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Background: Parkinson’s disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. Objective: Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson’s disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. Methods: Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients followed by amplification and sequencing of the V4 region of the 16 S rDNA gene on the MiSeq platform (Illumina). Results: IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson’s disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA + fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. Conclusion: IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analysis identified unique proinflammatory microbial signature in the IgA + fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches.

Esophageal cancer therapy is commonly multimodal. The CROSS trial demonstrated a survival benefit of neoadjuvant chemoradiation versus surgery alone in T1N1 or T2-3N0-1 patients. Theoretically, chemoradiation should be most beneficial to patients with advanced disease. Treating the intermediary stage, T2N0M0, is challenging as national guidelines offer multiple options. This study aims to compare survival outcomes and associated factors in clinical T2N0M0 esophageal cancer via treatment modality and compare clinical to pathological stage. The authors conclude that neoadjuvant therapy use has increased; however, there is no associated survival benefit, which may be due to over- or under-staging.A retrospective study was performed using the National Cancer Database (2006-2016). Patients who underwent neoadjuvant chemoradiation followed by surgery (NCRT + ESOPH) were compared to patients who underwent esophagectomy first (ESOPH). Multivariable logistic regression was used to determine factors associated with treatment pathway. Overall survival was compared using Kaplan-Meier estimates and log-rank tests at 1-, 3-, and 5-y post-treatment. Additionally, a multiple logistic regression analysis was conducted to identify factors associated with adjuvant therapy in ESOPH patients.There were 1662 patients (NCRT + ESOPH: 904 [54.4%], ESOPH: 758 [45.6%]). There was no difference in 5-y survival between NCRT + ESOPH and ESOPH patients. Despite this, NCRT + ESOPH treatment rates rose from 33% to 74% between 2006 and 2016. Patients who received NCRT + ESOPH were younger and more commonly had no Charlson-Deyo comorbidities. Notably, 41% of patients were over-staged (T1 or lower), and 32.8% were under-staged (N ≥ 1).T2N0M0 remains difficult to characterize, and pathological staging corresponds poorly to clinical staging. Neoadjuvant therapy use has increased; however, the lack of a significant survival benefit to correlate with such may be secondary to over- or under-staging.

Background: Virtual reality simulation in postlicensure nursing education, including community health, is an emerging instructional approach, and more research is needed on its effectiveness. The goal of this study was to evaluate the effectiveness of an innovative, computer-based community health nursing virtual reality simulation among postlicensure nursing students. Method: This mixed methods study consisted of 67 postlicensure community health nursing students who completed a pretest, computer-based virtual reality simulation, and a posttest and evaluation. Results: The majority of participant scores increased from pretest to posttest, and most participants agreed that the computer-based virtual reality simulation was effective; new knowledge and skills learned, the material that was found to be most helpful, and benefits to nursing practice were identified. Conclusion: This community health nursing computer-based virtual reality simulation was effective at increasing participants' knowledge and confidence with learning. [ J Contin Educ Nurs. 2023;54(3):109–116.]

COVID-19 vaccination rate disparities continue to persist in the U.S., despite their wide availability. A multidimensional host of sociodemographic, economic, political, and cultural factors have resulted in differences in vaccine coverage rates across the U.S. The present study descriptively explores one component of the complex relationship among what drives COVID-19 vaccination rate differences—specifically, the relationship between neighborhood sociodemographic characteristics and vaccination rates in Michigan. Data from the 2019 5-Year American Community Survey are merged with vaccine coverage rate data at the census tract level for the 18-years-and-older population for Michigan from 15 December 2020 to 19 November 2021. On the one hand, the results reveal that a neighborhood’s racial and ethnic composition and socioeconomic status characteristics are part of the complex bundle of characteristics affecting neighborhood vaccination coverage rates across Michigan. On the other hand, the findings also reveal a set of surprising patterns as they relate to the racial and ethnic composition of neighborhoods in Michigan. Future studies should further explore the extent to which race/ethnicity and class-related neighborhood characteristics are statistically relevant in examining the broader community effects on vaccine coverage rates in Michigan.

