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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.

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.

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.

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.

Graphical abstract, Highlights • Apicoplast LipB deletion leads to changed antioxidant expression that precedes and coincides with accelerated differentiation. • 3D7 Plasmodium exhibits changes in glycolysis and tricarboxylic acid cycle activity after deletion of apicoplast LipB. • When LipB is deleted from NF54 Plasmodium, the resulting parasites cannot complete their development in mosquitoes., Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient antimalarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in the redox environment. Understanding the mechanisms regulating parasite redox could contribute to the design of new drugs. Malaria parasites have a complex network of redox regulatory systems housed in their cytosol, in their mitochondrion and in their plastid (apicoplast). While the roles of enzymes of the thioredoxin and glutathione pathways in parasite survival have been explored, the antioxidant role of α-lipoic acid (LA) produced in the apicoplast has not been tested. To take a first step in teasing a putative role of LA in redox regulation, we analysed a mutant Plasmodium falciparum (3D7 strain) lacking the apicoplast lipoic acid protein ligase B (lipB) known to be depleted of LA. Our results showed a change in expression of redox regulators in the apicoplast and the cytosol. We further detected a change in parasite central carbon metabolism, with lipB deletion resulting in changes to glycolysis and tricarboxylic acid cycle activity. Further, in another Plasmodium cell line (NF54), deletion of lipB impacted development in the mosquito, preventing the detection of infectious sporozoite stages. While it is not clear at this point if the observed phenotypes are linked, these findings flag LA biosynthesis as an important subject for further study in the context of redox regulation in asexual stages, and point to LipB as a potential target for the development of new transmission drugs.

The challenges of managing an academic/grade grievance can be taxing on nursing faculty. Therefore, it is essential that faculty are well-equipped for these experiences. The purpose of this article is to enable nursing faculty to understand how to navigate a student academic/grade grievance. In this article, three nursing faculty with varying levels of teaching experience will share insightful information on the prevention, preparation, and processes for successfully navigating student academic/grade grievances. They will discuss steps for addressing an academic/grade grievance and lessons learned with helpful tips for nursing faculty to put into their toolbox for future use.

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.

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 (

In response to the COVID-19 pandemic, the American Board of Obstetrics and Gynecology canceled the 2020 in-person subspecialty certifying examinations and developed remote administration of 4 subspecialty certifying examinations in 2021 for both examiners and candidates. Because of the continued risks of the COVID-19 pandemic, the 2021 specialty certifying examinations and the 2022 subspecialty certifying examinations were also administered remotely for candidates. For these examinations, examiners participated remotely in 2021 and were at the American Board of Obstetrics and Gynecology testing center in 2022. Overall, the American Board of Obstetrics and Gynecology remote certifying examinations have been well-received by candidates and examiners according to posttest survey data. Candidate performance has been comparable to that observed in the previous in-person examinations. In this review, we describe our implementation, process modifications, successes, and challenges with remote testing. During this process, the American Board of Medical Specialties approval was required, and the Standards for Educational and Psychological Testing served as our testing-industry guideline to ensure valid interpretation of scores and fairness to candidates.

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.

Studies in recent years have strengthened the notion that neural mechanisms are involved in the control of immune responses. From initial studies that highlighted the vagus nerve control of inflammatory responses in vertebrates, many advances have been made, including the dissection of specific neural circuits that are involved in controlling immunity. Part of this has been facilitated by the use of a tractable model animal, Caenorhabditis elegans, in which individual neurons involved in sensing pathogens and controlling the immune response have been identified. Importantly, some of the underlying mechanisms involved in the neural control of immune pathways appear to be present in evolutionarily diverse species. This review focuses on some major developments in vertebrates and C. elegans, and how these discoveries may lead to advances in understanding neural-immune connections that govern inflammatory responses.

