this study were to evaluate outcomes after pancreatoduodenectomy (PD) for each subtype of AC and to compare these with pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC].PDs performed for AC between 2010 and 2018 were retrospectively evaluated. Histological subtype was obtained for all patients. One-year, 3-year and 5-year disease-free-survival (DFS) and overall survival (OS) rates were calculated. Kaplan-Meier survival analysis was performed to compare Pb-AC, In-AC and mixed-AC. Comparison with PDs performed for PDAC and DCC during the same period was also performed.A total of 97 patients undergoing PD for AC were evaluated: 34 (35.1%) In-AC, 54 (55.7%) Pb-AC and 9 mixed-AC (9.3%). DFS and OS rates for Pb-AC were significantly lower compared to In-AC (p 0.05 and p 0.01), but similar to mixed-AC (p = 0.3 and p = 0.4). Adjuvant therapy was not associated with increased survival, regardless of the histological subtype (p 0.05). During the same period, 337 and 53 PDs for PDAC and DCC, respectively, were performed. In-AC was associated with significantly better outcomes compared to PDAC and DCC (p 0.001); DFS and OS rates for Pb-AC and mixed AC were significantly higher compared to PDAC (p 0.001), but similar to DCC (p 0.05).Pb-AC has significantly worse survival compared to In-AC. Moreover, mixed-AC should be considered as Pb-AC. Pb-AC and mixed-AC seem to have better prognosis compared to PDAC, but similar to DCC.

Introduction Notwithstanding high prevalence of presumably bacterial infections in elderly persons (EP) in palliative care (PC), there exists no recommendation on the role of antibiotic therapy (ABP) in this type of situation. Objective To describe the determinants of antibiotic prescription by general practitioners (GP) and by doctors practicing in institutions (DPI) for patients > 75 years, in end-of-life situations in PC. Method Descriptive investigation by anonymous self-administered questionnaire disseminated in France by e-mail. Results A total of 301 questionnaires analyzed: 113 GP, 188 DPIs. The latter were mainly geriatricians (69, 36.6%) and infectologists/internists (41, 21.8%). Sixty-three (55,75%) GPs and 144 (78.7%) DPIs stated that they had prescribed antibiotics. Practice in "EHPAD" retirement homes or intensive care was often associated with non-prescription of antibiotics. Age, PC training and number of patients monitored bore no influence. Family involvement in decision-making was more frequent for GPs than for DPIs. The main purpose of antibiotic therapy was to relieve different symptoms (fever, respiratory congestion, functional urinary signs). Most of the doctors (81%) had previously encountered complications (allergy, adverse effect), which represented the main causes of treatment discontinuation. Conclusion Antibiotic use in end-of-life EPs in PC seems frequent. In accordance with the principle of beneficence, its goal of often symptom-related; that said, in the absence of scientific data, antibiotic prescription in end-of-life situations should be individualized in view of observing the other ethical caregiving principles (beneficence, non-maleficence, justice, patient autonomy) and re-evaluated daily.

ImportanceNursing home (NH) residents are particularly vulnerable to SARS-CoV-2 infections and coronavirus disease 2019 (COVID-19) lethality. However, excess deaths in this population have rarely been documented.ObjectivesThe primary objective was to assess the number of excess deaths among NH residents during the first wave of the COVID-19 pandemic in France. The secondary objectives were to determine the number of excess deaths as a proportion of the total excess deaths in the general population and determine whether a harvesting effect was present.DesignWe studied a cohort of 494,753 adults (as of March 1st, 2020) aged 60 and over in 6,515 NHs in mainland France. This cohort was exposed to the first wave of the COVID-19 pandemic (from March 1st to May 31st, 2020) and was compared with the corresponding, reference cohorts from 2014 to 2019 (using data from the French National Health Data System).Main outcome and measuresThe main outcome was all-cause death. Weekly excess deaths and standardized mortality ratios (SMRs) were estimated.ResultThere were 13,505 excess deaths among NH residents. Mortality increased by 43% (SMR: 1.43). The mortality excess was higher among males than among females (SMR: 1.51 and 1.38, respectively) and decreased with age (SMRs in females: 1.61 in the 60-74 age group, 1.58 for 75-84, 1.41 for 85-94, and 1.31 for 95 or over; Males: SMRs: 1.59 for 60-74, 1.69 for 75-84, 1.47 for 85-94, and 1.41 for 95 or over). We did not observe a harvesting effect (up until August 30th, 2020). By extrapolating to all NH residents nationally (N=570,003), the latter accounted for 51% of the total excess deaths in the general population (N=15,114 out of 29,563).ConclusionNH residents accounted for about half of the total excess deaths in France during the first wave of the COVID-19 pandemic. The excess death rate was higher among males than females and among younger residents than among older residents. We did not observe a harvesting effect. A real-time mortality surveillance system and the identification of individual and environmental risk factors might help to design the future model of care for older dependent adults.Key pointsDuring the first wave of the COVID-19 pandemic in France, the mortality among nursing home residents increased by 43%.Nursing home residents accounted for 51% of the total excess deaths in France.The excess mortality was higher among younger residents than among older residents.The excess mortality was higher among males than among females.We did not observe a harvesting effect during the study period (ending on August 30th, 2020, i.e., three months after the end of the first wave).