Early introduction to essential communication skills is important. We sought to determine if a handoff curriculum (HC) would improve confidence, decrease anxiety, and increase participation in clinical handoffs during the surgical clerkship.A multi-center prospective cohort study was performed at two medical schools. Training in the intervention group (HC) consisted of a didactic lecture, video review, and practice session. Students completed a pre-clerkship knowledge test and confidence/anxiety/handoff experience questionnaire pre- and post-clerkship.There were no significant differences in pre-clerkship handoff experiences between institutions except having previously witnessed a verbal handoff (School A 96.4% versus School B 76.2%, P = 0.01). While there were no significant differences in post-clerkship confidence or anxiety, HC students were significantly more involved with written sign-outs (52.9% versus 18.2%, P = 0.02) and verbal handoffs (29.4% versus 4.6%, P = 0.03).Medical students exposed to handoff training shared similar confidence and anxiety scores compared to those that were not, however, they were more involved in handoff experiences during their surgical clerkship. Early introduction to handoff skills may encourage greater participation during subsequent clinical experiences.

BACKGROUNDDonepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. The brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning.METHODSTo test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry.RESULTSThe highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum.CONCLUSIONSThe donepezil dose for maximally improving attention functions differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in the major brain systems supporting these cognitive functions. Thus, the non-selective acetylcholine esterase inhibitor donepezil inherently trades improvement in the attention domain for improvement in the cognitive flexibility domain at a given dose range.

Semiconductor nanocrystals (NCs) interfaced with molecular ligands that function as charge and energy acceptors are an emerging platform for the design of light-harvesting, photon-upconverting, and photocatalytic materials. However, NC systems explored for these applications often feature high concentrations of bound acceptor ligands, which can lead to ligand-ligand interactions that may alter each system's ability to undergo charge and energy transfer. Here, we demonstrate that aggregation of acceptor ligands impacts the rate of photoinduced NC-to-ligand charge transfer between lead(II) sulfide (PbS) NCs and perylenediimide (PDI) electron acceptors. As the concentration of PDI acceptors is increased, we find the average electron transfer rate from PbS to PDI ligands decreases by nearly an order of magnitude. The electron transfer rate slowdown with increasing PDI concentration correlates strongly with the appearance of PDI aggregates in steady-state absorption spectra. Electronic structure calculations and molecular dynamics (MD) simulations suggest PDI aggregation slows the rate of electron transfer by reducing orbital overlap between PbS charge donors and PDI charge acceptors. While we find aggregation slows electron transfer in this system, the computational models we employ predict ligand aggregation could also be used to speed electron transfer by producing delocalized states that exhibit improved NC-molecule electronic coupling and energy alignment with NC conduction band states. Our results demonstrate that ligand aggregation can alter rates of photoinduced electron transfer between NCs and organic acceptor ligands and should be considered when designing hybrid NC:molecule systems for charge separation.

Self-efficacy, the internal belief that one can perform a specific task successfully, influences behavior. To promote critical appraisal of medical literature, rheumatology training programs should foster both competence and self-efficacy for critical appraisal. This study aimed to investigate whether select items from the Clinical Research Appraisal Inventory (CRAI), an instrument measuring clinical research self-efficacy, could be used to measure critical appraisal self-efficacy (CASE).One hundred twenty-five trainees from 33 rheumatology programs were sent a questionnaire that included two sections of the CRAI. Six CRAI items relevant to CASE were identified a priori; responses generated a CASE score (total score range 0-10; higher = greater confidence in one's ability to perform a specific task successfully). CASE scores' internal structure and relation to domain-concordant variables were analyzed.Questionnaires were completed by 112 of 125 (89.6%) trainees. CASE scores ranged from 0.5 to 8.2. The six CRAI items contributing to the CASE score demonstrated high internal consistency (Cronbach's α = 0.95) and unidimensionality. Criterion validity was supported by the findings that participants with higher CASE scores rated their epidemiology and biostatistics understanding higher than that of peers (P 0.0001) and were more likely to report referring to studies to answer clinical questions (odds ratio 2.47, 95% confidence interval 1.41-4.33; P = 0.002). The correlation of CASE scores with percentage of questions answered correctly was only moderate, supporting discriminant validity.The six-item CASE instrument demonstrated content validity, internal consistency, discriminative capability, and criterion validity, including correlation with self-reported behavior, supporting its potential as a useful measure of critical appraisal self-efficacy.

Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.

