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Parasites sometimes expand their host range and cause new disease aetiologies. Genetic changes can then occur due to host-specific adaptive alterations, particularly when parasites cross between evolutionarily distant hosts. Characterizing genetic variation in Cryptosporidium from humans and other animals may have important implications for understanding disease dynamics and transmission. We analyse sequences from four loci (gp60, HSP-70, COWP and actin) representing multiple Cryptosporidium species reported in humans. We predicted low genetic diversity in species that present unusual human infections due to founder events and bottlenecks. High genetic diversity was observed in isolates from humans of Cryptosporidium meleagridis, Cryptosporidium cuniculus, Cryptosporidium hominis and Cryptosporidium parvum. A deviation of expected values of neutrality using Tajima's D was observed in C. cuniculus and C. meleagridis. The high genetic diversity in C. meleagridis and C. cuniculus did not match our expectations but deviations from neutrality indicate a recent decrease in genetic variability through a population bottleneck after an expansion event. Cryptosporidium hominis was also found with a significant Tajima's D positive value likely caused by recent population expansion of unusual genotypes in humans. These insights indicate that changes in genetic diversity can help us to understand host-parasite adaptation and evolution.
As faculty members, we rely on academic freedom to protect us as we teach, engage in scholarly research, and live as citizens of a community. The American Association of University Professors is the accepted authority in matters of academic freedom, and its guidelines explain protections in teaching, research, and extramural utterances. This article argues that the characteristics of social media and the concerns of academic institutions about their reputation have created an atmosphere that make extramural utterances more vulnerable and riskier than in the past. Some institutions even monitor the social media postings of faculty members and act on such postings, openly criticizing and even disavowing or punishing them for their utterances. I consider these issues and make a modest proposal that may improve the environment for extramural utterances by faculty members.
Cognitive impairment associated with lifetime major depressive disorder (MDD) is well-supported by meta-analytic studies, but population-based estimates remain scarce. Previous UK Biobank studies have only shown limited evidence of cognitive differences related to probable MDD. Using updated cognitive and clinical assessments in UK Biobank, this study investigated population-level differences in cognitive functioning associated with lifetime MDD.
Associations between lifetime MDD and cognition (performance on six tasks and general cognitive functioning [g-factor]) were investigated in UK Biobank (N-range 7,457–14,836, age 45–81 years, 52% female), adjusting for demographics, education, and lifestyle. Lifetime MDD classifications were based on the Composite International Diagnostic Interview. Within the lifetime MDD group, we additionally investigated relationships between cognition and (a) recurrence, (b) current symptoms, (c) severity of psychosocial impairment (while symptomatic), and (d) concurrent psychotropic medication use.
Lifetime MDD was robustly associated with a lower g-factor (β = −0.10, PFDR = 4.7 × 10−5), with impairments in attention, processing speed, and executive functioning (β ≥ 0.06). Clinical characteristics revealed differential profiles of cognitive impairment among case individuals; those who reported severe psychosocial impairment and use of psychotropic medication performed worse on cognitive tests. Severe psychosocial impairment and reasoning showed the strongest association (β = −0.18, PFDR = 7.5 × 10−5).
Findings describe small but robust associations between lifetime MDD and lower cognitive performance within a population-based sample. Overall effects were of modest effect size, suggesting limited clinical relevance. However, deficits within specific cognitive domains were more pronounced in relation to clinical characteristics, particularly severe psychosocial impairment.
The RemoveDEBRIS mission has been the first mission to successfully demonstrate, in-orbit, a series of technologies that can be used for the active removal of space debris. The mission started late in 2014 and was sponsored by a grant from the EC that saw a consortium led by the Surrey Space Centre to develop the mission, from concept to in-orbit demonstrations, that terminated in March 2019. Technologies for the capture of large space debris, like a net and a harpoon, have been successfully tested together with hardware and software to retrieve data on non-cooperative target debris kinematics from observations carried out with on board cameras. The final demonstration consisted of the deployment of a drag-sail to increase the drag of the satellite to accelerate its demise.
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
We present 0.″2–0.″4 resolution ALMA images of the submillimeter dust continuum and the CO, H2O, and H2O+ line emission in a z = 3.63 strongly lensed dusty starburst. We construct the lens model for the system with an MCMC technique. While the average magnification for the dust continuum is about 11, the magnification of the line emission varies from 5 to 22 across the source, resolving the source down to sub-kpc scales. The ISM content reveals that it is a pre-coalescence major merger of two ultra-luminous infrared galaxies, both with a large amount of molecular gas reservoir. The approaching galaxy in the south shows no apparent kinematic structure with a half-light radius of 0.4 kpc, while the preceding one resembles a 1.2 kpc rotating disk, separated by a projected distance of 1.3 kpc. The distribution of dust and gas emission suggests a large amount of cold ISM concentrated in the interacting region.
