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Background: Pyothorax in cats is routinely managed, at least initially, with thoracic tube placement associated with systemic antimicrobial administration. Traditionally, large-bore trocar-type thoracostomy tubes have preferentially been used for the drainage of thick material from the pleural space. In recent years, the use of small-bore wire-guided thoracic drains has increased in both small animals and in humans. Few studies have highlighted the efficacy of small-bore wire-guided thoracostomy tubes. Aim: The purpose of this study was to describe the use of small-bore wire-guided thoracostomy tubes in feline pyothorax in terms of efficacy, safety and outcome. Methods: Cats with pyothorax managed with small-bore thoracostomy tubes (2015-2018) were retrospectively studied. The number of drains inserted, the need for anesthesia and analgesia for chest tube placement and maintenance, and related major and minor complications were reviewed. Clinical data, diagnostic results, treatment and outcome were recorded. Results: Ten cats were enrolled. Thoracostomy tube placement was unilateral in 7/10 cats despite the presence of bilateral effusion in 9/10 cats, and required sedation (8/10) or anesthesia (2/10). Three cats experienced minor complications during the chest tube insertion, including self-limiting pneumothorax (1/3) and malpositioning (2/3). One cat had a major complication (non functional malposition) requiring reposition of the drain. Pain management was adequately achieved using opioids (8/10) or opioids plus nonsteroidal anti-inflammatory drugs (NSAIDs) (2/10). Partial chest tube occlusion occurred in 3 cases and it was resolved with lavage. In one case, the occlusion was complete, requiring drain removal. Three/10 cats were treated medically, combining thoracostomy tubes and antibiotics while 7/10 cats underwent surgery. All the cats survived. Conclusion: Small-bore thoracostomy tubes represent a safe and effective option for the initial management of feline pyothorax. In fact, mainly minor complications were reported during insertion and usage. The small-bore thoracostomy tubes were well tolerated by the cats with a satisfactory performance in terms of exudate drainage in most cases. The combined use of a small-bore thoracostomy drain together with the common practice of surgical treatment might have resulted in the successful management of the cases presented.

Friedreich’s ataxia (FA) is a neurodegenerative disease caused by the epigenetic repression of the Frataxin gene modulating mitochondrial activity in the brain, which has a diffuse phenotypic impact on patients’ motor behavior. Therefore, with current gold-standard clinical scales, it requires 18–24 month-long clinical trials to determine if disease-modifying therapies are at all beneficial. Our high-performance monitoring approach captures the full-movement kinematics from human subjects using wearable body sensor networks from a cohort of FA patients during their regular clinical visits. We then use artificial intelligence to convert these movement data using universal behavior fingerprints into a digital biomarker of disease state. This enables us to predict two different ‘gold-standard’ clinical scores (SCAFI, SARA) that serve as primary clinical endpoints. Crucially, by performing gene expression analysis on each patient their personal Frataxin gene expression levels were poorly, if at all, correlated with their clinical scores – fundamentally failing to establish a link between disease mechanism (dysregulated gene expression) and measures to quantify it in the behavioral phenotype. In contrast, our wearable digital biomarker can accurately predict for each patient their personal FXN gene expression levels, demonstrating the sensitivity of our approach and the importance of FXN levels in FA. Therefore, our data-derived biomarker approach can not only cross-sectionally predict disease and their gene expression levels but also their longitudinal disease trajectory: it is sensitive and accurate enough to detect disease progression with much fewer subjects or shorter time scales than existing primary endpoints. Our work demonstrates that data-derived wearable biomarkers have the potential to substantially reduce clinical trial durations and a first in-human demonstration of reconstructing FXN gene expression levels from behavioral data alone.

Behavioral disorders affect millions of people worldwide. Hypertension contributes to both the development and progression of brain damage and cognitive dysfunction and could represent the most powerful modifiable risk factor for cerebral vessel dysfunction and consequent behavioral impairment. Tomato contains antioxidants and bioactive molecules that might play an important role in the prevention of cardiovascular and brain diseases. The effects of the combined gel and serum from Lycopersicum esculentum L. var. “Camone” tomatoes and those of purified tomato glycoalkaloids (tomatine) and an antihypertensive drug (captopril) were investigated in male spontaneously hypertensive rats (SHRs) and compared with normotensive Wistar Kyoto (WKY) rats. Body weight, systolic blood pressure, behavioral parameters, as well as brain susceptibility to oxidative stress and brain cytokine contents, were assessed. Treating hypertensive rats with tomato gel/serum or captopril for four weeks caused a significant reduction in blood pressure, decreased locomotor activity and increased grooming behavior, the last two parameters were also significantly affected by tomatine treatment. Brain slices obtained from hypertensive rats treated with tomato gel/serum were more resistant to oxidative stress and contained lower levels of inflammatory cytokines than vehicle-treated ones. In contrast, tomatine treatment had no effect. In conclusion, the tomato-derived gel/serum can be considered a dietary supplement able to drive in vivo blood pressure towards healthier values and also control some central effects such as behavior and brain oxidative stress.

Auditory neural impairment is a key clinical feature of Friedreich’s Ataxia (FRDA). We aimed to characterize the phenotypical spectrum of the auditory impairment in FRDA in order to facilitate early identification and timely management of auditory impairment in FRDA patients and to explore the relationship between the severity of auditory impairment with genetic variables (the expansion size of GAA trinucleotide repeats, GAA1 and GAA2), when controlled for variables such as disease duration, severity of the disease and cognitive status. Twenty-seven patients with genetically confirmed FRDA underwent baseline audiological assessment (pure-tone audiometry, otoacoustic emissions, auditory brainstem response). Twenty of these patients had additional psychophysical auditory processing evaluation including an auditory temporal processing test (gaps in noise test) and a binaural speech perception test that assesses spatial processing (Listening in Spatialized Noise-Sentences Test). Auditory spatial and auditory temporal processing ability were significantly associated with the repeat length of GAA1. Patients with GAA1 greater than 500 repeats had more severe auditory temporal and spatial processing deficits, leading to poorer speech perception. Furthermore, the spatial processing ability was strongly correlated with the Montreal Cognitive Assessment (MoCA) score. To our knowledge, this is the first study to demonstrate an association between genotype and auditory spatial processing phenotype in patients with FRDA. Auditory temporal processing, neural sound conduction, spatial processing and speech perception were more severely affected in patients with GAA1 greater than 500 repeats. The results of our study may indicate that auditory deprivation plays a role in the development of mild cognitive impairment in FRDA patients.