Summary Objective Low skeletal muscle is a common characteristic of cancer-related malnutrition and a predictor of poorer prognosis in oncological patients. In this study we evaluated nutritional status and altered body composition using computed tomography (CT) and bioelectrical impedance analysis (BIA) in newly diagnosed patients. Our purpose was to compare the results of two available techniques to assess body composition suggested by the guidelines and some diagnostic criteria to identify malnutrition. Methods In a prospective study, patients with a new diagnosis of advanced solid tumour were enrolled and evaluated before starting first-line chemotherapy. Anthropometric, body composition and systemic inflammation measurements were collected and cut-off points from literature data were used for results classification. Malnutrition was expressed as weight loss (WL) in the previous 6 months >10% and underweight body mass index (BMI). Altered body composition was assessed as low index both skeletal muscle (SMI) derived by CT and fat-free mass by BIA (FFMI). Descriptive statistic was presented. Several statistical correlation analyses were performed. Results 67 patients were assessed: 40M/27F; average age 59 ± 13 years and BMI 23 ± 4; 43 (64%) upper gastrointestinal, 12 lung, 9 colorectal, 3 other cancers. Fourty-five (67%) were malnourished with WL criteria but only 8 (12%) resulted underweight. From analysis of CT images and BIA, 49 (73%) and 10 (15%) patients respectively reported lower cut-off point. Overall, 35 (52%) had both sarcopenia and WL > 10%. Conclusions Our results suggest that prevalence data of malnutrition expressed as WL are more in agreement with those of sarcopenia recognised using CT than BIA method. Further studies are required to confirm these findings and to identify the best and easiest methods for monitoring BC during nutritional intervention and oncological therapies.

Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expression[ISG] scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.Across the AGS cohort (n = 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test; p = 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly p = 0.0401, age onset p = 0.0355). While most subjects (n = 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS.

Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability.This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed.More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants.Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children.National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic cardiac condition whose prevalence continues to rise, with high social and economic burden, but with no specific approved treatment. Patients diagnosed with HFpEF have a high prevalence of comorbidities and exhibit a high misdiagnosis rate. True HFpEF is likely to have multiple pathophysiological causes - with these causes being clinically ill-defined due to limitations of current measurement techniques. Myocyte, interstitium, microvascular, and metabolic abnormalities have been regarded as key components of the pathophysiology and potential therapeutic targets. Cardiac magnetic resonance (CMR) has the capability to look deeper with a number of tissue characterization techniques which are closer to the underlying specific abnormalities and which could be linked to personalized medicine for HFpEF. This review aims to discuss the potential role of CMR to better define HFpEF phenotypes and to infer measurable therapeutic targets.

The COVID-19 epidemic that started in November in China became a national epidemic from March 16, 2020 with the declaration of population containment in order to reduce the spread of the virus in France. From March 17 to March 27, 2020, the monitoring unit of the French society of geriatrics and gerontology decided to conduct a survey to analyze the implementation of the mobilization of geriatric units, given that this epidemic had shown that it resulted in excess mortality mainly among the elderly. The survey was able to bring together the response of 34 services, nine of which were located in a high epidemic cluster zone. Dedicated acute geriatric units for patients infected with COVID-19 were present in eight facilities, only outside the cluster zones. Nine geriatric follow-up and rehabilitation services were dedicated, an additional telemedicine activity concerned 35% of the facilities, and family listening and tablet communication facilities concerned 36% of the facilities. This survey is a snapshot of an initial moment in the epidemic. It provides an opportunity to describe the context in which this epidemic occurred in terms of geriatric policy, and to assess the responsiveness and inventiveness of these services in meeting the needs of the elderly.

