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Abstract Genetic management is a critical component of threatened species conservation. Understanding spatial patterns of genetic diversity is essential for evaluating the resilience of fragmented populations to accelerating anthropogenic threats. Nowhere is this more relevant than on the Australian continent, which is experiencing an ongoing loss of biodiversity that exceeds any other developed nation. Using a proprietary genome complexity reduction‐based method (DArTSeq), we generated a data set of 3239 high quality Single Nucleotide Polymorphisms (SNPs) to investigate spatial patterns and indices of genetic diversity in the koala (Phascolarctos cinereus), a highly specialised folivorous marsupial that is experiencing rapid and widespread population declines across much of its former range. Our findings demonstrate that current management divisions across the state of New South Wales (NSW) do not fully represent the distribution of genetic diversity among extant koala populations, and that care must be taken to ensure that translocation paradigms based on these frameworks do not inadvertently restrict gene flow between populations and regions that were historically interconnected. We also recommend that koala populations should be prioritised for conservation action based on the scale and severity of the threatening processes that they are currently faced with, rather than placing too much emphasis on their perceived value (e.g., as reservoirs of potentially adaptive alleles), as our data indicate that existing genetic variation in koalas is primarily partitioned among individual animals. As such, the extirpation of koalas from any part of their range represents a potentially critical reduction of genetic diversity for this iconic Australian species.

Abstract Scavenging on carrion is critical and often fiercely competitive for a range of vertebrate species, from native apex predators to invasive species and even reptiles. Within Australia, a notable reptilian scavenger is the lace monitor (Varanus varius). In this study, we quantified lace monitor activity at carcasses and compared their use of the resource to common co‐occurring predators that also scavenge; the invasive red fox (Vulpes vulpes) and a native apex predator, the dingo (Canis dingo). To do so, we deployed 80 macropod carcasses equally across seasons (summer and winter) and habitats (open and closed canopy) in a temperate bioregion and monitored vertebrate scavenging with camera traps. Lace monitor activity (visitation at carcass sites inclusive of both non‐scavenging and scavenging events) was 1.67 times higher in summer than in winter, but it did not differ across closed and open habitats. Monitor activity occurred earlier after carcass deployment at sites deployed in summer than winter (1.47‐fold earlier), and at carcasses in open than closed habitats (0.22‐fold earlier). Lace monitors initially discovered carcass sites faster in summer than winter and before both red foxes and dingoes in summer. The species was active diurnally in both summer and winter, differing from the red fox, which was strictly a nocturnal scavenger and the dingo, which was significantly more active at night across both seasons. Finally, we found that lace monitor activity at carcass sites decreased slightly with higher rates of activity for dingoes (0.04‐fold decrease as dingo activity increased), but not with red fox activity. Our results have implications for understanding lace monitor foraging and scavenging and highlight the value of monitoring carcasses to provide important insights into the behaviour of varanid lizards that scavenge.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

Abstract External signs of disease are frequently used as indicators of disease susceptibility. However, immune profiling can be a more effective indicator to understand how host responses to infection may be shaped by host, pathogen and environmental factors. To better inform wildlife health assessment and research directions, we investigated the utility of a novel multivariate immunophenotyping approach examining innate and adaptive immune responses in differing climatic, pathogen co-infection and demographic contexts across two koala (Phascolarctos cinereus) populations in New South Wales: the Liverpool Plains (LP), and Southern Highlands to South-west Sydney (SHSWS). Relative to the comparatively healthy SHSWS, the LP had greater and more variable innate immune gene expression (IL-1β, IL-6), and KoRV transcription. During extreme heat and drought, koalas from the LP displayed upregulation of a stress pathway gene and reduced adaptive immune genes expression, haematocrit and plasma protein, suggesting the possibility of environmental impacts through multiple pathways. In those koalas, KoRV transcription status, Chlamydia pecorum infection loads, and visible urogenital inflammation were not associated with immune variation, suggesting that immune markers were more sensitive indicators of real-time impacts than observed disease outcomes.

Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry. Results This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5). Conclusions This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis. Trial registration ClinicalTrials.gov Identifier: NCT00628745.

Abstract Chlamydiosis is a significant disease affecting Eastern Australian koala (Phascolarctos cinereus) populations, impacting individual animal welfare and fecundity and therefore influencing population dynamics. The aim of this study was to investigate the effect of a synthetic peptide vaccine based on 4 components of the Chlamydia pecorum major outer membrane protein (MOMP), over an 18-month period in a koala population severely impacted by chlamydiosis. Wild koalas were recruited into a vaccination or a placebo treatment group on a random allocation, then followed through a period of 18 months, with recapture at 6 monthly intervals. Vaccination did not alter clinical disease expression or chlamydial shedding from the ocular or urogenital sites. Vaccination did not stimulate a significant plasma anti-MOMP IgG response, when compared to the placebo group. There was no significant effect of vaccination on IFN-γ and IL-17A mRNA expression of peripheral blood lymphocytes when stimulated with rMOMP. We have demonstrated that a synthetic peptide vaccination against chlamydiosis is not an effective management tool in a koala population with a high prevalence of C. pecorum infection and related disease. The lack of antigenic response found in this study suggests that further research utilising a larger, full-length antigen is an avenue worth investigation if we are to consider vaccination as a part of a management strategy in diseased koala populations.

