Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aß Status Groups in the A4 Study.

BACKGROUND: Disparities in Alzheimer's disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities. OBJECTIVES: To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and ß-amyloid (Aß) status groups. DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan. MEASUREMENTS: Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aß status. RESULTS: Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aß- and 1309 were classified as Aß+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aß status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aß status groups. CONCLUSIONS: Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aß status groups examined in this study.

Indications of a ferromagnetic quantum critical point in [Formula: see text].

We investigate the previously observed superconductivity in ferromagnetic SmN in the context of the breakdown of order between two magnetic phases. Nitrogen vacancy doped SmN[Formula: see text] is a semiconductor which lies in the intermediary between ferromagnetic SmN and anti-ferromagnetic Sm. Optical data reported here corroborate the prediction that electrical transport is mediated by Sm 4f defect states, and electrical transport measurements characterise the metal-insulator transition over the doping range. Our measurements show that the superconducting state in nitrogen vacancy doped [Formula: see text] is the most robust near the breakdown of magnetic order, and indicate the location of a quantum critical point. Furthermore we provide additional evidence that the superconducting state is formed from majority spin electrons and thus of unconventional S = 1 type.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Standardization of a SNP panel for parentage verification and identification in the domestic cat (Felis silvestris catus).

The domestic cat (Felis silvestris catus) is a valued companion animal throughout the world. Over 60 different cat breeds are accepted for competition by the cat fancy registries in different countries. Genetic markers, including short tandem repeats and SNPs, are available to evaluate and manage levels of inbreeding and genetic diversity, population and breed structure relationships, and individual identification for forensic and registration purposes. The International Society of Animal Genetics (ISAG) hosts the Applied Genetics in Companion Animals Workshop, which supports the standardization of genetic marker panels and genotyping for the identification of cats via comparison testing. SNP panels have been in development for many species, including the domestic cat. An ISAG approved core panel of SNPs for use in cat identification and parentage analyses is presented. SNPs (n = 121) were evaluated by different university-based and commercial laboratories using 20 DNA samples as part of the ISAG comparison testing procedures. Different SNP genotyping technologies were examined, including DNA arrays, genotyping-by-sequencing and mass spectroscopy, to select a robust and efficient panel of 101 SNPs as the ISAG core panel for cats. The SNPs are distributed across all chromosomes including two on the X chromosome and an XY pseudo-autosomal sexing marker (zinc-finger XY; ZFXY). A population study demonstrated that the markers have an average polymorphic information content of 0.354 and a power of exclusion greater than 0.9999. The SNP panel should keep testing affordable while also allowing for the development of additional panels to monitor health, phenotypic traits, hybrid cats and highly inbred cats.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus).

Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta ; a.k.a. ticked), mackerel (Tm ; a.k.a. striped) and blotched (tb ; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby - Abyssinian (Ta ; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine-rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B.

Go to gate: COVID-19 imported cases in Madrid and the potential role of airport transmissions.

Data on imported cases of COVID-19 are scarce. Recorded imported cases in Madrid, Spain represented 0.08% of the total cases from May to December 2020, as reported by the Epidemiology Service of Madrid Autonomous Community. We reflect on the potential role of airports in infection transmission, the current preventive measures to avoid travelling-related infections and discuss if there is a real need to focus on strict airport controls when community transmission is ongoing.

Social distancing to combat COVID-19 led to a marked decrease in food-borne infections and sexually transmitted diseases in Spain.

Data from a recent epidemiological surveillance network showed a decrease in the reported number of sexually transmitted diseases (STDs) and food-borne infections. We reflect on the possible drivers and consequences of a decrease in these transmittable infectious diseases linked to human contact in relation to social distancing due to the COVID-19 pandemic in Madrid (Spain).

Assisted reproduction mediated resurrection of a feline model for Chediak-Higashi syndrome caused by a large duplication in LYST.