Memory for events from the distant past relies on multiple brain regions, but little is known about the underlying neural dynamics that give rise to such abilities. We recorded neural activity in the hippocampus and retrosplenial cortex of two female rhesus macaques as they visually selected targets in year-old and newly acquired object-scene associations. Whereas hippocampal activity was unchanging with memory age, the retrosplenial cortex responded with greater magnitude alpha oscillations (10–15 Hz) and greater phase locking to memory-guided eye movements during retrieval of old events. A similar old-memory enhancement was observed in the anterior cingulate cortex but in a beta2/gamma band (28–35 Hz). In contrast, remote retrieval was associated with decreased gamma-band synchrony between the hippocampus and each neocortical area. The increasing retrosplenial alpha oscillation and decreasing hippocampocortical synchrony with memory age may signify a shift in frank memory allocation or, alternatively, changes in selection among distributed memory representations in the primate brain.SIGNIFICANCE STATEMENTMemory depends on multiple brain regions, whose involvement is thought to change with time. Here, we recorded neuronal population activity from the hippocampus and retrosplenial cortex as nonhuman primates searched for objects embedded in scenes. These memoranda were either newly presented or a year old. Remembering old material drove stronger oscillations in the retrosplenial cortex and led to a greater locking of neural activity to search movements. Remembering new material revealed stronger oscillatory synchrony between the hippocampus and retrosplenial cortex. These results suggest that with age, memories may come to rely more exclusively on neocortical oscillations for retrieval and search guidance and less on long-range coupling with the hippocampus.

Background: Human noroviruses are a leading cause of acute and sporadic gastroenteritis worldwide. The evolution of human noroviruses in immunocompromised persons has been evaluated in many studies. Much less is known about the evolutionary dynamics of human norovirus in healthy adults. Methods: We used sequential samples collected from a controlled human infection study with GI.1/Norwalk/US/68 virus to evaluate intra- and inter-host evolution of a human norovirus in healthy adults. Up to 12 samples from day 1 to day 56 post-challenge were sequenced using a norovirus-specific capture probe method. Results: Complete genomes were assembled, even in samples that were below the limit of detection of standard RT-qPCR assays, up to 28 days post-challenge. Analysis of 123 complete genomes showed changes in the GI.1 genome in all persons, but there were no conserved changes across all persons. Single nucleotide variants resulting in non-synonymous amino acid changes were observed in all proteins, with the capsid VP1 and nonstructural protein NS3 having the largest numbers of changes. Conclusions: These data highlight the potential of a new capture-based sequencing approach to assemble human norovirus genomes with high sensitivity and demonstrate limited conserved immune pressure-driven evolution of GI.1 virus in healthy adults.

Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes correlated with SARS-CoV-2 viral load over time were similarly differentially expressed across independent datasets of SARS-CoV-2 infected lung and upper airway cells, from both in vitro systems and patient samples. We also generated expression data on the human nose organoid model during SARS-CoV-2 infection. The human nose organoid-generated host transcriptional response captured many aspects of responses observed in the above patient samples while suggesting the existence of distinct host responses to SARS-CoV-2 depending on the cellular context, involving both epithelial and cellular immune responses. Our findings provide a catalog of SARS-CoV-2 host response genes changing over time.

Every viral infection entails an evolving population of viral genomes. High-throughput sequencing technologies can be used to characterize such populations, but to date there are few published examples of such work. In addition, mixed sequencing data are sometimes used to infer properties of infecting genomes without discriminating between genome-derived reads and reads from the much more abundant, in the case of a typical active viral infection, transcripts. Here we apply capture probe-based short read high-throughput sequencing to nasal wash samples taken from a previously described group of adult hematopoietic cell transplant (HCT) recipients naturally infected with respiratory syncytial virus (RSV). We separately analyzed reads from genomes and transcripts for the levels and distribution of genetic variation by calculating per position Shannon entropies. Our analysis reveals a low level of genetic variation within the RSV infections analyzed here, but with interesting differences between genomes and transcripts in 1) average per sample Shannon entropies; 2) the genomic distribution of variation ‘hotspots’; and 3) the genomic distribution of hotspots encoding alternative amino acids. In all, our results suggest the importance of separately analyzing reads from genomes and transcripts when interpreting high-throughput sequencing data for insight into intra-host viral genome replication, expression, and evolution.

The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults < 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8 × 106 or 2.7 × 106 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6–11 months and 1–5, 6–10, 11–17, 18–35, and 36–61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6–61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group (P ≥ 0.17). There were no significant differences between vaccinees and controls with respect to the rates or severity of unsolicited AEs or laboratory abnormalities. Development of antibodies to P. falciparum circumsporozoite protein occurred in 67/69 vaccinees (97%) and 0/15 controls. Median antibody levels were highest in infants and 1–5-year-olds and declined progressively with age. Antibody responses in children were greater than in adults protected against controlled human malaria infection. Robust immunogenicity, combined with a benign AE profile, indicates children are an ideal target for immunization with PfSPZ Vaccine.