Neurophysiological studies suggest that music reading facilitates sensorimotor cortex. The aim of this study was to evaluate (1) whether in pianists, reading notes in bass and treble clef selectively enhances right and left primary motor cortex (M1) excitability; and (2) whether reading notes played with the thumb or little finger selectively modulates the excitability of specific muscles. Twenty musicians (11 pianists, 9 non-pianists) participated. Transcranial magnetic stimulation (TMS) was applied while subjects read the bass or the treble clef of sheets music and during the observation of a blank staff (baseline). When pianists read the treble clef, the excitability of the left M1 was higher compared to that recorded in the right M1. Moreover, in the treble clef condition motor evoked potentials (MEPs) induced by TMS of the left M1 were higher when pianists read notes to be played with the 5° finger (little finger) with respect to 1° finger (thumb) notes, whereas in the bass clef condition TMS of the right M1 induced higher MEPs for 1° finger note compared to 5° finger notes. No significant modulation was observed in non-pianists. These data support the view that music reading may induce specific inter- and intra-hemispheric modulation of the motor cortex excitability.

Hyperthermia treatment planning (HTP) is valuable to optimize tumor heating during thermal therapy delivery. Yet, clinical hyperthermia treatment plans lack quantitative accuracy due to uncertainties in tissue properties and modeling, and report tumor absorbed power and temperature distributions which cannot be linked directly to treatment outcome. Over the last decade, considerable progress has been made to address these inaccuracies and therefore improve the reliability of hyperthermia treatment planning. Patient-specific electrical tissue conductivity derived from MR measurements has been introduced to accurately model the power deposition in the patient. Thermodynamic fluid modeling has been developed to account for the convective heat transport in fluids such as urine in the bladder. Moreover, discrete vasculature trees have been included in thermal models to account for the impact of thermally significant large blood vessels. Computationally efficient optimization strategies based on SAR and temperature distributions have been established to calculate the phase-amplitude settings that provide the best tumor thermal dose while avoiding hot spots in normal tissue. Finally, biological modeling has been developed to quantify the hyperthermic radiosensitization effect in terms of equivalent radiation dose of the combined radiotherapy and hyperthermia treatment. In this paper, we review the present status of these developments and illustrate the most relevant advanced elements within a single treatment planning example of a cervical cancer patient. The resulting advanced HTP workflow paves the way for a clinically feasible and more reliable patient-specific hyperthermia treatment planning.

Whether the presence of bacteria in the bile or postoperative infections sustained by microorganisms with different levels of drug-resistance are associated with changes in the oncologic prognosis of patients undergoing surgery for pancreatic cancer has not been thoroughly investigated. The aim was to study the association of bile contamination, postoperative infections, and multi-level resistance with long-term outcome.Prospectively maintained databases were queried for patients who underwent pancreatoduodenectomy (PD). Patients who underwent preoperative biliary stenting prior to PD and an intraoperative bile culture were included. The levels of bacterial resistance of intraoperative bile cultures and of specimens of postoperative infections were stratified into multidrug sensitive (MDS), multidrug-resistant (MDR), and extensive drug-resistant (XDR).A total of 267 patients met the inclusion criteria. The Kaplan-Meier survival curves for overall survival (OS) of patients having no bacteriobilia or positive cultures with MDS versus MDR/XDR bacteria were not statistically different (log-rank=0.9). OS of patients stratified for no postoperative infection or infections by MDS was significantly better than those having MRD/XDR isolates (log-rank=0.04). A Cox multivariate model showed that having MRD/XDR postoperative infections was and independent variable for worse OS (HR=1.227; 95%CI=1.189-1.1918; p=0.036).Postoperative drug resistant infections are a significant risk factor for poor OS after pancreatoduodenectomy for ductal adenocarcinoma.

ObjectiveAutoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of ‘points to consider’ to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases.MethodsMembers of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, ‘points to consider’ to guide patient management were developed.ResultsThe Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS.ConclusionThese points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.

