Search

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.

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.

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.

The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naive adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or 1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose group = −6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group. The PfSPZ Vaccine does not protect infants from infection with Plasmodium falciparum, the major cause of malaria.

We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance were compared between short vs. normal sleepers, followed by multivariable analysis. A false discovery rate-adjusted p value (q value) < 0.05 indicated statistical significance. The bacterial community composition differed in short and normal sleepers. The relative abundance of Sutterella was significantly lower (0.38% vs. 1.25%) and that of Pseudomonas was significantly higher (0.14% vs. 0.08%) in short sleepers than in normal sleepers (q values < 0.01). The difference was confirmed in the multivariable analysis. Nocturnal sleep duration was associated with the bacterial community composition and structure in the colonic gut microbiota in adults.

Background Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality, but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against P. falciparum is planned for 2022. This study assessed the incidence of malaria at the phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. Methods A cohort of 240 randomly selected individuals aged 6 months to 45 years from selected areas of North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitaemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every 2 weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. Results There were 58 malaria infection episodes observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6–59-month-olds, 0.26 in 5–17-year-olds, 0.20 in 18–45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6–59-month-olds, 0.10 in 5–17-year-olds, 0.11 in 18–45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. Conclusion Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread evenly throughout age groups. These incidence rates indicate moderate malaria transmission which may be sufficient to support future larger trials of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programmes to halt transmission and eliminate P. falciparum malaria.

Recent data has suggested that primary anastomosis (PA), with or without a diverting loop ileostomy (DLI), is a safe option for the treatment of acute complicated diverticulitis. This study aimed to evaluate risk factors associated with anastomotic leak in patients who underwent a sigmoid colectomy with PA and to determine whether a DLI was protective against a clinically significant anastomotic leak. Patients with acute complicated diverticulitis who underwent a laparoscopic or open sigmoid colectomy with PA, with or without a DLI, were identified in the NSQIP PUF(2016–2017). The rates of anastomotic leak, receipt of DLI, and type of leak management were compared. Multivariate logistic regression was performed. There were 497 patients identified. Seventy-nine(15.9%) patients had a DLI, while 418 (84.1%) did not. Twenty-six anastomotic leaks were identified (5.2%). On multivariate analysis, current smoking (OR 4.02; 95% CI 1.44–11.26) and chronic steroid use (OR 3.84; 95% CI 1.16–12.69) were significantly associated with an increased risk of leak. Of the 26 patients with anastomotic leaks, 5 (19.2%) had a DLI. There was no significant difference in the rate of leak between those with a DLI(5; 6.3%) and those without(21; 5.3%; p = 0.59). Patients who had a DLI were significantly less likely to experience an anastomotic leak requiring re-operation (p

Background: Hallux rigidus is a common and painful degenerative condition of the great toe limiting a patient’s physical function and quality of life. The purpose of this study was to investigate pre- and postoperative physical function (PF) and pain interference (PI) levels of patients undergoing synthetic cartilage implant hemiarthroplasty (SCI) vs arthrodesis (AD) for treatment of hallux rigidus using the Patient-Reported Outcomes Measurement Information System (PROMIS). Methods: PROMIS PF and PI t scores were analyzed for patients who underwent either SCI or AD. Postoperative final PROMIS t scores were obtained via phone survey. Linear mixed model analysis was used to assess differences in PF and PI at each follow-up point. Final follow-up scores were analyzed using independent sample t tests. Results: Total 181 (59 SCI, 122 AD) operatively managed patients were included for analysis of PROMIS scores. Final phone survey was performed at a minimum of 14 (mean 33, range, 14-59) months postoperatively, with 101 patients (40 SCI, 61 AD) successfully contacted. The mean final follow-up was significantly different for SCI and AD: 27 vs 38 months, respectively ( P < .01). The mean age of the SCI cohort was lower than the AD cohort (57.5 vs 61.5 years old, P = .01). Average PF t scores were higher in the SCI cohort at baseline (47.1 and 43.9, respectively, P = .01) and at final follow-up (51.4 vs 45.9, respectively, P < .01). A main effect of superior improvement in PF was noted in the SCI group (+4.3) vs the AD group (+2) across time intervals ( P < .01). PI t scores were similar between the 2 procedures across time points. Conclusion: The SCI cohort reported slightly superior PF t scores preoperatively and at most follow-up time points compared with the arthrodesis group. No differences were found for PI or complication rates between the 2 treatment groups during this study time frame. Level of Evidence: Level IV, case series.

Domestic dogs are terrific companions in a variety of contexts. However, not all dogs have followed the same trajectory regarding domestication. In fact, little is known about how some dogs, includ...

Plasmodium falciparum sporozoite (PfSPZ) Vaccine (radiation-attenuated, aseptic, purified, cryopreserved PfSPZ) and PfSPZ-CVac (infectious, aseptic, purified, cryopreserved PfSPZ administered to subjects taking weekly chloroquine chemoprophylaxis) have shown vaccine efficacies (VEs) of 100% against homologous controlled human malaria infection (CHMI) in nonimmune adults. Plasmodium falciparum sporozoite-CVac has never been assessed against CHMI in African vaccinees. We assessed the safety, immunogenicity, and VE against homologous CHMI of three doses of 2.7 × 106 PfSPZ of PfSPZ Vaccine at 8-week intervals and three doses of 1.0 × 105 PfSPZ of PfSPZ-CVac at 4-week intervals with each arm randomized, double-blind, placebo-controlled, and conducted in parallel. There were no differences in solicited adverse events between vaccinees and normal saline controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6 days after administration of investigational product. However, from days 7–13, PfSPZ-CVac recipients had significantly more AEs, probably because of Pf parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine recipients than PfSPZ-CVac recipients at time of CHMI. Vaccine efficacy at a median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, P = 0.051) and at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, P = 0.32). The higher VE in PfSPZ-CVac recipients of 55% with a 27-fold lower dose was likely a result of later stage parasite maturation in the liver, leading to induction of cellular immunity against a greater quantity and broader array of antigens.

