Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production.

Antibodies are key immune effectors that confer protection against pathogenic threats. The nature and longevity of the antibody response to SARS-CoV-2 infection are not well defined. We charted longitudinal antibody responses to SARS-CoV-2 in 92 subjects after symptomatic COVID-19. Antibody responses to SARS-CoV-2 are unimodally distributed over a broad range, with symptom severity correlating directly with virus-specific antibody magnitude. Seventy-six subjects followed longitudinally to ∼100 days demonstrated marked heterogeneity in antibody duration dynamics. Virus-specific IgG decayed substantially in most individuals, whereas a distinct subset had stable or increasing antibody levels in the same time frame despite similar initial antibody magnitudes. These individuals with increasing responses recovered rapidly from symptomatic COVID-19 disease, harbored increased somatic mutations in virus-specific memory B cell antibody genes, and had persistent higher frequencies of previously activated CD4+ T cells. These findings illuminate an efficient immune phenotype that connects symptom clearance speed to differential antibody durability dynamics.

Motivational profiles for eating behavior and their associations with intuitive eating.

Intuitive eating is an adaptive eating approach shown to have positive psychological and physical health outcomes. Understanding the motivation behind eating behavior can provide valuable information for why some women eat intuitively and others do not. Using self-determination theory (SDT), this study aimed to identify motivational profiles for eating behavior and examine differences in intuitive eating across these motivational profiles. A nationally representative sample of New Zealand women (n = 1,447) aged 40 to 50 years (M = 45.4; SD = 3.2) completed questionnaires assessing motivation and intuitive eating. Latent profile analysis identified five profiles characterized by varying levels of the global and specific forms of behavioral regulation described by SDT. The self-determined profile, characterized by high levels of global self-determination, had higher intuitive eating scores. The internalized profile, characterized by high levels of identified and integrated regulation, had average intuitive eating scores. The conflicted profile, characterized by high levels on most forms of behavioral regulation, and the unmotivated profile, characterized low levels on all forms of behavioral regulation, had a mix of high and low intuitive eating subscale scores. The amotivated profile, characterized by very high levels of amotivation, had lower intuitive eating scores. A motivational profile characterized by higher levels of self-determination and lower levels of the extrinsic forms of behavioral regulation appears to be beneficial for intuitive eating. Therefore, SDT-informed eating behavior interventions that enhance women's self-determined motivation should be created to facilitate intuitive eating in midlife women.

Quantification of antimicrobial use on Irish dairy farms: A comparison of three recording methods.

Antimicrobial use (AMU) data are essential for monitoring usage over time, facilitating reduction strategies to combat the threat of antimicrobial resistance (AMR) to both human and animal health. The objective of this study was to measure and describe AMU over a 12-mo period in Irish dairy herds and compare 3 different recording methods to a reference method. A sample of 33 Irish dairy herds were randomly selected from 6 private veterinary practices across Ireland. The herds were followed for a 12-mo period and their AMU was monitored using 3 recording methods: 1. Veterinary prescription data (VET), 2. The inventory of medicine bins on the farms (BIN), and 3. Farmer treatment records from herd recording software (APP). Each recording method was compared with a previously developed reference method for AMU. The reference method used was based on pre- and poststudy medicine stock on the farms combined with veterinary prescription data. Antimicrobial use was analyzed using both mass- and dosed-based metrics, including mass (mg) of antimicrobial active ingredient per population correction unit (mg/PCU), defined daily doses for animals (DDDVET) and defined course doses for animals (DCDVET). Median AMU was 16.24, 10.47, 8.87 and 15.55 mg/PCU by mass, and 2.43, 1.55, 1.19 and 2.26 DDDVET by dose for VET, BIN, APP, and reference method data, respectively. Reliability of the agreement between each pair of methods was quantified using the concordance correlation coefficient (CCC). When compared with the reference method, VET data had excellent reliability [95% confidence interval (CI) of CCC: 0.992-0.998]. The BIN data had good to excellent reliability [95% CI of CCC: 0.776-0.936]. The APP data had poor reliability when compared with the reference method [95% CI of CCC: -0.167-0.156]. Our results highlight that a small number of herds were contributing most to overall use and farmers showed varying levels of consistency in recording AMU. Veterinary data were the most reliable approach for assessing AMU when compared with a reference method of AMU. This is an important finding for the future monitoring of AMU at a national level.