There are sex differences in vulnerability to Coronavirus disease 2019 (COVID-19). The coronavirus S protein mediates viral entry into target cells employing the host cellular serine protease TMPRSS2 for S-protein priming. The TMPRSS2 gene expression is responsive to androgen stimulation and it could partially explain sex differences. We hypothesized that men chronically exposed to 5-alpha reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) have a lower risk of hospitalization for COVID-19.This is a population-based case-control study on consecutive patients positive for SARS-CoV-2 virus who required hospitalization for COVID-19 (cases), age-matched to beneficiaries of the Lombardy Regional Health Service (controls). Data were collected by two high-volume COVID-19 regional centers of Lombardy (Italy). The primary outcome was to compare the prevalence of patients chronically exposed to 5ARIs, who required hospitalization for COVID-19, with the one of controls.Overall, 943 males were enrolled; 45 (4.77%) were exposed to 5ARI. COVID-19 patients aged55 years under 5ARI treatment were significantly less than expected on the basis of the prevalence of 5ARI treatment among age-matched controls (5.57 vs. 8.14%; P=0.0083, 95% CI: 0.75-3.97%). This disproportion was higher for men aged65 (7.14 vs. 12.31%; P=0.0001, 95% CI: 2.83-6.97%). Eighteen 5ARIs-patients died; the mean age of men who died was higher than those who did not: 75.98±9.29 vs. 64.78±13.57 (P0.001). Cox-regression and multivariable models did not show correlation between 5ARIs exposure and protection against intensive care unit admission/death.Men exposed to 5ARIs might be less vulnerable to severe COVID-19, supporting its use in disease prophylaxis.

The lifting of non-pharmaceutical measures preventing transmission of SARS-CoV-2 (and other viruses, including influenza viruses) raises concerns about healthcare resources and fears of an increased number of cases of influenza and COVID-19. For the 2021-2022 influenza season, the WHO and20 European countries promoted coadministration of influenza and COVID-19 vaccines. Recently, the French Health Authority recommended coupling the COVID-19 vaccination with the 2022-2023 influenza vaccination campaign for healthcare professionals and people at risk of severe COVID-19. The present systematic review examines published data on the safety, immunogenicity, efficacy/effectiveness, and acceptability/acceptance of coadministration of influenza and COVID-19 vaccines. No safety concerns or immune interferences were found whatever the vaccines or the age of vaccinated subjects (65- or 65+). No efficacy/effectiveness data were available. The results should reassure vaccinees and vaccinators in case of coadministration and increase vaccine coverage. Healthcare systems promoting coupled campaigns must provide the necessary means for successful coadministration.The lifting of non-pharmaceutical measures recommended to prevent transmission of SARS-CoV-2 (and other viruses, including influenza viruses) raises concerns about healthcare resources, already under pressure. It also raises fears of an increase in the number of cases of influenza or COVID-19 infection during the winter season. For the 2021–2022 influenza season, the World Health Organization and several European countries promoted concomitant administration in distinct anatomic sites (i.e., coadministration) of influenza and COVID-19 vaccines to avoid additional stress on healthcare systems. In May 2022, the French Health Authority recommended coupling the COVID-19 vaccination with the 2022–2023 influenza vaccination campaign (i.e., starting COVID-19 vaccination at the date of influenza vaccination) for healthcare professionals and people at risk of severe COVID-19, in case of epidemic wave. Coadministration of influenza and COVID-19 vaccines is one of the factors of success for a coupled campaign. The present systematic review examines all published data (articles or reports, clinical trials, or surveys) on the safety, immunogenicity, efficacy/effectiveness, and acceptability/acceptance of coadministration of influenza and COVID-19 vaccines. The PRISMA method was used to collect information. No safety concerns or immune interferences were found whatever the vaccines or the age of vaccinated subjects (65- or 65+). No efficacy/effectiveness data were available. Acceptability and acceptance were good but could be improved. By reassuring vaccinees and vaccinators, these results are expected to favor coadministration and ultimately increase vaccine coverage, thus offering better protection. Healthcare systems promoting coupled campaigns with coadministration must provide the necessary means for their successful implementation.

