Qualitative interviews to support development of a patient-reported companion measure to the Glucocorticoid Toxicity Index.

INTRODUCTION: Glucocorticoids (GCs) are associated with multiple toxicities that have substantial impact on patients. We conducted qualitative interviews with patients to identify the toxicities that are most relevant from their perspective, with the goal of creating a patient-reported companion measure to the Glucocorticoid Toxicity Index (GTI), a clinician-facing instrument. METHODS: Thirty-one patients with recent or current GC use participated in concept elicitation interviews. Participants received GC treatment for myasthenia gravis, chronic inflammatory demyelinating polyradiculoneuropathy, vasculitis, or systemic lupus erythematosus. Transcripts were coded following a thematic analysis approach. RESULTS: Participants reported more than 100 toxicities they believed to be associated with their GC medications. Common toxicities included weight gain (87%), increased appetite (84%), insomnia/sleep problems (77%), cognitive impairment/brain fog (71%), easy bruising (68%), anxiety (65%), irritability/short temper (65%), and osteoporosis (39%). These toxicities often centered on self-esteem, neuropsychiatric effects, skin toxicities, and musculoskeletal function. They can be categorized into domains such emphasizing neuropsychiatric, metabolic/endocrine, musculoskeletal, and dermatological effects, highlighting aspects of GC toxicity that patients are uniquely positioned to appreciate and report. CONCLUSION: Our results confirm that the toxicities associated with GCs are pervasive and diverse, with substantial impact on patients' lives. These data will be used to inform the development of a patient-reported outcome measure assessing GC toxicity. This patient-reported instrument will be designed to complement the clinician-reported GTI, facilitating a more detailed understanding of the nuances of change in GC toxicity.

Hormonal basis of sex differences in anesthetic sensitivity.

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

The Glucocorticoid Toxicity Index-Metabolic Domains, an abridged version of the Glucocorticoid Toxicity Index: post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians. METHODS: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set. FINDINGS: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001). INTERPRETATION: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems. FUNDING: ChemoCentryx.

Animal Shelters' Response to the COVID-19 Pandemic: A Pilot Survey of 14 Shelters in the Northeastern United States.

Anecdotal reports indicate that many animal shelters experienced increased adoption and foster care rates during the COVID-19 pandemic, yet peer-reviewed evidence is lacking. In this pilot survey of 14 animal shelters in the Northeastern United States, we aimed to investigate the impact of the COVID-19 pandemic on animal intakes, foster care and five outcome types and describe operational changes reported by shelters in response to COVID-19. Paired sample t-tests and Wilcoxon signed-rank tests were used to compare intake, adoption, euthanasia and foster care rates and numbers between March-June 2019 and 2020. The number of dogs and cats that entered shelters was significantly lower during the COVID-19 pandemic compared with the same months of 2019 (t = 3.41, p = 0.01, t = 2.69, p = 0.02). Although the overall rate of adoption and euthanasia did not differ, the numbers adopted and euthanized decreased significantly for both dogs and cats, reflecting the significantly decreased intake. We also found significant variability between shelters. During the pandemic, several shelters sought to expand their foster care networks through operational changes (n = 6) and statements made to the public (n = 7). However, the proportion of dogs and cats housed in foster care did not differ between March-June 2019 and 2020 in our sample. Our findings offer preliminary insights regarding the impact of a worldwide pandemic on the functioning of animal shelters.

Clinician Experiences of Care Provision in the Correctional Setting: A Scoping Review.

Little is known about the experiences of correctional health care providers and how their experiences impact the correctional health care system. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines, multiple databases were searched. Each abstract was read by two reviewers with a third for consensus as needed. Full-text articles were selected through a second round of review. Of 4,467 citations, 61 were selected for full-text evaluation and 23 were ultimately included. Major themes identified were the distinctive working environment, burnout, and the presence of ethical dilemmas, including the tension between security and clinical considerations. This scoping review identified a limited number of articles centered on the health care provider experience in the correctional setting.

