Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.

Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.

Impact of COVID-19 on emergency department attendance in an Australia hospital: a parallel convergent mixed methods study.

OBJECTIVES: The COVID-19 pandemic has changed the way people are accessing healthcare. The aim of this study was to examine the impact of COVID-19 on emergency department (ED) attendance for frequent attenders and to explore potential reasons for changes in attendance. DESIGN: This convergent parallel mixed methods study comprised two parts. SETTING: An interrupted time-series analysis evaluated changes in ED presentation rates; interviews investigated reasons for changes for frequent ED users in a culturally and linguistically diverse setting. PARTICIPANTS: A total of 4868 patients were included in the time series. A subgroup of 200 patients were interviewed, mean age 66 years (range 23-99). RESULTS: Interrupted time-series analysis from 4868 eligible participants showed an instantaneous decrease in weekly ED presentations by 36% (p<0.001), with reduction between 45% and 67% across emergency triage categories. 32% did not know they could leave home to seek care with differences seen in English versus non-English speakers (p<0.001). 35% reported postponing medical care. There was a high fear about the health system becoming overloaded (mean 4.2 (±2) on 6-point scale). Four key themes emerged influencing health-seeking behaviour: fear and/or avoidance of hospital care; use of telehealth for remote assessment; no fear or avoidance of hospital care; not leaving the house for any reason. CONCLUSIONS: This study demonstrated reduced ED use by a vulnerable population of previously frequent attenders. COVID-19 has resulted in some fear and avoidance of hospitals, but has also offered new opportunity for alternative care through telehealth.

Review of 3-year outcomes of a very-low-energy diet-based outpatient obesity treatment programme.

Obesity is a complex disorder that requires a multidisciplinary treatment approach. This review evaluated 3-year outcomes of a very-low-energy diet (VLED)-based programme at a tertiary hospital multidisciplinary weight management clinic. Medical records of all patients who agreed to undertake the VLED programme and who did not undergo bariatric surgery during the 3-year follow-up period were examined. Baseline data collection included demographic and anthropometric characteristics, childhood onset of obesity and co-existing medical conditions. Weight was modelled using a linear mixed effects analysis. Logistic regression analyses were used to model the probability of continuing to attend the clinic and to identify pre-treatment factors associated with longer duration of attendance. Data from 1109 patients were included. A total of 231 patients (19.2%) were still attending the clinic 3 years after their initial appointment. Mean weight loss among patients who attended the clinic for 3 years was 6.4 kg (3.5%, 95% confidence interval [CI] 2.8, 4.2%). People who were prescribed pharmacotherapy maintained greater weight loss at 3 years (7.7% vs. 2.3% without pharmacotherapy, 95% CI for difference 3.9, 7.0%). People who had an onset of obesity in childhood, who had co-existing hypertension or coronary artery disease, and who did not currently smoke were more likely to continue to attend the clinic for up to 3 years. In summary, in an outpatient weight management clinic, patients who undertook a VLED-based programme and continued in follow-up achieved a clinically significant weight loss at 3 years, particularly if pharmacotherapy was used for weight loss maintenance.

The Association between Educational Attainment and Patterns of Emergency Department Utilization among Adults with Sickle Cell Disease.

PURPOSE: Patients with low educational attainment may be at increased risk for unplanned health care utilization. This study aimed to determine what factors are related to emergency department (ED) visits in hopes of guiding treatments and early interventions. METHODS: At two medical centers in the Mid-Atlantic United States, 258 adults with sickle cell disease aged 19-70 years participated in a retrospective study where we examined whether education level is independently associated with ED visits after accounting for other socioeconomic status (SES) variables, such as pain and disease severity and psychosocial functioning. RESULTS: The data showed that patients without a high school education visited the ED three times as frequently as patients with post secondary education. Controlling for poverty and employment status decreased the effect of education on ED visits by 33.24 %. Further controlling for disease severity and/or psychosocial functioning could not account for the remaining association between education and ED visits, suggesting that education is independently associated with potentially avoidable emergency care. CONCLUSIONS: Early interventions addressing disparities in academic performance, especially for those children most at risk, may lead to improved long-term health outcomes in this population.

Venous thromboembolism incidence in the Cooperative Study of Sickle Cell Disease.