Purpose Bariatric surgery, as Roux-en-Y gastric bypass (RYGB), laparoscopic gastric banding (LGB), and laparoscopic sleeve gastrectomy (LSG), is considered the gold standard treatment to achieve long-term weight loss in severe obesity. In patients who fail to maintain the achieved weight, pharmacological treatment may be required. Here, we reported our real-life experience on the efficacy of liraglutide therapy in 62 patients who regained weight after bariatric surgery. Methods We retrospectively evaluated 62 (60 F-2 M; mean age: 43.6 ± 9.9 years) patients received liraglutide for weight loss after bariatric surgery (17 RYGB, 22 LGB, and 23 LSG). Body mass index (BMI) before and after surgery was, respectively, of 45.4 ± 5.5 kg/m2 and 29.5 ± 4.9 kg/m2. Patients were followed up from 2016 until 2021. Liraglutide was administered after weight regain once-daily subcutaneously at starting dose of 0.6 mg and with weekly increases up to 3.0 mg. Treatments were administered when a weight regain of 10–15% occurred after reaching a minimum weight loss from bariatric surgery or if weight loss after bariatric surgery was unsatisfactory. Results After a mean of 70.7 ± 43.7 months from any bariatric surgery, all patients started liraglutide therapy. At this time, mean BMI was 34.2 ± 4.8 kg/m2 (mean increased BMI: 4.7 ± 2.8 kg/m2). After a mean of 10.5 ± 4.4 months from the beginning of liraglutide, 9 patients achieved normal weight (BMI 24.1 ± 0.9 kg/m2), and 28 were overweight (BMI 26.9 ± 1.6 kg/m2). Twenty patients achieved grade I (BMI 32.1 ± 1.5 kg/m2), 5 grade II (BMI 37.3 ± 2.0 kg/m2) obesity, and none had grade III obesity (mean BMI change: − 5.1 ± 2.5 kg/m2). The treatment was well tolerated, and no serious adverse events were recorded. Conclusion These data confirm the efficacy and safety of liraglutide in patients who experienced weight regain after bariatric surgery. Considering the long-term follow-up, patients should be followed up regularly and the pharmacological treatment should be adapted to the weight fluctuations observed during the clinical history. Level of evidence V. Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

International audience; BackgroundIn France, each year, influenza viruses are responsible for seasonal epidemics leading to 2–6 million cases. Influenza can cause severe disease that may lead to hospitalization or death. As severe disease may be due to the virus itself or to disease complications, estimating the burden of severe influenza is complex. The present study aimed at estimating the epidemiological and economic burden of severe influenza in France during eight consecutive influenza seasons (2010–2018).MethodsInfluenza-related hospitalization and mortality data and patient characteristics were taken from the French hospital information database, PMSI. An ecological approach using cyclic regression models integrating the incidence of influenza syndrome from the Sentinelles network supplemented the PMSI data analysis in estimating excess hospitalization and mortality (CépiDc—2010–2015) and medical costs.ResultsEach season, the average number of influenza-related hospitalizations was 18,979 (range: 8627–44,024), with an average length of stay of 8 days. The average number of respiratory hospitalizations indirectly related with influenza (i.e., influenza associated) was 31,490 (95% confidence interval [CI]: 24,542–39,012), with an average cost of €141 million (range: 54–217); 70% of these hospitalizations and 77% of their costs concerned individuals ≥65 years of age (65+). More than 90% of excess mortality was in 65+ subjects.ConclusionsThe combination of two complementary approaches allowed estimation of both influenza-related and associated hospitalizations and deaths and their burden in France, showing the substantial impact of complications. The present study highlighted the major public health burden of influenza and its severe complications, especially in 65+ subjects.

Introduction Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues. Cases presentation The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI. Discussion Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity. Conclusion The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features.

Patients with fistula risk score (FRS) ≥7 are at the highest risk of developing clinically relevant post-operative pancreatic fistula (CR-POPF). There is no agreement on the management of this subpopulation. The primary outcome of the study was the definition of the role of intraoperative completion pancreatectomy (ICP) in patients at high risk for CR-POPF, as an alternative to high-risk pancreaticoduodenectomy (PD). This is an observational study set in a single tertiary referral center. Patients scheduled for PD in our center between 2010 and 2019 with FRS ≥7 were included in the study. Data were prospectively collected. A total of 738 patients were scheduled for between 2010 and 2019, and 62 had FRS ≥7. Thirty-five patients were managed with PD and pancreatico-jejunal anastomosis (group A), and 27 with ICP (group B). Overall complication rate was significantly higher in group A than group B (95 versus 59%; p=0.005) and there was a not significantly higher rate of major complications (Clavien-Dindo ≥3) (43 versus 26%; p=0.192). In group A, 49% of patients had a CR-POPF. Median post-operative length of stay was 15 days in group A and 12 in group B (p=0.043). Readmission was observed only in group A (26%). In multivariate analysis, PD was an independent predictive factor of major post-operative morbidity (RR 9.27; CI 1.74–49.31). No patients in either group suffered major adverse events related to endocrine and exocrine insufficiency. In high-FRS patients, ICP has good short-term outcomes relative to PD without major long-term events related to endocrine and exocrine insufficiency. ICP could be considered as a feasible alternative in selected cases.