Metabotropic glutamate receptor subtype-5 (mGluR5) activity regulates a variety of behavioral pathologies associated with alcohol addiction. The main goal of this study was to determine if mGluR5 regulates the induction of ethanol-induced locomotor sensitization, which is a model of experience-dependent plasticity following initial exposure to drugs of abuse. The extracellular signal-regulated kinase (ERK(1/2)) pathway is downstream of mGluR5 and implicated in alcohol addiction; however, its role in sensitization remains unexplored. We sought to determine if mGluR5-mediated changes in ethanol-induced sensitization are associated with changes in ERK(1/2) phosphorylation (pERK(1/2)) in specific brain regions. Adult male DBA/2J mice were tested for acute locomotor response to ethanol (0 or 2 g/kg, IP) followed by a 10-day induction period in which the mGluR5 antagonist MPEP (0 or 30 mg/kg, IP) was administered prior to ethanol (0 or 2.5 g/kg, IP). One day later, ethanol (2 g/kg) produced a robust within- and between-group increase in locomotor activity, indicating sensitization in mice that received MPEP (0 mg/kg) during induction. MPEP (30 mg/kg) treatment during induction resulted in locomotor response to ethanol (2 g/kg) challenge that was equivalent to an acute response, indicating full blockade of sensitization. Sensitization was associated with increased pERK(1/2) immunoreactivity (IR) in nucleus accumbens shell (AcbSh) and a reduction in lateral habenula (LHb), both of which were blocked by MPEP treatment during induction. Sensitization was also associated with mGluR5-independent increases in pERK(1/2) IR in the nucleus accumbens core and decreases in the dentate gyrus and lateral septum. These data indicate that mGluR5 activity is required for the induction of ethanol locomotor sensitization and associated changes in ERK(1/2) phosphorylation in the AcbSh and LHb, which raises the hypothesis that mGluR5-mediated cell signaling in these brain regions may mediate the induction of sensitization. Elucidating mechanisms of sensitization may increase understanding of how ethanol hijacks behavioral functions during the development of addiction.

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.

Healthy 18-45 year olds were enrolled in a double-blind, placebo-controlled trial in Bougoula-Hameau, Mali, randomized 1:1 to 2.048 × 1062 participants were enrolled in April/May 2017. Proportions of participants experiencing at least one solicited systemic AE were similar between treatment arms: 6/31 (19.4%, 95%CI 9.2-36.3) of PfSPZ-CVac recipients versus 7/31 (22.6%, 95%CI 29.2-62.2) of controls (PfSPZ-CVac (CQ) was well-tolerated. The tested dosing regimen failed to significantly protect against Pf infection in this very high transmission setting.U.S. National Institutes of Health, Sanaria.ClinicalTrials.gov identifier (NCT number): NCT02996695.

Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F(1)). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F(1) female MHFD offspring would likewise impair F(2) social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F(1) MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F(2) mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain fatty acid-producing taxa and rescues MHFD-descendant F(2) social deficits. L. reuteri exerts a sexually dimorphic impact on gut microbiota configuration, increasing discriminant taxa between female cohorts. Collectively, these results show multigenerational impacts of HFD-induced dysbiosis in the maternal lineage and highlight the potential of maternal microbiome-targeted interventions for neurodevelopmental disorders.

Prolonged observation could avoid invasive mechanical ventilation (IMV) and related risks in patients with Covid-19 acute respiratory failure (ARF) compared to initiating early IMV. We aimed to determine the association between ARF management strategy and in-hospital mortality.Patients in the Weill Cornell Covid-19 registry who developed ARF between March 5 - March 25, 2020 were exposed to an early IMV strategy; between March 26 - April 1, 2020 to an intermediate strategy; and after April 2 to prolonged observation. Cox proportional hazards regression was used to model in-hospital mortality and test an interaction between ARF management strategy and modified sequential organ failure assessment (mSOFA).Among 632 patients with ARF, 24% of patients in the early IMV strategy died versus 28% in prolonged observation. At lower mSOFA, prolonged observation was associated with lower mortality compared to early IMV (at mSOFA = 0, HR 0.16 [95% CI 0.04-0.57]). Mortality risk increased in the prolonged observation strategy group with each point increase in mSOFA score (HR 1.29 [95% CI 1.10-1.51], p = 0.002).In Covid-19 ARF, prolonged observation was associated with a mortality benefit at lower mSOFA scores, and increased mortality at higher mSOFA scores compared to early IMV.

