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.

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.

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.

Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support.

DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp2)-C(sp3) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.

Is High Blood Pressure Self-Protection for the Brain?

RATIONALE: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients. OBJECTIVE: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. METHODS AND RESULTS: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). CONCLUSIONS: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.

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.

Conservative interventions for treating hyperextension injuries of the proximal interphalangeal joints of the fingers.

BACKGROUND: Immobilisation and early motion (protected or unrestricted) are both used following hyperextension injuries to the proximal interphalangeal (PIP) joint of the finger. OBJECTIVES: To assess the effects of conservative interventions (non-surgical management) for treating hyperextension injuries of the proximal interphalangeal joints of the fingers. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2012), the Cochrane Central Register of Controlled Trials (in The Cochrane Library 2012, Issue 1), MEDLINE (1946 to January Week 2 2012), EMBASE (1980 to 2012 Week 03), CINAHL (1950 to 24 January 2012), PEDro (1929 to March 2012), trial registers and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing immobilisation/protected mobilisation/unrestricted mobilisation in participants with PIP joint hyperextension injuries managed non-surgically. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. There was no pooling of data. MAIN RESULTS: Three trials involving 366 people were identified. All three trials, which were over 15 years old, were methodologically flawed with unclear or high risk of bias. None of the studies reported on self assessment of function. One trial compared unrestricted mobility with immobilisation; one trial compared protected mobilisation with immobilisation; and the remaining trial compared immobilisation for one week versus three weeks. None of these trials found statistically significant differences between their intervention groups in various measures of poor outcome, pain and range of movement at six months follow-up. This lack of difference applied at three years for the comparison between unrestricted mobility with immobilisation. AUTHORS' CONCLUSIONS: There is insufficient evidence from trials testing the need for, and the extent and duration of, immobilisation to inform on the key conservative management decisions for treating hyperextension injuries of the proximal interphalangeal joints.

(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.

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.

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.

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.

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.

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.