White matter changes in corticobasal degeneration syndrome and correlation with limb apraxia

BACKGROUND: Data on white matter changes in corticobasal degeneration syndrome (CBDS) are not yet available, whereas cortical gray matter loss is a feature of this condition. The structural abnormalities related to a key feature of CBDS (limb apraxia) are unknown. OBJECTIVES: To measure selective structural changes in early CBDS using diffusion tensor imaging and voxel-based morphometry and to evaluate the structural correlates of limb apraxia. DESIGN: Patient and control group comparison. SETTING: Referral center for dementia and movement disorders. PARTICIPANTS: Twenty patients with CBDS and 21 matched control subjects. INTERVENTIONS: Clinical and standardized neuropsychological evaluations, including assessment of limb apraxia. MAIN OUTCOME MEASURES: Gray and white matter changes in early CBDS. RESULTS: Diffusion tensor imaging revealed decreases in fractional anisotropy in the long frontoparietal connecting tracts, the intraparietal associative fibers, and the corpus callosum. Fractional anisotropy was also reduced in the sensorimotor projections of the cortical hand areas. Voxel-based morphometry showed a prevalent gray matter reduction in the left hemisphere (in the inferior frontal and premotor cortices, parietal operculum, superotemporal gyrus, and hippocampus). The pulvinar, bilaterally, and the right cerebellar cortex also showed atrophy. Limb apraxia correlated with parietal atrophy and with fractional anisotropy reductions in the parietofrontal associative fibers (P < .01). The limb-kinetic component of apraxia correlated with reduction of hand sensorimotor connecting fibers. CONCLUSIONS: The present integrative approach to in vivo structural anatomy combines hodologic imaging, describing patterns of white matter connections between cortical areas, with neuropsychological data. This provides new evidence of gray matter and fiber tract abnormalities in early-phase disease and contributes to clarifying the neural basis of apraxia in CBDS

Comparison between hospitalized patients affected or not by COVID-19 (RESILIENCY study)

Dear Editor, in the recent report of Munblit and coworkers [1], authors observed that the combination of clinical features was sufficient to diagnose COVID-19 indicating that laboratory testing is not critical in real-life clinical practice. To date, all patients admitted to Emergency Department with acute respiratory failure and/or fever should be considered as a suspected SARS-CoV-2 infection [2-3], and an early recognition of etiology and the prompt therapeutic management are crucial to improve survival [4-5]. From March to July 2020, we performed a prospective, multicenter study (RESILIENCY study). During the study period, all patients hospitalized for suspected or confirmed COVID-19 were prospectively recruited in 3 large hospitals in Rome, Italy. All patients with suspected SARS-CoV-2 infection, admitted to the hospital in case of fever and/or hypoxemic respiratory failure (PaO2 &lt;60 mmHg at rest in ambient air) or of exacerbation of underlying diseases or severe symptoms not manageable outside the hospital, were evaluated according to a predefined protocol (see Figure 1). Overall, 653 patients were included in the study: 309 (47.3%) patients with confirmed COVID-19 and 344 (52.7%) without COVID-19, hospitalized for other causes. Baseline characteristics and outcomes of the study population showed that the main causes of hospitalization among patients without COVID-19 were: acute heart failure (47%), bacterial pneumonia (38.5%), and pulmonary embolism (9.2%). Overall, 67 (21.7%) patients of COVID-19 group and 45 (13.1%) hospitalized for other causes were admitted to intensive care unit; 30-day mortality was observed in 59 (19%) patients of COVID-19 group and 62 (18%) of non-COVID-19 group. The multivariate analysis about risk factors for COVID-19 etiology at time of hospitalization showed that dry cough (OR 3.76, CI 95% 1.98-7.92, P&lt;0.001), duration of fever&gt;3 days (OR 5.21, CI 95% 2.34-9.21, P&lt;0.001), lymphocytopenia (OR 1.98, CI 95% Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1745/5989494 by Sapienza Università di Roma user on 01 December 2020 Accepted Manuscript 3 1.27-4.22, P=0.002) and PaO2/FiO2 ratio&lt;250 (OR 4.98, CI 95% 2.22-9.71, P&lt;0.001) were independently associated with COVID-19 etiology, while procalcitonin value&gt;1 ng/ mL (OR 0.21, CI 95% 0.08-0.82, p&lt;0.001), and lactate&gt;2 mmol/L (OR 0.41, CI 95% 0.15-0.77, p&lt;0.001) were associated with non-COVID-19 etiology. Finally, analysis about predictors of 30-day mortality showed that age (per-year increase OR 1.33; CI 95% 1.11-2.10; p&lt;0.001), cardiovascular disease (OR 4.58; CI 95% 2.07-8.25; p&lt;0.001), and ICU admission (OR 2.1; CI 95% 1.48-4.4; p&lt;0.001) were independently associated with all-cause 30-day mortality, while the use of low-molecularweight heparin (OR 0.22, CI 95% 0.03-0.45, p=0.002) was associated with survival. The findings of the present study can be summarized as follows:1) the prompt identification of specific clinical characteristics (like dry cough or duration of fever&gt;3 days), and laboratory findings (like lymphocytopenia, PaO2/FiO2 ratio&lt;250, procalcitonin value&gt;1 ng/ mL, and lactate&gt;2 mmol/L) can help physicians to distinguish rapidly between COVID19 or other etiologies [6]; 2) the application of a standard approach to management of patients with acute respiratory failure and/or fever associated with the knowledge of clinical and laboratory characteristics of COVID-19 can early drive physicians to therapeutic choices; and 3) age, cardiovascular disease, and ICU admission show an independent association with all-cause 30-day mortality [7], while the use of low-molecular-weight heparin was associated with survival [8]. In conclusion, COVID-19 syndrome is characterized by a heterogeneous clinical, laboratoristic, and radiological presentation, especially at its onset [9]. However, the application of a standard approach to management of patients with acute respiratory failure and/or fever and the knowledge of clinical and laboratory characteristics of COVID-19 can early drive therapeutic choic

Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.

Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.Work in I.A.’s group is funded by the WellcomeTrust (grant number 210634), BBSRC (BB/R007195/1), and Cancer ResearchUK (C35050/A22284). Work in D.A.’s group is funded by the Cancer ResearchUK Career Development Fellowship (grant number 16304). Work in the S.J.B.lab is supported by the Coun, which receives its core fundingfrom Cancer Research UK (FC0010048), the UK Medical Research Council(FC0010048), and the Wellcome Trust (FC0010048); a European Research Council (ERC) Advanced Investigator Grant (TelMetab); and Wellcome TrustSenior Investigator and Collaborative Grants. S.S.-B. was the recipient of an EMBO Long Term Fellowship (ALTF 707-2019) and a MSCA individual fellow-ship (grant 886577). Work in the J.R.C. group is funded by CRUK Career Devel-opment Fellowship (C52690/A19270) with infrastructural support from Well-come core award 090532/Z/09/ZS

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

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

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 &lt; 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