Chediak-Higashi Syndrome (CHS) is a well-characterized, autosomal recessively inherited lysosomal disease caused by mutations in lysosomal trafficking regulator (LYST). The feline model for CHS was originally maintained for ~20 years. However, the colonies were disbanded and the CHS cat model was lost to the research community before the causative mutation was identified. To resurrect the cat model, semen was collected and cryopreserved from a lone, fertile,  CHS carrier male. Using cryopreserved semen, laparoscopic oviductal artificial insemination was performed on three queens, two queens produced 11 viable kittens. To identify the causative mutation, a fibroblast cell line, derived from an affected cat from the original colony, was whole genome sequenced. Visual inspection of the sequence data identified a candidate causal variant as a ~20 kb tandem duplication within LYST, spanning exons 30 through to 38 (NM_001290242.1:c.8347-2422_9548 + 1749dup). PCR genotyping of the produced offspring demonstrated three individuals inherited the mutant allele from the CHS carrier male. This study demonstrated the successful use of cryopreservation and assisted reproduction to maintain and resurrect biomedical models and has defined the variant causing Chediak-Higashi syndrome in the domestic cat.

Timing of major fracture care in polytrauma patients - An update on principles, parameters and strategies for 2020.

OBJECTIVES: Sustained changes in resuscitation and transfusion management have been observed since the turn of the millennium, along with an ongoing discussion of surgical management strategies. The aims of this study are threefold: a) to evaluate the objective changes in resuscitation and mass transfusion protocols undertaken in major level I trauma centers; b) to summarize the improvements in diagnostic options for early risk profiling in multiply injured patients and c) to assess the improvements in surgical treatment for acute major fractures in the multiply injured patient. METHODS: I. A systematic review of the literature (comprehensive search of the MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials databases) and a concomitant data base (from a single Level I center) analysis were performed. Two authors independently extracted data using a pre-designed form. A pooled analysis was performed to determine the changes in the management of polytraumatized patients after the change of the millennium. II. A data base from a level I trauma center was utilized to test any effects of treatment changes on outcome. INCLUSION CRITERIA: adult patients, ISS > 16, admission < less than 24 h post trauma. Exclusion: Oncological diseases, genetic disorders that affect the musculoskeletal system. Parameters evaluated were mortality, ICU stay, ICU complications (Sepsis, Pneumonia, Multiple organ failure). RESULTS: I. From the electronic databases, 5141 articles were deemed to be relevant. 169 articles met the inclusion criteria and a manual review of reference lists of key articles identified an additional 22 articles. II. Out of 3668 patients, 2694 (73.4%) were male, the mean ISS was 28.2 (SD 15.1), mean NISS was 37.2 points (SD 17.4 points) and the average length of stay was 17.0 days (SD 18.7 days) with a mean length of ICU stay of 8.2 days (SD 10.5 days), and a mean ventilation time of 5.1 days (SD 8.1 days). Both surgical management and nonsurgical strategies have changed over time. Damage control resuscitation, dynamic analyses of coagulopathy and lactate clearance proved to sharpen the view of the worsening trauma patient and facilitated the prevention of further complications. The subsequent surgical care has become safer and more balanced, avoiding overzealous initial surgeries, while performing early fixation, when patients are physiologically stable or rapidly improving. Severe chest trauma and soft tissue injuries require further evaluation. CONCLUSIONS: Multiple changes in management (resuscitation, transfusion protocols and balanced surgical care) have taken place. Moreover, improvement in mortality rates and complications associated with several factors were also observed. These findings support the view that the management of polytrauma patients has been substantially improved over the past 3 decades.

Assessment and management of dry eye disease.

The topic of the 1984 Cambridge Ophthalmological Symposium was 'The Dry Eye'; it was chaired by my colleague and mentor Mr Peter Wright. In the 33 years that have passed since then we have learned a great deal more about this condition. This short paper sets out to review some of the more recent developments.

Computerized Cognitive Testing for Use in Clinical Trials: A Comparison of the NIH Toolbox and Cogstate C3 Batteries.