Malaria is a life-threatening epidemic disease with half of the world's population at risk. Although its incidence rate has fallen since 2010, this ratio dramatically stalled between 2014 and 2018. New fast and optimized tools in vaccine analysis and seroconversion testing are critically needed. We developed a clinical diagnostic device based on piezo-actuated nanoresonators that perform as quantitative in situ calibrated nano-bio sensors for specific detection of multiple target molecules in serum samples. The immunoassay successfully diagnoses humoral immune responses induced by malaria vaccine candidates and reveals the timeline and stage of the infection. We applied the newly developed strategy to a variety of different samples, from pure antibody/vaccine solutions, to blood samples from clinical trials on both naïve and pre-exposed malaria volunteers from sub-Saharan countries. Our nanomechanical assay provides a direct one-step label-free quantitative immunoassay that is on par with the gold-standard, multi-step enzyme-linked immunosorbent assay (ELISA). We achieve a limit of detection of few pg ml-1, or sub-pM concentrations. The 6 μl sample volume allows more than 50 experiments from one finger prick. Furthermore, we simultaneously detected multiple analytes by differential functionalization of multiple sensors in parallel. The inherent differential read-out with in situ controls reduces false positive results. Due to the faster turnaround time, the minimal volume required and the automatized handling system, this technique has great potential for miniaturization and routine diagnostics in pandemic emergencies.

ObjectiveNecrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother’s own breast milk (MOM) is protective, possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC.DesignWe performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644).ResultsConcentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of Bifidobacterium longum and higher relative abundance of Enterobacter cloacae in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC.ConclusionThese results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.

We have recently demonstrated that dietary nitrate, a source of nitric oxide (NO) via the nitrate → nitrite → NO enterosalivary pathway, can improve muscle contractility in healthy older men and women. Nitrate ingestion has also been shown to reduce blood pressure in some, but not all, studies of older individuals. However, the optimal dose for eliciting these beneficial effects is unknown. A pilot randomized, double-blind, placebo-controlled crossover study was therefore performed to determine the effects of ingesting 3.3 mL/kg of concentrated beetroot juice containing 0, 200, or 400 µmol/kg of nitrate in 9 healthy older subjects (mean age 70 ± 1 years). Maximal knee extensor power (Pmax) and speed (Vmax) were measured ~2.5 hours after nitrate ingestion using isokinetic dynamometry. Blood pressure was monitored periodically throughout each study. Pmax (in W/kg) was higher (p < .05) after the lower dose (3.9 ± 0.4) compared to the placebo (3.7 ± 0.4) or higher dose (3.7 ± 0.4). Vmax (in rad/s) also tended to be higher (p = .08) after the lower dose (11.9 ± 0.7) compared to the placebo (10.8 ± 0.8) or higher dose (11.2 ± 0.8). Eight out of 9 subjects achieved a higher Pmax and Vmax after the lower versus the higher dose. These dose-related changes in muscle contractility generally paralleled changes in breath NO levels. No significant changes were found in systolic, diastolic, or mean arterial blood pressure. A lower dose of nitrate increases muscle speed and power in healthy older individuals, but these improvements are lost at a higher dose. Blood pressure, on the other hand, is not reduced even with a higher dose.

Recent advances in artificial intelligence and natural language processing are gradually transforming how humans search, shop, and express their preferences. Leveraging the new affordances and modalities of human–machine interaction through voice-controlled interfaces will require a nuanced understanding of the physics and psychology of speech formation as well as the systematic extraction and analysis of vocal features from the human voice. In this paper, we first develop a conceptual framework linking vocal features in the human voice to experiential outcomes and emotional states. We then illustrate the effective processing, editing, analysis, and visualization of voice data based on an Amazon Alexa user interaction, utilizing state-of-the-art signal-processing packages in R. Finally, we offer novel insight into the ways in which business research might employ voice and sound analytics moving forward, including a discussion of the ethical implications of building multi-modal databases for business and society.

Background Preference for a gender concordant surgeon has been demonstrated when the chief complaint is perceived as private. We aimed to investigate this phenomenon among colorectal patients. Methods A 3-week prospective, observational, quality improvement study was performed. Schedulers recorded all new patient calls and factors influencing patient selection of surgeon. Demographic information was obtained. Descriptive statistics were performed. Results There were 60 new patients scheduled; 35 (58.3%) female. Ten(16.7%) chose a surgeon based on gender; 70% of those with gender requests (GR) were female (70%), and 80% were gender-concordant. Seven (70%) of those with GR had anorectal complaints. Of all patients with anorectal complaints, 20.6% had a GR vs. 11.5% non-anorectal (p = 0.49). Conclusions A considerable percentage of patients make a GR when seeking treatment, especially for anorectal disease. Departments should be mindful of the sensitive nature of many colorectal diseases and strive to diversify accordingly in order to create safe environments for the optimal delivery of patient-centered care.

Methamphetamine is a highly abused psychostimulant drug and its use remains a major public health concern worldwide with limited effective treatment options. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood. We sought to determine whether methamphetamine exposure and cessation or withdrawal alter the intestinal gut microbiota as well as characterize cessation-induced behavioral changes. Male, Sprague-Dawley rats were administered methamphetamine (2 mg/kg; s.c.) or vehicle (n = 8 per group) twice per day for 14 consecutive days. On various days before, during, and after administration, fecal samples were collected and tests of anxiety- and depressive-like behaviors were conducted. Methamphetamine administration and cessation did not alter the relative abundance of bacteria but significantly changed the composition of gut bacteria through 16S rRNA sequencing. These changes were normalized after 7 days of methamphetamine cessation. Moreover, acute methamphetamine cessation induced depressive-like behavior, with an increase in immobility in the forced swim test but did not alter anxiety-like behaviors in tests of open field test or elevated plus maze. These findings provide direct evidence that methamphetamine and its cessation cause gut dysbiosis and that the latter associates with depressive-like behavior in rodents. Our observation will contribute to a better understanding of the function of gut microbiota in the process of substance use disorders and guide the choice of target therapeutics.

