Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.

The majority of patients with acute myeloid leukemia (AML) succumb to the disease or its complications, especially among older patients. Natural killer (NK) cells have been shown to have antileukemic activity in patients with AML; however, to our knowledge, primary NK cells armed with a chimeric antigen receptor (CAR) targeting antigens associated with AML as an "off-the-shelf" product for disease control have not been explored. We developed frozen, off-the-shelf allogeneic human NK cells engineered with a CAR recognizing FLT3 and secreting soluble interleukin-15 (IL-15) (FLT3 CAR_sIL-15 NK) to improve in vivo NK cell persistence and T-cell activation. FLT3 CAR_sIL-15 NK cells had higher cytotoxicity and interferon gamma secretion against FLT3+ AML cell lines when compared with activated NK cells lacking an FLT3 CAR or soluble IL-15. Frozen and thawed allogeneic FLT3 CAR_sIL-15 NK cells prolonged survival of both the MOLM-13 AML model as well as an orthotopic patient-derived xenograft AML model when compared with control NK cells. FLT3 CAR_sIL-15 NK cells showed no cytotoxicity against healthy blood mononuclear cells or hematopoietic stem cells. Collectively, our data suggest that FLT3 is an AML-associated antigen that can be targeted by frozen, allogeneic, off-the-shelf FLT3 CAR_sIL-15 NK cells that may provide a novel approach for the treatment of AML.

Clinical efficacy of Azithromycin for COVID-19 management: A systematic meta-analysis of meta-analyses.

BACKGROUND: Azithromycin has been adopted as a component of the COVID-19 management protocol throughout the global healthcare settings but with a questionable if not downright unsubstantiated evidence base. OBJECTIVES: In order to amalgamate and critically appraise the conflicting evidence around the clinical efficacy of Azithromycin (AZO) vis a vis COVID-19 management outcomes, a meta-analysis of meta-analyses was carried out to establish an evidence-based holistic status of AZO vis a vis its efficacy as a component-in-use of the COVID-19 management protocol. METHODS: A comprehensive systematic search was carried out through PubMed/Medline, Cochrane and Epistemonikos with a subsequent appraisal of abstracts and full-texts, as required. The Quality of Reporting of Meta-analyses (QUOROM) checklist and the Assessment of Multiple Systematic Reviews (AMSTAR) methodology were adopted to assess the methodological quality of the included meta-analyses. Random-effects models were developed to calculate summarized pool Odds Ratios (with 95% confidence interval) for the afore determined primary and secondary outcomes. RESULTS: AZO, when compared with best available therapy (BAT) including or excluding Hydroxychloroquine, exhibited statistically insignificant reduction in mortality [(n= 27,204 patients) OR= 0.77 (95% CI: 0.51-1.16) (I2= 97%)], requirement of mechanical ventilation [(n= 14,908 patients) OR= 1.4 (95% CI: 0.58-3.35) (I2= 98%)], induction of arrhythmia [(n= 9,723 patients) OR= 1.21 (95% CI: 0.63-2.32) (I2= 92%)] and QTc prolongation (a surrogate for torsadogenic effect) [(n= 6,534 patients) OR= 0.62 (95% CI: 0.23-1.73) (I2= 96%)]. CONCLUSION: The meta-analysis of meta-analyses portrays AZO as a pharmacological agent that does not appear to have a comparatively superior clinical efficacy than BAT when it comes to COVID-19 management. Secondary to a very real threat of anti-bacterial resistance, it is suggested that AZO be discontinued and removed from COVID-19 management protocols.

Exploring medical students' perceptions of the challenges and benefits of volunteering in the intensive care unit during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: In March 2020, the WHO declared SARS-CoV-2 a pandemic. Hospitals across the world faced staff, bed and supply shortages, with some European hospitals calling on medical students to fill the staffing gaps. This study aimed to document the impact of volunteering during the COVID-19 pandemic on students' professional development, resilience and future perceived career choices. DESIGN: This is a retrospective, qualitative study of student reflections, using purposive sampling.The Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences recruited 26 medical student volunteers to assist in pronation and supination of ventilated patients affected by SARS-CoV-2. These students were invited to complete an anonymous survey based on their experiences as volunteers. Thematic analysis was performed on these written reflections. RESULTS: The results showed that volunteering during the COVID-19 pandemic developed key skills from RCSI's medical curriculum, significantly fostered medical students' resilience and guided their career choices. Major areas of development included communication, teamwork, compassion and altruism, which are not easily developed through the formal curriculum. A further area that was highlighted was the importance of evidence-based health in a pandemic. Finally, our respondents were early stage medical students with limited clinical exposure. Some found the experience difficult to cope with and therefore supports should be established for students volunteering in such a crisis. CONCLUSION: These results suggest that clinical exposure is an important driver in developing students' resilience and that volunteering during a pandemic has multiple benefits to students' professional development and professional identity formation.

Prefrontal GABA Levels Correlate with Memory in Older Adults at High Risk for Alzheimer's Disease.