Background: Three different phenotypes of septic shock based on changes in blood pressure and lactate are recognized in people. Dysoxic shock, representing the combination of fluid-refractory hypotension and hyperlactatemia, is characterized by greater disease severity and mortality compared to cryptic shock (hyperlactatemia alone) and vasoplegic shock (hypotension with normal blood lactate). Little is known about septic shock and specifically its phenotypes in cats.Objective: To analyze the characteristics and prognostic implications of three septic shock phenotypes in cats with sepsis.Methods: Cats with septic shock were prospectively included. Septic shock was defined by the presence of hypotension (mean blood pressure 4 mmol/L) and classified in three subgroups: dysoxic shock, vasoplegic shock and cryptic shock. Clinical and clinicopathological variables including APPLEfast and APPLEfull scores, occurrence of multi-organ dysfunction syndrome (MODS; presence of at least two dysfunctional organs simultaneously) and outcome were compared among subgroups. Cats with sepsis showing normal blood pressure and lactate concentrations hospitalized during the study period were included as uncomplicated sepsis, and compared to cats with septic shock for selected variables. Length of hospital stay and mortality were evaluated in the whole study population. Odds ratios for mortality were calculated using logistic regression analysis. Significance was set at P < 0.05.Results: The study enrolled 48 cats with uncomplicated sepsis and 37 cats with septic shock (dysoxic shock n = 17; vasoplegic shock n = 11; cryptic shock n = 7). Cats with dysoxic shock had significantly higher APPLEfast and APPLEfull scores compared to vasoplegic and cryptic shock. Mortality rates were not significantly different among cryptic (57%), dysoxic (65%) and vasoplegic shock (91%), while MODS occurrence was significantly lower in cats with cryptic shock (57%) compared to patients affected by dysoxic (94%) and vasoplegic (100%) shock. Cats with septic shock had higher frequency of MODS and greater mortality rate than cats with uncomplicated sepsis.Conclusion: Despite similar in-hospital mortality, cats with dysoxic and vasoplegic shock are characterized by having higher occurrence of multi- organ dysfunction compared to cats affected by cryptic shock. Results from this study suggest novel means of identifying high-risk subgroups of septic cats.

The family Tephritidae (Diptera) includes species that are highly invasive and harmful to crops. Due to globalization, international trade, and human displacement, their spread is continuously increasing. Unfortunately, the control of tephritid flies is still closely linked to the use of synthetic insecticides, which are responsible for detrimental effects on the environment and human health. Recently, research is looking for alternative and more eco-friendly tools to be adopted in Integrated Pest Management (IPM) programs. In this regard, essential oils (EOs) and their main compounds represent a promising alternative to chemical insecticides. EOs are made up of phytoconstituents formed from the secondary metabolism of many plants and can act as attractants or toxics, depending on the dose. Because of this unique characteristic, EOs and their main constituents are promising tools that can be used both in Sterile Insect Technique (SIT) programs and in the “lure and kill” technique, exploiting the attractiveness of the product in the former case and its toxicity in the latter. In this article, current knowledge on the biological and behavioral effects of EOs and their main constituents on tephritid fruit flies is reviewed, mainly focusing on species belonging to the Anastrepha, Bactrocera, Ceratitis, and Zeugodacus genera. The mechanisms of action of EOs, their real-world applications, and challenges related to their use in IPM are critically discussed.

Background Urine neutrophil gelatinase‐associated lipocalin (NGAL) is a promising biomarker of acute kidney injury (AKI) in dogs. Objectives To evaluate the utility of urinary NGAL for characterizing AKI according to volume responsiveness, presence of inflammation and sepsis, and prognosis. Animals Dogs with AKI (n = 76) and healthy controls (n = 10). Methods Prospective study. Clinical and clinicopathologic data including absolute urine NGAL concentration (uNGAL) and NGAL normalized to urine creatinine concentration (uNGALC) were measured upon admission. Dogs were graded according to International Renal Interest Society (IRIS) AKI guidelines and compared based on AKI features: volume‐responsive (VR‐) AKI vs. intrinsic (I‐) AKI based on IRIS criteria; VR‐AKI and I‐AKI based on urine chemistry; inflammatory versus noninflammatory; septic versus nonseptic; and survivors versus nonsurvivors. Nonparametric statistics were calculated, and significance set at P

Heinz bodies (HBs) are known to interfere with automated hematology in cats, particularly with the white blood cell (WBC) count. We evaluated the influence of feline HBs on the complete blood count (CBC) results obtained using a flow cytometry–based analyzer. We retrospectively selected cats with circulating HBs and reviewed the results of their CBCs, including red blood cell (RBC) indices, basophil/lobularity (Baso) WBC count (WBCB), peroxidase (Perox) WBC count (WBCP), and cytograms. Based on the presence or absence of HB-related artifacts in their Baso cytogram, cats were grouped into Baso-HBs and HBs groups, respectively, for comparison. The WBCB and WBCP were compared to manual counts of WBCs carried out on blood smears at 400× (MC-WBC). We included 32 cats in our study: 9 of 32 were in the Baso-HBs group, and 23 of 32 were in the HBs group. Baso-HBs cats had a significantly increased HB percentage ( p < 0.001), WBCB ( p < 0.001), difference between WBCB and WBCP ( p < 0.001), lymphocyte count ( p < 0.001), mean corpuscular hemoglobin concentration ( p < 0.001), and difference between calculated and measured erythrocyte hemoglobin concentrations ( p < 0.001) compared to HBs cats. In Baso-HBs cats, the WBCB was significantly higher than the WBCP ( p = 0.02); no significant difference was detected between the WBCP and the MC-WBC ( p = 0.88). Evaluation of automated CBC results raised the suspicion of HB-related interference when using a hematology analyzer in cats; hence, blood smear examination remains essential in routine practice.