BACKGROUND: Systemic diseases have been associated with oral health and gut microbiota. We examined the association between oral health and the community composition and structure of the adherent colonic gut microbiota. METHODS: We obtained 197 snap-frozen colonic biopsies from 62 colonoscopy-confirmed polyp-free individuals. Microbial DNA was sequenced for the 16S rRNA V4 region using the Illumina MiSeq, and the sequences were assigned to the operational taxonomic unit based on SILVA. We used a questionnaire to ascertain tooth loss, gum disease, and lifestyle factors. We compared biodiversity and relative abundance of bacterial taxa based on the amount of tooth loss and the presence of gum disease. The multivariable negative binomial regression model for panel data was used to estimate the association between the bacterial count and oral health. False discovery rate-adjusted P value (q value) < .05 indicated statistical significance. RESULTS: More tooth loss and gum disease were associated with lower bacterial alpha diversity. The relative abundance of Faecalibacterium was lower (q values < .05) with more tooth loss. The association was significant after adjusting for age, ethnicity, obesity, smoking, alcohol use, hypertension, diabetes, and the colon segment. The relative abundance of Bacteroides was higher in those with gum disease. CONCLUSIONS: Oral health was associated with alteration in the community composition and structure of the adherent gut bacteria in the colon. The reduced anti-inflammatory Faecalibacterium in participants with more tooth loss may indicate systemic inflammation. Future studies are warranted to confirm our findings and investigate the systemic role of Faecalibacterium.

Aim To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). Materials and methods The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. Results After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. Conclusions The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (

Background Despite available control strategies, malaria morbidity and mortality, especially in infants and young children in sub-Saharan Africa, remain intractable. Malaria vaccination could substantially reduce malaria episodes and deaths. One vaccine candidate is the whole sporozoite PfSPZ Vaccine, consisting of irradiated cryopreserved sporozoites administered by direct venous inoculation (DVI). DVI may be less acceptable than more familiar administration routes, particularly intramuscular. As part of a PfSPZ Vaccine trial among infants in western Kenya, a qualitative study was conducted to explore caregiver and community perceptions of the malaria vaccine trial, including the unique DVI administration procedure. Methods Twelve focus groups and 28 in-depth interviews explored perceptions of the DVI procedure in infants, factors influencing trial acceptability, and barriers to sustained trial participation. Purposively sampled participants included mothers of enrolled children, fathers and mothers who withdrew their children from the trial, village elders, and study clinicians from two trial enrollment sites. An iterative, multi-stage analytic approach, adapted from the Framework Method, was used to synthesize and interpret textual data. Results Desires to prevent malaria and participation incentives (e.g., free consultations and medication) motivated caregivers to enroll their children in the trial. However, numerous factors also demotivated trial participation. Family members’ (i.e., fathers') objections to required blood draws were cited most frequently as drivers of early trial withdrawal, in many cases prior to receiving any vaccine. Among mothers whose children received PfSPZ Vaccine (or placebo), many spoke favourably of DVI administration, describing improved tolerability relative to intramuscularly administered immunizations. Other trial-related challenges cited by caregivers included negative interactions with study clinicians and perceived delays in administering trial procedures. Conclusions Despite high acceptance of DVI among caregivers whose children received PfSPZ Vaccine (or placebo), objections to trial procedures from other non-sensitized household and family members prompted early trial withdrawal and inhibited successful completion of trial procedures for some infants. Implications for future trials include targeting heads of household during sensitization and recruitment activities, as well as equipping trial staff to effectively respond to participant and community concerns regarding trial procedures.

Background Progress towards malaria elimination has stagnated, partly because infections persisting at low parasite densities comprise a large reservoir contributing to ongoing malaria transmission and are difficult to detect. This study compared the performance of an ultrasensitive rapid diagnostic test (uRDT) designed to detect low density infections to a conventional RDT (cRDT), expert microscopy using Giemsa-stained thick blood smears (TBS), and quantitative polymerase chain reaction (qPCR) during a controlled human malaria infection (CHMI) study conducted in malaria exposed adults (NCT03590340). Methods Blood samples were collected from healthy Equatoguineans aged 18–35 years beginning on day 8 after CHMI with 3.2 × 103 cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ Challenge, strain NF54) administered by direct venous inoculation. qPCR (18s ribosomal DNA), uRDT (Alere™ Malaria Ag P.f.), cRDT [Carestart Malaria Pf/PAN (PfHRP2/pLDH)], and TBS were performed daily until the volunteer became TBS positive and treatment was administered. qPCR was the reference for the presence of Plasmodium falciparum parasites. Results 279 samples were collected from 24 participants; 123 were positive by qPCR. TBS detected 24/123 (19.5% sensitivity [95% CI 13.1–27.8%]), uRDT 21/123 (17.1% sensitivity [95% CI 11.1–25.1%]), cRDT 10/123 (8.1% sensitivity [95% CI 4.2–14.8%]); all were 100% specific and did not detect any positive samples not detected by qPCR. TBS and uRDT were more sensitive than cRDT (TBS vs. cRDT p = 0.015; uRDT vs. cRDT p = 0.053), detecting parasitaemias as low as 3.7 parasites/µL (p/µL) (TBS and uRDT) compared to 5.6 p/µL (cRDT) based on TBS density measurements. TBS, uRDT and cRDT did not detect any of the 70/123 samples positive by qPCR below 5.86 p/µL, the qPCR density corresponding to 3.7 p/µL by TBS. The median prepatent periods in days (ranges) were 14.5 (10–20), 18.0 (15–28), 18.0 (15–20) and 18.0 (16–24) for qPCR, TBS, uRDT and cRDT, respectively; qPCR detected parasitaemia significantly earlier (3.5 days) than the other tests. Conclusions TBS and uRDT had similar sensitivities, both were more sensitive than cRDT, and neither matched qPCR for detecting low density parasitaemia. uRDT could be considered an alternative to TBS in selected applications, such as CHMI or field diagnosis, where qualitative, dichotomous results for malaria infection might be sufficient.