Wastewater is a discarded human by-product but analyzing it may help us understand the health of communities. Epidemiologists first analyzed wastewater to track outbreaks of poliovirus decades ago, but so-called wastewater-based epidemiology was reinvigorated to monitor SARS-CoV-2 levels. Current approaches overlook the activity of most human viruses and preclude a deeper understanding of human virome community dynamics. We conducted a comprehensive sequencing-based analysis of 363 longitudinal wastewater samples from ten distinct sites in two major cities. Over 450 distinct pathogenic viruses were detected. Sequencing reads of established pathogens and emerging viruses correlated to clinical data sets. Viral communities were tightly organized by space and time. Finally, the most abundant human viruses yielded sequence variant information consistent with regional spread and evolution. We reveal the viral landscape of human wastewater and its potential to improve our understanding of outbreaks, transmission, and its effects on overall population health.One-Sentence SummaryWastewater contains a trickle of circulating human viruses, and now we can sequence them to better track community transmission.

Nested hippocampal oscillations in the rodent give rise to temporal dynamics that may underlie learning, memory, and decision making. Although theta/gamma coupling in rodent CA1 occurs during exploration and sharp-wave ripples emerge in quiescence, it is less clear that these oscillatory regimes extend to primates. We therefore sought to identify correspondences in frequency bands, nesting, and behavioral coupling of oscillations taken from macaque hippocampus. We found that, in contrast to rodent oscillations, theta and gamma frequency bands in macaque CA1 were segregated by behavioral states. In both stationary and freely moving designs, beta2/gamma (15–70 Hz) had greater power during visual search whereas the theta band (3–10 Hz; peak ~8 Hz) dominated during quiescence and early sleep. Moreover, theta-band amplitude was strongest when beta2/slow gamma (20–35 Hz) amplitude was weakest, instead occurring along with higher frequencies (60–150 Hz). Spike-field coherence was most frequently seen in these three bands (3–10 Hz, 20–35 Hz, and 60–150 Hz); however, the theta-band coherence was largely due to spurious coupling during sharp-wave ripples. Accordingly, no intrinsic theta spiking rhythmicity was apparent. These results support a role for beta2/slow gamma modulation in CA1 during active exploration in the primate that is decoupled from theta oscillations. The apparent difference to the rodent oscillatory canon calls for a shift in focus of frequency when considering the primate hippocampus.

Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

RATIONALE: The coronavirus disease (COVID-19) pandemic has led to a dramatic increase in the number of survivors of critical illness. These survivors are at increased risk for physical, psychological, and cognitive impairments known collectively as post-intensive care syndrome (PICS). Little is known about the prevalence of PICS in COVID-19 survivors. OBJECTIVES: To report the prevalence of physical, psychological, and cognitive impairment among COVID-19 intensive care unit (ICU) survivors receiving follow-up care in an ICU recovery clinic, to assess for associations between PICS and ICU-related factors, and to compare the cohort of ICU survivors who attended a post-ICU clinic with a cohort of ICU survivors who did not. METHODS: We performed a retrospective cohort study of COVID-19 ICU survivors admitted from March to May 2020 who were subsequently seen in a post-ICU recovery clinic in New York City. We abstracted medical chart data on available clinical screening instruments for physical, psychological, and cognitive impairment. Associations between these outcomes and care-related variables were tested. Baseline characteristics and in-hospital treatments of the post-ICU clinic cohort were compared with those of COVID-19 ICU survivors from the same institution who were not seen in the post-ICU clinic. RESULTS: Eighty-seven COVID-19 ICU survivors were seen in our post-ICU recovery clinic. The median age was 62 years, and 74% were male. The median length of hospitalization was 51 days, and the median length of ICU stay was 22 days. At the post-ICU follow-up visit, 29%, 21%, and 13% of patients reported clinically significant levels of depressive symptoms, anxiety, and post-traumatic stress disorder symptoms, respectively. Twenty-five percent had cognitive impairment. The overall prevalence of PICS was 90%. There were no associations between length of ICU stay, delirium, and exposure to benzodiazepines, steroids, or systemic paralytics with positive screening results for physical, psychological, or cognitive impairment. Baseline characteristics and ICU-related factors were similar in the cohort of COVID-19 ICU survivors who attended the ICU recovery clinic and those who did not. CONCLUSIONS: PICS is common in COVID-19 survivors. We did not find any association with length of ICU stay or the use of benzodiazepines, steroids, or paralytics.