Abstract Aims Prior studies have suggested causal relationships between obesity and acute cardiovascular events. It has been also known that the risk of acute cardiovascular events is reduced by bariatric surgery. However, little is known about whether bariatric surgery lowers the risk of acute cardiovascular events in patients with obesity and hypertrophic cardiomyopathy (HCM). In this context, we aimed to investigate whether bariatric surgery is associated with a reduced risk of cardiovascular‐related acute care use in patients with HCM. Methods and results In this population‐based study, the bariatric surgery group consisted of patients with HCM who underwent bariatric surgery from January 2004 to December 2014. The control group included those who have obesity and HCM and received non‐bariatric elective intra‐abdominal surgery during the same period. The outcome was cardiovascular‐related acute care use (i.e. emergency department (ED) visits or unplanned hospitalizations for cardiovascular disease) during a 1‐year post‐surgery period. We used the SPARCS database, a population‐based ED and inpatient database in New York State. We constructed logistic regression models with generalized estimating equations to compare the risk of the outcome events during sequential 6‐month post‐surgery periods. We adjusted for age, sex, number of ED visits and hospitalizations for cardiovascular disease within 2 years before the index surgery, and the Elixhauser co‐morbidity measures. We also performed propensity score (PS)‐matching and inverse probability treatment weighting analyses using these variables. The analytic cohort consisted of 207 adults with obesity and HCM, including 147 patients who underwent bariatric surgery and 60 in the control group. The risk was not significantly different in the 1–6 months post‐surgery period. By contrast, in the 7–12 months post‐surgery period, the risk of cardiovascular‐related acute care use was significantly lower in the bariatric surgery group (adjusted odds ratio 0.23; 95% CI 0.068–0.71; P = 0.01) compared with the control group. In the PS‐matched cohort, there were no significant differences in the baseline characteristics. The PS‐matched analysis demonstrated lower risk of the outcome event in the bariatric surgery group in the 7–12 months post‐surgery period. The inverse probability treatment weighting analysis replicated the findings. Conclusions Bariatric surgery was associated with a lower risk of cardiovascular‐related acute care use in the 7–12 months post‐surgery period in this population‐based study.

Background: Deficits of physical function are associated with poor quality of life and adverse health outcomes, but data informing the association of these assessments among Black and Hispanic outpatients with heart failure (HF) are limited. Methods: The multicentre, prospective Screening for Cardiac Amyloidosis With Nuclear Imaging for Minority Populations (SCAN-MP) study identified Black and Hispanic subjects with stable HF, collected baseline characteristics, and took measures using the short physical performance battery. Subjects completed a Kansas City Cardiomyopathy Questionnaire (KCCQ), and the clinical outcomes of HF hospitalization and death were ascertained by telephone and review of the electronic health record. Results: Of 320 participants, 227 (70.9%) had physical deficits, defined by a battery score of ≤ 9. Patients with severe physical deficits reported overall lower KCCQ scores compared to those with no deficits (KCCQ score of 57.0 vs 72.4, P < 0.001). Physical limitation was significantly associated with risk of HF hospitalization, after adjustments for age, sex, and New York Heart Association class (severe physical deficit hazard ratio, 3.61; 95% confidence interval [CI], 1.19-10.93; P = 0.024; mild physical deficit hazard ratio, 2.59; 95% CI, 0.86-7.75; P = 0.090). Conclusions: Reduced physical performance is highly prevalent among Black and Hispanic outpatients with HF, and it is associated with overall KCCQ score, as well as an increased risk for HF hospitalization. Résumé: Contexte: La limitation physique est associée à une détérioration de la qualité de vie et à une aggravation de l’état de santé, mais il y a peu de données sur la corrélation entre ces paramètres chez les patients externes noirs et hispaniques atteints d’insuffisance cardiaque. Méthodologie: Dans l’étude multicentrique et prospective de dépistage de l’amylose cardiaque chez les populations minoritaires (SCAN-MP), on a ciblé des sujets noirs et hispaniques atteints d’insuffisance cardiaque stable, recueilli les caractéristiques initiales et mesuré les capacités au moyen du court test d’évaluation de la performance physique (short physical performance battery [SPPB]). Les sujets ont répondu au questionnaire de cardiomyopathie de Kansas City (KCCQ), et les critères cliniques des hospitalisations et des décès liés à l’insuffisance cardiaque ont été évalués par téléphone et par examen des dossiers de santé électroniques. Résultats: Des 320 participants, 227 (70,9 %) avaient des déficits physiques, définis par un score au SPPB de 9 ou moins. Les patients ayant des déficits physiques graves ont obtenu des scores globaux au KCCQ inférieurs aux patients sans déficit (score KCCQ de 57,0 contre 72,4; p < 0,001). La limitation physique est fortement associée au risque d’hospitalisation liée à l’insuffisance cardiaque, après ajustement pour tenir compte de l’âge, du sexe et de la classe d’insuffisance cardiaque de la New York Heart Association (rapport des risques instantanés [RRI] du déficit physique grave : 3,61; intervalle de confiance [IC] à 95 % de 1,19 à 10,93; p = 0,024; RRI du déficit physique léger : 2,59; IC à 95 % de 0,86 à 7,75; p = 0,090). Conclusions: La diminution de la performance physique est très fréquente chez les patients externes noirs et hispaniques atteints d’insuffisance cardiaque, et elle est corrélée au score global au KCCQ ainsi qu’à une augmentation du risque d’hospitalisation liée à l’insuffisance cardiaque.

We present tomographic measurements of structure growth using cross-correlations of Atacama Cosmology Telescope (ACT) DR6 and Planck cosmic microwave background (CMB) lensing maps with the unWISE Blue and Green galaxy samples, which span the redshift ranges 0.2 ≲ z ≲ 1.1 and 0.3 ≲ z ≲ 1.8, respectively. We improve on prior unWISE cross-correlations not just by making use of the new, high-precision ACT DR6 lensing maps, but also by including additional spectroscopic data for redshift calibration and by analyzing our measurements with a more flexible theoretical model. We determine the amplitude of matter fluctuations at low redshifts ( z ≃ 0.2–1.6), finding ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{m}/0.3)}^{0.5}=0.813\pm 0.021$ using the ACT cross-correlation alone and S _8 = 0.810 ± 0.015 with a combination of Planck and ACT cross-correlations; these measurements are fully consistent with the predictions from primary CMB measurements assuming standard structure growth. The addition of baryon acoustic oscillation data breaks the degeneracy between σ _8 and Ω _m , allowing us to measure σ _8 = 0.813 ± 0.020 from the cross-correlation of unWISE with ACT and σ _8 = 0.813 ± 0.015 from the combination of cross-correlations with ACT and Planck. These results also agree with the expectations from primary CMB extrapolations in ΛCDM cosmology; the consistency of σ _8 derived from our two redshift samples at z ∼ 0.6 and 1.1 provides a further check of our cosmological model. Our results suggest that structure formation on linear scales is well described by ΛCDM even down to low redshifts z ≲ 1.