The sural sensory nerve, which innervates the lower extremities, is a useful model for studying the structural and functional characteristics of peripheral sensory nerves. Its development and myelination extends across the early postnatal through to the juvenile stage. Myelination of the sural nerve depends on interactions between axons and Schwann cells and requires a variety of factors including hormones, neurotrophic factors, nerve impulses, and transcription factors. Maternal deprivation or malnutrition during early life reduces the thickness of myelin and decreases the area and amplitude of the compound action potential of the sural nerve. Importantly, the replacement of tactile or social stimuli during experimental maternal isolation in rats prevents such effects. Electrical stimulation or neurotrophic factors favor the remyelination and regeneration of nerves damaged by crushing or neuropathies derived from genetic, infectious, or metabolic diseases such as diabetes mellitus.

BackgroundResting state beta band (13 – 30 Hz) oscillations represent pathological neural activity in Parkinson’s disease (PD). It is unknown how the peak frequency or dynamics of beta oscillations may change among fine, limb and axial movements and different disease phenotypes. This will be critical for the development of personalized closed loop deep brain stimulation (DBS) algorithms during different activity states.MethodsSubthalamic (STN) local field potentials (LFPs) were recorded from a sensing neurostimulator (Activa® PC+S, Medtronic PLC.,) in fourteen PD participants (six tremor-dominant, 8 akinetic-rigid) off medication/off STN DBS during thirty seconds of repetitive alternating finger tapping, wrist-flexion extension, stepping in place, and free walking. Beta power peaks and beta burst dynamics were identified by custom algorithms and were compared among movement tasks and between tremor-dominant and akinetic-rigid groups.ResultsBeta power peaks were evident during fine, limb, and axial movements in 98% of movement trials; the peak frequencies were similar during each type of movement. Burst power and duration were significantly larger in the high beta band, but not in the low beta band, in the akinetic-rigid group compared to the tremor-dominant group.ConclusionsThe conservation of beta peak frequency during different activity states supports the feasibility of patient-specific closed loop DBS algorithms driven by the dynamics of the same beta band during different activities. Akinetic-rigid participants had greater power and longer burst durations in the high beta band than tremor-dominant participants during movement, which may relate to the difference in underlying pathophysiology between phenotypes.

Background Schizophrenia (SCH) and bipolar disorder (BD) have both shared and unique genetic risk factors and clinical characteristics. The aim of the present study was to identify potential risk factors significantly associated with SCH, relative to a BD reference group. Methods Data were obtained from medical records of patients that entered a major Mexico City hospital during 2009–2010 presenting psychotic symptoms (n = 1132; 830 cases of SCH, 302 cases of BD; 714 men and 418 women). SCH and BD diagnoses were compared with respect to a number of family and clinical characteristics. Logistic and linear regression analyses were used to respectively identify factors selectively associated with the SCH diagnosis relative to the BD diagnosis and explore the relationship between PANSS scores and parental age at time of birth to the age of SCH onset. Results Patients with SCH showed greater functional impairment than those with BD. Family history of mental illness, premorbid schizoid-like personality, and obstetric trauma were significantly associated with the SCH diagnosis. The association of obstetric trauma with SCH was greatest in male patients with a family history of mental illness. In women, increased paternal and decreased maternal age at time of the patient’s birth were associated with an earlier age of SCH onset. Conclusion Male gender, showing premorbid schizoid-like personality, familial SCH, and obstetric trauma are risk factors that distinguish SCH from BD. Additionally, our results suggest that risk for SCH relative to BD may be importantly influenced by interactions between familial risk, gender, and obstetric trauma.

BACKGROUND Cranial CT is routinely taught to be the gold standard for diagnosis of craniosynostosis and used by craniofacial teams for suspected nonsyndromic single suture craniosynostosis. Given the risks associated with infant CTs, do these scans provide significantly enhanced diagnostic accuracy compared to the physical exam when performed by an experienced clinical provider? METHOD A retrospective chart review was performed for children who underwent corrective surgery for nonsyndromic, single-suture craniosynostosis over an 11 year period by a single craniofacial team. Ages at presentation and surgery, preoperative clinical diagnosis and imaging, co-existing radiographic findings, and correlation with the intraoperative diagnosis were analyzed. RESULTS A total of 138 patients were included in this study. The mean age was 4.2 months at initial craniofacial evaluation, and 8.0 months at time of surgery. Twenty-seven patients received imaging prior to our clinic. Of those, 21 had plain radiography and 6 had CT scans. Of the remaining 111 patients referred without imaging, craniosynostosis was clinically diagnosed in 102 (92%), whereas 9 (8%) had an unclear clinical diagnosis. Of these 9, 1 (1%) was diagnosed clinically at follow-up exam, and the remaining 8 (7%) were diagnosed using radiography (3 CT scans, 5 plain radiographs). In all patients, the preoperative diagnosis was confirmed during intraoperative assessment. CONCLUSIONS Cranial CT was not needed by experienced craniofacial providers in 93% of nonsyndromic, single-suture craniosynostosis. Imaging obtained before craniofacial clinic referral may have been unnecessary. These findings question the classic teaching that preoperative cranial CT is the gold standard for diagnosis in infants with nonsyndromic, single-suture craniosynostosis.

Maternal programming can affect offspring health postnatally. We hypothesized that high milk production and/or mastitis infection during pregnancy will adversely affect calf blood biochemical analytes. Holstein bull calves (n = 45) were transported to the University of Rhode Island within 24 hrs of birth. Calves were classified by dam production and somatic cell counts (SCC) during pregnancy; HI (top 25% for herd M305, n = 7), MOD (lower 60% for herd M305, n = 16), HIMAST (HI with SCC ≥ 200,000 cells/mL; n = 15), and MODMAST (MOD with high SCC; n=6). Calves were sampled once a week for 8 wks. Serum was sent to the Missouri State Veterinary Medical Diagnostic Laboratory (Columbia, MO) for analyses. Results were analyzed in SAS using proc mixed. At wk 1, Calcium (Ca) concentrations were greater in HI calves (11±0.61mg/dL; P =.05) than MOD calves (10± 0.25mg/dL). At wk 3, Ca concentrations were greater in HIMAST (10± 0.13mg/dL) compared to HI (8±.048mg/dL; P