Background and purpose The cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is assumed to be due to a cortical-subcortical disconnection secondary to damage to the cerebral white matter (WM). Using resting state functional MRI (rsfMRI) and analysis of the regional homogeneity (ReHo), we examined a group of CADASIL patients and a group of healthy subjects in order to: (1) explore possible differences between the two groups; and (2) to assess, in CADASIL patients, whether any ReHo abnormalities correlate with individual burdens of WM T2 -weighted hyperintensity and diffusion tensor imaging (DTI)-derived index of mean diffusivity (MD) of the cerebral WM, an index reflecting microstructural damage in CADASIL. Methods Twenty-three paucisymptomatic CADASIL patients (13 females; age mean ± standard deviation = 43.6 ± 11.1 years; three symptomatic and 20 with no or few symptoms) and 16 healthy controls (nine females; age 46.6 ± 11.0 years) were examined with T1 -weighted, T2 -weighted fluid attenuated inversion recovery images, DTI, and rsfMRI. Results When compared to controls, CADASIL patients showed four clusters of significantly lower ReHo values in cortical areas belonging to networks involved in inhibition and attention, including the right insula, the left superior frontal gyrus, and the bilateral anterior cingulated cortex. ReHo changes did not correlate with an individual patient's lesion burden or MD. Conclusions This study reveals decreased ReHo of rsfMRI signals in cortical areas involved in inhibition and attention processes, suggesting a potential role for these functional cortical changes in CADASIL.

The different oncological outcomes of invasive intraductal papillary mucinous neoplasm (I-IPMN) and pancreatic ductal adenocarcinoma (PDAC) are debated. This study aimed to compare disease recurrence patterns and histopathological characteristics in patients with resected I-IPMN and PDAC.Consecutive patients undergoing surgical resection for stage I-III I-IPMN or PDAC between 2010 and 2016 were retrospectively analyzed. Patients treated with neoadjuvant therapy or resected for Tis neoplasia were excluded. All surgical specimens were re-staged according to AJCC-8th-edition.A total of 330 patients were included, of whom 43 had I-IPMN and 287 had PDAC. Median follow-up time was 26.7 (1.3-92.3) months and estimated median disease-free survival (DFS) was 60.3 months (47.2-73.4) for I-IPMN and 23.8 (19.3-28.2) months for PDAC (p 0.001). During follow-up, 32.6% of I-IPMN and 67.9% of PDAC patients experienced recurrence (p 0.001). The sites of first recurrence were the lungs (38.5% vs 13.1%, p = 0.027), liver (28.6% vs 45.0%, p = 0.180) and local (15.4% vs 36.6%, p = 0.101) for I-IPMN and PDAC, respectively. At multivariate analysis, I-IPMN histology remained an independent predictive factor for longer DFS (OR 0.528, CI 95% 0.278-1.000, p = 0.050), regardless of stage or adjuvant chemotherapy. I-IPMN and PDAC differed in rates of neuroinvasion (51.2% vs 97.2%) and positive lymph node status (N+) (46.5% vs 82.7%), especially in patients with lower T status.I-IPMN showed a different recurrence pattern compared to PDAC, with a higher lung tropism, and longer DFS. This different biological behavior is associated with lower rates of neuroinvasion and nodal involvement, especially in early-stage disease.

Background Leukodystrophies are a rare class of disorders characterized by severe neuromotor disability. There is a strong need for research regarding the functional status of people with leukodystrophy which is limited by the need for in-person assessments of mobility. The purpose of this study is to assess the reliability of the Gross Motor Function Measure-88 (GMFM-88) using telemedicine compared with standard in-person assessments in patients with leukodystrophy. Methods A total of 21 subjects with a diagnosis of leukodystrophy (age range = 1.79-52.82 years) were evaluated by in-person and by telemedicine evaluations with the GMFM-88 by physical therapists. Inter-rater reliability was assessed through evaluation of the same subject by two independent raters within a three-week period (n = 10 encounters), and intrarater reliability was assessed through blinded rescoring of video-recorded assessments after a one-week time interval (n = 6 encounters). Results Remote assessments were performed by caregivers in all 21 subjects using resources found in the home with remote guidance. There was agreement between all paired in-person and remote measurements (Lin's concordance correlation ≥0.995). The Bland-Altman analysis indicated that the paired differences were within ±5%. Intrarater and inter-rater reliability demonstrated an intraclass correlation coefficient of >0.90. Conclusions These results support that remote application of the GMFM-88 is a feasible and reliable approach to assess individuals with leukodystrophy. Telemedicine application of outcome measures may be of particular value in rare diseases and those with severe neurologic disability that impacts the ability to travel.