This paper estimates the effect of international remittances on healthcare expenditures, taking into account both the interdependence with other consumption goods and the effects of health shocks. More precisely, we assess whether the budget allocation decisions of remittance-receiving households reveal different preferences to invest in health capital, even when the simultaneous effect that health shocks may have on the demand of remittances and on other types of nondurable expenditures is accounted for. Using data from the “Peruvian National Survey of Households,” we find that remittances have a positive impact on healthcare budget shares, net of the remittance-related income effect and independently of the occurrance of a health shock. They also have a positive impact on housing and a negative one on other expenditure items, that is, clothing, transport, and education. Hence, our results indicate a “pure” tendency of remittance-receiving households to devote larger shares of their budget to health capital investment, rather than to other types of consumption goods.

Background: Little information is available in spinocerebellar ataxias (SCAs) regarding pelvic organ symptoms. The aim of this study was to characterize the lower urinary tract (LUT) and bowel dysfunction in autosomal dominant spinocerebellar ataxias. Methods: Patients with confirmed SCAs attending a tertiary care service were approached about LUT and bowel complaints, and completed validated questionnaires: urinary symptom profile (USP), QualiveenShort form, International Prostate Symptom Score, and Neurogenic Bowel Dysfunction Score. SCA3 and SCA7 patients with urological complaints additionally underwent urodynamic studies (UDS). Patients’ characterization included demographic, clinical (Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS)), and genetic variables. Descriptive and comparative analyses were performed. Results: Fifty-one patients participated: SCA1 (n = 4), SCA2 (n = 11), SCA3 (n = 13), SCA6 (n = 17), and SCA7 (n = 6). The prevalence of self-reported LUT symptoms was 60.8% (n = 31), whereas LUT symptoms was reported in 86.3%(n = 44) using the USP. Both storage and voiding symptoms were reported, urinary frequency and urgency being the most frequent (n = 34, 68%). Although LUT symptoms were most often classed as mild (n = 27, 61.4%), they impacted QoL in 38 patients (77.6%). Of these, 21 (55.3%) were not on pharmacological treatment for urinary dysfunction. Most common abnormalities in UDS (n = 14) were detrusor overactivity (storage phase) and detrusor underactivity (voiding phase). Bowel symptoms were less common (31.4%, n = 16) and of mild severity. Conclusion: LUT symptoms are prevalent in SCA patients and impact QoL, whereas bowel symptoms tend to be mild. These symptoms are overlooked by patients and physicians due to the complexity of neurological involvement in SCA, and therefore a multidisciplinary management approach should be adopted.

Objective Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. Methods We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. Results One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

In the following pages, we share a collection of photos, drawings, and mixed-media creations, most of them especially made for this JoN issue, manifesting C. elegans researchers' affection for their model organism and the founders of the field. This is a celebration of our community's growth, flourish, spread, and bright future. Descriptions provided by the contributors, edited for space. 1.

The contraction of lowland forests throughout Europe began in remote times and then intensified strongly with land reclamation by agriculture and urbanization during the first half of the last century. We present a map of the Floodplain Woods of Tuscany on a scale of 1:300,000 as a synthesis of that built at the scale of 1:10,000 and the methods used to obtain it. Nearly 90% of the patches contain habitats of concern to conservation, according to the Habitat Directive. The Tuscan Floodplain Woods remained prevalent in coastal areas, where some levels of protection are guaranteed by the presence of several protected areas, whereas they have practically vanished in the other parts of the regional territory. The resulting patches are very small and distant from each other, so only in-depth management of all potential floodplain forest areas, taking into consideration patches for their regeneration, can be useful to assure their conservation.

Background The development of new therapies may rely on the conduct of human experimentation as well as later clinical trials of therapeutic interventions. Ethical considerations seek to protect the patient from risk but few have sought to ascertain the attitude to such risk of patients with progressive debilitating or terminal conditions, for which no mitigating or curative therapies exist. Such understanding is also important if recruitment is to be maximized. We therefore sought to define the motivations for and barriers to trial participation amongst patients with progressive ataxias, as well as their condition-specific trial preferences. Methods We conducted an online survey consisting of 29 questions covering four key domains (demographics, personal motivation, drug therapy and study design) relating to the design of clinical trials. Two major ataxia charities, Ataxia UK and the Friedreich’s Ataxia Research Alliance (FARA) sent the survey to their members. Responses were analysed by disease and by ambulatory status. Results Of 342 respondents, 204 reported a diagnosis of Friedreich’s ataxia (FRDA), 55 inherited cerebellar ataxia (CA) and 70 idiopathic CA. The most important symptoms to be addressed by a trial were considered to be balance problems and ambulation, although these were superseded by speech problems in wheelchair users. Common motivations for participation were potential benefits to self and others. Reasons for non-participation included concerns about side effects, and the burden and cost of travel. Financial reimbursement for expenses was reported to be likely to increase trial engagement, Phase two trials were the most popular to participate in, and the use of a placebo arm was seen as a disincentive. Across all disease subgroups, drug repurposing trials proved popular and just under 70% of participants would be prepared to undergo intrathecal drug administration. Conclusions Knowledge of motivations for and barriers to trial participation as well as the acceptability of investigations, time commitments and routes of drug administration should inform better, more patient focused trial design. This in turn may improve recruitment and retention of participants to future trials.

The lifespan of older people is growing together with their proportion in the population growth in the older population. This leads to an increasing need for support services for older adults who will inevitably experience a significant decrease in their cognitive capabilities and mental health conditions. Cognitive functions, including memory, attention, sleeping, problem-solving activities, or speed processing, are playing a crucial role in everyone’s independent daily life. Technologies can help maintain their independence and improve quality of life, reducing the care costs. In this regard, Smart home applications (SMAs) offer a solution to the complex needs of older adults and their families, monitoring physiological and functional issues, as well as aiding in emergency detection and response. This chapter provides an overview of current applications reported in the scientific literature, identifies the frameworks proposed for designing these types of applications, and defines evidence-based recommendations for designing SMAs for cognitive health of older adults.