We investigate the impact and mitigation of extragalactic foregrounds for the cosmic microwave background (CMB) lensing power spectrum analysis of Atacama Cosmology Telescope (ACT) data release 6 (DR6) data. Two independent microwave sky simulations are used to test a range of mitigation strategies. We demonstrate that finding and then subtracting point sources, finding and then subtracting models of clusters, and using a profile bias-hardened lensing estimator together reduce the fractional biases to well below statistical uncertainties, with the inferred lensing amplitude, A _lens , biased by less than 0.2 σ . We also show that another method where a model for the cosmic infrared background (CIB) contribution is deprojected and high-frequency data from Planck is included has similar performance. Other frequency-cleaned options do not perform as well, either incurring a large noise cost or resulting in biased recovery of the lensing spectrum. In addition to these simulation-based tests, we also present null tests on the ACT DR6 data for sensitivity of our lensing spectrum estimation to differences in foreground levels between the two ACT frequencies used, while nulling the CMB lensing signal. These tests pass whether the nulling is performed at the map or bandpower level. The CIB-deprojected measurement performed on the DR6 data is consistent with our baseline measurement, implying that contamination from the CIB is unlikely to significantly bias the DR6 lensing spectrum. This collection of tests gives confidence that the ACT DR6 lensing measurements and cosmological constraints presented in companion papers to this work are robust to extragalactic foregrounds.

We present cosmological constraints from a gravitational lensing mass map covering 9400 deg ^2 reconstructed from measurements of the cosmic microwave background (CMB) made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with measurements of baryon acoustic oscillations and big bang nucleosynthesis, we obtain the clustering amplitude σ _8 = 0.819 ± 0.015 at 1.8% precision, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.840\pm 0.028$ , and the Hubble constant H _0 = (68.3 ± 1.1) km s ^−1 Mpc ^−1 at 1.6% precision. A joint constraint with Planck CMB lensing yields σ _8 = 0.812 ± 0.013, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.831\pm 0.023$ , and H _0 = (68.1 ± 1.0) km s ^−1 Mpc ^−1 . These measurements agree with ΛCDM extrapolations from the CMB anisotropies measured by Planck. We revisit constraints from the KiDS, DES, and HSC galaxy surveys with a uniform set of assumptions and find that S _8 from all three are lower than that from ACT+Planck lensing by levels ranging from 1.7 σ to 2.1 σ . This motivates further measurements and comparison, not just between the CMB anisotropies and galaxy lensing but also between CMB lensing probing z ∼ 0.5–5 on mostly linear scales and galaxy lensing at z ∼ 0.5 on smaller scales. We combine with CMB anisotropies to constrain extensions of ΛCDM, limiting neutrino masses to ∑ m _ν < 0.13 eV (95% c.l.), for example. We describe the mass map and related data products that will enable a wide array of cross-correlation science. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the ΛCDM model, while paving a promising path for neutrino physics with lensing from upcoming ground-based CMB surveys.

We present new measurements of cosmic microwave background (CMB) lensing over 9400 deg ^2 of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB data set, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at 2.3% precision (43 σ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure that our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. Our CMB lensing power spectrum measurement provides constraints on the amplitude of cosmic structure that do not depend on Planck or galaxy survey data, thus giving independent information about large-scale structure growth and potential tensions in structure measurements. The baseline spectrum is well fit by a lensing amplitude of A _lens = 1.013 ± 0.023 relative to the Planck 2018 CMB power spectra best-fit ΛCDM model and A _lens = 1.005 ± 0.023 relative to the ACT DR4 + WMAP best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination ${S}_{8}^{\mathrm{CMBL}}\equiv {\sigma }_{8}{\left({{\rm{\Omega }}}_{m}/0.3\right)}^{0.25}$ of ${S}_{8}^{\mathrm{CMBL}}=0.818\pm 0.022$ from ACT DR6 CMB lensing alone and ${S}_{8}^{\mathrm{CMBL}}=0.813\pm 0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with ΛCDM model constraints from Planck or ACT DR4 + WMAP CMB power spectrum measurements. Our lensing measurements from redshifts z ∼ 0.5–5 are thus fully consistent with ΛCDM structure growth predictions based on CMB anisotropies probing primarily z ∼ 1100. We find no evidence for a suppression of the amplitude of cosmic structure at low redshifts.

The corneal endothelium, comprising densely packed corneal endothelial cells (CECs) adhering to Descemet’s membrane (DM), plays a critical role in maintaining corneal transparency by regulating water and ion movement. CECs have limited regenerative capacity within the body, and globally, there is a shortage of donor corneas to replace damaged corneal endothelia. The development of a carrier for cultured CECs may address this worldwide clinical need. In this study we successfully manufactured a gelatin nanofiber membrane (gelNF membrane) using electrospinning, followed by crosslinking with glutaraldehyde (GA). The fabricated gelNF membrane exhibited approximately 80% transparency compared with glass and maintained a thickness of 20 µm. The gelNF membrane demonstrated desirable permeability and degradability for a Descemet’s membrane analog. Importantly, CECs cultured on the gelNF membrane at high densities showed no cytotoxic effects, and the expression of key CEC functional biomarkers was verified. To assess the potential of this gelNF membrane as a carrier for cultured CEC transplantation, we used it to conduct Descemet’s membrane endothelial keratoplasty (DMEK) on rabbit eyes. The outcomes suggest this gelNF membrane holds promise as a suitable carrier for cultured CEC transplantation, offering advantages in terms of transparency, permeability, and sufficient mechanical properties required for successful transplantation.

