Carotid body dysregulation contributes to Long COVID symptoms.

BACKGROUND: The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. METHODS: Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student's unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason's correlation coefficient was used to examine relationships between variables. RESULTS: During cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (-0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (-0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = -0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. CONCLUSIONS: The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

Patients with long COVID suffer from breathlessness during exercise, leading to exercise intolerance. We know that SARS-CoV-2, the virus that causes COVID-19, can infect carotid bodies which is a small sensory organ that sends signals to the brain for regulating breathing and blood pressure. This is called the carotid chemoreflex. However, it is not clear if SARS-CoV-2 infection affects carotid chemoreflex. Here, we examine whether the normal functioning of carotid chemoreflex is disrupted in non-hospitalised patients with long COVID and if this is linked to excessive breathing during exercise. Our study shows that carotid chemoreflex is more sensitive in long COVID patients, who are otherwise healthy. The carotid bodies could be a good therapeutic target for treating breathlessness in patients with long COVID.

Exploratory assessment of right ventricular structure and function during prolonged endurance cycling exercise.

BACKGROUND: A reduction in right ventricular (RV) function during recovery from prolonged endurance exercise has been documented alongside RV dilatation. A relative elevation in pulmonary artery pressure and therefore RV afterload during exercise has been implicated in this post-exercise dysfunction but has not yet been demonstrated. The current study aimed to assess RV structure and function and pulmonary artery pressure before, during and after a 6-h cycling exercise bout. METHODS: Eight ultra-endurance athletes were recruited for this study. Participants were assessed prior to exercise supine and seated, during exercise at 2, 4 and 6 h whilst cycling seated at 75% maximum heart rate, and post-exercise in the supine position. Standard 2D, Doppler and speckle tracking echocardiography were used to determine indices of RV size, systolic and diastolic function. RESULTS: Heart rate and RV functional parameters increased from baseline during exercise, however RV structural parameters and indices of RV systolic and diastolic function were unchanged between in-exercise assessment points. Neither pulmonary artery pressures (26 ± 9 mmHg vs 17 ± 10 mmHg, P > 0.05) nor RV wall stress (7.1 ± 3.0 vs 6.2 ± 2.4, P > 0.05) were significantly elevated during exercise. Despite this, post-exercise measurements revealed RV dilation (increased RVD1 and 3), and reduced RV global strain (- 21.2 ± 3.5 vs - 23.8 ± 2.3, P = 0.0168) and diastolic tissue velocity (13.8 ± 2.5 vs 17.1 ± 3.4, P = 0.019) vs pre-exercise values. CONCLUSION: A 6 h cycling exercise bout at 75% maximum heart rate did not alter RV structure, systolic or diastolic function assessments during exercise. Pulmonary artery pressures are not elevated beyond normal limits and therefore RV afterload is unchanged throughout exercise. Despite this, there is some evidence of RV dilation and altered function in post-exercise measurements.

Rapid Methadone Induction in a General Hospital Setting: A Retrospective, Observational Analysis.

BACKGROUND: Outpatient methadone guidelines recommend starting at a low dose and titrating slowly. As fentanyl prevalence and opioid-related mortality increases, there is a need for individuals to rapidly achieve a therapeutic methadone dose. Hospitalization offers a monitored setting for methadone initiation, however dosing practices and safety are not well described. METHODS: Retrospective, observational analysis of hospitalized patients with opioid use disorder seen by an inpatient addiction consult team in an academic medical center who were newly initiated on methadone between 2016 and 2022. We calculated initial daily dose, maximum daily dose, timing interval of dose escalation, whether patients were connected to an opioid treatment program (OTP) prior to discharge, whether adverse effects or safety events occurred during the hospitalization, and whether such events were definitely or probably related versus possibly related or unrelated to methadone. RESULTS: One hundred twelve patients were included. The mean initial daily methadone dose administered was 32 mg (range: 10-90 mg). The mean maximum dose reached was 76.8 mg (range 30-165 mg). The mean number of days from initial to peak dose was 5.6 days (range 1-19 days). Overall, 30% of patients experienced a safety event, most commonly sedation. Only 4 safety events were deemed probably or definitely related to methadone. In regression analyses, there was no significant difference between starting doses among patients with or without sedation but there was a relationship between last dose and the likelihood of any possibly related event, with those ending at a dose of 100 mg or higher having a higher likelihood event, compared to those ending at lower doses (47.8% vs 12.4%, P < .001). Seventy-six percent were connected to OTP before discharge. CONCLUSION: Among hospitalized patients initiating methadone, rapid dose titration was infrequently associated with related safety events and most were connected to community-based methadone treatment before discharge.