Movement disorders 37(2), 405-410 (2022). doi:10.1002/mds.28844, Published by Wiley, New York, NY

Reliable diagnostic and prognostic markers of sepsis are lacking, but essential in veterinary medicine. We aimed to assess the accuracy of C-Reactive Protein (CRP), protein carbonyls (PCO) and paraoxonase-1 (PON1) in differentiating dogs with sepsis from those with sterile inflammation and healthy ones, and predict the outcome in septic dogs. These analytes were retrospectively evaluated at admission in 92 dogs classified into healthy, septic and polytraumatized. Groups were compared using the Kruskal–Wallis test, followed by a Mann–Whitney U test to assess differences between survivors and non-survivors. Correlation between analytes was assessed using the Spearman’s test, and their discriminating power was assessed through a Receiver Operating Characteristic (ROC) curve. PON1 and CRP were, respectively, significantly lower and higher in dogs with sepsis compared with polytraumatized and clinically healthy dogs (p < 0.001 for both the analytes), and also in dogs with trauma compared with healthy dogs (p = 0.011 and p = 0.017, respectively). PCO were significantly increased in septic (p < 0.001) and polytraumatized (p < 0.005) as compared with healthy dogs. PON1 and CRP were, respectively, significantly lower and higher in dogs that died compared with survivors (p < 0.001 for both analytes). Ultimately, evaluation of CRP and PON1 at admission seems a reliable support to diagnose sepsis and predict outcomes.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. Methods EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov , NCT02069509 . Findings Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. Interpretation Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. Funding European Commission, Voyager Therapeutics, and EuroAtaxia.

Objective: To compare the impact of an IV bolus of hydroxyethyl starch 130/0.4 (HES) or hypertonic saline 7.5% (HS) on hemostasis in dogs resuscitated for gastric-dilation-volvulus (GDV). Design: Open-label, parallel-group randomized clinical trial. Animals: Twenty-three client-owned dogs. Interventions: Dogs affected by GDV and shock were randomly assigned to receive HES at 10mL/kg or HS at 4mL/kg every 15 minutes. Blood samples were collected for blood gas analysis, PCV, total plasma protein, albumin, standard coagulation profile, and thromboelastometry (ROTEM) at baseline (T0) and at the end of bolus (T1). To assess the differences between the 2 groups at T1, Student's t-test or Wilcoxon rank-sum test was used. To evaluate the differences between T0 and T1, ANOVA for paired data or Wilcoxon matched-pairs signed-ranks test was used. P&nbsp

A 4-year-old Dachshund was referred for management of a mandibular fracture. The dog underwent cardiopulmonary arrest after sedation for skull radiography. Cardiopulmonary resuscitation was started immediately, and return of spontaneous circulation was rapidly obtained. However, after resuscitation, the dog was hemodynamically unstable. Additionally, global left ventricular systolic dysfunction and a focal hyperechoic myocardial lesion were found echocardiographically, and serum cardiac troponin I was severely elevated (82.80 ng/mL, upper hospital limit

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Introduction: To evaluate the clinical utility of placental growth factor (PlGF) for the prediction of preeclampsia (PE). Materials and methods: This prospective cohort study included women divided into three groups: (1) pregnancies without preconceptional risk of developing PE; (2) pregnancies with a preconceptional and/or current risk of developing PE; (3) PE-complicated pregnancies (control group). Blood samples were collected every 4-5 weeks or during hospitalization from early second trimester until delivery in the group 1 and 2, at the diagnosis of PE in the group 3. Plasma levels of PlGF were measured using The Triage PlGF test (Alere) and considered pathological under the 5th centile for gestational age. Sensitivity (Sn), specificity (Sp), positive and negative predictive value (PPV, NPV) were calculated. Results: In group 1, 30% of women (3/10) had pathological test but none of them developed PE (Sp 70%, NPV 100%). In group 2 (n = 75), none of the patients with normal test developed PE (0/24), while 39% of women with PlGF < 5th centile (20/51) developed PE (Sn 100%, Sp 44%, PPV 39%, NPV 100%). In group 3 (n = 11) all women except one had a pathological PlGF test (Sn 90%, PPV 100%). Conclusions: Our data support recent studies which identify PlGF as a biochemical marker not only of PE, but also of placental dysfunction. In fact, it is useful for ruling out PE in women at risk because of the high Sn and high NPV: a normal PlGF is related with a positive pregnancy outcome. Therefore, the measurement of this biomarker would simplify PE clinical management and would reduce costs.

Background: Sepsis is a life-threatening condition associated with an exacerbated production of both pro- and anti-inflammatory cytokines that can promote a hyperactive response to infection or induce immunoparalysis. Data regarding the immune response to sepsis in cats are scarce. Establishing the profiles of cytokines and chemokines in feline sepsis to characterize the nature of the immune responses to sepsis might enable individualized treatments to be developed and targeted. Objective: To evaluate the cytokine and chemokine network in cats with sepsis and septic shock, and to investigate the associations of these analytes with disease severity and outcome. Methods: Blood samples prospectively collected at presentation of cats with sepsis and septic shock to two veterinary teaching hospitals were analyzed. Forty healthy cats were included as controls. A 19-plex feline cytokine/chemokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Cytokine concentrations were compared between groups using the Kruskal-Wallis test with Dunn's post-hoc correction for multiple comparisons. Cytokine concentrations were compared between survivors and non-survivors with the Mann-Whitney U test. Odds ratios were calculated using logistic regression. A multivariable logistic regression model for prediction of septic shock was constructed. Results: The study enrolled 35 septic cats. Many cytokines were undetectable in both sick and healthy control cats and were excluded from subsequent analyses. Comparisons of cytokine concentrations among healthy controls, cats with sepsis (n = 12) and cats with septic shock (n = 23) revealed that sick cats (sepsis or septic shock) had significantly higher plasma concentrations of IL-6, IL-8, KC-like, and RANTES compared to healthy controls. The combination of MCP-1, Flt-3L, and IL-12 was predictive of septic shock. None of the cytokines analyzed was predictive of outcome in this study population. Conclusion: Plasma concentrations of IL-6, IL-8, KC-like, and RANTES are increased in cats with sepsis and may play important roles in pathogenesis. Multivariable modeling suggested that analysis of cytokines might aid differentiation of septic shock from sepsis. None of the cytokines analyzed was predictive of outcome. Measurement of these cytokines might enable future studies to better diagnose and characterize feline sepsis and septic shock.