Despite the critical link between visual exploration and memory, little is known about how neuronal activity in the human mesial temporal lobe (MTL) is modulated by saccades. Here, we characterize saccade-associated neuronal modulations, unit-by-unit, and contrast them to image onset and to occipital lobe neurons. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies saccades, inhibiting/exciting a unique population of broad-/narrow-spiking units, respectively, before and during saccades and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking neuronal activity to event-related potentials (ERPs), which are directionally modulated following saccades, we recontextualize the ERP associated with saccades as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded saccade-related ERP in the human brain.

The purpose of vaccines is to prevent and/or reduce morbidity and mortality in individuals and interrupt transmission of infectious agents within populations Vaccines have saved many millions of lives and are forefront in the struggle to contain new emerging diseases including Ebola and Covid-19 Vaccines to ∼25 human viral and bacterial diseases are licensed in the US On the horizon is the first licensed human vaccine against a eukaryotic pathogen, Plasmodium falciparum, responsible for >98% of deaths from malaria Vaccine stabilization methods are designed to minimize potency loss during manufacture and losses during storage, distribution, and in-clinic storage/use Methods vary according to the immunogen, whether an adjuvant is incorporated and anticipated shelf life Liquid or lyophilized formulations with storage and distribution at 2-8 °C utilize refrigerators that are particularly unreliable, and vaccine efficacy is often compromised The Ebola vaccine, ERBEVO, is stored/distributed at -60 to -80 °C in specialized freezers or on dry ice, which is even more difficult than 2 to 8 °C Alternative stabilization methods that maintain adequate vaccine potency at ambient temperatures – increasingly foam drying and spray drying – are used experimentally, but not yet for any licensed vaccines Eukaryotic whole cell vaccines including PfSPZ Vaccine and several veterinary vaccines (as well as CAR-T and cellular therapies), require cryopreservation with storage and distribution below -150 °C Little to no loss in potency occurs below Tg, compared to ∼1 log loss over 12 months typical of lyophilized vaccines at 2 to 8 °C Cryogenic storage is favored for some RNA- and DNA-based vaccines particularly in anticipation of future epidemics requiring long term stockpiling Cryogenic storage in standard vaccine vials is problematic: these tolerate temperatures down to -80 °C but for CAR-T products and PfSPZ Vaccine new custom cryovials that incorporate a septum for needle access and maintain CCIT at liquid nitrogen temperatures have been developed And the -150 °C cold chain is more practical than one based on -80 °C or dry ice Funding: NIH/NIAID 5SB1AI077262-07 DoD W81XWH18C0326 Conflict of Interest: None to disclose

A subset of patients who undergo colon cancer surgery may be at a high risk of multiple subsequent admissions. We developed a simplified model to predict the preoperative risk of multiple postoperative admissions (MuAdm) among patients undergoing colon resection to aid in preoperative planning.Patients aged ≥18 y with colon cancer who underwent elective surgical resection identified in discharge claims from California and New York (2008-2011) were included. The primary outcome, MuAdm, was defined as 2 or more admissions in the year following resection. Logistic regression models were developed to identify factors predictive of MuAdm. A weighted point system was developed using beta-coefficients (P 0.05). A random sample of 75% of the data was used for model development, which was validated in the remaining 25% sample.A total of 14,780 patients underwent colon resection for cancer. Almost 30% had an admission in the year after index surgery and 9.8% had MuAdm. The significant predictors of MuAdm were higher Elixhauser comorbidity index score, metastatic disease, payer system, and the number of admissions in the year before surgery. Scores ranged from 0 to 8. Scores ≤1 had a 7% risk of MuAdm, and scores ≥6 had a30% risk of MuAdm.In the year following discharge after resection of colon cancer, nearly 10% of patients are admitted 2 or more times. A simple, preoperative clinical model can prospectively predict the likelihood of multiple admissions in patients anticipating resection. This model can be used for preoperative planning and setting postoperative expectations more accurately.