Introduction: Emergency Department (ED) health care professionals are responsible for providing team-based care to critically ill patients. Given this complex responsibility, simulation training is paramount. In situ simulation (ISS) has many cited benefits as a training strategy that targets on-duty staff and occurs in the actual patient environment. Several evidence-based frameworks identify staff buy-in as essential for successful ISS implementation, however, the attitudes of interdisciplinary front-line ED staff in this regard are unknown. The purpose of this study is to identify contextual trends in interdisciplinary opinions on routine ISS in the ED. Methods: Qualitative and quantitative review, exploring the self-reported attitudes of interdisciplinary ED staff: before, during and after the implementation of a routine ISS pilot program (5 sessions in 5 months) at the Charles V Keating Emergency and Trauma Center in Halifax from Feb-Nov, 2018. Results: 149 surveys were received. Baseline support for ISS was high; 83% of respondents believed that the advantages of ISS outweigh the challenges and 47% favoured simulation in the ED, relative the sim bay (26%) and 28% were indifferent. The attitudes of direct participants in ISS were very positive, with 88% believing that the benefits outweighed the challenges after participation and 91% believing that they personally benefited from participating. A department wide post-ISS pilot survey suggested a slight decrease in support. Support for ISS dropped from 83% to 67%, a statistically insignificant reduction (p = 0.098) but a sizeable change that warrants further investigation. Most notably respondents reported increased support for simulation training in a simulation bay relative to ISS in the ED. Respondents still regarded simulation highly overall. Interestingly, when the results were stratified by position, staff physicians were the least positive. Conclusion: Pre-pilot or baseline opinions of ISS were very positive, and participants all responded positively to the simulations. This study generates valuable insight into the perceptions of interdisciplinary ED staff regarding the implementation and perceived impact of routine ISS. This evidence can be used to inform future programming, though further investigation is warranted into why opinions post-intervention may have changed at the department level.
In June 2012, the Botswana Ministry of Health and Wellness (MOHW; Gaborone, Botswana) initiated a national Emergency Medical Services (EMS) system in response to significant morbidity and mortality associated with prehospital emergencies. The MOHW requested external expertise to train its developing workforce. Simulation-based training was planned to equip these health care providers with clinical knowledge, procedural skills, and communication techniques.
The objective of this study was to assess the educational needs of the pioneer Botswana MOHW EMS providers based on retrospective EMS logbook review and EMS provider feedback to guide development of a novel educational curriculum.
Data were abstracted from a representative sample of the Gaborone, Botswana MOHW EMS response log from 2013-2014 and were quantified into the five most common call types for both adults and children. Informal focus groups with health professionals and EMS staff, as well as surveys, were used to rank common response call types and self-perceived educational needs.
Based on 1,506 calls, the most common adult response calls were for obstetric emergencies, altered mental status, gastrointestinal/abdominal pain, trauma, gynecological emergencies, and cardiovascular and respiratory distress-related emergencies. The most common pediatric response calls were for respiratory distress, gastrointestinal complaints/dehydration, trauma and musculoskeletal injuries, newborn delivery, seizures, and toxic ingestion/exposure. The EMS providers identified these same chief complaints as priorities for training using the qualitative approach. A locally relevant, simulation-based curriculum for the Botswana MOHW EMS system was developed and implemented based on these data.
: Trauma, respiratory distress, gastrointestinal complaints, and puerperal/perinatal emergencies were common conditions for all age groups. Other age-specific conditions were also identified as educational needs based on epidemiologic data and provider feedback. This needs assessment may be useful when designing locally relevant EMS curricula in other low-income and middle-income countries.GlombNW, KosokoAA, DoughtyCB, RusMC, ShahMI, CoxM, GalapiC, ParkesPS, KumarS, LabaB.Needs Assessment for Simulation Training for Prehospital Providers in Botswana. Prehosp Disaster Med. 2018;33(6):621–626.