Decreased serum apolipoprotein A1 (Apo-A1) concentration is associated with mortality in human sepsis. The diagnostic and prognostic role of serum Apo-A1 concentrations in canine sepsis was evaluated. Serum samples from septic dogs (n = 91) and healthy controls (n = 15) were retrospectively analyzed. According to the sepsis origin, four categories were identified: parvoviral enteritis (n = 26), pyometra (n = 20), septic peritonitis (n = 19), and miscellanea (n = 26). The canine acute patient physiologic and laboratory evaluation fast score (APPLEfast), serum C-reactive protein (CRP) and albumin concentrations were reviewed in all enrolled dogs. Increased CRP (252.6 ± 119.2 mg/L; Reference Interval: 0–8.5 mg/L) and significant lower serum albumin and Apo-A1 concentrations were documented in dogs with sepsis (22.8 ± 5.3 g/L and 1.17 ± 0.27 g/L, respectively) compared to healthy ones (33.1 ± 2.5 g/L and 1.32 ± 0.05 g/L, respectively) (P < 0.0001). According to the origin of sepsis, only the subgroup of dogs with septic peritonitis had significantly lower Apo-A1 (1.03 ± 0.26 g/L) concentrations compared to healthy dogs (P < 0.001). No significant differences were found in serum albumin and CRP concentrations, and in APPLEfast score values among the different subgroups of sepsis. Diagnosis of septic peritonitis was associated with a higher frequency of death (P = 0.006). In septic dogs, significant lower Apo-A1 concentrations were detected in non-survivors (1.02 ± 0.28 g/L; n = 27) compared to survivors (1.23 ± 0.24 g/L; n = 64; P = 0.0007). Moreover, significant higher values of the APPLEfast score were calculated in non-survivors (26 ± 4; n = 19) compared to survivors (23 ± 4; n = 51) (P = 0.0114). According to the area under the ROC curve analysis, Apo-A1

Large amount of nitric oxide (NO) can be released in patients with sepsis. Methemoglobin is formed from the interaction between NO and hemoglobin. Mild methemoglobinemia reflecting NO overproduction has been reported in septic people, and occasionally associated to septic shock and organ dysfunction. The aim of this retrospective study was to evaluate circulating methemoglobin fraction in dogs with sepsis and to assess its prognostic value. Methemoglobin reference interval (RI) was calculated in 41 healthy dogs and was set at 0–2.2%. A total of 131 dogs with sepsis were included in the study; 24/131 had a circulating methemoglobin ≥2.2%. The median methemoglobin fraction was significantly higher in dogs with sepsis compared to healthy ones (1.7%, 0.4–3.5% vs. 1.0, 0.3–2.2%, P = 0.0005). No significant difference was observed between dogs with uncomplicated sepsis (n = 98) vs. dogs with septic shock (n = 33) (1.8%, 0.4–2.8% vs. 1.5%, 0.4–3.5%, P = 0.74), between dogs with and without multi-organ dysfunction (n = 38 and n = 93, respectively) (1.7%, 0.4–3.5% vs. 1.7%, 0.5–2.8%, P = 0.27), and between survivors (n = 77) vs. non survivors (n = 54) (1.5%, 0.4–2.8% vs. 1.8%, 0.4–3.5%, P = 0.05). Dogs with methemoglobin fraction above or equal to the upper limit of the RI had a significantly higher frequency of death compared to dogs with methemoglobin levels

This preliminary study was designed to contribute to the evaluation of reliability of plasma lactate concentration (PLC) and its clearance as predictive and prognostic factors of gastric necrosis and clinical outcome of dogs affected by gastric dilatation-volvulus (GDV). Main aims of the study were: 1) to evaluate the prognostic reliability of PLC at presentation (T0) in dogs with GDV, 2) to compare the obtained data and considerations with the veterinary literature, and 3) to introduce the possible validity of PLC values at 24 (T24) and 48 (T48) hours after surgery as a predictive factor. Dogs with GDV were retrospectively evaluated. PLC at T0, T24 and T48 were recorded and correlated to the presence or absence of macroscopic necrosis of the stomach and to outcome. Forty-five dogs met the inclusion criteria. Significant differences were not detected in the mean values between the initial PLC in dogs with and without necrosis of the gastric wall, as well as between surviving and non-surviving dogs; these values were not associated with higher risk of gastric necrosis or death. At T24 and T48 no significant differences were recorded between necrosis and non-necrosis, and surviving and non-surviving categories. A median plasma lactate concentration clearance from arrival to T24 ≥ 50% was identified in both groups (with and without necrosis), and this parameter failed in identifying dogs that survived to discharge. In conclusion, the results presented here failed to detect PLC at T0 and its clearance at T24 as prognostic factors in this population of dogs with GDV., Surgery; Veterinary Medicine; Health Sciences; Surgery; Abdominal Surgery; Emergency Medicine; Plasma lactate concentration; Prognostic factor; Gastric dilatation-volvulus; dog; Gastric necrosis

Background Procalcitonin (PCT) is a valuable prognostic biomarker in human sepsis that is predictive of organ dysfunction, septic shock and mortality. Data on PCT in dogs is limited. This study aimed to investigate the prognostic value of baseline and serial PCT measurements in dogs with sepsis and to determine the association between PCT and sepsis severity and the presence of organ dysfunction. PCT concentrations were measured in citrated plasma samples collected from 53 dogs with sepsis at the time of admission (T0, n = 53) and at 24 h (T1, n = 35) and 48 h (T2, n = 30) post-admission using a commercial ELISA. Dogs were classified by sepsis severity (sepsis without organ dysfunction; severe sepsis; septic shock) and outcome (survivors; non-survivors). Organ dysfunctions were recorded at T0 and during hospitalization, and the APPLEfast score calculated at T0. Healthy dogs (n = 12) were used as controls. Results There were 18 septic dogs without organ dysfunction, 24 dogs with severe sepsis and 11 with septic shock. Baseline PCT concentrations were significantly greater in dogs with sepsis compared to healthy controls (P

In the past decades, the improving knowledge of genes implicated in the pathogenesis of psychiatric disorders together with the advancements in genetic engineering has led to the creation of mice in which one or more genes are inactivated or 'knocked out'. Knockout mice are extensively used to better investigate the molecular and cellular mechanisms underlying these diseases as well as the biological role of specific genes. Moreover, they are also useful tools for developing new therapeutic strategies. The success of using knockout mice is possible due to availability of several models used to mimic some clinical manifestations reported in psychiatric patients. In the present review, we will give an update of the most used gene knockout models in the field of psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder.