In March 2020, Americans began experiencing numerous lifestyle changes due to the COVID-19 pandemic. Some reports have suggested that pet acquisition and ownership increased during this period, and some have suggested shelters and rescues will be overwhelmed once pandemic-related restrictions are lifted and lifestyles shift yet again. In May 2021, the ASPCA hired the global market research company Ipsos to conduct a general population survey that would provide a more comprehensive picture of pet ownership and acquisition during the pandemic. Although pet owners care for a number of species, the term pet owner in this study specifically refers to those who had dogs and/or cats. One goal of the survey was to determine whether data from a sample of adults residing in the United States would corroborate findings from national shelter databases indicating that animals were not being surrendered to shelters in large numbers. Furthermore, this survey gauged individuals' concerns related to the lifting of COVID-19 restrictions, and analyses examined factors associated with pet owners indicating they were considering rehoming an animal within the next 3 months. The data showed that pet ownership did not increase during the pandemic and that pets may have been rehomed in greater numbers than occurs during more stable times. Importantly, rehomed animals were placed with friends, family members, and neighbors more frequently than they were relinquished to animal shelters and rescues. Findings associated with those who rehomed an animal during the pandemic, or were considering rehoming, suggest that animal welfare organizations have opportunities to increase pet retention by providing resources regarding pet-friendly housing and affordable veterinary options and by helping pet owners strategize how to incorporate their animals into their post-pandemic lifestyles.

Malaria causes more than 200 million clinical illnesses and 45 million deaths every year, making mass production of an effective vaccine increasingly urgent. A Plasmodium falciparum sporozoites (PfSPZ) based vaccine has been proved to be a promising choice to defend against the malaria pandemic. However, large scale industrial production of PfSPZ vaccine is currently sub-optimal as the process for sporozoite extraction from salivary glands of infected mosquitoes is performed by manual microdissection, a relatively inefficient process requiring many hours of training. This paper reports continued progress in our development of a robotic system for automating the extraction of salivary glands. Compared to our previous versions, the structure of the new system is optimized to be more compact and allows different steps in workflow to be performed in parallel. We also report continued progress in developing key subsystem components. Finally, experiments show encouraging results with success rates of 90% in robotic mosquito manipulation, 95.6% in salivary gland extraction and 92.7% in debris disposal.

BackgroundCardiac hypertrophy can be considered a maladaptive response which in many cases results in heart failure and sudden death. Genetic predisposition to cardiac hypertrophy is ill-defined, but current research has given credence to a role of non-protein-coding RNAs in the development of cardiac hypertrophy.ResultsWe used microarrays, RNA-Seq and quantitative genetics with the spontaneously hypertensive, SHR (SHR/OlaIpcv) rat strain, the normotensive Brown Norway (BN-Lx/Cub) rat strain, and a recombinant inbred (RI) panel of rats (HXB/BXH) derived from these strains to examine the areas of the genome associated with cardiac hypertrophy. We identified circular (circ) RNAs coded within these areas. Of the 122 differentially expressed circRNAs in left ventricle of SHR and BN-Lx rats, three were transcribed from areas corresponding to the QTLs we identified for cardiac hypertrophy using the HXB/BXH rat panel. We then identified microRNAs which are “sponged” by the circ RNAs and the mRNAs which are destabilized by the microRNAs. 265 miRNAs could be identified as targets for the three circRNAs. We focused on the four miRNAs that were also differentially expressed between SHR and BN-Lx rats. One of the miRNAs (Mir-210-5p) was a target of the differentially expressed circ H2afy and circ H2afy was located within the QTL on Chr 17 (genome wide p-value = 0.011). Mir-210-5p has a binding site on the 3’ UTR of DR6, which is differentially expressed and in turn controls the expression level of NFκB. NFκB is an important component of the oxidative stress response leading to hypertrophy.ConclusionsOur work identified a novel circRNA that may be the mediator of a cascade of events that influence a cardiac hypertrophy phenotype. The circRNA and miRNA which we identified may become useful as markers of the risk for cardiac hypertrophy.

Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection.A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT-qPCR was performed in parallel.All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia.Ivermectin - at the dose used - has no clinically relevant activity against the pre-erythrocytic stages of P. falciparum.L'ivermectine est sûr et largement utilisé pour traiter les helminthiases. Il tue également les arthropodes se nourrissant sur les sujets traités, y compris les vecteurs du paludisme. Ainsi, l'administration en masse d'ivermectine en tant qu'outil supplémentaire de lutte contre le paludisme est actuellement évaluée par l'OMS. Comme les données in vitro, les expériences sur animaux et les observations épidémiologiques suggèrent que l'ivermectine a un effet direct sur les stades hépatiques du parasite du paludisme, cette étude a été conçue pour évaluer l'effet prophylactique de l'ivermectine sur l'infection paludéenne humaine par Plasmodium falciparum contrôlée. MÉTHODES: Quatre volontaires ont été randomisés pour un placebo et 8 volontaires ont été randomisés pour recevoir de l'ivermectine à 0,4 mg/kg en une fois par voie orale, 2 heures avant d'être expérimentalement infectés par voie intraveineuse avec 3.200 sporozoïtes de P. falciparum. Le critère d'évaluation principal était le temps à la parasitémie détectée par un frottis sanguin épais positif. Une RT-qPCR a été réalisée en parallèle. RÉSULTATS: Tous les volontaires sauf un sont devenus positifs pour les frottis sanguins épais entre le jour 11 et le jour 12 après l'infection et il n'y avait aucun effet significatif de l'ivermectine sur la parasitémie.L'ivermectine - à la dose utilisée - n'a aucune activité cliniquement pertinente contre les stades pré-érythrocytaires de P. falciparum.