Aging in females is associated with changes in respiratory modulation of sympathetic nerve activity and blood pressure.

Sympathetic nerve activity (SNA) is tightly coupled with the respiratory cycle. In healthy human males, respiratory modulation of SNA does not change with age. However, it is unclear how this modulation is affected by age in females. We investigated whether respiratory sympathetic modulation is altered in healthy postmenopausal (PMF) versus premenopausal female (YF), and younger male (YM) adults, and determined its relationship to resting blood pressure. Muscle SNA (MSNA; microneurography), respiration (transducer belt), ECG, and continuous blood pressure were measured in 12 YF, 13 PMF, and 12 YM healthy volunteers. Respiratory modulation of MSNA was quantified during two phases of the respiratory cycle: mid-late expiration and inspiration/postinspiration. All groups showed respiratory modulation of MSNA (P < 0.0005). There was an interaction between the respiratory phase and group for MSNA [bursts/100 heartbeats (HB) (P = 0.004) and bursts/min (P = 0.029)], with smaller reductions in MSNA during inspiration observed in PMF versus the other groups. Respiratory modulation of blood pressure was also reduced in PMF versus YF (6 [2] vs. 12 [9] mmHg, P = 0.008) and YM (13 [13] mmHg, P = 0.001, median [interquartile range]). The magnitude of respiratory sympathetic modulation was related to resting blood pressure in PMF only, such that individuals with less modulation had greater resting blood pressure. The data indicate that aging in postmenopausal females is associated with less inspiratory inhibition of MSNA. This correlated with a higher resting blood pressure in PMF only. Thus, the reduced modulation of MSNA could contribute to the age-related rise in blood pressure that occurs in females.NEW & NOTEWORTHY The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Stretching Peptides to Generate Small Molecule ß-Strand Mimics.

Advances in the modulation of protein-protein interactions (PPIs) enable both characterization of PPI networks that govern diseases and design of therapeutics and probes. The shallow protein surfaces that dominate PPIs are challenging to target using standard methods, and approaches for accessing extended backbone structures are limited. Here, we incorporate a rigid, linear, diyne brace between side chains at the i to i+2 positions to generate a family of low-molecular-weight, extended-backbone peptide macrocycles. NMR and density functional theory studies show that these stretched peptides adopt stable, rigid conformations in solution and can be tuned to explore extended peptide conformational space. The diyne brace is formed in excellent conversions (>95%) and amenable to high-throughput synthesis. The minimalist structure-inducing tripeptide core (<300 Da) is amenable to further synthetic elaboration. Diyne-braced inhibitors of bacterial type 1 signal peptidase demonstrate the utility of the technique.

Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma.

Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, we modeled heterogeneous tumors comprised of a pro-inflammatory ("hot") and an immunosuppressive ("cold") tumor population, labeled with YFP and RFP tags respectively to enable precise spatial tracking. The resulting mixed-population tumors exhibited distinct regions comprised of YFP+ (hot) cells, RFP+ (cold) cells, or a mixture. We found that tumor regions occupied by hot tumor cells (YFP+) harbored more total T cells and a higher frequency of Th1 cells and IFNγ+ CD8 T cells compared to regions occupied by cold tumor cells (RFP+), whereas immunosuppressive macrophages showed the opposite spatial pattern. We identified the chemokine CX3CL1, produced at higher levels by our cold tumors, as a mediator of intratumoral macrophage accumulation, particularly immunosuppressive CD206Hi macrophages. Furthermore, we examined the response of heterogeneous tumors to a therapeutic combination of PD-1 blockade and CD40 agonist on a region-by-region basis. While the combination successfully increases Th1 abundance in "cold" tumor regions, it fails to bring overall T cell activity to the same level as seen in "hot" regions. The presence of the "cold" cells thus ultimately leads to a failure of the therapy to induce tumor rejection. Collectively, our results demonstrate that the organization of heterogeneous tumor cells has a profound impact on directing the spatial organization and function of tumor-infiltrating immune cells as well as on responses to immunotherapy.

(Why) Is Misinformation a Problem?

In the last decade there has been a proliferation of research on misinformation. One important aspect of this work that receives less attention than it should is exactly why misinformation is a problem. To adequately address this question, we must first look to its speculated causes and effects. We examined different disciplines (computer science, economics, history, information science, journalism, law, media, politics, philosophy, psychology, sociology) that investigate misinformation. The consensus view points to advancements in information technology (e.g., the Internet, social media) as a main cause of the proliferation and increasing impact of misinformation, with a variety of illustrations of the effects. We critically analyzed both issues. As to the effects, misbehaviors are not yet reliably demonstrated empirically to be the outcome of misinformation; correlation as causation may have a hand in that perception. As to the cause, advancements in information technologies enable, as well as reveal, multitudes of interactions that represent significant deviations from ground truths through people's new way of knowing (intersubjectivity). This, we argue, is illusionary when understood in light of historical epistemology. Both doubts we raise are used to consider the cost to established norms of liberal democracy that come from efforts to target the problem of misinformation.

Variation in medical humanities program mission statements in United States and Canadian Medical Schools.

PURPOSE: In 2019, the American Association of Medical Colleges (AAMC) identified the discipline of medical humanities as a priority in medical education. Although medical humanities programs have existed in medical and osteopathic schools in the U.S. and Canada since the late 1960's, this interdisciplinary field remains difficult to define. We studied the mission statements of medical humanities programs to identify core themes and priorities. MATERIALS AND METHODS: We conducted a content analysis of U.S. and Canada medical humanities MD and DO mission statements and associated descriptions (n = 56). We compared themes across programs whose directors had a clinical degree versus a terminal research degree, conducted comparisons between medical humanities programs housed in medical schools ranked in Top 20 U.S. News and World Report for Research or Primary Care, and conducted a word frequency analysis. RESULTS: Content analysis revealed five themes: improving patient care, improving the provider experience, generating scholarship, cultivating community relationships, and promoting diversity/sociocultural awareness. 70% of programs emphasized patient care and provider experience. Only 34% included the promotion of diversity/sociocultural awareness as a theme. Word frequency analysis corroborated our findings. CONCLUSIONS: U.S. and Canada medical humanities programs focus primarily on improving patient care and provider wellness.

Self-reported Side-effects of Ultraviolet-C Disinfection Devices.

The COVID-19 pandemic increased sales of portable UV-C devices as a means of inactivating the SARS-CoV-2 virus. Research suggests that excessive UV-C exposure to the eyes and skin can lead to side-effects, primarily photokeratitis and erythema, but these findings are limited to case studies. This study explores self-reported side-effects of UV-C devices by collating five waves of UK consumer survey data from April 2020-December 2021 (N = 26 864). 30%-46% of owners report a side-effect after using a device claiming to emit UV-C. However, detailed analysis of Wave 4 data (N = 309) highlights inconsistencies between reported and plausible side-effect(s) associated with skin or eye exposure from UV-C devices. Alternative explanations are considered, namely that the reported side-effect(s) were psychosomatic or misattributed to direct exposure of UV-C radiation. Data regarding awareness of warnings about device side-effect(s) supports the misattribution explanation. For risk assessment purposes, limited reliable information about specific irritation or injury to the eye and skin was found from self-reporting surveys. To optimize future data collection, we recommend addressing recall errors by: reducing the period under investigation, supplementing responses with empirical measures, and incentivizing respondents to provide accurate information about the make and model of the UV-C device.