Recording antimicrobial use on Irish dairy farms: Barriers and facilitators to using technology and sharing data.

Antimicrobial use (AMU) data are essential to monitor the effect of AMU reduction strategies in animal health. The use of technology and herd recording software to record AMU will be vital to scale the collation of these data in the future. The aim of this study was to determine the barriers and facilitators to Irish dairy farmers recording their AMU using a herd recording software and sharing AMU data. Thirty-three Irish dairy farmers involved in a study on AMU monitoring were asked to record their AMU using a herd recording software over a 12-mo period. At the end of the 12-mo period, 10 of these farmers were selected to take part in semi-structured interviews exploring their opinions on recording AMU, the use of herd recording software, and sharing AMU data. Interviews were transcribed and qualitatively analyzed using inductive thematic analysis. Several barriers and facilitators to farmers recording their AMU using a herd recording software and sharing AMU data were identified. Barriers included the age and generation of the farmer, farm infrastructure, a lack of training and education, a lack of knowledge around the benefits of digital data, a lack of incentive to digitize records, and a fear of repercussions. Facilitators identified by the farmers included the benefits of having instantly available data for making herd management decisions, reduced paperwork, increased organization for inspections, and a potential positive effect on the image of the dairy industry. To increase the uptake of new technology to record AMU at farm-level, farmers will need support in terms of education and training around the software available to them and reassurance around the perceived risks of repercussions with sharing data in a digital format.

Diverse Roles of the Exon Junction Complex Factors in the Cell Cycle, Cancer, and Neurodevelopmental Disorders-Potential for Therapeutic Targeting.

The exon junction complex (EJC) plays a crucial role in regulating gene expression at the levels of alternative splicing, translation, mRNA localization, and nonsense-mediated decay (NMD). The EJC is comprised of three core proteins: RNA-binding motif 8A (RBM8A), Mago homolog (MAGOH), eukaryotic initiation factor 4A3 (eIF4A3), and a peripheral EJC factor, metastatic lymph node 51 (MLN51), in addition to other peripheral factors whose structural integration is activity-dependent. The physiological and mechanistic roles of the EJC in contribution to molecular, cellular, and organismal level function continue to be explored for potential insights into genetic or pathological dysfunction. The EJC's specific role in the cell cycle and its implications in cancer and neurodevelopmental disorders prompt enhanced investigation of the EJC as a potential target for these diseases. In this review, we highlight the current understanding of the EJC's position in the cell cycle, its relation to cancer and developmental diseases, and potential avenues for therapeutic targeting.

Probing the Role of Chirality in Phospholipid Membranes.

Nucleotides, amino acids, sugars, and lipids are almost ubiquitously homochiral within individual cells on Earth. While oligonucleotides and proteins exist as one natural chirality throughout the tree of life, two stereoisomers of phospholipids have separately emerged in archaea and bacteria, an evolutionary divergence known as "the lipid divide". Within this review, we focus on the emergence of phospholipid homochirality and compare the stability of synthetic homochiral and heterochiral membranes in vitro. We discuss chemical probes designed to study the stereospecific interactions of lipid membranes in vitro. Overall, we aim to highlight studies that help elucidate the determinants of stereospecific interactions between lipids, peptides, and small molecule ligands. Continued work in understanding the drivers of favorable interactions between chiral molecules and biological membranes will lead to the design of increasingly selective chemical tools for bioorthogonal labeling of lipid membranes and safer membrane-associating pharmaceuticals.