The neonatal cutaneous mycobiome has not been characterized in preterm infants. Invasive fungal infections in preterm neonates are associated with high mortality. The immaturity of the preterm skin predisposes neonates to invasive infection by skin colonizers. We report the clinical and host determinants that influence the skin mycobiome. Skin swabs from the antecubital fossa, forehead, and gluteal region of 15 preterm and 15 term neonates were obtained during the first 5 weeks of life. The mycobiome was sequenced using the conserved pan-fungal ITS2 region. Blood samples were used to genotype immune modulating genes. Clinical metadata was collected to determine the clinical predictors of the abundance and diversity of the skin mycobiome. The neonatal mycobiome is characterized by few taxa. Alpha diversity of the mycobiome is influenced by antibiotic exposure, the forehead body site, and the neonatal intensive care unit (NICU) environment. Beta diversity varies with mode of delivery, diet, and body site. The host determinants of the cutaneous microbiome include single-nucleotide polymorphisms in TLR4, NLRP3,CARD8, and NOD2. The neonatal cutaneous mycobiome is composed of few genera and is influenced by clinical factors and host genetics, the understanding of which will inform preventive strategies against invasive fungal infections.

Context Comprehensive assessments are recommended to evaluate sport-related concussion (SRC). The degree to which the King-Devick (KD) test adds novel information to an SRC evaluation is unknown. Objective To describe relationships at baseline among the KD and other SRC assessments and explore whether the KD provides unique information to a multimodal baseline concussion assessment. Design Cross-sectional study. Setting Five National Collegiate Athletic Association institutions participating in the Concussion Assessment, Research and Education (CARE) Consortium. Patients or Other Participants National Collegiate Athletic Association student-athletes (N = 2258, age = 20 ± 1.5 years, 53.0% male, 68.9% white) in 11 men's and 13 women's sports. Main Outcome Measure(s) Participants completed baseline assessments on the KD and (1) the Symptom Inventory of the Sport Concussion Assessment Tool–3rd edition, (2) the Brief Symptom Inventory-18, (3) the Balance Error Scoring System, (4) the Standardized Assessment of Concussion (SAC), (5) the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) test battery, and (6) the Vestibular/Ocular Motor Screening tool during their first year in CARE. Correlation coefficients between the KD and the 6 other concussion assessments in isolation were determined. Assessments with ρ magnitude >0.1 were included in a multivariate linear regression analysis to evaluate their relative association with the KD. Results Scores for SAC concentration, ImPACT visual motor speed, and ImPACT reaction time were correlated with the KD (ρ = −0.216, −0.276, and 0.164, respectively) and were thus included in the regression model, which explained 16.8% of the variance in baseline KD time (P < .001, Cohen f2 = 0.20). Better SAC concentration score (β = −.174, P < .001), ImPACT visual motor speed (β = −.205, P < .001), and ImPACT reaction time (β = .056, P = .020) were associated with faster baseline KD performance, but the effect sizes were small. Conclusions Better performance on cognitive measures involving concentration, visual motor speed, and reaction time was weakly associated with better baseline KD performance. Symptoms, psychological distress, balance, and vestibular-oculomotor provocation were unrelated to KD performance at baseline. The findings indicate limited overlap at baseline among the CARE SRC assessments and the KD.

BackgroundMouse and human studies support the promise of dry beans to improve metabolic health and to lower cancer risk. In overweight/obese patients with a history of colorectal polyps or cancer, the Beans to Enrich the Gut microbiome vs. Obesity’s Negative Effects (BE GONE) trial will test whether and how an increase in the consumption of pre-cooked, canned dry beans within the context of usual diet and lifestyle can enhance the gut landscape to improve metabolic health and reduce cancer risk.Methods/designThis randomized crossover trial is designed to characterize changes in (1) host markers spanning lipid metabolism, inflammation, and obesity-related cancer risk; (2) compositional and functional profiles of the fecal microbiome; and (3) host and microbial metabolites. With each subject serving as their own control, the trial will compare the participant’s usual diet with (intervention) and without (control) dry beans. Canned, pre-cooked dry beans are provided to participants and the usual diet continually assessed and monitored. Following a 4-week run-in and equilibration period, each participant provides a total of 5 fasting blood and 6 stool samples over a total period of 16 weeks. The intervention consists of a 2-week ramp-up of dry bean intake to 1 cup/d, which is then continued for an additional 6 weeks. Intra- and inter-individual outcomes are assessed across each crossover period with consideration of the joint or modifying effects of the usual diet and baseline microbiome.DiscussionThe BE GONE trial is evaluating a scalable dietary prevention strategy targeting the gut microbiome of high-risk patients to mitigate the metabolic and inflammatory effects of adiposity that influence colorectal cancer risk, recurrence, and survival. The overarching scientific goal is to further elucidate interactions between diet, the gut microbiome, and host metabolism. Improved understanding of the diet-microbiota interplay and effective means to target these relationships will be key to the future of clinical and public health approaches to cancer and other major diet- and obesity-related diseases.Trial registrationThis protocol is registered with the U.S. National Institutes of Health trial registry,ClinicalTrials.gov, under the identifier NCT02843425. First posted July 25, 2016; last verified January 25, 2019.

Background A vaccine would be an ideal tool for reducing malaria’s impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). Methods To increase VE in Tanzania, we increased PfSPZ/dose (9 × 105 or 1.8 × 106) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial. Results All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 × 105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 × 106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37–40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 × 105 PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 × 106 PfSPZ group. Conclusions In Tanzania, increasing the dose from 2.7 × 105 to 9 × 105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8 × 106 PfSPZ significantly reduced VE. Clinical Trials Registration NCT02613520.

Animal shelters tend to be stressful environments for dogs because of the sights, sounds, odors, and schedules that characterize shelter living. Levels of activity, including the amount of time spent resting or engaging in sedentary behaviors, may provide insights into overall welfare, especially when comparing shelter dogs' activity patterns to those of dogs in a home setting. The goal of this study was to compare the intensity and consistency of shelter dogs' and owned dogs' activity levels using three distinct methods for analyzing actigraphy data. Activity levels were measured for 19 owned dogs and 19 shelter dogs using triaxial accelerometers affixed to nylon collars on each dog's neck. Shelter dogs were more active than owned dogs during the first three quarters of the day, whereas owned dogs were more active than shelter dogs during the final quarter. Comparisons of shelter dogs' and owned dogs' ten consecutive hours of greatest activity also indicated that shelter dogs were more active earlier in the day than owned dogs. Furthermore, shelter dogs exhibited higher activity levels than owned dogs during this period of greatest activity. During the five consecutive hours of least activity, shelter dogs were more active than owned dogs. Finally, individual shelter dogs' activity patterns were more consistent day to day than owned dogs'. Our findings suggest that the shelter environment may inhibit dogs from resting. Further research is needed to assess the impacts of activity patterns on the health of shelter-housed dogs and to determine how quickly these dogs adjust to their owner’ schedules after adoption.