Actions Do Not Always Speak Louder Than Words.

Financial (dis)incentives (e.g., bonuses, taxes) and social incentives (e.g., public praise) have typically been proposed as methods to encourage greater cooperation for the benefit of all. However, when cooperation requires exertion of effort, such interventions might not always be effective. While incentives tend to be highly motivating when choosing to exert effort, evidence suggests that they have less of an effect on behavior during effort execution. The aim of this exploratory study was to incorporate these insights into empirical investigation of the effects of social incentives on cooperative effort. To this end, we modified a public goods game task to require effort contributions to a common good. Crucial manipulation involved incorporating social incentives into this task and linking them to (a) choices that people made or (b) effortful actions they exerted. Our findings suggest, in line with recent effort-based decision-making models, that social incentives have a stronger effect on cooperative effort when they are linked to choices that people make, rather than the actual effort they exert. This study demonstrates potential benefits of eliciting a priori declarations of cooperative effort tied to social incentives to encourage greater effort for the benefit of all.

Direct observation of peptide hydrogel self-assembly.

The characterization of self-assembling molecules presents significant experimental challenges, especially when associated with phase separation or precipitation. Transparent window infrared (IR) spectroscopy leverages site-specific probes that absorb in the "transparent window" region of the biomolecular IR spectrum. Carbon-deuterium (C-D) bonds are especially compelling transparent window probes since they are non-perturbative, can be readily introduced site selectively into peptides and proteins, and their stretch frequencies are sensitive to changes in the local molecular environment. Importantly, IR spectroscopy can be applied to a wide range of molecular samples regardless of solubility or physical state, making it an ideal technique for addressing the solubility challenges presented by self-assembling molecules. Here, we present the first continuous observation of transparent window probes following stopped-flow initiation. To demonstrate utility in a self-assembling system, we selected the MAX1 peptide hydrogel, a biocompatible material that has significant promise for use in drug delivery and medical applications. C-D labeled valine was synthetically introduced into five distinct positions of the twenty-residue MAX1 ß-hairpin peptide. Consistent with current structural models, steady-state IR absorption frequencies and linewidths of C-D bonds at all labeled positions indicate that these side chains occupy a hydrophobic region of the hydrogel and that the motion of side chains located in the middle of the hairpin is more restricted than those located on the hairpin ends. Following a rapid change in ionic strength to initiate self-assembly, the peptide absorption spectra were monitored as function of time, allowing determination of site-specific time constants. We find that within the experimental resolution, MAX1 self-assembly occurs as a cooperative process. These studies suggest that stopped-flow transparent window FTIR can be extended to other time-resolved applications, such as protein folding and enzyme kinetics.

Overlapping needs for sexual and reproductive health and HIV prevention in women with substance use disorders.

OBJECTIVES: Women with substance use disorders have high unmet needs for HIV prevention and drug treatment and face challenges accessing care for other unique health issues, including their sexual and reproductive health. METHODS: We did a cross-sectional evaluation of sexual and reproductive health behaviors and outcomes among women with substance use disorders, who were enrolled in one of two concurrent clinical trials of pre-exposure prophylaxis for HIV prevention. Descriptive analyses and bivariate logistic regression were used to assess factors driving contraceptive use, and other essential sexual and reproductive health services utilization and outcomes. RESULTS: Among 226 women, 173 (76.5%) were of reproductive age. Most women had histories of unintended pregnancy (79.2%) or miscarriage (45.1%) and high HIV risk behaviors (53.5%). Most (61%) participants did not use any form of contraception at the time of assessment, although few (15%) reported pregnancy intentions. In bivariate models, ongoing criminal justice involvement was associated with 2.22 higher odds of not using contraception (95% confidence interval = 1.09-4.53; p = 0.03) and hazardous drinking was protective against not using contraception (odds ratio = 0.33, 95% confidence interval = 0.13-0.81; p = 0.02). Contraception use was not significantly associated with any other individual characteristics or need factors. CONCLUSIONS: This is the first study that identifies the unmet sexual and reproductive health needs of women with substance use disorders who are engaging with pre-exposure prophylaxis. We found that women accessed some health services but not in a way that holistically addresses the full scope of their needs. Integrated sexual and reproductive care should align women's expressed sexual and reproductive health intentions with their behaviors and outcomes, by addressing social determinants of health.