High-SiO2 rocks referred to as oceanic plagiogranites are common within the crustal sequences of ophiolites; however, their mode of petrogenesis is controversial with both late-stage fractional crystallization and partial melting models being proposed. Here, we present new whole-rock data from plagiogranitic dyke-like bodies and lenses from the lower and middle sections of the sheeted dyke complex of the Cretaceous Muslim Bagh Ophiolite, northwestern Pakistan. The plagiogranites have similar geochemical signatures that are inconsistent with them being the fractionation products of the mafic units of the Muslim Bagh Ophiolite. However, the plagiogranites all display very low TiO2 contents (<0.4 wt%), implying that they formed by partial melting of mafic rocks. Melt modelling of a crustal gabbro from the Muslim Bagh Ophiolite shows that the trace-element signature of the plagiogranites can be replicated by 5–10% melting of a crustal hornblende gabbro with amphibole as a residual phase, resulting in a concave-up middle rare Earth element pattern. Compositional similarities between the Muslim Bagh Ophiolite plagiogranites and Archaean TTG (trondhjemite–tonalite–granodiorite) has implications for the generation of juvenile Archaean continental crust. As the Muslim Bagh Ophiolite was derived in a supra-subduction zone, it is suggested that some Archaean TTG may have been derived from melting of mafic upper crust in early subduction-like settings. However, due to the small volume of Muslim Bagh Ophiolite plagiogranites, it is inferred that they can be instructive on the petrogenesis of some, but not all, Archaean TTG.
Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns.
To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE 4) allele.
Participants were 22 SMC carrying the APOE ɛ4 allele (ɛ4+; mean age 72.18 years) and 58 SMC non-carriers (ɛ4–; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored.
ɛ4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC–SMA connectivity.
The results provide the first evidence that ɛ4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity.
We introduce a path theoretic framework for understanding the representation theory of (quantum) symmetric and general linear groups and their higher-level generalizations over fields of arbitrary characteristic. Our first main result is a ‘super-strong linkage principle’ which provides degree-wise upper bounds for graded decomposition numbers (this is new even in the case of symmetric groups). Next, we generalize the notion of homomorphisms between Weyl/Specht modules which are ‘generically’ placed (within the associated alcove geometries) to cyclotomic Hecke and diagrammatic Cherednik algebras. Finally, we provide evidence for a higher-level analogue of the classical Lusztig conjecture over fields of sufficiently large characteristic.
OBJECTIVES/SPECIFIC AIMS: The purpose of this study is to use the baboon as a novel animal model for breath research and to identify and characterize baboon breath metabolites that reflect cardiometabolic function to inform us in the development of a noninvasive, cost-effective, and repeatable point-of-care diagnostic breath test. METHODS/STUDY POPULATION: Blood and urine was collected from control and IUGR at the approximate age of 3.5 years. Both groups were then placed on a high fat, high sugar, high salt diet for 7 weeks, after which blood, urine, and breath were collected. The breath samples were then subjected to comprehensive, 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Using ChromaTOF software, breath VOCs were identified with at least an 80% spectral match against the National Institute of Standards and Technology (NIST) chemical reference library. The raw data were then statistically analyzed using MetaboAnalyst. We then interrogated multiple online databases to characterize and identify the role of VOCs that were present in both control and IUGR groups. RESULTS/ANTICIPATED RESULTS: Preliminary analyses of the breath VOCs indicate differences in expression between sexes and in control Versus IUGR groups. These results indicate unique “breath signatures.” Further analysis of the breath VOCs reveals the presence of metabolites that are involved in β-oxidation and oxidative stress pathways. DISCUSSION/SIGNIFICANCE OF IMPACT: This breath study, a first of its kind, will develop the baboon as a superior animal model for breath biomarker research. Our observed unique “breath signatures” indicate changes in lipid metabolism and oxidative stress pathways, which we hypothesize are the early metabolic changes at the cellular level that are not yet reflected in clinical lab measures. Future directions include analyzing breath VOCs that did not meet 80% spectral match, validation using SPME technology and commercial standards, and initiating a human pilot study in clinically obese, at-risk children in collaboration with physicians at the Children’s Hospital of San Antonio to develop a noninvasive, cost-effective, rapid, and repeatable point-of-care diagnostic breath test.
