Ultrasound-mediated gene delivery specifically targets liver sinusoidal endothelial cells for sustained FVIII expression in hemophilia A mice.

The ability to target the native production site of factor VIII (FVIII)-liver sinusoidal endothelial cells (LSECs)-can improve the outcome of hemophilia A (HA) gene therapy. By testing a matrix of ultrasound-mediated gene delivery (UMGD) parameters for delivering a GFP plasmid into the livers of HA mice, we were able to define specific conditions for targeted gene delivery to different cell types in the liver. Subsequently, two conditions were selected for experiments to treat HA mice via UMGD of an endothelial-specific human FVIII plasmid: low energy (LE; 50 W/cm2, 150 µs pulse duration) to predominantly target endothelial cells or high energy (HE; 110 W/cm2, 150 µs pulse duration) to predominantly target hepatocytes. Both groups of UMGD-treated mice achieved persistent FVIII activity levels of ∼10% over 84 days post treatment; however, half of the HE-treated mice developed low-titer inhibitors while none of the LE mice did. Plasma transaminase levels and histological liver examinations revealed minimal transient liver damage that was lower in the LE group than in the HE group. These results indicate that UMGD can safely target LSECs with a lower-energy condition to achieve persistent FVIII gene expression, demonstrating that this novel technology is highly promising for therapeutic correction of HA.

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Sleep Health among Children Adopted from Foster Care: The Moderating Effect of Parent-Child Sleep Interactions.

OBJECTIVES: Sleep disruption is prevalent among children placed in foster care, elevating risk for a range of deleterious outcomes. Theoretically, achieving permanency via adoption may have a positive influence on children's sleep via the presence of various factors, but little is known about the sleep health of children adopted from foster care, including predictors and moderators of sleep health. METHOD: The current study included 226 parents who adopted a child from foster care in the U.S. (aged 4-11 years) within the past two years and a propensity score matched sample of 379 caregivers of children currently in foster care. Both samples completed online questionnaires about their child's sleep, physical, and mental health. RESULTS: Comparatively, children in foster care experienced more nightmares, night terrors, moving to someone else's' bed during the night, and worse overall sleep quality, whereas adopted children were reported to experience significantly more nighttime awakenings. In the adopted sample, a greater number of prior foster placements unexpectedly predicted lower total sleep disturbance scores, but this relationship was moderated by parent-child interactions around sleep. In general, greater parental involvement in children's sleep was associated with lower levels of child sleep disturbance. CONCLUSIONS: Findings suggest that while specific sleep problems might remit after children in foster care achieve permanence, nighttime sleep fragmentation often persists. Parent-child interactions surrounding sleep may be pivotal in improving sleep health in this population.

Development of parallel forms of a brief smell identification test useful for longitudinal testing.

Although there are numerous brief odor identification tests available for quantifying the ability to smell, none are available in multiple parallel forms that can be longitudinally administered without potential confounding from knowledge of prior test items. Moreover, empirical algorithms for establishing optimal test lengths have not been generally applied. In this study, we employed and compared eight machine learning algorithms to develop a set of four brief parallel smell tests employing items from the University of Pennsylvania Smell Identification Test that optimally differentiated 100 COVID-19 patients from 132 healthy controls. Among the algorithms, linear discriminant analysis (LDA) achieved the best overall performance. The minimum number of odorant test items needed to differentiate smell loss accurately was identified as eight. We validated the sensitivity of the four developed tests, whose means and variances did not differ from one another (Bradley-Blackwood test), by sequential testing an independent group of 32 subjects that included persons with smell dysfunction not due to COVID-19. These eight-item tests clearly differentiated the olfactory compromised subjects from normosmics, with areas under the ROC curve ranging from 0.79 to 0.83. Each test was correlated with the overall UPSIT scores from which they were derived. These brief smell tests can be used separately or sequentially over multiple days in a variety of contexts where longitudinal olfactory testing is needed.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