Effects of time and temperature during melanging on the volatile profile of dark chocolate.

Chocolate made from small-batch production is known for distinct sensory properties that differentiate its products from large-scale production. Specifically, small-batch processing includes a melanging step, a chocolate refining (a process involving time and temperature to refine texture and flavor) process that occurs in a stone wet-grinder. Chocolatiers understand that melanging is essential to flavor and overall quality, however the influence of melanging on the aroma chemistry of the finished chocolate is anecdotal and largely uncharacterized. Here, we evaluated the effects of time and temperature of melanging on the volatile chemistry of the finished chocolate. Specifically, chocolate aroma was profiled using HS/SPME-GC-MS for three different time and temperature combinations. A total of 88 compounds were annotated by mass spectrometry and included a diverse set of chemical classes such as pyrazines, aldehydes, terpenes, alcohols, esters, and ketones. Analysis of variance (ANOVA), principal component analysis (PCA), and partial least squares analysis (PLS) revealed that the overall aroma profile was influenced by the type of melanging, and time had a greater effect than temperature. Example compounds affected by time include 2-methylpropanal, dimethyl sulfide, and benzaldehyde. Particle size was also measured for each sample. Majority particle size was found to be below 25 microns generally at all time points beyond 8 h. Analysis showed significant p-values for the temperature variable for several compounds, but significant p-values for the time variable were apparent for a greater number of compounds. For compounds which showed dependency on both time and temperature, the p-value for the time variable was much smaller in most cases. Both PCA and OPLS analyses suggested the same trends. These data support that time is a critical factor in determining the aroma chemistry of chocolate and affects a diverse set of known flavor active compounds.

Henry Jacob Bigelow Inhaled Nitrous Oxide While an Undergraduate at Harvard College.

When teenaged Henry Jacob Bigelow was an undergraduate at Harvard College in 1833-1837, he prepared nitrous oxide gas for demonstrations to other students. Bigelow's son, William Sturgis Bigelow, related the claim, and there is an eyewitness account from Augustus Goddard Peabody, a fellow Harvard undergraduate with Bigelow. Peabody wrote to Henry David Thoreau about a nitrous frolic. College chemistry primed Bigelow to support the concept of inhaled surgical anesthesia when the idea came to Boston in 1845-1846. Bigelow's chemistry professor was John White Webster. According to Harvard alumnus Edward Everett Hale, in addition to demonstrating effects of nitrous oxide, Webster presciently treated two cases of carbon monoxide poisoning with copious volumes of synthetic oxygen gas. The career of Webster was inhibited by financial difficulties that were suspected to be contributory when he was convicted of the 1849 murder of physician George Parkman at the Harvard Medical School, then adjacent to Massachusetts General Hospital and its Ether Dome. Webster suffered the death penalty in 1850.

Spinal Cord Stimulation vs Conventional Therapies for the Treatment of Chronic Low Back and Leg Pain: A Systematic Review of Health Care Resource Utilization and Outcomes in the Last Decade.

OBJECTIVE: The purpose of this review is to critically appraise the literature for evidence supporting the health care resource utilization and cost-effectiveness of spinal cord stimulation (SCS) compared with conventional therapies (CTs) for chronic low back and leg pain. METHODS: The PubMed, MEDLINE, Embase, CINAHL, and Rehabilitation & Sports Medicine databases were searched for studies published from January 2008 through October 2018, using the following MeSH terms: "spinal cord stimulation," "chronic pain," "back pain," "patient readmission," "economics," and "costs and cost analysis." Additional sources were added based on bibliographies and consultation with experts. The following data were extracted and analyzed: demographic information, study design, objectives, sample sizes, outcome measures, SCS indications, complications, costs, readmissions, and resource utilization data. RESULTS: Of 204 studies screened, 11 studies met inclusion criteria, representing 31,439 SCS patients and 299,182 CT patients. The mean age was 53.5 years for SCS and 55.6 years for CT. In eight of 11 studies, SCS was associated with favorable outcomes and found to be more cost-effective than CT for chronic low back pain. Compared with CT, SCS resulted in shorter hospital stays and lower complication rates and health care costs at 90 days. SCS was associated with significant improvement in health-related quality of life, health status, and quality-adjusted life-years. CONCLUSIONS: For the treatment of chronic low back and leg pain, the majority of studies are of fair quality, with level 3 or 4 evidence in support of SCS as potentially more cost-effective than CT, with less resource expenditure but higher complication rates. SCS therapy may yet play a role in mitigating the financial burden associated with chronic low back and leg pain.