Objectives Friedreich's ataxia is the most common inherited ataxia, and pathogenesis is known to involve mitochondrial oxidative stress. Idebenone is a potent antioxidant which has already been evaluated in several clinical trials in FRDA, with reports of symptomatic benefit but inconclusive objective results. Following patient consultation on design, we have completed a treatment-withdrawal study to establish whether patients could correctly determine their treatment allocation to placebo or idebenone. Our aim was to capture subjective experiences of symptoms such as fatigue, which can be difficult to measure with questionnaires or semi-quantitative scales, particularly in chronic, slowly progressive conditions. Materials and methods Patients taking idebenone for at least 12 months as part of the open-label MICONOS Extension Study were randomized to receive either placebo or idebenone continuation for 2-month treatment cycles. The primary endpoint was patient assessment of treatment assignment. Results A total of 29 patients were randomized, forming the idebenone group (n = 16) and the placebo group (n = 13). No significant differences were detected between the idebenone and placebo groups on assessment of treatment assignment or early study withdrawal. A small but significant difference in ataxia rating scale scores was detected between treatment groups when considering ambulatory patients only. Conclusions This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2-month period. We hope that this study design will help inform future trials so that patients' experiences of symptoms are more reliably measured.

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed (‘idiopathic’ ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify ‘structural’ causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of ‘next-generation sequencing’, have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals’ input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. Objective To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. Methods We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Results Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Conclusions Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

The aim of the present study was to evaluate the size of the penis in flaccidity and in erection of Italian men. A total of 4,685 men living in Italy and who have been visited at the Italian urology operating units were involved in the study between January 2019 and January 2020. Each patient was given details on how to measure their penis (erect length and circumference) in flaccidity and in erection, from the lower base to the distal penile tip. Mean (standard deviation [SD]) flaccid penis length was 9.47 (2.69), mean (SD) flaccid penis circumference was 9.59 (3.08), mean (SD) erect penis length was 16.78 (2.55) and mean (SD) erect penis circumference was 12.03 (3.82). At the linear regression analysis, height was associated with flaccid penis length (β = 0.04; p‐value = .01), and erect penis length was (β = 0.05; p‐value

Pediatric high-grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0-32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild-type patients at 20 months was 68% [confidence interval (CI): 38-85%] compared with 28% (CI: 0.4-60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild-type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low-grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma.

Part 2: Communications: Types and Implemenations; International audience; Detecting programming errors and vulnerabilities in software is increasingly important, and building tools that help developers with this task is a crucial area of investigation on which the industry depends. In object-oriented languages, one naturally defines stateful objects where the safe use of methods depends on their internal state; the correct use of objects according to their protocols is then enforced at compile-time by an analysis based on behavioral types.We present Java Typestate Checker (JATYC), a tool based on the Checker Framework that verifies Java programs with respect to typestates. These define the object’s states, the methods that can be called in each state, and the states resulting from the calls. The tool offers the following strong guarantees: sequences of method calls obey to object’s protocols; completion of objects’ protocols; detection of null-pointer exceptions; and control of the sharing of resources through access permissions.To the best of our knowledge, there are no research or industrial tools that offer all these features. In particular, the implementation of sharing control in a typestate-based tool seems to be novel, and has an important impact on programming flexibility, since, for most programs, the linear discipline imposed by behavioral types is too strict.Sharing of objects is enabled by means of an assertion language incorporating fractional permissions; to lift from programmers the burden of writing the assertions, JATYC infers all of these by building a constraint system and solving it with Z3, producing general assertions sufficient to accept the code, if these exist.

Glioblastoma (GBM) is one of the most aggressive tumors known. For many years, the most varied therapeutic strategies have been adopted without obtaining significant prognostic results. Intrinsic resistance of GBM is due to the interaction between tumor and microglia cells, especially in a hypoxic microenvironment. Instead, the blood–brain barrier (BBB) plays an essential role of extrinsic resistance to certain drugs preventing their release into the brain. Although in vitro and in vivo studies show that doxorubicin is a highly toxic chemotherapy agent for glioma cells, its effectiveness in the treatment of GBM is limited by efflux pumps that actively expel this agent at the BBB level. Realistically, mechanical damage induced by radiation therapy temporarily modifies the BBB making it more permeable to anthracyclines. Whole brain radiotherapy (WBRT) could be a novel approach to alter the whole BBB allowing effective drugs, such as doxorubicin, to reach diffuse GBM stem cells at therapeutic doses.

In October 2019 the central 28m telescope of the H.E.S.S. experiment has been upgraded with a new camera. The camera is based on the FlashCam design which has been developed in view of a possible future implementation in the medium-sized telescopes of the Cherenkov Telescope Array (CTA). We report here on the results of the science verification program that has been performed after commissioning of the new camera, to show that the camera and software pipelines are working up to expectations., Comment: Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021)

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society Funding agencies: This publication is an outcome of ESMI, an EU Joint Programme - Neurodegenerative Disease Research (JPND) Project (see www.jpnd.eu). The project is supported under the aegis of JPND through the following funding organizations: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology and Regional Fund for Science and Technology of the Azores; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 643417. At the US sites this work was in part supported y the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080816. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061, and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and S10 OD017974 grant.

Copyright: © 2021 by the authors. Friedreich’s ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5′ and 3′ ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3′ interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5′ interruption, 3′ interruption, both 5′ and 3′ interruptions or lacking interruption. Those patients with 3′ interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3′ interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5′ and 3′ interruptions. This highlights the key role of interruptions at the 3′ end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient. European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 242193/EFACTS; National Brain Appeal—Small Acorns Fund; The Wellcome Centre for Human Neuroimaging is supported by core funding from the Wellcome (203147/Z/16/Z); Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme; CRN; North Thames, National Institute for Health Research (NIHR). Medical Research Council (MR/N028767/1).