Mutations in TUBB4A are associated with a spectrum of neurologic disorders categorized as TUBB4A-related leukoencephalopathy. Affected children can present with global developmental delay or normal early development, followed by a variable loss of skills over time. Further research is needed to characterize the factors associated with the divergent developmental trajectories in this rare monogenic disorder because this phenotypic spectrum is not fully explained by genotype alone. To characterize early psychomotor features, developmental milestones and age of disease onset were collected from medical records (n=54 individuals). Three subcohorts were identified: individuals with the common p.Asp249Asn variant vs all other genotypes with either early ( Our results suggest multiple influences on developmental trajectory, including a strong contribution from genotype and age of onset. Further studies are needed to identify additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

Summary Introduction No recent national guidelines exist regarding the management of urinary tract infections (UTIs) in the presence of ureteral stent. This situation could lead to discrepancies in clinical management and less opportunity for a favorable patient's outcome. Methods All available data published on Medline® between 1998 and 2018 were systematically searched and reviewed. All papers assessing adult patients carrying ureteral stent were included for analysis. After studies critical analysis, national guidelines for clinical management were elaborated in order to answer clinical questions. Results A total of 451 articles were identified, of which 58 have been included. The prevalence of urinary tract infections in the presence of ureteral stent remains unknown. After 3 months, all endo-ureteral devices were colonized on microbiological study. These patients also presented a positive urine culture in 25 to 70% of the cases, often polymicrobial. Staphylococci, E. coli, Klebsiella, Pseudomonas, Enterococcus and Candida were the commonest micro-organisms responsible for urinary colonization or infection. The risk of UTI on endo-ureteral devices seemed higher the longer it stayed implanted. There is no justification in the literature to recommend a systematic change of endo-ureteral devices following a urinary tract infection. Discussion The existing literature is rich but of poor methodological quality, and therefore does not allow to draw robust conclusions. The greatest difficulty faced in this work was to accurately differentiate urinary colonizations from true infections, including clinical symptoms and not only microbiological results. Conclusion These guidelines propose a standardized management of such common clinical situations. Well-designed studies are needed to upgrade the level of evidence of these guidelines.

Background Natriuretic peptides and diastolic dysfunction have prognostic value in asymptomatic subjects at risk for heart failure. Their integration might further refine the risk stratification process in this setting. Aim of this paper was to explore the possibility to predict heart failure and death combining diastolic dysfunction and natriuretic peptides in an asymptomatic population at risk for heart failure. Methods Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for heart failure. Baseline evaluation included electrocardiogram, echocardiogram, and natriuretic peptides collection. Based on diastolic dysfunction and natriuretic peptides, subjects were classified in four groups: control group (no diastolic dysfunction/normal natriuretic peptides, 57%), no diastolic dysfunction/high natriuretic peptides (9%), diastolic dysfunction/normal natriuretic peptides (24%), and diastolic dysfunction/high natriuretic peptides (11%). We applied Cox multivariable and Classification and Regression Tree analyses. Results The mean age of the population was 69 ± 7 years, 44% were women, mean left ventricular ejection fraction was 61%, and 35% had diastolic dysfunction. During a median follow-up of 5.7 years, 95 heart failure/death events occurred. Overall, diastolic dysfunction and natriuretic peptides were predictive of adverse events (respectively, hazard ratio 1.91, confidence interval 1.19–3.05, padjusted = 0.007, and hazard ratio 2.25, confidence interval 1.35–3.74, padjusted = 0.002) with Cox analysis. However, considering the four study subgroups, only the group with diastolic dysfunction/high natriuretic peptides had a significantly worse prognosis compared to the control group (hazard ratio 4.48, confidence interval 2.31–8.70, padjusted Conclusions The DAVID-Berg data suggest that we look for the quite common combination of diastolic dysfunction/high natriuretic peptides to correctly identify asymptomatic subjects at greater risk for incident heart failure/death, thus more suitable for preventive interventions.