Plasmodium knowlesi has risen in importance as a zoonotic parasite that has been causing regular episodes of malaria throughout South East Asia. The P. knowlesi genome sequence generated in 2008 highlighted and confirmed many similarities and differences in Plasmodium species, including a global view of several multigene families, such as the large SICAvar multigene family encoding the variant antigens known as the schizont-infected cell agglutination proteins. However, repetitive DNA sequences are the bane of any genome project, and this and other Plasmodium genome projects have not been immune to the gaps, rearrangements and other pitfalls created by these genomic features. Today, long-read PacBio and chromatin conformation technologies are overcoming such obstacles. Here, based on the use of these technologies, we present a highly refined de novo P. knowlesi genome sequence of the Pk1(A+) clone. This sequence and annotation, referred to as the ‘MaHPIC Pk genome sequence’, includes manual annotation of the SICAvar gene family with 136 full-length members categorized as type I or II. This sequence provides a framework that will permit a better understanding of the SICAvar repertoire, selective pressures acting on this gene family and mechanisms of antigenic variation in this species and other pathogens.
Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi – macaque model systems and summarizing exciting new progress in this area of research.
Introduction: Point of care ultrasound (PoCUS) has become an established tool in the initial management of patients with undifferentiated hypotension in the emergency department (ED). Current established protocols (e.g. RUSH and ACES) were developed by expert user opinion, rather than objective, prospective data. Recently the SHoC Protocol was published, recommending 3 core scans; cardiac, lung, and IVC; plus other scans when indicated clinically. We report the abnormal ultrasound findings from our international multicenter randomized controlled trial, to assess if the recommended 3 core SHoC protocol scans were chosen appropriately for this population. Methods: Recruitment occurred at seven centres in North America (4) and South Africa (3). Screening at triage identified patients (SBP<100 or shock index>1) who were randomized to PoCUS or control (standard care with no PoCUS) groups. All scans were performed by PoCUS-trained physicians within one hour of arrival in the ED. Demographics, clinical details and study findings were collected prospectively. A threshold incidence for positive findings of 10% was established as significant for the purposes of assessing the appropriateness of the core recommendations. Results: 138 patients had a PoCUS screen completed. All patients had cardiac, lung, IVC, aorta, abdominal, and pelvic scans. Reported abnormal findings included hyperdynamic LV function (59; 43%); small collapsing IVC (46; 33%); pericardial effusion (24; 17%); pleural fluid (19; 14%); hypodynamic LV function (15; 11%); large poorly collapsing IVC (13; 9%); peritoneal fluid (13; 9%); and aortic aneurysm (5; 4%). Conclusion: The 3 core SHoC Protocol recommendations included appropriate scans to detect all pathologies recorded at a rate of greater than 10 percent. The 3 most frequent findings were cardiac and IVC abnormalities, followed by lung. It is noted that peritoneal fluid was seen at a rate of 9%. Aortic aneurysms were rare. This data from the first RCT to compare PoCUS to standard care for undifferentiated hypotensive ED patients, supports the use of the prioritized SHoC protocol, though a larger study is required to confirm these findings.
Introduction: Point of care ultrasound (PoCUS) is an established tool in the initial management of patients with undifferentiated hypotension in the emergency department (ED). While PoCUS protocols have been shown to improve early diagnostic accuracy, there is little published evidence for any mortality benefit. We report the findings from our international multicenter randomized controlled trial, assessing the impact of a PoCUS protocol on survival and key clinical outcomes. Methods: Recruitment occurred at 7 centres in North America (4) and South Africa (3). Scans were performed by PoCUS-trained physicians. Screening at triage identified patients (SBP<100 or shock index>1), randomized to PoCUS or control (standard care and no PoCUS) groups. Demographics, clinical details and study findings were collected prospectively. Initial and secondary diagnoses were recorded at 0 and 60 minutes, with ultrasound performed in the PoCUS group prior to secondary assessment. The primary outcome measure was 30-day/discharge mortality. Secondary outcome measures included diagnostic accuracy, changes in vital signs, acid-base status, and length of stay. Categorical data was analyzed using Fishers test, and continuous data by Student T test and multi-level log-regression testing. (GraphPad/SPSS) Final chart review was blinded to initial impressions and PoCUS findings. Results: 258 patients were enrolled with follow-up fully completed. Baseline comparisons confirmed effective randomization. There was no difference between groups for the primary outcome of mortality; PoCUS 32/129 (24.8%; 95% CI 14.3-35.3%) vs. Control 32/129 (24.8%; 95% CI 14.3-35.3%); RR 1.00 (95% CI 0.869 to 1.15; p=1.00). There were no differences in the secondary outcomes; ICU and total length of stay. Our sample size has a power of 0.80 (α:0.05) for a moderate effect size. Other secondary outcomes are reported separately. Conclusion: This is the first RCT to compare PoCUS to standard care for undifferentiated hypotensive ED patients. We did not find any mortality or length of stay benefits with the use of a PoCUS protocol, though a larger study is required to confirm these findings. While PoCUS may have diagnostic benefits, these may not translate into a survival benefit effect.