Background The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. Methods We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5–9 years, 13–59 months, and 5–12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. Results Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). Conclusions PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. Clinical Trials Registration NCT02687373.

BACKGROUND Acute alcohol produces effects on cerebral metabolism and blood flow. Alcohol is converted to acetate, which serves as a source of energy for the brain and is an agonist at G protein-coupled receptors distributed in different cell types in the body including neurons. Acetate has been hypothesized to play a role in the cerebral blood flow (CBF) response after alcohol ingestion. We tested whether administration of acetate would alter CBF in a pattern similar to or different from that of alcohol ingestion in healthy individuals. METHODS Twenty-four healthy participants were assigned by convenience to receive either 0.6 g/kg alcohol orally (n = 12) or acetate intravenously (n = 12). For each participant, CBF maps were acquired using an arterial spin labeling sequence on a 3T magnetic resonance scanner after placebo and after drug administration. Whole-brain CBF maps were compared between placebo and drug using a paired t-test, and set at a threshold of p

Recommendations for the management of rectal cancer have been incredibly dynamic over the last several decades and accurate staging is required to make informed decisions and guide patient discussions. A complete staging evaluation should include a physical examination, complete colonoscopy, serum carcinoembryonic antigen level, and imaging to include a CT chest, MRI of the pelvis, and either a CT or MRI of the abdomen. Assessment of the circumferential resection margin with a rectal cancer protocol MRI is the cornerstone of this staging workup. Accurate staging is of paramount importance when considering treatment options for this complex disease.

In 2016, there were more cases and deaths caused by malaria globally than in 2015. An effective vaccine would be an ideal additional tool for reducing malaria’s impact. Sanaria® PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups. We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Because all age groups received three doses of 9.0 × 105 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults. T-cell responses were highest in 6–10-year olds after one dose and 1–5-year olds after three doses; infants had no significant positive T-cell responses. The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea. Because PfSPZ Vaccine–induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.

The present mini-review focuses on animal models of schizophrenia that have explored the effects of cannabidiol (CBD; a non-psychoactive component of cannabis) or the pharmacological manipulation of the endocannabinoid system on behavioral and cognitive outcome measures. First, results of some relevant clinical studies in this area are summarized, and then pre-clinical work on animal models of schizophrenia based on NMDA receptor antagonism or neurodevelopmental manipulations are discussed. A brief overview is given of the theoretical framework on which these models are based, along with a concise summary of results that have been obtained. Clinical results using CBD for schizophrenia seem promising and its effects in animal models of schizophrenia support its potential as a useful pharmacotherapy. Animal models have been paramount for elucidating the actions of CBD and the function of the endocannabinoid system and for identifying novel pharmacological targets, such as cannabinoid receptors and anandamide. However, more attention needs to be placed on defining and applying independent variables and outcome measures that are comparable between pre-clinical and clinical studies. The objective of this review is, on the one hand, to emphasize the potential of such models to predict clinical response to experimental drugs, and on the other hand, to highlight areas in which research on such models could be improved.

The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identified. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a novel network of protein-metabolite interactions in COVID-19 patients through targeted metabolomic and proteomic profiling of serum samples in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity, such as acute kidney injury. Finally, we developed a novel composite outcome measure for COVID-19 disease severity and created a clinical prediction model using a set of 33 metabolites. The model significantly improved the identification of key events of critical illness such as prolonged hospitalization, supplemental oxygen requirement, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS), beyond those achieved using the more traditional risk factors of age, gender, and BMI.

While many academic conferences are transitioning to online events, this article aims to share several strategies used by the organizers of a well-established online-only conference. The Teaching, Colleges, and Community (TCC) Worldwide Online Conference recently celebrated its 25th anniversary. After a brief review of TCC’s history, four strategies that organizers have identified as helping conference goers feel oriented, welcomed, connected and engaged are described. These strategies include offering a “pre-conference” orientation, including regional keynote speakers, creating opportunities for informal exchange, and encouraging participation with digital credentials.

PfSPZ-CVac combines ‘PfSPZ Challenge’, which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x104 PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x104 PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x105 PfSPZ-CVac five days apart. CHMI (3.2x103 PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity. Clinical trials registration: NCT02773979., Author summary The world needs a protective malaria vaccine. One approach is to repeatedly administer whole sporozoites, the parasite form that is transmitted from mosquitos to humans. Without treatment, sporozoites enter the liver, grow for a week, and then infect red blood cells, causing clinical disease. Here, we gave a vaccine consisting of sporozoites with a drug that prevents red blood cell infections to eliminate clinical illness. This approach was protective in other studies so we initially evaluated a faster schedule where the vaccine was given weekly. Surprisingly, there was no protection observed. We determined that weekly intervals led the second and third vaccine doses to be administered just as the previous dose of sporozoites was transitioning from the liver to the blood stage. Even though blood stage infection was stopped in this study by the co-administered drug (chloroquine), we hypothesized that it was problematic to administer a vaccine during blood stage infection. Therefore, we gave the vaccinations every five days so that upon the second and third doses, there were no blood-stage parasites present. With five-day spacing and a higher dose, the vaccine protected 75% of participants. These findings suggest that blood-stage infections may hinder formation of protective responses to malaria.