When neurons oscillate together in one brain area, they often synchronize to oscillations in other areas. By artificially entraining long range connections during beta oscillations, their strength is modified in the wake of that oscillation.

Background Inflammatory Bowel Disease (IBD) has not historically been a focus of racial health disparities research. IBD has been increasing in the black community. We hypothesized that outcomes following surgery would be worse for black patients. Methods A retrospective cohort study of death and serious morbidity (DSM) of patients undergoing surgery for IBD was performed using data from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP 2011–2014). Multivariable logistic regression modeling was performed to evaluate associations between race and outcomes. Results Among 14,679 IBD patients, the overall rate of DSM was 20.3% (white: 19.3%, black 27.0%, other 23.8%, p Conclusions Black patients are at increased risk of post-operative DSM following surgery for IBD. The elevated rates of DSM are not explained by traditional risk factors like obesity, ASA class, emergent surgery, or stoma creation.

Iron (Fe)-poor surface waters limit phytoplankton growth and their ability to remove carbon (C) from the atmosphere and surface ocean. Over the past few decades, research has focused on constraining the global Fe cycle and its impacts on the global C cycle. Hydrothermal vents have become a highly debated potential source of Fe to the surface ocean. Two main mechanisms for transport of Fe over long distances have been proposed: Fe-bearing nanoparticles and organic C complexation with Fe in the dissolved (dFe) and particulate (pFe) pools. However, the ubiquity and importance of these processes is unknown at present, and very few vents have been investigated for Fe-Corg interactions or the transport of such materials away from the vent. Here we describe the near-field contributions (first ~100 km from ridge) of pFe and Corg to the Southern East Pacific Rise (SEPR) plume, one of the largest known hydrothermal plume features in the global ocean. Plume particles (>0.2 μm) were collected as part of the U.S. GEOTRACES Eastern Pacific Zonal Transect cruise (GP16) by in-situ filtration. Sediment cores were also collected to investigate the properties of settling particles. In this study, X-ray absorption near edge structure (XANES) spectroscopy was used in two complementary X-ray synchrotron approaches, scanning transmission X-ray microscopy (STXM) and X-ray microprobe, to investigate the Fe and C speciation of particles within the near-field non-buoyant SEPR plume. When used in concert, STXM and X-ray microprobe provide fine-scale and representative information on particle morphology, elemental co-location, and chemical speciation. Bulk chemistry depth profiles for particulate Corg (POC), particulate manganese (pMn), and pFe indicated that the source of these materials to the non-buoyant plume is hydrothermal in origin. The plume particles at stations within the first ~100 km down-stream of the ridge were composites of mineral (oxidized Fe) and biological materials (organic C, Corg). Iron chemistry in the plume and in the core-top sediment fluff layer were both dominated by Fe(III) phases, such as Fe(III) oxyhydroxides and Fe(III) phyllosilicates. Particulate sulfur (pS) was a rare component of our plume and sediment samples. When pS was detected, it was in the form of an Fe sulfide mineral phase, composing ≤0.4% of the Fe on a per atom basis. The sediment fluff layer contained a mixture of inorganic (coccolith fragments) and Corg bearing (lipid-rich biofilm-like) materials. The particle morphology and co-location of C and Fe in the sediment was different from that in plume particles. This indicates that if the Fe-Corg composite particles settle rapidly to the sediments, then they experience strong alteration during settling and/or within the sediments. Overall, our observations indicate that the particles within the first ~100 km of the laterally advected plume are S-depleted, Fe(III)-Corg composites indicative of a chemically oxidizing plume with strong biological modification. These findings confirm that the Fe-Corg relationships observed for non-buoyant plume particles within ~100 m of vent sites are representative of particles within the first ~100 km of the advecting non-buoyant plume, and demonstrate that the export of hydrothermal pFe is facilitated through physical-chemical association with Corg.