Divine's CO2 Absorber of 1867.

Chemist and inventor Silas R. Divine (1838-1912) sold ammonium nitrate and other anesthesia supplies in New York City. He offered a carbon dioxide absorber for the purpose of rebreathing nitrous oxide. Like his colleague Gardner Q. Colton, he denied the need for nitrous oxide to be supplemented with O2 gas.

George Washington Frost Mellen and Resuscitation with Nitrous Oxide in 1847.

In The Boston Medical and Surgical Journal of 1847 (later to be called The New England Journal of Medicine), Boston chemist George Washington Frost Mellen claimed that inhaled nitrous oxide gas supports human life in the manner of oxygen gas, and he proposed the use of nitrous oxide in resuscitation from drowning and from carbon monoxide poisoning. The claim was reprinted in at least one dental journal and was long cited as justification for the use of 100% nitrous oxide for inhaled anesthesia. Advocates included anesthesia pioneer and painless dentist Gardner Quincy Colton. Though misguided as to nitrous oxide, Mellen was a prominent member of the Boston community for the abolition of slavery.

Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis.

OBJECTIVE: To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer. METHODS: Published data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment. RESULTS: Thirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13-2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09-2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01-1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06-1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09-1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control. CONCLUSIONS: VEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

Combined effects of storage and processing on the bioactive compounds and pro-apoptotic properties of color-fleshed potatoes in human colon cancer cells.

Potatoes can be stored for up to 1 year before being processed and consumed. The objective of this study was to determine the extent to which fresh and stored color-fleshed potatoes retain their anticancer properties after baking and chipping compared with unprocessed potatoes. We utilized white-, yellow-, and purple-fleshed potato clones and tested their phenolic and anthocyanin content, antioxidant activity, metabolite profile, and antiproliferative and pro-apoptotic properties. When compared with unprocessed samples, baking or chipping led to significant losses in the phenolic and anthocyanin content and antioxidant activity of the potatoes. However, with storage, total phenolic and anthocyanin content and antioxidant activity increased in baked samples while in the chipped samples they remained constant. Ethanolic extracts of baked and chipped samples suppressed proliferation and elevated apoptosis (p < 0.05) in HCT-116 (p53 wild-type; ras mutated) and HT-29 (p53 mutated; ras wild-type) human colon cancer cell lines. Antiproliferative and pro-apoptotic properties of baked potatoes were similar to that of fresh potatoes, while chipping caused a significant suppression. Phenolic content and antioxidant activity of purple-fleshed potatoes, after baking, were comparable with those of anthocyanin-rich berries. Hence, purple-fleshed potatoes can be a healthier choice for consumers as they possess greater levels of bioactive compounds and anticancer properties even after processing as compared with their white- and yellow-fleshed counterparts.

Amygdala stimulation evokes time-varying synaptic responses in the gustatory cortex of anesthetized rats.