Observer Agreement of Vertebral Fracture Grading Using Dual Energy Absorptiometry Vertebral Fracture Assessment in Duchenne Muscular Dystrophy.

Routine screening of the spine for vertebral fracture is recommended in the recent international standards of care for boys with Duchenne muscular dystrophy (DMD). Recent international consensus endorses the use of dual energy absorptiometry vertebral fracture assessment for identification of vertebral fractures in children, which could be used instead of spine radiographs. This study aims to evaluate the inter-observer agreement for vertebral fracture classification in boys with DMD, and the impact on clinical management. Dual energy absorptiometry vertebral fracture assessment and morphometric analysis in 39 boys was performed by a reader with no prior experience (R1) and 2 readers with experience (R2 and R3). Inter-observer concordance of vertebral fracture grading comparing R1 with R2 and R3 was substantial (Kappa 0.66, 95% CI 0.56, 0.76). Concordance between R2 and R3 was almost perfect (Kappa 0.93, 95% CI 0.89, 0.97) which did not lead to differences in clinical management. Grading by R1 in comparison to R2 and R3 would have led to change in management of 5/39 boys (13%), according to recent standards of care guidance. Structured education programme on identification of vertebral fractures should be explored to ensure consistency of reporting of this important health outcome measure in DMD.

The immunologic response to severe acute respiratory syndrome coronavirus 2.

Background: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated the worst global pandemic in a century, which has caused millions of infections and deaths as well as massive economic repercussions. Objective: As with any pathogenic virus, it is crucial to understand its unique interactions with the human immune system so that pharmaceutical and prophylactic interventions can be deployed to effectively control the pandemic. Methods: A literature search by using PubMed was conducted in 2020 with variants of the terms "COVID-19," "SARS-CoV-2," and "immunological response." English language articles that presented original data about the immunologic response to coronavirus disease 2019 (COVID-19) were selected for review. This article reviewed the current understanding of the innate and adaptive immune responses to SARS-CoV-2 infection, including their relationship to current therapeutic and diagnostic strategies. Results: SARS-CoV-2 uses several unique molecular techniques to evade detection by the innate immune system early in the course of infection, and upregulation of these innate immune pathways may possibly accelerate the time to recovery and prevent severe disease. Although the majority of cases results in the patients' recovery, a significant proportion of infections result in deaths prompted by the host's inflammatory overreaction to the infection, a response that can be attenuated with corticosteroids and potentially other immune modulators. Conclusion: Current work by the scientific community to further understand how SARS-CoV-2 interacts with the human immune system will be invaluable to our response and preparedness for future coronavirus pandemics.

Performance Evaluation of a New Point of Care Viscoelastic Coagulation Monitoring System in Major Abdominal, Orthopaedic and Vascular Surgery.

Viscoelastic Coagulation Testing (VCT), or Thromboelastography has the potential to improve the cost and clinical effectiveness of surgical and medical care by preventing unnecessary treatment and by improving treatment for bleeding, via targeted transfusion strategies. Recently a new viscoelastic coagulation monitoring system, the VCM System, has been developed, which has several advantages over existing systems. The VCM system is a small, portable device, that is designed to be simple to operate and can be used to reliably perform viscoelastic testing at the patient's bedside. The aim of this study was to evaluate the performance of the VCM system by comparing it to that of the ROTEM® delta. The CT, CFT, alpha angle, A10, A20, MCF and lysis results obtained from blood samples run in parallel on the VCM System and the ROTEM® NATEM test were compared for 86 patients undergoing planned abdominal, major orthopedic or vascular surgery. There was good correlation between the VCM and ROTEM® NATEM tests results for CT, A10, A20 and MCF, with Spearman Rank values of 0.70, 0.80, 0.80 and 0.73 respectively. The correlation between the two systems for CFT and alpha was moderate (Spearman Rank values of 0.68 and 0.51). There was also good agreement between the lysis parameters for the two systems. No problems with the usability of the VCM system, or difficulties with training on the system were reported by any of the clinical staff involved in the study. The VCM system is capable of making viscoelastic measurements of the hemostasis of blood samples within a rapid timeframe and addresses the accessibility, robustness and training issues associated with the larger traditional systems.