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroin flammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Objective To investigate the pharmacokinetics of buprenorphine and its main active metabolite, norbuprenorphine, after administration of an intravenous loading dose followed by constant rate infusion (CRI) in dogs. Study design Prospective, clinical study. Animals A total of seven healthy dogs undergoing elective ovariectomy. Methods Buprenorphine was administered as a loading dose (intravenous bolus of 15 μg kg−1) followed by CRI (2.5 μg kg−1 hour−1 for 6 hours). Moreover, intraoperative analgesia was supplemented by an intramuscular carprofen (4 mg kg−1) injection, administered prior to surgery, and by lidocaine, administrated through subcutaneous infiltration and through a splash on the ovarian vascular pedicle during surgery. Pain and sedation were scored for all animals throughout the 24-hour study period and rescue analgesia was administered when a visual analogue scale score was > 40 mm. Blood samples were collected from a jugular catheter at regular intervals, and plasma concentrations of buprenorphine and norbuprenorphine were determined by a validated liquid chromatography–tandem mass spectrometry method. Results Buprenorphine showed a two-compartment kinetic profile. Maximum concentration was 23.92 ± 8.64 ng mL−1 at 1 minute (maximum time); elimination half-life was 41.87 ± 17.35 minutes; area under the curve was 486.68 ± 125.66 minutes ng−1 mL−1; clearance was 33.61 ± 13.01 mL minute−1 kg−1, and volume of distribution at steady state was 1.77 ± 0.50 L kg−1. In no case was rescue analgesia required. Norbuprenorphine resulted below the lower limit of quantification in almost all samples. Conclusions and clinical relevance The results suggest that a buprenorphine CRI can be a useful tool for providing analgesia in postoperative patients, considering its minor side effects and the advantages of a CRI compared to frequent boluses. The negligible contribution of norbuprenorphine to the therapeutic effect was confirmed.

Polytrauma is a common emergency condition in small animals and is frequently associated with higher morbidity and mortality rates compared to minor trauma. Multiple Organ Dysfunction Syndrome (MODS) is a major complication of extensive traumatic injury, carrying a high risk of death despite intensive care treatment. Little is known about the prevalence and the prognostic impact of MODS in feline polytrauma. The current study aimed to prospectively evaluate the occurrence and the prognostic significance of organ dysfunction at admission in a population of polytraumatized cats. Cats with polytrauma requiring intensive care unit hospitalization were included and categorized according to outcome (survivors/non-survivors). Clinical and clinicopathological data, including scores of disease severity [Animal Trauma Triage Score (ATTS), APPLEfast, and APPLEfull], selected organ dysfunction and presence of MODS were evaluated upon admission, and analyzed with respect to mortality. Non-parametric statistics was performed and P < 0.05 was considered significant. Thirty-eight cats met the inclusion criteria: 8/38 (21%) had penetrating trauma, while 30/38 (79%) had blunt trauma. The overall in-hospital mortality was 37% (14/38). Cats with evidence of MODS upon admission had significantly higher frequency of death compared to cats without MODS (9/14 vs. 2/24 P = 0.0004). Hemostatic dysfunction, respiratory dysfunction, and MODS upon admission were significantly associated with mortality in the univariate logistic regression analysis (P = 0.005, P = 0.001, P = 0.001, respectively). The values of APPLEfast, APPLEfull, and ATTS were independently associated with a higher risk of death and positively correlated with the number of dysfunctional organs (P = 0.025, P = 0.004, P = 0.003, r = 0.57, P = 0.0002; r = 0.59, P = 0.0001; r = 0.55, P = 0.0003, respectively). Multiple Organ Dysfunction Syndrome is a common complication of feline polytrauma and its development is associated with increased disease severity and worse outcomes. The presence of hemostatic dysfunction and respiratory dysfunction upon admission is associated with a higher risk of death. The ATTS and the APPLE scores are useful prognostic tools for the assessment of cats with polytrauma.

Objectives The aim of this study was to evaluate the efficacy and safety of lispro insulin for the treatment of feline diabetic ketoacidosis (DKA). Times to resolution of hyperglycaemia, ketosis and acidosis were compared between cats treated with continuous rate infusion (CRI) of lispro insulin and cats treated with CRI of regular insulin. Methods Client-owned cats with naturally occurring DKA, newly diagnosed with diabetes mellitus (DM) or already receiving treatment for DM, were included. Diagnosis of DKA involved the presence of at least two clinical signs consistent with DKA (eg, polyuria/polydipsia, anorexia, severe lethargy, vomiting and dehydration), blood glucose (BG) concentration >13.9 mmol/l (>250 mg/dl), blood beta hydroxybutyrate (BHB) concentration >2.5 mmol/l and venous pH 13.9 mmol/l [>250 mg/dl]), ketosis (BHB concentration >1 mmol/l) and acidosis (venous pH Results Eighteen DKA cases (nine per group) were enrolled into the study. There were no significant differences in the median time to resolution of three variables (hyperglycaemia, ketosis and acidosis) between the two groups. Two cats in group R developed hypoglycaemia during the CRI of insulin. One cat in group L and three cats in group R developed hypophosphataemia, which required phosphate supplementation. Conclusions and relevance IV CRI of lispro insulin has few side effects and appears to be as effective as IV CRI of regular insulin in the treatment of cats with DKA.

BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.FindingsWGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Background Advanced sensor, measurement, and analytics technologies are enabling entirely new ways to deliver health care. The increased availability of digital data can be used for data-driven personalization of care. Data-driven personalization can complement expert-driven personalization by providing support for decision making or even by automating some parts of decision making in relation to the care process. Objective The aim of this study was to analyze how digital data acquired from posture scanning can enhance physiotherapy services and enable more personalized delivery of physiotherapy. Methods A case study was conducted with a company that designed a posture scan recording system (PSRS), which is an information system that can digitally record, measure, and report human movement for use in physiotherapy. Data were collected through interviews with different stakeholders, such as health care professionals, health care users, and the information system provider, and were analyzed thematically. Results Based on the results of our thematic analysis, we propose three different types of support that posture scanning data can provide to enhance and enable more personalized delivery of physiotherapy: 1) modeling the condition, in which the posture scanning data are used to detect and understand the health care user’s condition and the root cause of the possible pain; 2) visualization for shared understanding, in which the posture scanning data are used to provide information to the health care user and involve them in more collaborative decision-making regarding their care; and 3) evaluating the impact of the intervention, in which the posture scanning data are used to evaluate the care progress and impact of the intervention. Conclusions The adoption of digital tools in physiotherapy has remained low. Physiotherapy has also lacked digital tools and means to inform and involve the health care user in their care in a person-centered manner. In this study, we gathered insights from different stakeholders to provide understanding of how the availability of digital posture scanning data can enhance and enable personalized physiotherapy services.