Contains fulltext : 282684.pdf (Publisher’s version ) (Closed access) The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss-of-function variants in PRPF8. These individuals have clinical features that may represent a new neurodevelopmental syndrome.

Background Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new β-lactam/β-lactamase inhibitors may improve outcomes. Methods We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. Results Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16–.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). Conclusions In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.

Loa loa microfilariae were found on thick blood smears (TBSs) from 8 of 300 (2.7%) residents of Bioko Island, Equatorial Guinea, during a Plasmodium falciparum sporozoite malaria vaccine clinical trial. Only one subject was found to have microfilaraemia on his first exam; parasites were not discovered in the other seven until subsequent TBSs were performed, at times many weeks into the study. All infected individuals were asymptomatic, and were offered treatment with diethylcarbamazine, per national guidelines. L. loa microfilaraemia complicated the enrolment or continued participation of these eight trial subjects, and only one was able to complete all study procedures. If ruling out loiasis is deemed to be important during clinical trials, tests that are more sensitive than TBSs should be performed.

We examine consumers’ interactions with smart objects using a novel mixed-method approach, guided by assemblage theory, to discover the emergence of automation practices. We use a unique text data set from the web service IFTTT, (“If This Then That”), representing hundreds of thousands of applets that represent “if–then” connections between pairs of Internet services. Consumers use these applets to automate events in their daily lives. We quantitatively identify and qualitatively interpret automation assemblages that emerge bottom-up as different consumers create similar applets within unique social contexts. Our data discovery approach combines word embeddings, density-based clustering, and nonlinear dimensionality reduction with an inductive approach to the thematic analysis. We uncover 127 nested automation assemblages that correspond to automation practices. Practices are interpreted in terms of four higher-order categories: social expression, social connectedness, extended mind, and relational AI. To investigate the future trajectories of automation practices, we use the concept of the possibility space, a fundamental theoretical idea from assemblage theory. Using our empirical approach, we translate this theoretical possibility space of automation assemblages into a data visualization to predict how existing practices can grow and new practices can emerge. Our new approach makes conceptual, methodological, and empirical contributions with implications for consumer research and marketing strategy.

Repeated intravenous (IV) administration of radiation-attenuated sporozoite (RAS) vaccines induces Plasmodium-specific CD8+ liver-resident memory T (Trm) cells in mice and achieves sterile protection against challenge. Our heterologous “prime-and-trap” vaccine strategy was previously shown to simplify and improve upon RAS vaccination. Prime-and-trap vaccination combines epidermal priming by DNA-encoded circumsporozoite protein (CSP) antigen followed by a single IV dose of freshly dissected RAS (fresh-RAS) to direct and trap activated and expanding CD8+ T cells in the liver. Prime-and-trap vaccination protects mice against wild-type sporozoite (spz) challenge. Assessment of prime-and-trap vaccines in nonhuman primate (NHP) models and/or humans would be greatly enabled if fresh-RAS could be replaced by cryopreserved RAS (cryo-RAS). Here, we investigated if fresh-RAS could be replaced with cryo-RAS for prime-and-trap vaccination in BALB/cj mice. Despite a reduction in spz vaccine liver burden following cryo-RAS administration compared with fresh-RAS, cryo-RAS induced a similar level of Plasmodium yoelii (Py) CSP-specific CD8+ liver Trm cells and completely protected mice against Py spz challenge 112 days after vaccination. Additionally, when the glycolipid adjuvant 7DW8-5 was co-administered with cryo-RAS, 7DW8-5 permitted the dose of cryo-RAS to be reduced four-fold while still achieving high rates of sterile protection. In summary, cryo-RAS with and without 7DW8-5 were compatible with prime-and-trap malaria vaccination in a mouse model, which may accelerate the pathway for this vaccine strategy to move to NHPs and humans.

To evaluate the effectiveness of an online human trafficking awareness program for healthcare providers.Mixed-methods study.Sample (Participants indicated their knowledge of human trafficking increased, attitudes toward victims improved, and competence and confidence engaging with victims increased. Satisfaction with program, and information utilization plans for practice were revealed.Human trafficking awareness program was effective in increasing participants' knowledge, competence and confidence, and improving attitudes.Educational intervention is a strategy to improve students' knowledge of human trafficking.