Background Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. Methods Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. Results 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO2/FiO2 was similar between men and women (228 [IQR, 134–273] vs 238 mmHg [150–281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan–Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687). Conclusion Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

International audience; OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200?mL (60-400) vs 300?mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P \textless 0.001] were lower after MIDP. Clavien-Dindo grade >=3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P \textgreater 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P \textless 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P \textless 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Sleep disordered breathing (SDB) and neurocognitive impairment (NI) are a typical feature of HF (heart failure), especially with preserved ejection fraction (HFpEF). So far, very few data exist regarding changes in the severity of SDB, the degree of NI, and the diastolic function in acute HF (AHF) patients and during follow up. In a population of 24 AHF patients (12 with reduced ejection fraction-HFrEF- and 12 HFpEF) with SDB a complete echocardiogram, a set of NI tests, and a polysomnography were performed in the acute phase and after 90days. A control group of 12 non-HF patients hospitalized for other cardiovascular causes was considered. At baseline, SDB were present both in HFpEF and HFrEF, and a consistent reduction of apneic events was observed at follow up. Improvements in diastolic and right ventricular function were documented at three months compared to baseline, both in HFpEF and in HFrEF. Compared to HFrEF patients and controls, HFpEF patients showed lower NI scores at baseline tests, but a more significant improvement at three months follow-up. In AHF patients with SDB the achievement of a better compensation could lead to important beneficial effect not only on echocardiographic variables and nocturnal respiratory profile, but also on NI, especially in HFpEF.

Background In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. Aim To examine the neurobiology of transgender persons in a large sample. Methods Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. Outcomes Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. Clinical Translation The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. Strengths and Limitations While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype.

Trans-duodenal ampullectomy (TDA) is a surgical option for the treatment of selected ampullary neoplasms. The aim of this study was to evaluate our experience with TDA for the treatment of ampullary neoplasms, focusing on indications, technical aspects, and short- and long-term outcomes. All TDAs for ampullary neoplasms performed between January 2010 and December 2018 at our institution were retrospectively evaluated. Patients had ampullary neoplasms with low-grade dysplasia or in situ carcinoma (Tis) not suitable for an endoscopic approach, ampullary carcinoma unfit for pancreaticoduodenectomy (PD), or ampullary neuroendocrine G1-tumours. Thirty-six patients were included in the study: 9 (25.0%) with neoplasms with low-grade dysplasia, 4 (11.1%) with G1 neuroendocrine tumours and 23 (63.9%) with Tis or invasive carcinoma. Mean operative time was 252.5 min. Overall and severe (Clavien–Dindo > IIIa) morbidity rate was 44.4% and 13.9%, respectively. No 90-day mortality was observed. At follow-up, no deaths were observed and local recurrence rate was 11.1% for patients with ampullary adenomas with low-grade dysplasia. Among four patients with neuroendocrine neoplasms, only one developed recurrence (pulmonary). Tis, T1 and T2 lesions were found in 16 (69.6%), 2 (8.7%) and 5 (21.7%) patients, respectively: recurrence occurred in 3 patients with Tis lesions (one malignant), no patients with T1 neoplasms and 2 patients with T2 lesions (3 patients had a survival of > 3 years). TDA is a feasible and effective surgical procedure for the treatment of ampullary adenomas with low-grade dysplasia when endoscopic approach is contraindicated or has failed. For lesions with evidence of malignancy, TDA seems to be an oncological safe procedure for Tis ampullary cancer and a good palliative procedure for patients unfit for PD. Moreover, TDA may be appropriate for the treatment of G1 ampullary neuroendocrine neoplasms. A large multicentre study of TDA for early ampullary cancers is needed.

BACKGROUND Nutrition plays an important role in the aging process. Adherence to the Mediterranean diet (MedDiet) has been shown to be associated with lower rates of diseases. Cognitive status seems to be strongly interrelated with physical well-being, so that one influences the other. Physical performance measures are not only associated with clinical and subclinical age-related modifications, but are also able to predict disability, institutionalization, and mortality. OBJECTIVE To evaluate prospectively the associations between Mediterranean-Style Dietary Pattern Score (MSDPS), clinical characteristics, and cognition of the population sample of The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. METHODS Global cognition, physical performance measures, MSDPS, and other clinical features were detected in 2010 in 82 men and 108 women. These characteristics were evaluated in relation to the physical performance measures identified 3.8 years later in 2013 in the same subjects, using a semantic connectivity map, through Auto-CM system, to grasp further and non-linear associations between variables which might remain, otherwise, undetected. RESULTS The Auto-CM system's map showed a close association between better levels of global cognition and MSDPS in 2010 and higher physical performance in 2013. On the other hand, worse levels of global cognition and MSDPS in 2010 were associated with lower physical performance in 2013. CONCLUSION The prevention models for successful aging may benefit from integrated programs that include cognitive, physical, and dietary interventions, since these aspects are mutually interrelated.