Effect of chimeric antigen receptor T cells against protease-activated receptor 1 for treating pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year survival rate of 6% following a diagnosis, and novel therapeutic modalities are needed. Protease-activated receptor 1 (PAR1) is abundantly overexpressed by both tumor cells and multiple stroma cell subsets in the tumor microenvironment (TME), thereby offering a suitable immunotherapy target. METHODS: A chimeric antigen receptor (CAR) strategy was applied to target PAR1 using a human anti-PAR1 scFv antibody fused to the transmembrane region with two co-stimulatory intracellular signaling domains of cluster of differentiation 28 (CD28) and CD137 (4-1BB), added to CD3ζ in tandem. RESULTS: The engineered PAR1CAR-T cells eliminated PAR1 overexpression and transforming growth factor (TGF)-ß-mediated PAR1-upregulated cancer cells by approximately 80% in vitro. The adoptive transfer of PAR1CAR-T cells was persistently enhanced and induced the specific regression of established MIA PaCa-2 cancer cells by > 80% in xenograft models. Accordingly, proinflammatory cytokines/chemokines increased in CAR-T-cell-treated mouse sera, whereas Ki67 expression in tumors decreased. Furthermore, the targeted elimination of PAR1-expressing tumors reduced matrix metalloproteinase 1 (MMP1) levels, suggesting that the blocking of the PAR1/MMP1 pathway constitutes a new therapeutic option for PDAC treatment. CONCLUSIONS: Third-generation PAR1CAR-T cells have antitumor activity in the TME, providing innovative CAR-T-cell immunotherapy against PDAC.

Cryptic resolution sites in the vector plasmid lead to the heterogeneities in the rAAV vectors.

Recombinant adeno-associated virus (rAAV) vectors carry a cassette of interest retaining only the inverted terminal repeats (ITRs) from the wild-type virus. Conventional rAAV production primarily uses a vector plasmid as well as helper genes essential for AAV replication and packaging. Nevertheless, plasmid backbone related contaminants have been a major source of vector heterogeneity. The mechanism driving the contamination phenomenon has yet to be elucidated. Here we identified cryptic resolution sites in the plasmid backbone as a key source for producing snapback genomes, which leads to the increase of vector genome heterogeneity in encapsidated virions. By using a single ITR plasmid as a model molecule and mapping subgenomic particles, we found that there exist a few typical DNA break hotspots in the vector DNA plasmid backbone, for example, on the ampicillin DNA element, called aberrant rescue sites. DNA around these specific breakage sites may assume some typical secondary structures. Similar to normal AAV vectors, plasmid DNA with a single ITR was able to rescue and replicate efficiently. These subgenomic DNA species significantly compete for trans factors required for rAAV rescue, replication, and packaging. The replication of single ITR contaminants during AAV production is independent of size. Packaging of these species is greatly affected by its size. A single ITR and a cryptic resolution site in the plasmid work synergistically, likely causing a source of plasmid backbone contamination.

IS26-mediated loss of the translocatable unit from Tn4352B requires the presence of the recA1 allele.

The pseudo-compound transposon Tn4352B is unusual in that the translocatable unit (TU) consisting of one of the bounding IS26 copies and the central portion containing the aphA1a gene has been found to be readily lost in the Escherichia coli strains used as host. Rapid loss required the presence of an additional 2 G residues adjacent to the internal end of one of the IS26 that flank the central portion and an active Tnp26 transposase. However, Tn4352B was found to be stable in wild-type Klebsiella pneumoniae strains. Though it was concluded that the difference may be due to the species background, the E. coli strains used were recombination-deficient. Here, we have further investigated the requirements for TU loss in E. coli and found that Tn4352B was stable in recombination-proficient strains. Among several recombination-deficient strains examined, rapid loss occurred only in strains that carry the recA1 allele but not in strains carrying different recA alleles, recA13 and a novel recA allele identified here, that also render the strain deficient in homologous recombination. Hence, it appears that a specific property of the RecA1 protein underlies the observed TU loss from Tn4352B.

Foster Caregivers' Perceptions of Children's Sleep Patterns, Problems, and Environments.

OBJECTIVE: The disparity of problems, impairments, and disorders among children in foster care is well-documented and spans virtually every domain of functioning. Sleep, however, has received minimal attention among this vulnerable group, which is concerning given the multitude of ways sleep affects children's development, health, and behavior. METHODS: A total of 485 foster caregivers from across the United States completed a survey including quantitative items and qualitative, open-ended questions about sleep and related health and behavior for one child (M = 6.4 years, SD = 2.2; range 4-11 years) currently in their care. RESULTS: Overall, caregivers reported developmentally appropriate child sleep and wake times; however, difficulty falling asleep (avg. 46 min per night) and staying asleep (avg. 34 min awake overnight) were common. Additionally, a high prevalence of sleep-related problems was reported including moving to someone else's bed during the night (85.8%), nightmares (51.2%), sleep terrors (26.4%), snoring (32.8%), bedwetting (31.6%), and teeth grinding (21.8%). Qualitative responses indicated emotional and behavioral challenges at bedtime, particularly elevated fear, and anxiety. CONCLUSIONS: Findings are consistent with previous work finding significant health disparities among children placed in foster care. Results highlight a need for trauma-informed, behavioral sleep interventions for this pediatric population which might serve to reduce other health disparities.