Current antimicrobial use in farm animals in the Republic of Ireland.

Antimicrobial resistance has been recognised as one of the most difficult challenges facing human and animal health in recent decades. The surveillance of antimicrobial use in animal health plays a major role in dealing with the growing issue of resistance. This paper reviews current data available on antimicrobial use in farmed animals in the Republic of Ireland, including each of the major livestock production sectors; pigs, poultry, dairy, beef and sheep. A systematic literature search was conducted to identify relevant published literature, and ongoing research was identified through the network of authors and searches of each of the research databases of the main agriculture funding bodies in Ireland. The varying quantities and quality of data available across each livestock sector underlines the need for harmonisation of data collection methods. This review highlights the progress that has been made regarding data collection in the intensive production sectors such as pigs and poultry, however, it is clear there are significant knowledge gaps in less intensive industries such as dairy, beef and sheep. To comply with European regulations an antimicrobial data collection system is due to be developed for all food-producing animals in the future, however in the short-term surveillance studies have allowed us to build a picture of current use within the Republic of Ireland. Further studies will allow us to fill current knowledge gaps and build a more comprehensive overview of antimicrobial use in farm animals in Ireland.

A PKD1L3 splice variant in taste buds is not cleaved at the G protein-coupled receptor proteolytic site.

Mutations in polycystin proteins PKD1 and TRPP2 lead to autosomal dominant polycystic kidney disease. These two proteins form a receptor-ion channel complex on primary cilia. PKD1 undergoes an autoproteolysis at the N terminal G-protein-coupled receptor proteolytic site (GPS), which is essential for the function of PKD1. Whether GPS cleavage happens in other PKD proteins and its functional consequence has remained elusive. Here we studied the GPS cleavage of PKD1L3, a protein that associates with TRPP3 in taste cells and may play a role in sour taste. Our results show that PKD1L3 also undergoes GPS cleavage. Mutation at the GPS abolishes the cleavage, and the non-cleavable mutant does not traffic to the plasma membrane when associated with TRPP3. We also found that a splice variant of PKD1L3, which was originally identified in taste buds, is not cleaved. Amino acids L708 and S709, which are missing in this splice variant, are crucial for the GPS cleavage of PKD1L3 and the trafficking of the PKD1L3/TRPP3 complex. Our results gain insight into the molecular mechanism of the GPS cleavage of PKD1L3. The presence of the non-cleavable variant suggests the potential in vivo function of uncleaved PKD proteins.

Extracellular Loops Are Essential for the Assembly and Function of Polycystin Receptor-Ion Channel Complexes.

Polycystin complexes, or TRPP-PKD complexes, made of transient receptor potential channel polycystin (TRPP) and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca2+ signals. For example, the TRPP2-PKD1 complex has a crucial function in renal physiology, with mutations in either protein causing autosomal dominant polycystic kidney disease. In contrast, the TRPP3-PKD1L3 complex responds to low pH and was proposed to be a sour taste receptor candidate. It has been shown previously that the protein partners interact via association of the C-terminal or transmembrane segments, with consequences for the assembly, surface expression, and function of the polycystin complexes. However, the roles of extracellular components, especially the loops that connect the transmembrane segments, in the assembly and function of the polycystin complex are largely unknown. Here, with an immunoprecipitation method, we found that extracellular loops between the first and second transmembrane segments of TRPP2 and TRPP3 associate with the extracellular loops between the sixth and seventh transmembrane segments of PKD1 and PKD1L3, respectively. Immunofluorescence and electrophysiology data further confirm that the associations between these loops are essential for the trafficking and function of the complexes. Interestingly, most of the extracellular loops are also found to be involved in homomeric assembly. Furthermore, autosomal dominant polycystic kidney disease-associated TRPP2 mutant T448K significantly weakened TRPP2 homomeric assembly but had no obvious effect on TRPP2-PKD1 heteromeric assembly. Our results demonstrate a crucial role of these functionally underexplored extracellular loops in the assembly and function of the polycystin complexes.