Introduction: In Ottawa, STEMI patients are transported directly to percutaneous coronary intervention (PCI) by advanced care paramedics (ACPs), primary care paramedics (PCPs), or transferred from PCP to ACP crew (ACP-intercept). PCPs have a limited skill set to address complications during transport.The objective of this study was to determine what clinically important events (CIEs) occurred in STEMI patients transported for primary PCI via a PCP crew, and what proportion of such events could only be treated by ACP protocols. Methods: We conducted a health record review of STEMI patients transported for primary PCI from Jan 1, 2011-Dec 21, 2015. Ottawa has a single PCI center and its EMS system employs both PCP and ACP paramedics. We identified consecutive STEMI bypass patients transported by PCP-only and ACP-intercept using the dispatch database. A data extraction form was piloted and used to extract patient demographics, transport times, and primary outcomes: CIEs and interventions performed during transport, and secondary outcomes: hospital diagnosis, and mortality. CIEs were reviewed by two investigators to determine if they would be treated differently by ACP protocols. We present descriptive statistics. Results: We identified 967 STEMI bypass cases among which 214 (118 PCP-only and 96 ACP-intercept) met all inclusion criteria. Characteristics were: mean age 61.4 years, 78% male, 31.8% anterior and 44.4% inferior infarcts, mean response time 6 min, total paramedic contact time 29 min, and in cases of ACP-intercept 7 min of PCP-only contact time.A CIE occurred in 127 (59%) of cases: SBP<90 mmHg 26.2%, HR<60 30.4%, HR>100 20.6%, malignant arrhythmias 7.5%, altered mental status 6.5%, airway intervention 2.3%, 2 patients (0.9%) arrested, both survived. Of the CIE identified, 54 (42.5%) could be addressed differently by ACP vs PCP protocols (25.2% of total cases). The majority related to fluid boluses for hypotension (44 cases; 35% of CIE). ACP intervention for CIEs within the ACP intercept group was 51.6%. There were 6 in-hospital deaths (2.8%) with no difference in transport crew type. Conclusion: CIEs are common in STEMI bypass patients however a smaller proportion of such CIE would be addressed differently by ACP protocols compared to PCP protocols. The vast majority of CIE appeared to be transient and of limited clinical significance.
Introduction: Point of Care Ultrasound (PoCUS) protocols are commonly used to guide resuscitation for emergency department (ED) patients with undifferentiated non-traumatic hypotension. While PoCUS has been shown to improve early diagnosis, there is a minimal evidence for any outcome benefit. We completed an international multicenter randomized controlled trial (RCT) to assess the impact of a PoCUS protocol on key resuscitation markers in this group. We report diagnostic impact and mortality elsewhere. Methods: The SHoC-ED1 study compared the addition of PoCUS to standard care within the first hour in the treatment of adult patients presenting with undifferentiated hypotension (SBP<100 mmHg or a Shock Index >1.0) with a control group that did not receive PoCUS. Scans were performed by PoCUS-trained physicians. 4 North American, and 3 South African sites participated in the study. Resuscitation outcomes analyzed included volume of fluid administered in the ED, changes in shock index (SI), modified early warning score (MEWS), venous acid-base balance, and lactate, at one and four hours. Comparisons utilized a T-test as well as stratified binomial log-regression to assess for any significant improvement in resuscitation amount the outcomes. Our sample size was powered at 0.80 (α:0.05) for a moderate effect size. Results: 258 patients were enrolled with follow-up fully completed. Baseline comparisons confirmed effective randomization. There was no significant difference in mean total volume of fluid received between the control (1658 ml; 95%CI 1365-1950) and PoCUS groups (1609 ml; 1385-1832; p=0.79). Significant improvements were seen in SI, MEWS, lactate and bicarbonate with resuscitation in both the PoCUS and control groups, however there was no difference between groups. Conclusion: SHOC-ED1 is the first RCT to compare PoCUS to standard of care in hypotensive ED patients. No significant difference in fluid used, or markers of resuscitation was found when comparing the use of a PoCUS protocol to that of standard of care in the resuscitation of patients with undifferentiated hypotension.