The sanctity of life: The role of purity in attitudes towards abortion and euthanasia.

Although abortion and euthanasia are highly contested issues at the heart of the culture war, the moral foundations underlying ideological differences on these issues are mostly unknown. Given that much of the extant debate is framed around the sanctity of life, we argued that the moral foundation of purity/sanctity-a core moral belief that emphasises adherence to the "natural order"-would mediate the negative relationship between conservatism and support for abortion and euthanasia. As hypothesised, results from a nation-wide random sample of adults in New Zealand (N = 3360) revealed that purity/sanctity mediated the relationship between conservatism and opposition to both policies. These results demonstrate that, rather than being motivated by a desire to reduce harm, conservative opposition to pro-choice and end-of-life decisions is (partly) based on the view that ending a life, even if it is one's own, violates God's natural design and, thus, stains one's spiritual purity.

Characterization of the specific DNA-binding properties of Tnp26, the transposase of insertion sequence IS26.

The bacterial insertion sequence (IS) IS26 mobilizes and disseminates antibiotic resistance genes. It differs from bacterial IS that have been studied to date as it exclusively forms cointegrates via either a copy-in (replicative) or a recently discovered targeted conservative mode. To investigate how the Tnp26 transposase recognizes the 14-bp terminal inverted repeats (TIRs) that bound the IS, amino acids in two domains in the N-terminal (amino acids M1-P56) region were replaced. These changes substantially reduced cointegration in both modes. Tnp26 was purified as a maltose-binding fusion protein and shown to bind specifically to dsDNA fragments that included an IS26 TIR. However, Tnp26 with an R49A or a W50A substitution in helix 3 of a predicted trihelical helix-turn-helix domain (amino acids I13-R53) or an F4A or F9A substitution replacing the conserved amino acids in a unique disordered N-terminal domain (amino acids M1-D12) did not bind. The N-terminal M1-P56 fragment also bound to the TIR but only at substantially higher concentrations, indicating that other parts of Tnp26 enhance the binding affinity. The binding site was confined to the internal part of the TIR, and a G to T nucleotide substitution in the TGT at positions 6 to 8 of the TIR that is conserved in most IS26 family members abolished binding of both Tnp26 (M1-M234) and Tnp26 M1-P56 fragment. These findings indicate that the helix-turn-helix and disordered domains of Tnp26 play a role in Tnp26-TIR complex formation. Both domains are conserved in all members of the IS26 family.

Specific triacylglycerol, diacylglycerol, and lyso-phosphatidylcholine species for the prediction of type 2 diabetes: a ~ 16-year prospective study in Chinese.

BACKGROUND: Bioactive lipids play an important role in insulin secretion and sensitivity, contributing to the pathophysiology of type 2 diabetes (T2D). This study aimed to identify novel lipid species associated with incident T2D in a nested case-control study within a long-term prospective Chinese community-based cohort with a median follow-up of ~ 16 years. METHODS: Plasma samples from 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) were first analyzed using untargeted lipidomics. Potential predictive lipid species selected by the Boruta analysis were then verified by targeted lipidomics. The associations between these lipid species and incident T2D were assessed. Effects of novel lipid species on insulin secretion in mouse islets were investigated. RESULTS: Boruta analysis identified 16 potential lipid species. After adjustment for body mass index (BMI), triacylglycerol/high-density lipoprotein (TG/HDL) ratio and the presence of prediabetes, triacylglycerol (TG) 12:0_18:2_22:6, TG 16:0_11:1_18:2, TG 49:0, TG 51:1 and diacylglycerol (DG) 18:2_22:6 were independently associated with increased T2D risk, whereas lyso-phosphatidylcholine (LPC) O-16:0, LPC P-16:0, LPC O-18:0 and LPC 18:1 were independently associated with decreased T2D risk. Addition of the identified lipid species to the clinical prediction model, comprised of BMI, TG/HDL ratio and the presence of prediabetes, achieved a 3.8% improvement in the area under the receiver operating characteristics curve (AUROC) (p = 0.0026). Further functional study revealed that, LPC O-16:0 and LPC O-18:0 significantly potentiated glucose induced insulin secretion (GSIS) in a dose-dependent manner, whereas neither DG 18:2_22:6 nor TG 12:0_18:2_22:6 had any effect on GSIS. CONCLUSIONS: Addition of the lipid species substantially improved the prediction of T2D beyond the model based on clinical risk factors. Decreased levels of LPC O-16:0 and LPC O-18:0 may contribute to the development of T2D via reduced insulin secretion.