Sepsis and multi-organ dysfunction associated with postgrooming furunculosis in a dog.

BACKGROUND: Postgrooming furunculosis, as previously described in the dog, is a type of pyoderma that typically responds to routine antimicrobial therapy. Systemic clinical signs are common but are usually mild. ANIMAL: A 3-year-old spayed female great dane was presented with marked dorsal furunculosis of 24 h duration. The clinical signs and blood analyses were consistent with sepsis, systemic inflammatory response syndrome and disseminated intravascular coagulopathy (DIC). METHODS AND RESULTS: Skin culture revealed multi-drug resistant Pseudomonas aeruginosa infection. The dog did not respond to aggressive medical therapy including intravenous antibiotic therapy, fresh frozen plasma and haemodynamic support, and was humanely euthanized. Postmortem findings were consistent with postgrooming furunculosis with associated sepsis and DIC affecting multiple organs including the lungs and brain. CONCLUSIONS AND CLINICAL IMPORTANCE: Postgrooming furunculosis can progress to sepsis and multiple organ dysfunction in the dog and can lead to death.

Automated red blood cell exchange for acute drug removal in a patient with sirolimus toxicity.

Sirolimus is an immunosuppressant used to prevent graft versus host disease in allogeneic hematopoietic stem cell transplant recipients. It has a large volume of distribution (12 ± 7.5 l/kg) and within the intravascular space ∼95% of it is bound to red blood cells. Because of potential toxic effects at high trough levels, therapeutic drug monitoring is recommended for sirolimus. We present a case of severe hepatic dysfunction due to Hepatitis B and sirolimus toxicity, in a 51-year-old male stem cell transplant recipient. An automated red cell exchange decreased his blood sirolimus level from 22.6 to 10.3 ng/ml (55% reduction) and improved his liver enzymes. Re-equilibration of sirolimus from other compartments to the blood necessitated a series of four red cell exchanges, after which the sirolimus level was 4.7 ng/ml. Although the patient ultimately succumbed to multiorgan failure, red cell exchange may be considered for acute removal of sirolimus in selected patients.

Social determinants of health and COVID-19 recovery after inpatient rehabilitation.

BACKGROUND: Neighborhoods with more social determinants of health (SDOH) risk factors have higher rates of infectivity, morbidity, and mortality from COVID-19. Patients with severe COVID-19 infection can have long-term functional deficits leading to lower quality of life (QoL) and independence measures. Research shows that these patients benefit greatly from inpatient rehabilitation facilities (IRF) admission, but there remains a lack of studies investigating long-term benefits of rehabilitation once patients are returned to their home environment. OBJECTIVE: To determine SDOH factors related to long-term independence and QoL of COVID-19 patients after IRF stay. DESIGN: Multisite cross-sectional survey. SETTING: Two urban IRFs. MAIN OUTCOME MEASURES: Primary outcome measures were Post-COVID Functional Status Scale (PCFS) and Short Form-36 (SF-36) scores. Secondary outcomes were quality indicator (QI) scores while at IRF and a health care access questionnaire. Results were analyzed using analysis of variance and multivariate logistic regression analyses. RESULTS: Participants (n = 48) who were greater than 1 year post-IRF stay for severe COVID-19 were enrolled in the study. Higher SF-36 scores were associated with male gender (p = .002), higher income (≥$70,000, p = .004), and living in the city (p = .046). Similarly, patients who were of the male gender (p = .004) and had higher income (≥$70,000, p = .04) had a greater odds of a 0 or 1 on the PCFS. Age was not associated with differences. Women were more likely to seek follow-up care (p = .014). Those who sought follow-up care reported lower SF-36 overall and emotional wellness scores, p = .041 and p = .007, respectively. Commonly reported barriers to health care access were financial and time constraints. CONCLUSIONS: Patients with SDOH risk factors need to be supported in the outpatient setting to maintain functional gains made during IRF stays. Female gender, income, and urban setting are potential predictors for long-term QoL and independence deficits after rehabilitation for COVID-19 infection. Low emotional wellness is an indicator for patients to seek out care as far out as 1 year from their rehabilitation stay.