BACKGROUND: Venous thromboembolism (VTE) has been recently recognized as a complication of sickle cell disease (SCD); however, the incidence of VTE in SCD is unknown. OBJECTIVES: The primary objective of this study was to determine the incidence of first VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), among SCD patients age ≥ 15 years. We also evaluated genotypic differences in VTE risk and determined the relationship between VTE and mortality. PATIENTS/METHODS: In this retrospective cohort study, we used data from the Cooperative Study of Sickle Cell Disease (CSSCD) to calculate incidence rates for first VTE. We used Cox proportional hazard models to estimate hazard ratios (HRs) for time to VTE by genotype and time to death by VTE status. RESULTS: We included 1523 SCD patients aged ≥ 15 years with 8862 years of follow-up in this analysis. The incidence rate for first VTE was 5.2 events/1000 person-years (95% confidence interval [CI] 3.8-6.9) with a cumulative incidence of 11.3% (95% CI 8.3-15.3) by age 40 years. Individuals with the SS/Sß(0) -thalassemia genotype had the highest rate of VTE (7.6 events/1000 person-years [95% CI 5.3-10.6]). The incidence of PE exceeded that of isolated DVT (3.6 [95% CI 2.5-5.1] events/1000 person-years vs. 1.6 [95% CI 0.9-2.7] events/1000 person-years), although this difference was not statistically significant. SCD patients with VTE had a higher mortality rate (adjusted HR 2.32 [95% CI 1.20-4.46]) than those without VTE. CONCLUSIONS: Patients with SCD are at substantial risk for VTE, and individuals with VTE are at higher risk of death than those without VTE.

Dental infections increase the likelihood of hospital admissions among adult patients with sickle cell disease.

THE OBJECTIVE: To determine if dental infections increase the likelihood of hospital admission among adult patients with sickle cell disease (SCD). BASIC RESEARCH DESIGN: Cross-sectional analysis of data from the Nationwide Emergency Department Sample (NEDS) pooled for the years 2006 through 2008. Prevalence ratios (PR) for the effects of interest were estimated using Poisson regression with robust estimates of the variance. PARTICIPANTS: Adults, aged 18 and over, diagnosed with SCD using ICD-9-CM codes excluding participants discharged with a code for sickle cell trait. MAIN OUTCOME MEASURE: Emergency department (ED) visit disposition, dichotomised to represent whether or not the ED visit ended in admission versus being treated and released. RESULTS: Among patients having a sickle cell crisis, those with dental infections were 72% more likely to be admitted compared to those not having dental infections (PR = 1.72, 95% CI 1.58-1.87). No association was observed among adult SCD patients not having a sickle crisis event. Based on preliminary data from this analysis, prevention of dental infection among patients with SCD could result in an estimated cost saving of $2.5 million dollars per year. CONCLUSIONS: Having a dental infection complicated by a sickle cell crisis significantly increases the likelihood of hospital admission among adult SCD patients presenting to the ED.

Clinical experience with 20 cases of group A streptococcus necrotizing fasciitis and myonecrosis: 1995 to 1997.

During the last decade, there has been a dramatic resurgence of necrotizing fasciitis caused by group A streptococcal disease with mortality rates from 43 to 58 percent. The objective of this study was to review recent clinical experience regarding the diagnosis and management of streptococcal necrotizing fasciitis, including the use of high-dose intravenous immunoglobulin. From April of 1995 to December of 1997, 20 consecutive adult patients meeting clinical and/or histopathologic criteria for streptococcal necrotizing fasciitis were identified in the Toronto area. Of those, 16 (80 percent) were treated with > or = 1 mg/kg of intravenous immunoglobulin. Fourteen men and 6 women ranging in age from 33 to 89 were identified (median age 55.5 years). Sixteen patients (80 percent) with necrotizing fasciitis survived. Ten patients had necrotizing fasciitis alone, none of whom died. Eight patients were identified with myonecrosis and necrotizing fasciitis, three of whom died. The case fatality rate of all patients who received intravenous immunoglobulin was 19 percent (3 of 16) and was not statistically significantly different (p = 1.0) from the case fatality rate of 25 percent (1 of 4) in those patients who did not receive intravenous immunoglobulin. A total of seven patients (35 percent) were diagnosed as having a cause for their signs and symptoms other than necrotizing fasciitis when they initially presented to a physician; one of these patients died. There was no correlation with the M type or the streptococcal pyrogenic exotoxin genotype and outcome.

Neuropsychological aspects of facial asymmetry during emotional expression: a review of the normal adult literature.

This review focuses on facial asymmetries during emotional expression. Facial asymmetry is defined as the expression intensity or muscular involvement on one side of the face ("hemiface") relative to the other side and has been used as a behavioral index of hemispheric specialization for facial emotional expression. This paper presents a history of the neuropsychological study of facial asymmetry, originating with Darwin. Both quantitative and qualitative aspects of asymmetry are addressed. Next, neuroanatomical bases for facial expression are elucidated, separately for posed/voluntary and spontaneous/involuntary elicitation conditions. This is followed by a comprehensive review of 49 experiments of facial asymmetry in the adult literature, oriented around emotional valence (pleasantness/unpleasantness), elicitation condition, facial part, social display rules, and demographic factors. Results of this review indicate that the left hemiface is more involved than the right hemiface in the expression of facial emotion. From a neuropsychological perspective, these findings implicate the right cerebral hemisphere as dominant for the facial expression of emotion. In spite of the compelling evidence for right-hemispheric specialization, some data point to the possibility of differential hemispheric involvement as a function of emotional valence.