γ-Aminobutyric acid (GABA), a primary inhibitory neurotransmitter in the brain, plays a significant role in aging and in neurodegenerative disorders, including Alzheimer's disease (AD). We investigated the relationship between GABA levels in the dorsomedial/dorsoanterolateral prefrontal cortex (DM/DA-PFC) and memory in high-AD risk participants. Thirty-eight participants (14 Cognitively Normal [CN], 11 with Subjective Cognitive Decline (SCD), and 13 Mild Cognitive Impairment [MCI]) underwent magnetic resonance spectroscopy at 3 Tesla. SCD and MCI participants were grouped together to form a single high-AD risk group (N = 24) for the purposes of statistical analyses. Partial correlations of GABA+/Cr level with verbal memory, assessed on California Verbal Learning Test-II, and nonverbal memory, assessed on Brief Visuospatial Memory Test and Rey-Osterrieth test, were examined separately within the high-AD risk and CN groups. GABA+/Cr levels were positively correlated with long-delayed verbal memory (r = 0.69, P = 0.009) and immediate nonverbal memory (r = 0.97, P = 0.03) in high-AD risk, but not in CN participants. These results remained significant after controlling for depression. These preliminary findings, which require replication due to the limited sample sizes, are the first report of an association between GABA+/Cr levels within the DM/DA-PFC and memory performance in high-AD risk individuals.

Toxicity of the spiny thick-foot Pachypodium.

PREMISE OF THE STUDY: Pachypodium (Apocynaceae) is a genus of iconic stem-succulent and poisonous plants endemic to Madagascar and southern Africa. We tested hypotheses about the mode of action and macroevolution of toxicity in this group. We further hypothesized that while monarch butterflies are highly resistant to cardenolide toxins (a type of cardiac glycoside) from American Asclepias, they may be negatively affected by Pachypodium defenses, which evolved independently. METHODS: We grew 16 of 21 known Pachypodium spp. and quantified putative cardenolides by HPLC and also by inhibition of animal Na+ /K+ -ATPase (the physiological target of cardiac glycosides) using an in vitro assay. Pachypodium extracts were tested against monarch caterpillars in a feeding bioassay. We also tested four Asclepias spp. and five Pachypodium spp. extracts, contrasting inhibition of the cardenolide-sensitive porcine Na+ /K+ -ATPase to the monarch's resistant form. KEY RESULTS: We found evidence for low cardenolides by HPLC, but substantial toxicity when extracts were assayed on Na+ /K+ -ATPases. Toxicity showed phylogenetic signal, and taller species showed greater toxicity (this was marginal after phylogenetic correction). Application of Pachypodium extracts to milkweed leaves reduced monarch growth, and this was predicted by inhibition of the sensitive Na+ /K+ -ATPase in phylogenetic analyses. Asclepias extracts were 100-fold less potent against the monarch compared to the porcine Na+ /K+ -ATPase, but this difference was absent for Pachypodium extracts. CONCLUSIONS: Pachypodium contains potent toxicity capable of inhibiting sensitive and cardenolide-adapted Na+ /K+ -ATPases. Given the monarch's sensitivity to Pachypodium, we suggest that these plants contain novel cardiac glycosides or other compounds that facilitate toxicity by binding to Na+ /K+ -ATPases.

Community-level risk factors for notifiable gastrointestinal illness in the Northwest Territories, Canada, 1991-2008.

BACKGROUND: Enteric pathogens are an important cause of illness, however, little is known about their community-level risk factors (e.g., socioeconomic, cultural and physical environmental conditions) in the Northwest Territories (NWT) of Canada. The objective of this study was to undertake ecological (group-level) analyses by combining two existing data sources to examine potential community-level risk factors for campylobacteriosis, giardiasis and salmonellosis, which are three notifiable (mandatory reporting to public health authorities at the time of diagnosis) enteric infections. METHODS: The rate of campylobacteriosis was modeled using a Poisson distribution while rates of giardiasis and salmonellosis were modeled using a Negative Binomial distribution. Rate ratios (the ratio of the incidence of disease in the exposed group to the incidence of disease in the non-exposed group) were estimated for infections by the three major pathogens with potential community-level risk factors. RESULTS: Significant (p≤0.05) associations varied by etiology. There was increased risk of infection with Salmonella for communities with higher proportions of 'households in core need' (unsuitable, inadequate, and/or unaffordable housing) up to 42% after which the rate started to decrease with increasing core need. The risk of giardiasis was significantly higher both with increased 'internal mobility' (population moving between communities), and also where the community's primary health facility was a health center rather than a full-service hospital. Communities with higher health expenditures had a significantly decreased risk of giardiasis. Results of modeling that focused on each of Giardia and Salmonella infections separately supported and expanded upon previous research outcomes that suggested health disparities are often associated with socioeconomic status, geographical and social mobility, as well as access to health care (e.g. facilities, services and professionals). In the campylobacteriosis model, a negative association was found between food prices in communities and risk of infection. There was also a significant interaction between trapping and consumption of traditional foods in communities. Higher rates of community participation in both activities appeared to have a protective effect against campylobacteriosis. CONCLUSIONS: These results raise very interesting questions about the role that traditional activities might play in infectious enteric disease incidence in the NWT, but should be interpreted with caution, recognizing database limitations in collection of case data and risk factor information (e.g. missing data). Given the cultural, socioeconomic, and nutritional benefits associated with traditional food practices, targeted community-based collaborative research is necessary to more fully investigate the statistical correlations identified in this exploratory research. This study demonstrates the value of examining the role of social determinants in the transmission and risk of infectious diseases.