Summary Background WHO recently approved a partially effective vaccine that reduces clinical malaria in children, but increased vaccine activity is required to pursue malaria elimination. A phase 1 clinical trial was done in Mali, west Africa, to assess the safety, immunogenicity, and protective efficacy of a three-dose regimen of Plasmodium falciparum sporozoite (PfSPZ) Vaccine (a metabolically active, non-replicating, whole malaria sporozoite vaccine) against homologous controlled human malaria infection (CHMI) and natural P falciparum infection. Methods We recruited healthy non-pregnant adults aged 18–50 years in Doneguebougou, Mali, and surrounding villages (Banambani, Toubana, Torodo, Sirababougou, Zorokoro) for an open-label, dose-escalation pilot study and, thereafter, a randomised, double-blind, placebo-controlled main trial. Pilot study participants were enrolled on an as-available basis to one group of CHMI infectivity controls and three staggered vaccine groups receiving: one dose of 4·5 × 105, one dose of 9 × 105, or three doses of 1·8 × 106 PfSPZ via direct venous inoculation at approximately 8 week intervals, followed by homologous CHMI 5 weeks later with infectious PfSPZ by direct venous inoculation (PfSPZ Challenge). Main cohort participants were stratified by village and randomly assigned (1:1) to receive three doses of 1·8 × 106 PfSPZ or normal saline at 1, 13, and 19 week intervals using permuted block design by the study statistician. The primary outcome was safety and tolerability of at least one vaccine dose; the secondary outcome was vaccine efficacy against homologous PfSPZ CHMI (pilot study) or against naturally transmitted P falciparum infection (main study) measured by thick blood smear. Combined artesunate and amodiaquine was administered to eliminate pre-existing parasitaemia. Outcomes were analysed by modified intention to treat (mITT; including all participants who received at least one dose of investigational product; safety and vaccine efficacy) and per protocol (vaccine efficacy). This trial is registered with ClinicalTrials.gov , number NCT02627456 . Findings Between Dec 20, 2015, and April 30, 2016, we enrolled 56 participants into the pilot study (five received the 4·5 × 105 dose, five received 9 × 105, 30 received 1·8 × 106, 15 were CHMI controls, and one withdrew before vaccination) and 120 participants into the main study cohort with 60 participants assigned PfSPZ Vaccine and 60 placebo in the main study. Adverse events and laboratory abnormalities post-vaccination in all dosing groups were few, mainly mild, and did not differ significantly between vaccine groups (all p>0·05). Unexpected severe transaminitis occured in four participants: one participant in pilot phase that received 1·8 × 106 PfSPZ Vaccine, one participant in main phase that received 1·8 × 106 PfSPZ Vaccine, and two participants in the main phase placebo group. During PfSPZ CHMI, approximately 5 weeks after the third dose of 1·8 × 106 PfSPZ, none of 29 vaccinees and one of 15 controls became positive on thick blood smear; subsequent post-hoc PCR analysis for submicroscopic blood stage infections detected P falciparum parasites in none of the 29 vaccine recipients and eight of 15 controls during CHMI. In the main trial, 32 (58%) of 55 vaccine recipients and 42 (78%) of 54 controls became positive on thick blood smear during 24-week surveillance after vaccination. Vaccine efficacy (1–hazard ratio) was 0·51 per protocol (95% CI 0·20–0·70; log-rank p=0·0042) and 0·39 by mITT (0·04–0·62; p=0·033); vaccine efficacy (1–risk ratio) was 0·24 per-protocol (0·02–0·41; p=0·031) and 0·22 mITT (0·01–0·39; p=0·041). Interpretation A three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial. Funding US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Sanaria. Translation For the French translation of the abstract see Supplementary Materials section.

Background Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of Plasmodium 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates. Methods For this analysis, 18S rRNA qRT-PCR data were compiled from 127 Plasmodium falciparum–infected participants treated with chloroquine or atovaquone-proguanil in 6 CHMI studies conducted in Seattle, Washington, over the past decade. A survival analysis approach was used to compare biomarker and TBS clearance times among studies. The effect of the parasite density at which treatment was initiated on clearance time was estimated using linear regression. Results The median time to biomarker clearance was 3 days (interquartile range, 3–5 days), while the median time to TBS clearance was 1 day (1–2 days). Time to biomarker clearance increased with the parasite density at which treatment was initiated. Parasite density did not have a significant effect on TBS clearance. Conclusions The Plasmodium 18S rRNA biomarker clears quickly and can be relied on to confirm the adequacy of Food and Drug Administration–approved treatments in CHMI studies at nonendemic sites.