Gustatory stimuli are characterized by a specific hedonic value; they are either palatable or aversive. Hedonic value, along with other psychological dimensions of tastes, is coded in the time-course of gustatory cortex (GC) neural responses and appears to emerge via top-down modulation by the basolateral amygdala (BLA). While the importance of BLA in modulating gustatory cortical function has been well established, the nature of its input onto GC neurons is largely unknown. Somewhat conflicting results from extracellular recordings point to either excitatory or inhibitory effects. Here, we directly test the hypothesis that BLA can evoke time-varying - excitatory and inhibitory - synaptic responses in GC using in vivo intracellular recording techniques in urethane anesthetized rats. Electrical stimulation of BLA evoked a post-synaptic potential (PSP) in GC neurons that resulted from a combination of short and long latency components: an initial monosynaptic, glutamatergic potential followed by a multisynaptic, GABAergic hyperpolarization. As predicted by the dynamic nature of amygdala evoked potentials, trains of five BLA stimuli at rates that mimic physiological firing rates (5-40 Hz) evoke a combination of excitation and inhibition in GC cells. The magnitude of the different components varies depending on the frequency of stimulation, with summation of excitatory and inhibitory inputs reaching its maximum at higher frequencies. These experiments provide the first description of BLA synaptic inputs to GC and reveal that amygdalar afferents can modulate gustatory cortical network activity and its processing of sensory information via time-varying synaptic dynamics.

Effects of seasonal variation on sensory properties and total phenolic content of 5 lettuce cultivars.

Butterhead, crisphead, green leaf, red leaf, and romaine types of lettuce (Lactuca sativa L.) are all commonly available in U.S. markets. Sensory properties of lettuce may vary in response to environmental factors that often fluctuate widely throughout the growing season. Bitterness is generally thought to increase in lettuce grown at higher temperatures and may be related to phenolic content. This study evaluated sensory properties and total phenolic content of 5 lettuce cultivars harvested early, midway, and late in the growing season and investigated possible correlations with environmental temperature and light intensity indexes. Thirty panelists rated bitterness, appearance, flavor, texture, and overall acceptability of "Crisp and Green" (green leaf), "Crispino" (crisphead), "Green Forest" (romaine), "Lochness" (butterhead), and "Vulcan" (red leaf) lettuce. There was considerable variation in sensory ratings among the 5 cultivars (P < 0.005) but few differences within cultivars across the growing season. The crisphead cultivar, Crispino, received higher scores (P < 0.01) for flavor, texture, and overall acceptability and was rated less bitter (P < 0.05) than other cultivars. Total phenolic content varied significantly (P < 0.001) among cultivars with the red leaf cultivar, Vulcan, exhibiting the highest levels. There was no correlation between bitterness and total phenolic content or environmental factors. Differences among lettuce cultivars appear to have a larger impact on sensory and phenolic profiles than environmental variation during the growing season.

Elton Romeo Smilie, the not-quite discoverer of ether anesthesia.

Like William T.G. Morton, Elton Romeo Smilie (1819-1889) was raised in Massachusetts, attended medical school in New England, practiced dentistry there, strove for clinical invention, and moved to Boston. In October 1846, both announced that inhaled ethereal preparations achieved reversible insensibility in surgical patients. Smilie published a report in the Boston Med Surg J 3 wk before Bigelow used that forum to broadcast Morton's Ether Day. Smilie's preparation was an ethereal tincture of opium, and, as he mistakenly believed the opium to be volatile and important, he ceded priority to Morton for ether anesthesia. The two authors collaborated on chloroform, but Smilie soon headed off in the Gold Rush to California. It is tempting to speculate that Charles T. Jackson and Morton were indebted in part to Smilie.

The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression.

Proper neuronal function and several forms of synaptic plasticity are highly dependent on precise control of mRNA translation, particularly in dendrites. We find that eIF4AIII, a core exon junction complex (EJC) component loaded onto mRNAs by pre-mRNA splicing, is associated with neuronal mRNA granules and dendritic mRNAs. eIF4AIII knockdown markedly increases both synaptic strength and GLUR1 AMPA receptor abundance at synapses. eIF4AIII depletion also increases ARC, a protein required for maintenance of long-term potentiation; arc mRNA, one of the most abundant in dendrites, is a natural target for nonsense-mediated decay (NMD). Numerous new NMD candidates, some with potential to affect synaptic activity, were also identified computationally. Two models are presented for how translation-dependent decay pathways such as NMD might advantageously function as critical brakes for protein synthesis in cells such as neurons that are highly dependent on spatially and temporally restricted protein expression.