Continental slope canyons off the United States Atlantic coast remain poorly studied, and in particular, the distributions of pelagic organisms in waters overlying these unique environments are not well documented. During the Early Career Scientist Deep Submergence Training cruise, AT36-EAGER, the distribution of organisms in the water column overlying Hydrographer Canyon, which cuts through the northwestern Atlantic continental margin, was investigated through daytime midwater observations using HOV Alvin (AD4831) at three depths. Mixed swarms of krill and Themisto sp. amphipods were observed at all depths surveyed. Observations centered at 250 m were also dominated by chaetognaths, copepods, and Phronima sp. amphipods, while at 500 and 750 m, the assemblages were dominated by the fishes in the families Paralepididae, Nemichthyidae, and Mytophidae. Additionally, measurements of methane, nitrous oxide, optical properties (absorbance and fluorescence), dissolved organic carbon, and base-extracted particulate organic carbon were made to better characterize the hydrography and biogeochemistry over Hydrographer Canyon. This study was aided by the use of telepresence to communicate between ship and shore-based researchers, and the expedition marks the first use of SMS messaging to communicate between the submersible and the ship. This study demonstrates the capabilities and utility of using Alvin for conducting water column science.

Background Individuals who sustain their first concussion during childhood may be at greater risk of sustaining multiple concussions throughout their lifetime because of a longer window of vulnerability. This article aims to estimate the association between age at first concussion and number of subsequent concussions. Patients and Methods A total of 23,582 collegiate athletes from 26 universities and military cadets from three military academies completed a concussion history questionnaire (65% males, age 19.9 ± 1.4 years). Participants self-reported concussions and age at time of each injury. Participants with a history of concussion (n = 3,647, 15.5%) were categorized as having sustained their first concussion during childhood (less than ten years old) or adolescence (≥10 and ≤18 years old). Poisson regression was used to model age group (childhood, adolescence) predicting the number of subsequent concussions (0, 1, 2+). A second Poisson regression was developed to determine whether age at first concussion predicted the number of subsequent concussions. Results Participants self-reporting their first concussion during childhood had an increased risk of subsequent concussions (rate ratio = 2.19, 95% confidence interval: 1.82, 2.64) compared with participants self-reporting their first concussion during adolescence. For every one-year increase in age at first concussion, we observed a 16% reduction in the risk of subsequent concussion (rate ratio = 0.84, 95% confidence interval: 0.82, 0.86). Conclusions Individuals self-reporting a concussion at a young age sustained a higher number of concussions before age 18. Concussion prevention, recognition, and reporting strategies are of particular need at the youth level.