Serial recovery of language during the intracarotid amobarbital procedure.

There is considerable variability among epilepsy centers in the methods and interpretations of the intracarotid amobarbital procedure. Prominent among these differences is the determination of language representation and assessment of language functions. Some centers rely on speech arrest following amobarbital injection as a marker for language representation, whereas other centers examine verbal output for the presence of aphasic errors. The present study assessed the pattern of language recovery following amobarbital injection in epilepsy patients who were candidates for temporal lobectomy. Language recovery from dominant hemisphere injection (left or right) followed a stereotypical progression, with 71.8% of patients showing return of vocalization followed by return of naming and comprehension. Repetition deficits with paraphasic errors persisted the longest (mean = 12'30"), with a conduction aphasia persisting after the acute global aphasia resolved. Although two patients interpreted as left hemisphere language dominant were mute following right hemisphere injection, all language functions were intact immediately upon resumption of vocalization and they showed no other signs of aphasia such as paraphasias or anomia. Possible explanations for serial language recovery and persistent conduction aphasia are discussed. These findings have significant implications for the determination of cerebral language dominance.

Left and right hemispheric contributions to discourse coherence and cohesion.

Linguistic coherence and cohesion were examined in patients with unilateral left brain damage (LBD), unilateral right brain damage (RBD), and normal control (NC) right-handed adults. Groups were matched for age, gender, occupation, and education. Brain-damaged groups did not differ for months post onset or intrahemispheric lesion site. Contrary to previous literature, results indicated that LBDs, all of whom were aphasic, demonstrated impairments in coherence but not cohesion, relative to NCs and RBDs. Surprisingly, among RBDs, overall coherence and cohesion were spared. When the relationship between measures of coherence and cohesion was examined, there were few significant correlations and no systematic patterns. Results support the notion that coherence and cohesion represent coexisting and independent linguistic systems. Further, the findings suggest that descriptions of discourse integrity need to account for the perspective of both the speaker and listener.

Hemispheric specialization for discourse reports of emotional experiences: relationships to demographic, neurological, and perceptual variables.

This study examined hemispheric specialization for discourse reports of emotional and nonemotional experience in 16 right-brain-damaged (RBD), 16 left-brain-damaged (LBD), and 16 demographically-matched normal control (NC) right-handed adults. Patient groups did not differ on etiology, months post-CVA onset, and intrahemispheric lesion location. Subjects were requested to produce monologues about positive and negative emotional and nonemotional experiences. The lexical content of written transcriptions of these monologues was later rated for "emotionality" by naive judges. Overall, RBDs described experiences with less emotional intensity than did NCs and LBDs, providing support for right hemisphere involvement in lexical emotion. Although the RBDs in the current study demonstrated similar patterns of deficits in a prior study [9] on tasks involving lexical emotional perception, there were no significant relationships between the current measures of emotional expression and the previous measures of emotional perception. Finally, the expression and the perception data were examined with respect to intrahemispheric factors. Among the brain-damaged subjects, subcortical structures were more involved in reports of emotional experience, and cortical structures were more involved in the perception of emotion.

Modality dependent changes in event-related potentials correlate with specific cognitive functions in nondemented patients with Parkinson's disease.

The relationship between event-related potentials (ERPs) and cognitive functioning was studied in patients with Parkinson's Disease (PD) but without dementia. Auditory and visual stimuli were used; 30 subjects participated in the auditory study and 20 in the visual study. Patient groups did not differ with respect to gender, age, education, illness duration, and level of cognitive functioning. Visual stimuli were 2.3 cpd sinusoidal grating patterns randomly presented in an oddball paradigm (oblique vs. vertical spatial orientation). Auditory stimuli were tones presented at 70 dB SPL at a rate of 1.1/second, also using the oddball paradigm (1.5K vs. 1K tones). All patients were given neuropsychological tests to measure verbal fluency, memory, visual spatial perception, and abstract reasoning. P300 and N200 abnormalities correlated with a number of these measures, such that longer ERP latencies were related to lower scores on tests of cognitive functioning. Patterns of results suggest that auditory and visual ERPs correlate with different subsets of neuropsychological functions in nondemented PD patients and that N200 may provide a new metric for clinical use.

Plasmapheresis decreases neuroelectric blocking activity in multiple sclerosis.

Serum neuroelectric blocking factor activity diminished after plasmapheresis in five of seven patients with MS but returned to baseline levels in 2 to 3 weeks. In the other two patients changes were insignificant. All patients studied had progressing symptoms. Five plasma exchanges of 2 liters were performed in 10 days. Two patients improved clinically, whereas five did not. There was no correlation between the level of neuroelectric blocking activity and changes in clinical status.