The term Episodic Ataxias (EA) was originally used for a few autosomal dominant diseases, characterized by attacks of cerebellar dysfunction of variable duration and frequency, often accompanied by other ictal and interictal signs. The original group subsequently grew to include other very rare EAs, frequently reported in single families, for some of which no responsible gene was found. The clinical spectrum of these diseases has been enormously amplified over time. In addition, episodes of ataxia have been described as phenotypic variants in the context of several different disorders. The whole group is somewhat confused, since a strong evidence linking the mutation to a given phenotype has not always been established. In this review we will collect and examine all instances of ataxia episodes reported so far, emphasizing those for which the pathophysiology and the clinical spectrum is best defined.

Background Multiple sclerosis (MS) is one of the world’s most common neurologic disorders leading to severe disability in young adults. MS-related fatigue directly impacts on the quality of life and activity levels of people with MS. Self-management strategies are used to support them in the care of their health. Mobile health (mHealth) solutions can offer tools to help symptom management. Following a user-centered design and evidence-based process, an mHealth solution called More Stamina was created to help persons with MS manage their fatigue. Objective The overall study aims are to explore the feasibility, acceptability, and usability of More Stamina, a mobile app for fatigue self-management for persons with MS. Methods A mixed-methods, multicenter study will be used to assess the feasibility, acceptability, and usability of More Stamina. The study will take place during the third and fourth quarters of 2020 (Q3-Q4 2020) in 3 locations: Argentina, Spain, and Switzerland. A longitudinal cohort study will take place, and think-aloud protocols, open-ended interviews, and short answer questionnaires will be used. Persons with MS will be recruited from the different locations. This study seeks to enroll at least 20 patients that meet the criteria from each site for the longitudinal cohort study (total n=60). Results Ethical approval has been granted in Argentina and is pending in Spain and Switzerland. Outcomes will be published in peer-reviewed medical journals and presented at international conferences. Conclusions Findings from this study will be used to help understand the role that mHealth can play in fatigue management in MS. Trial Registration ClinicalTrials.gov NCT04244214; https://clinicaltrials.gov/ct2/show/NCT04244214 International Registered Report Identifier (IRRID) PRR1-10.2196/18196

Liquidity constraints are known to significantly impede human capital investment decisions in developing countries. However, it is not obvious whether, and the extent to which, labelled microcredit - linked with the investment by name only - will boost human capital investments, particularly since money is fungible and a label is not a strong commitment. Drawing on a cluster randomised controlled trial of a sanitation microloan intervention in rural India, we show that labelled microcredit is effective in increasing sanitation investments. However, not all loans are used for sanitation investments. Testing predictions from a theoretical model that integrates loan labels provides novel evidence that loan labels influence household borrowing and investment decisions. Labelling of loans - which to date has not received much attention in the literature - is a viable strategy to improve uptake of lumpy preventive health investments.

Background and Aims Omaveloxolone, an Nrf2 activator, is an investigational drug that targets targets inflammation and mitochondrial dysfunction, metabolic, and bioenergetic pathways. Omaveloxolone is an analog of bardoxolone, methyl which has been shown to improve kidney function in multiple studies of chronic kidney diseases. The MOXIe Part 2 trial investigated omaveloxolone in patients with Friedreich’s ataxia (FA), a rare and serious hereditary disease caused by mitochondrial dysfunction that affects multiple organ systems resulting in ataxia, cardiomyopathy, and reduced lifespan. The study met its primary efficacy endpoint, and omaveloxolone improved neurological function, as assessed by the modified Friedreich’s ataxia rating scale (mFARS). We report the effect of omaveloxolone on kidney function in this patient population. Method The MOXIe trial (NCT02255435) was an international, multi-center, double-blind, placebo-controlled, randomized trial that enrolled 103 patients between 16 and 40 years of age with genetically confirmed FA. Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks. The trial included 24 patients that were younger than 18 years of age. Baseline eGFR for the overall patient population receiving placebo or omaveloxolone was 109.2 ± 21.7 and 113.4 ± 14.7 mL/min/1.73 m2, respectively. Baseline eGFR for the pediatric population receiving placebo or omaveloxolone was 99.1 ± 33.7 and 106.3 ± 15.6 mL/min/1.73 m2, respectively. Serum creatinine was collected at baseline, Weeks 4, 12, 18, 24, 36 and 48 on-treatment and 4-weeks off-treatment at Week 52. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for patients ≥ 18 years of age. For patients Results In placebo patients, mean (SD) eGFR decreased by 4.4 ± 11.0 mL/min/1.73 m2 from baseline whereas patients receiving omaveloxolone had an average increase of +7.0 ± 10.7 mL/min/1.73 m2 from baseline after 48 weeks, resulting in a difference of 11.4 mL/min/1.73 m2 between treatment groups. At Week 52, mean eGFR was -4.2 ± 10.9 mL/min/1.73 m2 relative to baseline in placebo patients and remained +0.9 ± 10.8 mL/min/1.73 m2 above baseline in omaveloxolone patients after 4-weeks off-treatment. In pediatric patients randomized to placebo, at week 48 eGFR decreased by -11.3 ± 14.3 mL/min/1.73 m2 whereas patients receiving omaveloxolone had an average increase of +5.5 ± 14.5 mL/min/1.73 m2 from baseline, resulting in a difference of 16.8 mL/min/1.73 m2 between treatment groups. Conclusion Patients with FA randomized to placebo in the MOXIe trial had eGFR declines over 48 weeks that were similar to rates of decline observed in the most rapidly progressing forms of chronic kidney disease. The rapid kidney function decline in FA reflects the multi-system nature of the disease whereby mitochondrial dysfunction, and associated chronic inflammation, affects not only the central nervous system but also the heart and possibly the kidney. In contrast to placebo, treatment with omaveloxolone improved eGFR in patients with FA and the effects were sustained through one year of treatment. The durability of eGFR improvements are consistent with those observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.