Poor maternal nutrition during gestation can negatively affect offspring growth, development, and health. Leptin and ghrelin, key hormones in energy homeostasis and appetite control, may mediate these changes. We hypothesized that restricted- and over-feeding during gestation would alter plasma concentrations of leptin and ghrelin in ewes and offspring. Pregnant ewes (n = 37) were fed 1 of 3 diets starting on d 30 ± 0.02 of gestation until necropsy at d 135 of gestation or parturition: restricted- [RES; 60% National Research Council (NRC) requirements for total digestible nutrients, n = 13], control- (CON; 100% NRC, n = 11), or over-fed (OVER; 140% NRC, n = 13). Blood samples were collected from pregnant ewes at days 20, 30, 44, 72, 100, 128, and 142 of gestation. Offspring blood samples were collected within 24 h after birth (n = 21 CON, 25 RES, 23 OVER). Plasma leptin and ghrelin concentrations were determined by RIA. Ewe data were analyzed using the MIXED procedure in SAS with ewe as the repeated subject. Offspring data were analyzed using the MIXED procedure. Correlations between BW and leptin and ghrelin concentrations were identified using PROC CORR. At d 100, RES (5.39 ± 2.58 ng/mL) had decreased leptin concentrations compared with OVER (14.97 ± 2.48 ng/mL; P = 0.008) and at d 128, RES (6.39 ± 2.50 ng/mL) also had decreased leptin concentrations compared with OVER (13.61 ± 2.47 ng/mL; P = 0.04). At d 142, RES (0.26 ± 0.04 ng/mL) had increased ghrelin concentrations compared with CON (0.15 ± 0.04 ng/mL; P = 0.04). Leptin and ghrelin concentrations were also altered between days of gestation within a dietary treatment. In CON ewes, plasma concentrations of leptin were increased at d 30 (19.28 ± 7.43 ng/mL) compared with d 44 (5.20 ± 3.10 ng/mL; P = 0.03), and the plasma concentrations of ghrelin at d 128 (0.20 ± 0.03 ng/mL) were increased compared with d 30 (0.16 ± 0.03 ng/mL; P = 0.01) and d 100 (0.17 ± 0.03 ng/mL; P = 0.04). Maternal diet did not alter plasma ghrelin or leptin concentrations in the offspring (P > 0.50). There were no strong, significant correlations between ewe BW and leptin (r 0.06) or ghrelin (r > -0.47; P > 0.001) concentrations or lamb BW and leptin or ghrelin concentrations (r > -0.32, P > 0.06). Maternal alterations in circulating leptin and ghrelin may program changes in energy balance that could result in increased adiposity in adult offspring. Alterations in energy homeostasis may be a mechanism behind the long-lasting changes in growth, body composition, development, and metabolism in the offspring of poorly nourished ewes.

Trichloroethene (TCE), a widely used industrial solvent, is associated with the development of autoimmune diseases (ADs), including systemic lupus erythematosus and autoimmune hepatitis. Increasing evidence support a linkage between altered gut microbiome composition and the onset of ADs. However, it is not clear how gut microbiome contributes to TCE-mediated autoimmunity, and initial triggers for microbiome-host interactions leading to systemic autoimmune responses remain unknown. To achieve this, female MRL+/+ mice were treated with 0.5 mg/ml TCE for 52 weeks and fecal samples were subjected to 16S rRNA sequencing to determine the microbiome composition. TCE exposure resulted in distinct bacterial community revealed by β-diversity analysis. Notably, we observed reduction in Lactobacillaceae, Rikenellaceae and Bifidobacteriaceae families, and enrichment of Akkermansiaceae and Lachnospiraceae families after TCE exposure. We also observed significantly increased colonic oxidative stress and inflammatory markers (CD14 and IL-1β), and decreased tight junction proteins (ZO-2, occludin and claudin-3). These changes were associated with increases in serum antinuclear and anti-smooth muscle antibodies and cytokines (IL-6 and IL-12), together with increased PD1 + CD4+ T cells in TCE-exposed spleen and liver tissues. Importantly, fecal microbiota transplantation (FMT) using feces from TCE-treated mice to antibiotics-treated mice induced increased anti-dsDNA antibodies and hepatic CD4+ T cell infiltration in the recipient mice. Our studies thus delineate how imbalance in gut microbiome and mucosal redox status together with gut inflammatory response and permeability changes could be the key factors in contributing to TCE-mediated ADs. Furthermore, FMT studies provide a solid support to a causal role of microbiome in TCE-mediated autoimmunity.

Summary Background Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. Methods After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Doneguebougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 10 5 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov, number NCT01988636. Findings Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three [7%] people in the vaccine group vs four [9%] in the placebo group) followed by fatigue (one [2%] person in the placebo group), fever (one [2%] person in the placebo group), and myalgia (one [2%] person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). Interpretation PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. Funding US National Institutes of Health Intramural Research Program, Sanaria.