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Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20–75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted Pdifference < 0.01) and distinct biological communities (Pdifference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded >8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14–20.94) and 10.72 (3.30–34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value < 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker.Prevention Relevance:Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.

BACKGROUND. Twitter provides an opportunity to examine misperceptions about nicotine and addiction as they pertain to electronic nicotine delivery systems (ENDS). The purpose of this study was to systematically examine a sample of ENDS-related tweets that presented information about nicotine or addiction for the presence of potential misinformation. METHODS. A total of 10.1 million ENDS-related tweets were obtained from April 2018 through March 2019 and were filtered for unique tweets containing keywords for nicotine and addiction. A subsample (n=3,116) were human coded for type of account (individual, group, commercial, or news) and presence of potential misinformation. RESULTS. Of tweets that presented ENDS-related nicotine or addiction information (n=904), 41.7% (n=377) contained potential misinformation coded as anti-vaping exaggeration, pro-vaping exaggeration, nicotine is not addictive or is never harmful, or unproven health benefits. CONCLUSIONS. Anti-vaping exaggeration tweets distorted or embellished claims about ENDS nicotine and addiction; pro-vaping exaggeration tweets misinterpreted results from scientific studies. Misinformation that nicotine is not addictive or is never harmful or has unproven health benefits appeared less but are potentially problematic. ENDS-related messaging should be designed to be easily understood by the public and monitored to detect the spread of misinterpretation or misinformation on social media.

Contains fulltext : 248576.pdf (Publisher’s version ) (Open Access) Single-cell antigen-receptor gene amplification and sequencing platforms have been used to characterize T cell receptor (TCR) repertoires but typically fail to generate paired full-length gene products for direct expression cloning and do not enable linking this data to cell phenotype information. To overcome these limitations, we established a high-throughput platform for the quantitative and qualitative analysis of human TCR repertoires that provides insights into the clonal and functional composition of human CD4(+) and CD8(+) αβ T cells at the molecular and cellular level. The strategy is a powerful tool to qualitatively assess differences between antigen receptors of phenotypically defined αβ T cell subsets, e.g. in immune responses to cancer, vaccination, or infection, and in autoimmune diseases.

Many sexually active, reproductive-aged persons capable of becoming pregnant use some method of contraception. To expand options for those desiring birth control, new choices include a vaginal ring, transdermal patch, progestin-only pill, and spermicide. Compared with currently available methods, additional technologies that are highly effective, easy to use, cost efficient, and well-tolerated lay on the horizon. During contraceptive counseling, patient choice, and reproductive autonomy should remain paramount.

Complementary and alternative medicine therapies can be used as adjuvant or preventive therapy, and have newer applications: cryotherapy, halotherapy, floatation therapy, and compression therapy. Nurse practitioners need to know about these therapies and their applicability to patient populations. Appropriate integration of these therapies is part of holistic care, which they strive to provide.

Background Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific therapies, multisystem involvement, and heterogeneous, poor patient outcomes. A molecular comparison of ARDS groups holds the potential to reveal common and distinct mechanisms underlying ARDS pathogenesis. Methods We performed a comparative analysis of urine-based metabolomics and proteomics profiles from COVID-19 ARDS patients (n = 42) and bacterial sepsis-induced ARDS patients (n = 17). To this end, we used two different approaches, first we compared the molecular omics profiles between ARDS groups, and second, we correlated clinical manifestations within each group with the omics profiles. Results The comparison of the two ARDS etiologies identified 150 metabolites and 70 proteins that were differentially abundant between the two groups. Based on these findings, we interrogated the interplay of cell adhesion/extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis through a multi-omic network approach. Moreover, we identified a proteomic signature associated with mortality in COVID-19 ARDS patients, which contained several proteins that had previously been implicated in clinical manifestations frequently linked with ARDS pathogenesis. Conclusion In summary, our results provide evidence for significant molecular differences in ARDS patients from different etiologies and a potential synergy of extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis. The proteomic mortality signature should be further investigated in future studies to develop prediction models for COVID-19 patient outcomes.