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) is an underdiagnosed cause of heart failure (HF) among patients ≥60 years of age. Although the V122I (valine to isoleucine substitution at position 122 of the transthyretin protein) variant associated with hereditary ATTR‐CM is present in 3.4% of self‐identified Black individuals in the United States (or 1.5 million people), the phenotypic penetrance is not known. Methods and Results The SCAN‐MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study is a currently accruing prospective multisite study designed to determine the prevalence of ATTR‐CM using technetium‐99m‐pyrophosphate imaging in older (≥60 years of age) self‐identified Black and Hispanic individuals with HF. Calculations of the penetrance and prevalence of the V122I allele, along with analyses of functional, biochemical, and echocardiographic parameters, were performed for the first 278 Black participants in SCAN‐MP. The prevalence of ATTR‐CM was 6.8% (95% CI, 4.2–10.5; n=19 cases), of whom 63% were ATTR wild‐type. The prevalence of V122I was 6.5% (n=18 carriers), of whom 7 had ATTR‐CM, yielding a phenotypic penetrance of 39% (95% CI, 17–64). V122I carriers with ATTR‐CM evidenced more advanced HF than carriers without ATTR‐CM. Prealbumin concentration was lowest among V122I carriers with ATTR‐CM (12.9 mg/dL) versus carriers without ATTR‐CM (21.0 mg/dL) and HF controls (25.0 mg/dL, P

Zia Ul Mustafa,1,2 Muhammad Nouman Manzoor,3 Arfah Shahid,4 Muhammad Salman,5 Khezar Hayat,6 Khalida Yasmin,7 Mohamed A Baraka,8,9 Smitha Mathew,10 Mahpara Kanwal,11 Samina Parveen,12 Irsa Jamal,13 Amer Hayat Khan,1 Brian Godman,14– 16 Fahad Saleem,17 Mohammad Bashaar18 1Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia; 2Department of Pharmacy Services, District Headquarter (DHQ) Hospital, Pakpattan 54700, Pakistan; 3Department of Medicine, Faisalabad Medical University, Faisalabad 38000, Pakistan; 4Department of Medicine, Rawalpindi Medical University, Rawalpindi 46000, Pakistan; 5Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan; 6Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan; 7Lahore School of Nursing, The University of Lahore, Lahore, Pakistan; 8Clinical Pharmacy Program, College of Pharmacy, Al Ain Campus, Al Ain University, Al Ain, Abu Dhabi, United Arab Emirates; 9Clinical Pharmacy Department, College of Pharmacy, Al-Azhar University, Nasr city, Cairo, Egypt; 10Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia; 11Department of Pharmacy Services, District Headquarter Hospital, Okara South City, Pakistan; 12Department of Pharmacy Services, District Headquarter Hospital, Chakwal, Pakistan; 13Department of Pharmacy Services, District Headquarter Hospital, Kasur, Pakistan; 14School of Pharmacy, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa; 15Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; 16Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK; 17Faculty of Pharmacy & Health Sciences, University of Balochistan, Quetta, Pakistan; 18SMART Afghan International Trainings and Consultancy, Kabul, AfghanistanCorrespondence: Mohammad Bashaar, SMART Afghan International Trainings and Consultancy, Shahri Naw, Hospital Street No. 1, Kabul, Afghanistan, Tel +93788233865, Email dr.mbashaar@gmail.comPurpose: Antimicrobial resistance (AMR) is leading to greater therapeutic cost, length of hospital stays, adverse events, morbidity and mortality. Hospital-based antimicrobial stewardship programs (ASPs) engaging physicians, pharmacists, microbiologists and nurses are considered as effective way to ensure appropriate use of antimicrobial agents. The aims of our study were to assess nurses’ perception, involvement, confidence and barriers towards hospital-based ASPs, and use the findings to provide future guidance.Methods: A web-based, cross-sectional study was conducted among the nurses serving at eleven hospitals of Punjab province of Pakistan during a period of two months (December 2021-January 2022). Data were collected using a validated self-administered questionnaire. All data were analyzed using SPSS version 22.Results: A total of 583 nurses participated in the study (response rate = 77.7%). All the participants were female staff nurses and 86% had a minimum of 3 years of working experience. The overall median score on the perception towards ASPs among the nurses was 18 (IQR: 16, 19) on a 0 to 20 scale whereas median score on the involvement in ASPs was 18 (IQR: 15, 37) on a 0 to 64 scale. Median perception and involvement score were statistically significantly differed by age (p < 0.001) and years of experience (p < 0.001). The overall median score on the confidence to perform ASP activities was 22 (IQR: 14, 24) on a 0 to 28 scale. Lack of knowledge, insufficient support from administration, and heavy workload were found to be the common barriers to perform ASP.Conclusion: Our study concluded that Pakistani nurses have positive perception but limited involvement in ASPs. Moreover, they are confident to perform ASP besides many barriers.Keywords: involvement, confidence, nurses, antimicrobial resistance, antimicrobial stewardship programs, Pakistan

Summary: Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) is an important cause of heart failure in older individuals. Misfolding and deposition of transthyretin or prealbumin protein causes ATTR‐CM in the context of a normal (wild‐type) or variant TTR sequence. Variant ATTR‐CM is most commonly caused by the substitution of valine for isoleucine at position 122 in transthyretin (Val122Ile or pV142I, almost exclusively observed in individuals of West African ancestry), demonstrated in 3.4% of self‐identified Black individuals in the United States with an estimated 1.5 million carriers. Despite the large number of known pV142I carriers, the proportion of older Black patients with heart failure attributable to ATTR‐CM remains unknown. Methods To address this knowledge gap, the SCAN‐MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL139671) to enroll a targeted population of self‐identified, community‐dwelling Black or Caribbean Hispanic patients (many of whom are of West African ancestry) >60 years of age with heart failure and identify ATTR‐CM by noninvasive nuclear imaging. The principal objective of SCAN‐MP is to determine the prevalence of ATTR‐CM in this population. Secondary objectives will explore TTR genotype, demographics, progression of variant versus wild‐type ATTR‐CM, and biochemical mechanisms of transthyretin amyloid fibril formation. Conclusions The SCAN‐MP study is the largest, prospective study of cardiac amyloidosis in Black and Hispanic individuals. Both wild‐type and variant ATTR‐CM are now treatable with the US Food and Drug–approved drug tafamidis. The insights gained from SCAN‐MP are likely to improve those at risk for or afflicted with ATTR‐CM. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03812172.

Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). Results This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation. Conclusions This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease. ClinicalTrials.gov Identifier: NCT00628745.

Abstract COVID-19 has imposed a very substantial direct threat to the physical health of those infected, although the corollary impact on mental health may be even more burdensome. Here we focus on assessing the mental health impact of COVID-19 and of other epidemics in the community. We searched five electronic databases until December 9, 2020, for all peer-reviewed original studies reporting any prevalence or correlates of mental disorders in the general population following novel epidemics in English, Chinese or Portuguese. We synthesised prevalence estimates from probability samples during COVID-19 and past epidemics. The meta-analytical effect size was the prevalence of relevant outcomes, estimated via random-effects model. I 2 statistics, Doi plots and the LFK index were used to examine heterogeneity and publication bias. This study is pre-registered with PROSPERO, CRD42020179105. We identified 255 eligible studies from 50 countries on: COVID-19 (n = 247 studies), severe acute respiratory syndrome (SARS; n = 5), Ebola virus disease (n = 2), and 1918 influenza (n = 1). During COVID-19, we estimated the point prevalence for probable anxiety (20.7%, 95% CI 12.9–29.7), probable depression (18.1%, 13.0–23.9), and psychological distress (13.0%, 0–34.1). Correlates for poorer mental health include female sex, lower income, pre-existing medical conditions, perceived risk of infection, exhibiting COVID-19-like symptoms, social media use, financial stress, and loneliness. Public trust in authorities, availability of accurate information, adoption of preventive measures and social support were associated with less morbidity. The mental health consequences of COVID-19 and other epidemics could be comparable to major disasters and armed conflicts. The considerable heterogeneity in our analysis indicates that more random samples are needed. Health-care professionals should be vigilant of the psychological toll of epidemics, including among those who have not been infected.

Abstract Expert elicitation can be valuable for informing decision‐makers on conservation and wildlife management issues. To date, studies eliciting expert opinions have primarily focused on identifying and building consensus on key issues. Nonetheless, there are drawbacks of a strict focus on consensus, and it is important to understand and emphasize dissent, too. This study adopts a dissensus‐based Delphi to understand conflict among dingo experts. Twenty‐eight experts participated in three rounds of investigation. We highlight disagreement on most of the issues explored. In particular, we find that disagreement is underpinned by what we call “conflict over values” and “conflict over evidence.” We also note the broader role played by distrust in influencing such conflicts. Understanding and recognizing the different elements shaping disagreement is critical for informing and improving decision‐making and can also enable critique of dominant paradigms in current practices. We encourage greater reflexivity and open deliberation on these aspects and hope our study will inform similar investigations in other contexts.

Patients with heart failure (HF) often have multiple chronic conditions and are at increased risk for severe disease and mortality when infected by SARS-CoV-2, the virus that causes COVID-19. Furthermore, disparities in outcomes with COVID-19 have been associated with both racial/ethnic identity but also social determinants of health. Among older, urban-dwelling, minority patients with HF, we sought to characterize medical and non-medical factors associated with SARS-CoV-2 infection. Patients with HF living in Boston and New York City over 60 years of age participating in the Screening for Cardiac Amyloidosis with Nuclear Imaging (SCAN-MP) study between 12/1/2019 and 10/15/2021 (n = 180) were tested for nucleocapsid antibodies to SARS-CoV-2 and queried for symptomatic infection with PCR verification. Baseline testing included the Kansas City Cardiomyopathy Questionnaire (KCCQ), assessment of health literacy, biochemical, functional capacity, echocardiography, and a novel survey tool that determined living conditions, perceived risk of infection, and attitudes towards COVID-19 mitigation. The association of infection with prevalent socio-economic conditions was assessed by the area deprivation index (ADI). There were 50 overall cases of SARS-CoV-2 infection (28%) including 40 demonstrating antibodies to SARS-CoV-2 (indicative of prior infection) and 10 positive PCR tests. There was no overlap between these groups. The first documented case from New York City indicated infection prior to January 17, 2020. Among active smokers, none tested positive for prior SARS-CoV-2 infection (0 (0%) vs. 20 (15%), p = 0.004) vs. non-smokers. Cases were more likely to be taking ACE-inhibitors/ARBs compared to non-cases (78% vs 62%, p = 0.04). Over a mean follow-up of 9.6 months, there were 6 total deaths (3.3%) all unrelated to COVID-19. Death and hospitalizations (n = 84) were not associated with incident (PCR tested) or prior (antibody) SARS-CoV-2 infection. There was no difference in age, co-morbidities, living conditions, attitudes toward mitigation, health literacy, or ADI between those with and without infection. SARS-CoV-2 infection was common among older, minority patients with HF living in New York City and Boston, with evidence of infection documented in early January 2020. Health literacy and ADI were not associated with infection, and there was no increased mortality or hospitalizations among those infected with SARS-CoV-2.