BACKGROUND: As prevention trials for Alzheimer's disease move into asymptomatic populations, identifying older individuals who manifest the earliest cognitive signs of Alzheimer's disease is critical. Computerized cognitive testing has the potential to replace current gold standard paper and pencil measures and may be a more efficient means of assessing cognition. However, more empirical evidence about the comparability of novel computerized batteries to paper and pencil measures is required. OBJECTIVES: To determine whether two computerized IPad batteries, the NIH Toolbox Cognition Battery and Cogstate-C3, similarly predict subtle cognitive impairment identified using the Preclinical Alzheimer Cognitive Composite (PACC). DESIGN, SETTING, PARTICIPANTS: A pilot sample of 50 clinically normal older adults (Mage=68.5 years±7.6, 45% non-Caucasian) completed the PACC assessment, and the NIH Toolbox and Cogstate-C3 at research centers of Massachusetts General and Brigham and Women's Hospitals. Participants made 3-4 in-clinic visits, receiving the PACC first, then the NIH Toolbox, and finally the Cogstate-C3.>= 0.5SD), versus subtle cognitive impairment (<0.5SD). Composites for each computerized battery were created using principle components analysis, and compared with the PACC using non-parametric Spearman correlations. Logistic regression analyses were used to determine which composite was best able to classify subtle cognitive impairment from typical performance. RESULTS: The NIH Toolbox formed one composite and exhibited the strongest within-battery alignment, while the Cogstate-C3 formed two distinct composites (Learning-Memory and Processing Speed-Attention). The NIH Toolbox and C3 Learning-Memory composites exhibited positive correlations with the PACC (ρ=0.49, p<0.001; ρ=0.58, p<0.001, respectively), but not the C3 Processing Speed-Attention composite, ρ=-0.18, p=0.22. The C3 Learning-Memory was the only composite that classified subtle cognitive impairment, and demonstrated the greatest sensitivity (62%) and specificity (81%) for that subtle cognitive impairment. CONCLUSIONS: Preliminary findings suggest that the NIH Toolbox has the advantage of showing the strongest overall clustering and alignment with standardized paper-and-pencil tasks. By contrast, Learning-Memory tasks within the Cogstate-C3 battery have the greatest potential to identify cross-sectional, subtle cognitive impairment as defined by the PACC.

Evaluation and quantification of geographical differences in wound complication rates following the extended lateral approach in displaced intra-articular calcaneal fractures - A systematic review of the literature.

INTRODUCTION: Calcaneal fracture surgery is often performed via the extended lateral approach (ELA). Large differences are reported in literature on wound complication rates. Aim was to perform a systematic review on reported postoperative wound complication (POWC) and postoperative wound infection (POWI) rates following the ELA and evaluate and quantify geographical differences. METHODS: A literature search was conducted in the MEDLINE and EMBASE databases and Cochrane Library. Studies before 2000, with <10 patients, biomechanical studies and reviews were excluded. No restrictions regarding language were applied. RESULTS: 3068 articles were identified of which 123 were included, with 8584 calcaneal fractures in 28 different countries. The average total number of POWC was 14.3%, with 3.8% of superficial and 2.2% of deep infections. The highest POWI rate was found in Europe (12.1%) and the lowest in North America (2.8%). A significant difference in incidence of deep POWI between continents was detected (median 0-3.8%). No differences were found in incidence of POWC and POWI between retro- and prospective studies (respectively p=0.970, p=0.748) or studies with <10 or ≥10 operations per year (respectively p=0.326, p=0.378). However, lower rates of POWI were found in studies with a follow up of >3months (p=0.01). CONCLUSION: Large differences were detected in incidence of POWC and POWI following calcaneal fracture surgery with the ELA between countries and continents. We did not find a lower POWC or POWI rate in retrospective studies compared to prospective studies, larger studies or in studies in which more patients were treated annually. However, the rate of POWI was significantly lower in studies with a follow up of >3months. We advise the use of a reliable postoperative complication registration system and uniformity in the use of standardized definitions of wound complications for calcaneal fracture surgery.

BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007).

This is an updated guideline for the diagnosis and management of allergic and non-allergic rhinitis, first published in 2007. It was produced by the Standards of Care Committee of the British Society of Allergy and Clinical Immunology, using accredited methods. Allergic rhinitis is common and affects 10-15% of children and 26% of adults in the UK, it affects quality of life, school and work attendance, and is a risk factor for development of asthma. Allergic rhinitis is diagnosed by history and examination, supported by specific allergy tests. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. Combination therapy with intranasal corticosteroid plus intranasal antihistamine is more effective than either alone and provides second line treatment for those with rhinitis poorly controlled on monotherapy. Immunotherapy is highly effective when the specific allergen is the responsible driver for the symptoms. Treatment of rhinitis is associated with benefits for asthma. Non-allergic rhinitis also is a risk factor for the development of asthma and may be eosinophilic and steroid-responsive or neurogenic and non- inflammatory. Non-allergic rhinitis may be a presenting complaint for systemic disorders such as granulomatous or eosinophilic polyangiitis, and sarcoidoisis. Infective rhinitis can be caused by viruses, and less commonly by bacteria, fungi and protozoa.