A descriptive analysis of notifiable gastrointestinal illness in the Northwest Territories, Canada, 1991-2008.

OBJECTIVES: To describe the major characteristics of reported notifiable gastrointestinal illness (NGI) data in the Northwest Territories (NWT) from January 1991 through December 2008. DESIGN: Descriptive analysis of 708 reported cases of NGI extracted from the Northwest Territories Communicable Disease Registry (NWT CDR). SETTING: Primary, secondary and tertiary health care centres across all 33 communities of the NWT. POPULATION: NWT residents of all ages with confirmed NGI reported to the NWT CDR from January 1991 through December 2008. MAIN OUTCOME MEASURE: Laboratory-confirmed NGI, with a particular emphasis on campylobacteriosis, giardiasis and salmonellosis. RESULTS: Campylobacteriosis, giardiasis and salmonellosis were the most commonly identified types of NGI in the territory. Seasonal peaks for all three diseases were observed in late summer to autumn (p<0.01). Higher rates of NGI (all 15 diseases/infections) were found in the 0-9-year age group and in men (p<0.01). Similarly, rates of giardiasis were higher in the 0-9-year age group and in men (p<0.02). A disproportionate burden of salmonellosis was found in people aged 60 years and older and in women (p<0.02). Although not significant, the incidence of campylobacteriosis was greater in the 20-29-years age group and in men (p<0.07). The health authority with the highest incidence of NGI was Yellowknife (p<0.01), while for salmonellosis and campylobacteriosis, it was Tlicho (p<0.01) and for giardiasis, the Sahtu region (p<0.01). Overall, disease rates were higher in urban areas (p<0.01). Contaminated eggs, poultry and untreated water were believed by health practitioners to be important sources of infection in cases of salmonellosis, campylobacteriosis and giardiasis, respectively. CONCLUSIONS: The general patterns of these findings suggest that environmental and behavioural risk factors played key roles in infection. Further research into potential individual and community-level risk factors is warranted.

A spatial and temporal analysis of notifiable gastrointestinal illness in the Northwest Territories, Canada, 1991-2008.

BACKGROUND: This is the first study to describe the geographical and temporal distribution of notifiable gastrointestinal illness (NGI) in the Northwest Territories (NWT), Canada. Understanding the distribution of NGI in space and time is important for identifying communities at high risk. Using data derived from the Northwest Territories Communicable Disease Registry (NWT CDR), a number of spatial and temporal techniques were used to explore and analyze NGI incidence from the years 1991 to 2008. Relative risk mapping was used to investigate the variation of disease risk. Scan test statistics were applied to conduct cluster identification in space, time and space-time. Seasonal decomposition of the time series was used to assess seasonal variation and trends in the data. RESULTS: There was geographic variability in the rates of NGI with higher notifications in the south compared to the north. Incidence of NGI exhibited seasonality with peaks in the fall months for most years. Two possible outbreaks were detected in the fall of 1995 and 2001, of which one coincided with a previously recognized outbreak. Overall, incidence of NGI fluctuated from 1991 to 2001 followed by a tendency for rates to decrease from 2002 to 2008. CONCLUSIONS: The distribution of NGI notifications varied widely according to geographic region, season and year. While the analyses highlighted a possible bias in the surveillance data, this information is beneficial for generating hypotheses about risk factors for infection.

A unilateral presentation of 'Satoyoshi syndrome'.

Satoyoshi syndrome is a rare, slowly progressive disorder of unknown etiology with a poor long-term prognosis. The syndrome consists of the following clinical features: (1) painful, intermittent muscle spasms; (2) alopecia; (3) diarrhea; and (4) skeletal abnormalities in cases of juvenile onset. The age of onset is typically less than 20 years of age, although three adult onset cases had been reported. There had been no case report of Satoyoshi syndrome with strict unilateral presentation. We present a 25-year-old man with progressive unilateral hair loss and muscle spasms. Although previous literature had postulated malabsorption and autoimmune mechanism as pathogenic for Satoyoshi syndrome, the presence of a strictly unilateral presentation argues against those hypotheses. However, these hypotheses should still be considered, as our patient did not fit a typical Satoyoshi syndrome. Therefore, more research is needed to understand the pathophysiology and develop an effective treatment to prevent the progression of the disease.