Molecular surveillance for operationally relevant genetic polymorphisms in Plasmodium falciparum in Southern Chad, 2016-2017.

BACKGROUND: Resistance to anti-malarials is a serious threat to the efforts to control and eliminate malaria. Surveillance based on simple field protocols with centralized testing to detect molecular markers associated with anti-malarial drug resistance can be used to identify locations where further investigations are needed. METHODS: Dried blood spots were collected from 398 patients (age range 5-59 years, 99% male) with Plasmodium falciparum infections detected using rapid diagnostic tests over two rounds of sample collection conducted in 2016 and 2017 in Komé, South-West Chad. Specimens were genotyped using amplicon sequencing or qPCR for validated markers of anti-malarial resistance including partner drugs used in artemisinin-based combination therapy (ACT). RESULTS: No mutations in the pfk13 gene known to be associated with artemisinin resistance were found but a high proportion of parasites carried other mutations, specifically K189T (190/349, 54.4%, 95%CI 49.0-59.8%). Of 331 specimens successfully genotyped for pfmdr1 and pfcrt, 52% (95%CI 46.4-57.5%) carried the NFD-K haplotype, known to be associated with reduced susceptibility to lumefantrine. Only 20 of 336 (6.0%, 95%CI 3.7-9.0%) had parasites with the pfmdr1-N86Y polymorphism associated with increased treatment failures with amodiaquine. Nearly all parasites carried at least one mutation in pfdhfr and/or pfdhps genes but 'sextuple' mutations in pfdhfr-pfdhps including pfdhps -A581G were rare (8/336 overall, 2.4%, 95%CI 1.2-4.6%). Only one specimen containing parasites with pfmdr1 gene amplification was detected. CONCLUSIONS: These results provide information on the likely high efficacy of artemisinin-based combinations commonly used in Chad, but suggest decreasing levels of sensitivity to lumefantrine and high levels of resistance to sulfadoxine-pyrimethamine used for seasonal malaria chemoprevention and intermittent preventive therapy in pregnancy. A majority of parasites had mutations in the pfk13 gene, none of which are known to be associated with artemisinin resistance. A therapeutic efficacy study needs to be conducted to confirm the efficacy of artemether-lumefantrine.

Mortality of workers employed in refractory ceramic fiber manufacturing: An update.

This study evaluates the possible association between refractory ceramic fiber (RCF) exposure and all causes of death. Current and former employees (n = 1,119) hired from 1952 to 1999 at manufacturing facilities in New York (NY) state and Indiana were included. Work histories and quarterly plant-wide sampling from 1987 to 2015 provided cumulative fiber exposure (CFE) estimates. The full cohort was evaluated as well as individuals with lower and higher exposure, <45 and ≥45 fiber-months/cc. The Life-Table-Analysis-System was used for all standardized mortality rates (SMRs). Person-years at risk were accumulated from start of employment until 12/31/2019 or date of death. There was no significant association with all causes, all cancers, or lung cancer in any group. In the higher exposed, there was a significant elevation in both malignancies of the "urinary organs" (SMR = 3.59, 95% confidence interval [CI] 1.44, 7.40) and "bladder or other urinary site" (SMR = 4.04, 95% CI 1.10, 10.36), which persisted in comparison to regional mortality rates from NY state and Niagara County. However, six of the nine workers with urinary cancers were known smokers. In the lower exposed, there was a significant elevation in malignancies of the lymphatic and hematopoietic system (SMR = 2.54, 95% CI 1.27, 4.55) and leukemia (SMR = 4.21, 95% CI 1.69, 8.67). There was one pathologically unconfirmed mesothelioma death. A second employee currently living with a pathologically confirmed mesothelioma was identified, but the SMR was non-significant when both were included in the analyses. The association of these two mesothelioma cases with RCF exposure alone is unclear because of potential past exposure to asbestos.

Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.

Different glycaemia-related risk factors for incident Alzheimer's disease in men and women with type 2 diabetes-A sex-specific analysis of the Hong Kong diabetes database.

AIMS: Sexual dimorphism has been reported in the epidemiology, neurobiologic susceptibility and clinical presentation of Alzheimer's disease (AD). As poor glycaemic control is associated with increased risks of AD, we aimed to investigate whether glycaemia-related risk factors also differ between men and women, using a retrospective, sex-specific analysis of a large Chinese cohort with diabetes. MATERIALS & METHODS: A total of 85,514 Chinese individuals with type 2 diabetes (T2D; 46,783 women and 38,731 men), aged ≥60 years, were identified from electronic health records and observed for incident AD. Multivariable Cox regression analysis was used to evaluate the associations with incident AD of several glycaemia-related risk factors, including severe hypoglycaemia, mean HbA1c and indices of HbA1c variability, in men and women separately. RESULTS: Over a median follow-up of 6 years, women had a higher incidence of AD than men (2.3% vs. 1.2%, p < 0.001). Both men and women shared the same independent non-glycaemic clinical predictors, which included older age, lower body mass index and longer duration of diabetes. However, for glycaemia-related risk factors, we observed that severe hypoglycaemia and indices of HbA1c variability were independent predictors of incident AD in women but not in men, and the associations were irrespective of their baseline glycaemic control and duration of diabetes. CONCLUSIONS: Our findings highlighted that glycaemia-related risk factors for incident AD differ between men and women with T2D. Strategies to maintain glycaemic stability and avoid severe hypoglycaemia might be especially important to preserve healthy cognition in older women with diabetes.

An X1α plasmid from a Salmonella enterica serovar Ohio isolate carrying a novel IS26-bounded tet(C) pseudo-compound transposon.

The sequence of a conjugative plasmid, pSRC22-2, found in a multiply antibiotic resistant Salmonella enterica serovar Ohio isolate SRC22 originally cultured from swine in 1999, was determined. Plasmid pSRC22-2 has a copy number of approximately 40 and transfers tetracycline resistance at very high frequency. It was typed as IncX1 using the three typing schemes proposed for X-type plasmids, which utilize the replication region, iteron region and taxC conjugation gene and pSRC22-2 belongs to the X1α subgroup. The plasmid backbone, derived by removing mobile elements, is shared with pOLA52, which was the first fully sequenced IncX1 plasmid, and five other X1α plasmids. The pSRC22-2 backbone is interrupted by a complete copy of an IS903 isoform, partial copies of IS1 and IS903 on either side of a 5930 bp IS26-bounded pseudo-compound transposon (PCT), and a novel 256 bp miniature inverted repeat transposable element (MITE). The MITE belongs to the Tn3 family and was named MITESen1. The PCT, which carries a tet(C) tetracycline resistance determinant, is bounded by copies of a novel IS26 variant, IS26-v4, and was designated PTn6184. Comparison of PTn6184 with other tet(C)-carrying PCTs revealed that it can be derived from the largest, PTntet(C), via a two-step process that re-orders the central fragment and involves both an IS26-mediated event and homologous recombination. IS26-v4, which encodes a variant transposase, Tnp26 G184D, has appeared in only 46 entries in the GenBank non-redundant database.

Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO).

Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC50 value of 2.4 µM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.

Impact of Patient Engagement on Tailored Education for Joint Replacement Population Using Technology.

Patient engagement and technology use for healthcare are important for optimal care. This study was designed to leverage technology in education among the adult joint population based on their engagement capacity and utilization of technology for care. A convenience sample of 80 patients undergoing joint replacement surgery and followed in the inpatient setting participated. Comparisons were made between an intervention group who completed the Person Engagement Index to measure their engagement capacity and received a technological educational plan based on their score versus those receiving the standard educational plan. The Person Engagement Index psychometrics were sound and indicated high engagement capacity. Overall, the groups did not differ in utilization, satisfaction, and education comprehension; however, the intervention group reported a higher unit mean for the extent they felt ready for discharge and instructions for care at home. Results of this study informed patients' engagement capacity and technology use for pre-/postoperative education for procedure expectations and self-management throughout the joint replacement process and recovery. Future research includes use of technology for engagement capacity and outcomes with other populations, collecting socio-demographic data to determine differences among groups and examining the patient and provider experience and satisfaction with using technology to enhance care and outcomes.