Raghad Hashim,1 Ruba Odeh,2 Afraa Hussain Salah,2 Simy Mathew3 1Department of Basic Medical and Dental Sciences, Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; 2Department of Clinical Sciences, Ajman University, Ajman, United Arab Emirates; 3Department of Basic Medical and Dental Sciences, Ajman University, Ajman, United Arab EmiratesCorrespondence: Raghad HashimDepartment of Basic Medical and Dental Sciences, Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, P.O. Box 346, Ajman, United Arab EmiratesTel +9716 705 6394Email r.hashim@ajman.ac.aeBackground and Objectives: The main objective of this study was to assess the impact of a lecture on dental trauma on the knowledge of undergraduate dental students at Ajman University in the United Arab Emirates (UAE).Methods: Fourth-year dental students were asked to attend a lecture on dental trauma and then respond to an online questionnaire containing 10 close-ended questions related to their approach to managing dental trauma cases and tooth avulsion before (T0) and directly after (T1) the lecture. They were given 5 min for filling the questionnaire either time. McNemars test was used to compare the accuracy of their answers based on the correct or incorrect response for each question. The level of significance was set at p < 0.05.Results: The questionnaire was sent to 164 students, out of which 157 responded, giving a response rate of 95.7%. After receiving the educational intervention, the students showed a significant improvement in their knowledge on managing permanent tooth avulsion, especially regarding the handling of an avulsed tooth before replantation, extra-alveolar time, and media used for the storage and transportation of avulsed teeth (< 0.001).Conclusion: The study reveals that the lecture on dental trauma had an excellent outcome on the knowledge of the students. Therefore, it is essential to emphasize the importance of this information among undergraduate dental students in order to save teeth exposed to trauma and to reduce the social burden of such cases. This study contributes to better understanding of the effect of dental trauma education on undergraduate dental students’ knowledge of the subject.Keywords: dental trauma education, dental injuries, dental students

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.

Diabetic peripheral neuropathy (DN) is a serious complication of diabetes mellitus (DM) that can lead to foot ulceration and eventual amputation if not treated properly. Therefore, detecting DN early is important. This study presents an approach for diagnosing various stages of the progression of DM in lower extremities using machine learning to classify individuals with prediabetes (PD; n = 19), diabetes without (D; n = 62), and diabetes with peripheral neuropathy (DN; n = 29) based on dynamic pressure distribution collected using pressure-measuring insoles. Dynamic plantar pressure measurements were recorded bilaterally (60 Hz) for several steps during the support phase of walking while participants walked at self-selected speeds over a straight path. Pressure data were grouped and divided into three plantar regions: rearfoot, midfoot, and forefoot. For each region, peak plantar pressure, peak pressure gradient, and pressure–time integral were calculated. A variety of supervised machine learning algorithms were used to assess the performance of models trained using different combinations of pressure and non-pressure features to predict diagnoses. The effects of choosing various subsets of these features on the model’s accuracy were also considered. The best performing models produced accuracies between 94–100%, showing the proposed approach can be used to augment current diagnostic methods.

Abstract Shortly after the enactment of restrictions aimed at limiting the spread of COVID-19, various local government and public health authorities around the world reported an increased sighting of rats. Such reports have yet to be empirically validated. Here we combined data from multi-catch rodent stations (providing data on rodent captures), rodent bait stations (providing data on rodent activity) and residents’ complaints to explore the effects of a six week lockdown period on rodent populations within the City of Sydney, Australia. The sampling interval encompassed October 2019 to July 2020 with lockdown defined as the interval from April 1st to May 15th, 2020. Rodent captures and activity (visits to bait stations) were stable prior to lockdown. Captures showed a rapid increase and then decline during the lockdown, while rodent visits to bait stations declined throughout this period. There were no changes in the frequency of complaints during lockdown relative to before and after lockdown. There was a non-directional change in the geographical distribution of indices of rodent abundance suggesting that rodents redistributed in response to resource scarcity. We hypothesize that lockdown measures initially resulted in increased rodent captures due to sudden shortage of human-derived food resources. Rodent visits to bait stations might not show this pattern due to the nature of the binary data collected, namely the presence or absence of a visit. Relocation of bait stations driven by pest management goals may also have affected the detection of any directional spatial effect. We conclude that the onset of COVID-19 may have disrupted commensal rodent populations, with possible implications for the future management of these ubiquitous urban indicator species.

Abstract Background The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient’s preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis. Main body ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19. Conclusion Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.

IntroductionIn hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) represents myocardial fibrosis and is associated with sudden cardiac death. However, CMR requires particular expertise and is expensive and time-consuming. Therefore, it is important to specify patients with a high pre-test probability of having LGE as the utility of CMR is higher in such cases. The objective was to determine whether plasma proteomics profiling can distinguish patients with and without LGE on CMR in the HCM population.Materials and MethodsWe performed a multicenter case-control (LGE vs. no LGE) study of 147 patients with HCM. We performed plasma proteomics profiling of 4,979 proteins. Using the 17 most discriminant proteins, we performed logistic regression analysis with elastic net regularization to develop a discrimination model with data from one institution (the training set; n = 111) and tested the discriminative ability in independent samples from the other institution (the test set; n = 36). We calculated the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity.ResultsOverall, 82 of the 147 patients (56%) had LGE on CMR. The AUC of the 17-protein model was 0.83 (95% confidence interval [CI], 0.75–0.90) in the training set and 0.71 in the independent test set for validation (95% CI, 0.54–0.88). The sensitivity of the training model was 0.72 (95% CI, 0.61–0.83) and the specificity was 0.78 (95% CI, 0.66–0.90). The sensitivity was 0.71 (95% CI, 0.49–0.92) and the specificity was 0.74 (95% CI, 0.54–0.93) in the test set. Based on the discrimination model derived from the training set, patients in the test set who had high probability of having LGE had a significantly higher odds of having LGE compared to those who had low probability (odds ratio 29.6; 95% CI, 1.6–948.5; p = 0.03).ConclusionsIn this multi-center case-control study of patients with HCM, comprehensive proteomics profiling of 4,979 proteins demonstrated a high discriminative ability to distinguish patients with and without LGE. By identifying patients with a high pretest probability of having LGE, the present study serves as the first step to establishing a panel of circulating protein biomarkers to better inform clinical decisions regarding CMR utilization.

Transthyretin amyloidosis involves the deposition of transthyretin amyloid fibrils in the body. We report an unusual case of a young Afro-Caribbean woman harboring a Thr60Ala mutation who presented with clinical signs of heart failure and polyneuropathy confirmed with genetic testing and results of an abdominal fat pad biopsy. (Level of Difficulty: Intermediate.)