Daily wellness behaviors in college students across a school year.

Objective: To establish the prevalence of mood and wellness behaviors in college students across a school year. Methods: 1,554 college students (69.4% female; average age 18.8 years) were followed with daily surveys on wellness behaviors for the school year. 1,207 participants completed at least 50% of daily surveys on mood, exercise, sleep, nutrition, mindfulness practice and singing/playing musical instrument. Results: Over 88.7% of college students reported at least one wellness behavior each day with 17.7% reporting 4 or more. Each of the wellness behaviors, however, displayed distinct prevalence patterns, varied significantly across the school year, and often across a given school week. Almost every individual wellness behavior was associated with a positive mood, and the cumulative number of daily wellness behaviors was a strongly associated with mood state. Conclusions: Daily wellness behaviors are collectively common, vary significantly within individuals, and are strongly associated with positive mood, both individual and cumulatively.

Sympathetic-transduction in untreated hypertension.

Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m2 vs. 26.0 ± 4.2 kg/m2; p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone.

Methadone Access for Opioid Use Disorder During the COVID-19 Pandemic Within the United States and Canada.

Importance: Methadone access may be uniquely vulnerable to disruption during COVID-19, and even short delays in access are associated with decreased medication initiation and increased illicit opioid use and overdose death. Relative to Canada, US methadone provision is more restricted and limited to specialized opioid treatment programs. Objective: To compare timely access to methadone initiation in the US and Canada during COVID-19. Design, Setting, and Participants: This cross-sectional study was conducted from May to June 2020. Participating clinics provided methadone for opioid use disorder in 14 US states and territories and 3 Canadian provinces with the highest opioid overdose death rates. Statistical analysis was performed from July 2020 to January 2021. Exposures: Nation and type of health insurance (US Medicaid and US self-pay vs Canadian provincial). Main Outcomes and Measures: Proportion of clinics accepting new patients and days to first appointment. Results: Among 268 of 298 US clinics contacted as a patient with Medicaid (90%), 271 of 301 US clinics contacted as a self-pay patient (90%), and 237 of 288 Canadian clinics contacted as a patient with provincial insurance (82%), new patients were accepted for methadone at 231 clinics (86%) during US Medicaid contacts, 230 clinics (85%) during US self-pay contacts, and at 210 clinics (89%) during Canadian contacts. Among clinics not accepting new patients, at least 44% of 27 clinics reported that the COVID-19 pandemic was the reason. The mean wait for first appointment was greater among US Medicaid contacts (3.5 days [95% CI, 2.9-4.2 days]) and US self-pay contacts (4.1 days [95% CI, 3.4-4.8 days]) than Canadian contacts (1.9 days [95% CI, 1.7-2.1 days]) (P < .001). Open-access model (walk-in hours for new patients without an appointment) utilization was reported by 57 Medicaid (30%), 57 self-pay (30%), and 115 Canadian (59%) contacts offering an appointment. Conclusions and Relevance: In this cross-sectional study of 2 nations, more than 1 in 10 methadone clinics were not accepting new patients. Canadian clinics offered more timely methadone access than US opioid treatment programs. These results suggest that the methadone access shortage was exacerbated by COVID-19 and that changes to the US opioid treatment program model are needed to improve the timeliness of access. Increased open-access model adoption may increase timely access.