A Brief Intervention in Primary Care to Improve Parents' Discipline Practices and Reach Other Caregivers.

Parents (N = 599) of 6-month-old to 10-year-old children were given a handbook intervention that educates about healthy discipline in a pediatric clinic serving low-income families in Nashville, Tennessee. A research assistant spent approximately 1 minute introducing the intervention. A total of 440 parents (73.4%) responded to a follow-up survey 2 to 4 months later. Most parents (88%) who completed the follow-up survey had read at least part of the handbook. Of parents who received the handbook, 63% reported that the handbook helped them discipline their children. Half of parents reported specific changes they made because of the handbook. The most frequently reported changes were more talking/explaining/communicating (25%), more redirecting (7.8%), more patience/listening (6.0%), less anger/yelling (10.8%), and less spanking (7.5%). 42% of parents reported that they shared the handbook with other caregivers, friends, relatives, and children. A brief clinic intervention improves parents' discipline practices and reaches other caregivers.

Influence of donor point modifications on the assembly of chalcogen-bonded organic frameworks.

Incremental, single-atom substitutions of Se-based chalcogen bond (Ch-bond) donors with stronger donating Te centers were implemented in two new triptycene tris(1,2,5-chalcogenadiazole) tectons. The appreciably more favorable Ch-bonding ability of the Te-based donors promotes assembly of low-density networks and more stable Ch-bonded organic frameworks (ChOFs).

The relationship between patient-specific factors and functional progression of COVID-19 survivors admitted to an inpatient rehabilitation facility.

BACKGROUND: Survivors of hospitalization for severe acute COVID-19 infection faced significant functional impairments necessitating discharge to inpatient rehabilitation facilities (IRFs) for intensive rehabilitation prior to discharge home. There remains a lack of large cohort studies of the functional outcomes of patients admitted to IRFs with COVID-19-related impairments and the relationship to patient-specific factors. OBJECTIVE: To characterize functional outcomes of patients admitted to IRFs for COVID-19-related debility and to investigate associations between functional outcomes and patient-specific factors. DESIGN: Multisite retrospective cohort study. SETTING: Multiple IRFs in a large urban city. PARTICIPANTS: Adult patients admitted to IRFs for rehabilitation after hospitalization for acute COVID-19 infection. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Primary outcomes included change in GG Self-Care and Mobility Activities subscales and Functional Independence Measure scores from admission to discharge from inpatient rehabilitation. Linear regression analysis was used to relate functional changes to demographic, medical, and hospitalization-specific factors. Secondary outcomes included discharge destination from the IRF. RESULTS: The analysis included n = 362 patients admitted to IRFs for COVID-19-related rehabilitation needs. This cohort showed significant improvements in mobility, self-care, and cognition congregate scores (216.0%, 174.3%, 117.6% respectively). Patient-specific factors associated with functional improvement, included age, body mass index, premorbid employment status, history of diabetes and cardiac disease and medications received in acute care, and muscle strength upon admission to IRF. CONCLUSIONS: Patients admitted to inpatient rehabilitation for COVID-19-related functional deficits made significant functional improvements in mobility, self-care, and cognition. Many significant associations were found between patient-specific factors and functional improvement, which support further investigation of these factors as possible predictors of functional improvement in an IRF for COVID-19-related deficits.

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy.

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αß T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αß T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αß T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.