Purpose: To describe an atypical case of acanthamoeba keratitis with positive in vivo confocal microscopy in a non-contact lens user who presented with signs and symptoms suggestive of central toxic keratopathy. Observations: The patient presented with bilateral, though sequential, decreased visual acuity with mild pain. Examination showed stromal haze with corneal flattening and thinning without epithelial defects. Optical coherence tonometry of the right eye revealed an inverse dome-shaped appearance of the opacity and in-vivo confocal imaging showed double-walled cysts consistent with acanthamoeba. Corneal haze, stromal loss, resolved and visual acuity improved over time. Conclusion and importance: Acanthamoeba is a rare cause of infectious keratitis that is most often associated with contact lens wear in developed countries. Typically, it presents with a unilateral decrease in visual acuity, photophobia, watering, and pain that is out of proportion to slit lamp examination findings. However, many atypical presentations have been reported in the literature. Consequently, it may be misdiagnosed, especially early in the course of the disease. This delay in diagnosis can lead to progressive ulceration and visual impairment. In addition, cyst formation can make eradication with anti-amoebic treatment especially difficult.Central toxic keratopathy is a non-inflammatory clinical syndrome of unknown etiology that is most often associated with excimer laser ablation, though other associated causes have been reported. It is characterized by a central or paracentral opacity with corneal stromal loss and resultant hyperopic shift. The opacification and stromal loss mostly resolve over the course of months with an improvement in visual acuity. This report may help physicians broaden their differential and correctly diagnose atypical presentations of amoebic infection.

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes — myocarditis and cardiac necrosis — have proved uncommon. To elucidate the pathophysiology of COVID-19–associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non–COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19–associated cardiac microthrombi.

Moraxella canis was first identified in 1993 as normal flora of the oral cavities of dogs and cats. The species has been reported to cause localized infections in immunocompromised humans only three times. We report the first description of severe disseminated infection attributed to M. canis.

Background: With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative. Objectives: We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores. Methods: Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration. Results: 309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively. Conclusions: Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.

Abstract Background Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. Methods These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. Results The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. Conclusions A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

Judy Munday,1– 4 Niall Higgins,1,2,5 Saira Mathew,1,2 Lizanne Dalgleish,1,2,5 Anthony S Batterbury,1,2,5 Luke Burgess,1,2,4 Jill Campbell,1,2,5 Lori J Delaney,1,2,6 Bronwyn R Griffin,1,2 James A Hughes,1,2,5 Jessica Ingleman,1,2 Samantha Keogh,1,2,5,7 Fiona Coyer1,2,5 1Centre for Healthcare Transformation, Faculty of Health, Queensland University of Technology (QUT), Brisbane, QLD, Australia; 2School of Nursing, Queensland University of Technology (QUT), Brisbane, QLD, Australia; 3 Department of Health and Nursing Science, University of Agder, Grimstad, 4879, Norway; 4Mater Research Institute-UQ, South Brisbane, QLD 4101, Australia; 5Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia; 6Colleges of Health and Medicine, Australian National University, Acton, ACT 2601, Australia; 7Alliance for Vascular Access Teaching and Research, Griffith University, Brisbane, QLD, 4111, AustraliaCorrespondence: Judy MundaySchool of Nursing, Rm 529, Level 5, N Block, Victoria Park Road, Kelvin Grove, QLD 4059, AustraliaTel +61 3138 8209Email judy.munday@qut.edu.auPurpose: Nurses provide care at each phase of the complex, perioperative pathway and are well placed to identify areas of care requiring investigation in randomized controlled trials. Yet, currently, the scope of nurse-led randomized controlled trials conducted within the perioperative setting are unknown. This scoping review aims to identify areas of perioperative care in which nurse-led randomized controlled trials have been conducted, to identify issues impacting upon the quality of these trials and identify gaps for future investigation.Methods: This scoping review was conducted in reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. Searches were conducted in PubMed, Embase, Cumulative Index for Nursing and Allied Health Literature and the Cochrane Central Register of Controlled Trials, with a date range of 2014– 19. Sources of unpublished literature included Open Grey, and ProQuest Dissertation and Theses, Clinical Trials.gov and the Australian and New Zealand Clinical Trials Registry. After title and abstract checking, full-text retrieval and data extraction, studies were appraised using the Joanna Briggs Institute Critical Appraisal Checklists for randomized controlled trials. Data were synthesized according to the main objectives. Key information was tabulated.Results: From the 86 included studies, key areas where nurses have led randomized controlled trials include patient or caregiver anxiety; postoperative pain relief; surgical site infection prevention: patient and caregiver knowledge; perioperative hypothermia prevention; postoperative nausea and vomiting; in addition to other diverse outcomes. Issues impacting upon quality (including poorly reported randomization), and gaps for future investigation (including a focus on vulnerable populations), are evident.Conclusion: Nurse-led randomized controlled trials in the perioperative setting have focused on key areas of perioperative care. Yet, opportunities exist for nurses to lead experimental research in other perioperative priority areas and within different populations that have been neglected, such as in the population of older adults undergoing surgery.Keywords: perioperative, nursing, randomized controlled trial, scoping review

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β‐blocker [βB], angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time‐varying use, and in an inverse probability treatment weighted model. Primary outcome was all‐cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow‐up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time‐varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings.