BACKGROUND: A prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self-administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ-8 (TARP γ-8). This study evaluated the preclinical efficacy of JNJ-55511118, a novel, selective, high-affinity inhibitor of TARP γ-8-bound AMPARs, in reducing chronic operant alcohol self-administration. METHODS: Separate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR-4 schedule of reinforcement. After a 40-day baseline, JNJ-55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self-administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded. RESULTS: During baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ-55511118 decreased multiple parameters of alcohol self-administration but did not reduce behavior-matched sucrose-only self-administration. JNJ-55511118 had no effect on sweetened alcohol or sucrose self-administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ-55511118 (1 mg/kg) had no effect on open-field activity in male mice. CONCLUSIONS: This study shows for the first time that TARP γ-8-bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ-55511118 in reducing alcohol self-administration in male mice suggests that inhibition of TARP γ-8-bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.

Microbiome composition and function have been implicated as contributing factors in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune hepatitis (AIH). Furthermore, dysbiosis of gut microbiome is associated with impaired barrier function and mucosal immune dysregulation. However, mechanisms by which gut microbiome contributes to the ADs and whether antioxidant treatment can restore gut homeostasis and ameliorate the disease outcome are not known. This study was, therefore, focused on examining the involvement of gut microbiome and host responses in the pathogenesis of SLE using unique female mouse models (C57BL/6, MRL+/+ and MRL/lpr) of 6 and 18 weeks with varying degrees of disease progression. Fecal microbiome diversity and composition, gut oxidative stress (OS), barrier function and inflammation, as well as systemic autoimmunity were determined. Interestingly, each mouse strain had distinct bacterial community as revealed by β-diversity. A lower Firmicutes/Bacteroidetes ratio in 6-week-old MRL/lpr mice was observed, evidenced by decrease in Peptostreptococcaceae under Firmicutes phylum along with enrichment of Rikenellaceae under Bacteroidetes phylum. Additionally, we observed increases in colonic OS [4-hydroxynonenal (HNE)-adducts and HNE-specific immune complexes], permeability changes (lower tight junction protein ZO-2; increased fecal albumin and IgA levels) and inflammatory responses (increased phos-NF-κB, IL-6 and IgG levels) in 18-week-old MRL/lpr mice. These changes were associated with markedly elevated AD markers (antinuclear and anti-smooth muscle antibodies) along with hepatic portal inflammation and severe glomerulonephritis. Notably, antioxidant N-acetylcysteine treatment influenced the microbial composition (decreased Rikenellaceae; increased Akkeransiaceae, Erysipelotrichaceae and Muribaculaceae) and attenuated the systemic autoimmunity in MRL/lpr mice. Our data thus show that gut microbiome dysbiosis is associated with increased colonic OS, barrier dysfunction, inflammatory responses and systemic autoimmunity markers. These findings apart from delineating a role for gut microbiome dysbiosis, also support the contribution of gut OS, permeability changes and inflammatory responses in the pathogenesis of ADs.

Background Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection. Methods Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified. Results Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1–3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination. Conclusions In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.

BackgroundNonhuman primates (NHPs) are self-motivated to perform cognitive tasks on touchscreens in their animal housing setting. To leverage this ability, fully integrated hardware and software solutions are needed, that work within housing and husbandry routines while also spanning cognitive task constructs of the Research Domain Criteria (RDoC).New MethodWe describe a Kiosk Station (KS-1) that provides robust hardware and software solutions for running cognitive tasks in cage-housed NHPs. KS-1 consists of a frame for mounting flexibly on housing cages, a touchscreen animal interface with mounts for receptables, reward pumps and cameras, and a compact computer cabinet with an interface for controlling behavior. Behavioral control is achieved with a unity3D program that is virtual-reality capable, allowing semi-naturalistic visual tasks to assess multiple cognitive domains.ResultsKS-1 is fully integrated into the regular housing routines of monkeys. A single person can operate multiple KS-1s. Monkeys engage with KS-1 at high motivation and cognitive performance levels at high intra-individual consistency.Comparison with Existing MethodsKS-1 is optimized for flexible mounting onto standard apartment cage systems. KS-1 has a robust animal interface with options for gaze/reach monitoring. It has an integrated user interface for controlling multiple cognitive task using a common naturalistic object space designed to enhance task engagement. All custom KS-1 components are open-sourced.ConclusionsKS-1 is a versatile tool for cognitive profiling and enrichment of cage-housed monkeys. It reliably measures multiple cognitive domains which promises to advance our understanding of animal cognition, inter-individual differences and underlying neurobiology in refined, ethologically meaningful behavioral foraging contexts.

Calves are prone to health issues with high mortality observed during the first 3 weeks of life. We hypothesized that dam milk production levels and/or mastitis infection during gestation will lead to reduced insulin production and increased circulating glucose concentration in response to an Intravenous Glucose Tolerance Test (IVGTT) in young dairy bull calves. Calves (n = 45) were selected from dams classified has high producers (HI; Top 25% for herd M305; n = 7), high producers with high somatic cell count (SCC; HIMAST; SCC test during gestation over 200,000 cells/mL; n = 15), moderate producers (MOD; lower 60% for herd M305; n =17) or moderate producers with high SCC (MODMAST; n = 6). IVGTT were performed on the calves at 7 weeks of age. Blood samples were collected prior to (-30, -15 and 0 min) infusion of glucose. After glucose (0.15 grams /kg bw) administration, samples were collected at 2, 5, 10, 15, 30, 60, and 120-minutes post infusion. Serum insulin and glucose concentrations were determined at Cornell Veterinary Medical Diagnostic Laboratory (Ithica, NY). Data were analysed in SAS using Proc Mixed. Insulin:glucose ratio was analysed using Proc Mixed with repeated measures for treatment x time. No effect of maternal milk production and/or mastitis infection during gestation was observed on calf baseline insulin, insulin AUC, baseline glucose or glucose AUC (P ≥ 0.12). Similarly, no difference in Insulin:Glucose ratio was observed in these calves (P = 0.66). In conclusion, high maternal milk production and/or mastitis infection may not have an effect on circulating insulin production in calves in response to an IVGTT. Correlation analyses will be performed on these data, as well as additional analyses, to determine if insulin sensitivity or response (ie: phase 1 response) was altered further.