Background As payment shifts toward bundled reimbursement, decreasing unnecessary inpatient care may provide cost savings. This study examines the association between discharge status, hospital duration of stay, and cost for colorectal operation patients without complications and uses risk factors to predict the need for post–acute care. Methods We used the New York Statewide Planning and Research Cooperative System and the California Healthcare Cost and Utilization Project State Inpatient Databases to identify all patients who underwent operative resection for colorectal cancer in 2009–2010 and were discharged to home or post–acute care. Patients with complications were excluded. Duration of stay and inpatient costs were calculated. Risk factors associated with discharge to post–acute care were identified using multivariable logistic regression and were incorporated into a model to predict discharge status. Results A total of 5.4% of 23,942 patients were discharged to a post–acute care facility. Duration of sty was 2 days greater and $3,823 more costly for patients discharged to post–acute care. Significant risk factors included age, number of comorbidities, emergency admission, open operation, admission in the previous year, and a new ostomy. A scoring system using these factors accurately predicted discharge to post–acute care. Conclusion Admissions after colorectal operations were greater and more costly for patients discharged to post–acute care even without operative complications. Risk factors can predict the need for post–acute care early in the postoperative course, thereby potentially facilitating early discharge planning.

Bacillus thuringiensis is a bacteria known for its bioinsecticidal toxins and it has been proposed as an alternative in the treatment of several parasites that infect domestic animals (helminths, ticks, mites). In this work, we evaluated the clinical efficiency of the Bacillus thuringiensis GP532 strain in the treatment of six rabbits naturally infested with the P. cuniculi mite. GP532 extract (10mg/ml) was applied by aspersion in both pinna, with a second application after seven days, and the therapeutic effect was measured in both qualitative and quantitative manner. GP532 application resulted in a decreased infestation rate, which was observed as early as 3days post-treatment. At day 14, a decrease from 4.66±0.61 to 0.50±0.10 in the left pinna and from 1.66±0.21 to 0.66±0.16 (P

Standardized assessments have been developed to assess dogs’ behaviors around other dogs, but there currently is no validated way to predict how a dog in an animal shelter will behave around cats, unless the dog’s previous history is known. This study explored dogs’ responses to visual, auditory, and olfactory cat-related and control stimuli, and tested whether dogs known to interact safely with cats and other small animals responded differently to the stimuli than dogs known to have injured or killed such animals. We video recorded 69 dogs’ responses to the stimuli, and raters who were blind to the dogs’ behavioral histories coded the dogs’ reactions. Dogs differed in the amount of time they spent orienting to the cat and control visual stimuli and sounds. They spent significantly more time orienting to the cat sound than to the visual cat stimulus, to the visual cat stimulus than to the visual control stimulus, and to the control sound than to the visual control stimulus (for all, p

We propose that maternal nest building in the female laboratory rabbit is a useful model for compulsions in obsessive-compulsive disorder (OCD). This repetitive behavior comprises collecting straw, depositing it into the nest box, and then returning to collect more straw. We reasoned that if "straw carrying" behavior is homologous to compulsive behavior, then it should be associated with activation of prefrontal regions associated with OCD, namely, the orbitofrontal and anterior cingulate cortices (OFC and ACC, respectively). In the present study, we quantified c-FOS immunoreactivity in the ACC, OFC, premotor (PM), infralimbic (IL), prelimbic (PL), and piriform (PI) cortices of: (1) pregnant female rabbits that were given straw (PREG+STRAW); (2) pregnant rabbits that were not given straw (PREG); (3) estrous rabbits that were given straw (ESTROUS+STRAW); (4) estrous rabbits that were not given straw (ESTROUS). After 1h, all females were sacrificed and processed for brain c-FOS immunoreactivity. We found that pregnant rabbits showed lower latencies to interact with the straw than estrous rabbits, and that pregnant rabbits displayed straw carrying, while estrous rabbits did not. c-FOS expression was increased in the OFC, ACC, and PI in the PREG+STRAW compared to all other groups. By contrast, c-FOS expression in all other regions was greater in PREG+STRAW compared to PREG, but not different from ESTROUS+STRAW. These results point to an important role for the OFC, ACC, and PI in initiating repetitive straw-carrying behavior, and further support the proposal that this behavior can serve as a model for compulsions in OCD.