Genetic testing provides valuable insights into family screening strategies, diagnosis, and prognosis in patients with hypertrophic cardiomyopathy (HCM). On the other hand, genetic testing carries socio-economical and psychological burdens. It is therefore important to identify patients with HCM who are more likely to have positive genotype. However, conventional prediction models based on clinical and echocardiographic parameters offer only modest accuracy and are subject to intra- and inter-observer variability. We therefore hypothesized that deep convolutional neural network (DCNN, a type of deep learning) analysis of echocardiographic images improves the predictive accuracy of positive genotype in patients with HCM. In each case, we obtained parasternal short- and long-axis as well as apical 2-, 3-, 4-, and 5-chamber views. We employed DCNN algorithm to predict positive genotype based on the input echocardiographic images. We performed 5-fold cross-validations. We used 2 reference models—the Mayo HCM Genotype Predictor score (Mayo score) and the Toronto HCM Genotype score (Toronto score). We compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus DCNN-derived probability and the reference model. We calculated the p-value by performing 1,000 bootstrapping. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, we examined the net reclassification improvement. We included 99 adults with HCM who underwent genetic testing. Overall, 45 patients (45%) had positive genotype. The new model combining Mayo score and DCNN-derived probability significantly outperformed Mayo score (AUC 0.86 [95% CI 0.79–0.93] vs. 0.72 [0.61–0.82]; p < 0.001). Similarly, the new model combining Toronto score and DCNN-derived probability exhibited a higher AUC compared to Toronto score alone (AUC 0.84 [0.76–0.92] vs. 0.75 [0.65–0.85]; p = 0.03). An improvement in the sensitivity, specificity, PPV, and NPV was also achieved, along with significant net reclassification improvement. In conclusion, compared to the conventional models, our new model combining the conventional and DCNN-derived models demonstrated superior accuracy to predict positive genotype in patients with HCM.

In addition to feeding on animal remains, many scavengers also function as predators. Carcasses may therefore affect local animal communities by attracting facultative scavengers and increasing predation risk for other species in the vicinity of the carcasses. This risk may be elevated in low productivity environments, especially where humans increase carcass production and where facultative scavengers include invasive species. In June and October 2018, we monitored experimentally placed red kangaroo (Osphranter rufus) carcasses and artificial bird nests in two different habitats in the Simpson Desert, Australia, to identify the nest predators attracted to the carcasses, and to determine how carcasses affect overall and predator-specific nest predation. We modelled our nests to approximate those of the ground nesting little buttonquail (Turnix velox) and the endangered night parrot (Pezoporus occidentalis). Native Corvus spp. and then invasive red foxes (Vulpes vulpes) were the top carcass visitors and nest egg predators. Carcass presence and open habitat increased overall nest predation and fewer artificial parrot nest eggs were depredated compared to those of quail. Open habitat and carcass presence only increased predator-specific nest predation by foxes, but corvid nest predation was highest in June 2018, and for the artificial quail nest types. Foxes were the main predator of eggs from night parrot nests. Our study shows that carcass provisioning by humans may have indirect, deleterious effects on ground nesting birds, and indicates that foxes might pose a greater threat to night parrot populations than previously recognised.

Aims: Patients undergoing aortic valve replacement (AVR) for severe aortic stenosis have a 6–16% prevalence of occult cardiac amyloidosis. Carpal tunnel syndrome (CTS) is common in cardiac amyloidosis, but whether prior CTS surgery has a prognostic impact in patients undergoing AVR is unknown. This study examined the association between prior CTS surgery and adverse cardiovascular outcomes in patients treated with AVR. Methods and results: Using Danish nationwide registries, we retrospectively identified patients undergoing first-time AVR from 2005 to 2018, examining the association between previous CTS and adverse cardiovascular outcomes the following 5 years after the AVR procedure. Cumulative incidence functions and adjusted Cox proportional hazard models were used to assess differences. Among 19,211 patients undergoing AVR, 2.5% (n = 472) had prior CTS surgery. Patients in the CTS-cohort were significantly older (median age 75.7 [IQR 68.1–82.3] vs 73.7 [IQR 66.0–79.6]), more often female and had more comorbidities. Prior CTS surgery was not associated with differences in hospitalization for heart failure (11.2% [95% CI 8.3–14.7] vs 9.4% [95% CI 9.0–9.9]), atrial fibrillation (11.1% [95% CI 8.2–14.5] vs 11.2% [95% CI 10.8–11.7]) or pacemaker implantation (6.2% [95% CI 4.0–9.0] vs 5.1% [95% CI 4.8–5.5]). The 5-year mortality (32.8% [27.6–38.0] vs 25.2% [24.5–25.9]) was higher in the CTS-cohort. CTS was significantly associated with increased 5-year mortality (HR 1.27 [1.05–1.53]) in crude models, however, after multivariable adjustment prior CTS surgery was not associated with adverse cardiovascular outcomes. Conclusion: Previous CTS surgery was not associated with increased risk for adverse cardiovascular outcomes after AVR.

We present tomographic measurements of structure growth using cross-correlations of Atacama Cosmology Telescope (ACT) DR6 and Planck cosmic microwave background (CMB) lensing maps with the unWISE Blue and Green galaxy samples, which span the redshift ranges 0.2 ≲ z ≲ 1.1 and 0.3 ≲ z ≲ 1.8, respectively. We improve on prior unWISE cross-correlations not just by making use of the new, high-precision ACT DR6 lensing maps, but also by including additional spectroscopic data for redshift calibration and by analyzing our measurements with a more flexible theoretical model. We determine the amplitude of matter fluctuations at low redshifts (z ≃ 0.2-1.6), finding S 8 ≡ σ 8 ( Ω m / 0.3 ) 0.5 = 0.813 ± 0.021 using the ACT cross-correlation alone and S 8 = 0.810 ± 0.015 with a combination of Planck and ACT cross-correlations; these measurements are fully consistent with the predictions from primary CMB measurements assuming standard structure growth. The addition of baryon acoustic oscillation data breaks the degeneracy between σ 8 and Ωm , allowing us to measure σ 8 = 0.813 ± 0.020 from the cross-correlation of unWISE with ACT and σ 8 = 0.813 ± 0.015 from the combination of cross-correlations with ACT and Planck. These results also agree with the expectations from primary CMB extrapolations in ΛCDM cosmology; the consistency of σ 8 derived from our two redshift samples at z ∼ 0.6 and 1.1 provides a further check of our cosmological model. Our results suggest that structure formation on linear scales is well described by ΛCDM even down to low redshifts z ≲ 1.