Venous-plexus-associated lymphoid hubs support meningeal humoral immunity.

There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.

The formation and function of the neutrophil phagosome.

Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.

Advances in the World of Bacterial Microcompartments.

Bacterial microcompartments (MCPs) are extremely large (100-400 nm) and diverse proteinaceous organelles that compartmentalize multistep metabolic pathways, increasing their efficiency and sequestering toxic and/or volatile intermediates. This review highlights recent studies that have expanded our understanding of the diversity, structure, function, and potential biotechnological uses of MCPs. Several new types of MCPs have been identified and characterized revealing new functions and potential new associations with human disease. Recent structural studies of MCP proteins and recombinant MCP shells have provided new insights into MCP assembly and mechanisms and raised new questions about MCP structure. We also discuss recent work on biotechnology applications that use MCP principles to develop nanobioreactors, nanocontainers, and molecular scaffolds.

Life history changes associated with over 400 generations of artificial selection on body size in Drosophila.

Body size is a trait that shapes many aspects of a species' development and evolution. Larger body size is often beneficial in animals, but it can also be associated with life history costs in natural systems. Similarly, miniaturization, the evolution of extremely small adult body size, is found in every major animal group, yet carries its own life history trade-offs. Given that these effects can depend on an animal's environment and life stage and have mainly been studied in species that are already specialized for their size, the life history changes associated with evolutionary shifts in body size warrant additional investigation. Here, we used Drosophila melanogaster populations that had undergone over 400 generations of artificial selection on body size to investigate the changes in life history traits associated with the evolution of extremely large and extremely small body sizes. Populations selected for small body size experienced strong trade-offs in multiple life history traits, including reduced female fecundity and lower juvenile viability. Although we found positively correlated changes in egg size associated with selection for both large and small body size, after adjusting for female body size, females from populations selected for large size had the lowest relative investment per egg and females from populations selected for small size had the highest relative investment per egg. Taken together, our results suggest that egg size may be a key constraint on the evolution of body size in D. melanogaster, providing insight into the broader phenomenon of body size evolution in insects.

Engineering Synthetic Electron Transfer Chains from Metallopeptide Membranes.

The energetic and geometric features enabling redox chemistry across the copper cupredoxin fold contain key components of electron transfer chains (ETC), which have been extended here by templating the cross-ß bilayer assembly of a synthetic nonapeptide, HHQALVFFA-NH2 (K16A), with copper ions. Similar to ETC cupredoxin plastocyanin, these assemblies contain copper sites with blue-shifted (λmax 573 nm) electronic transitions and strongly oxidizing reduction potentials. Electron spin echo envelope modulation and X-ray absorption spectroscopies define square planar Cu(II) sites containing a single His ligand. Restrained molecular dynamics of the cross-ß peptide bilayer architecture support metal ion coordination stabilizing the leaflet interface and indicate that the relatively high reduction potential is not simply the result of distorted coordination geometry (entasis). Cyclic voltammetry (CV) supports a charge-hopping mechanism across multiple copper centers placed 10-12 Å apart within the assembled peptide leaflet interface. This metal-templated scaffold accordingly captures the electron shuttle and cupredoxin functionality in a peptide membrane-localized electron transport chain.

Histone H3 dopaminylation in nucleus accumbens, but not medial prefrontal cortex, contributes to cocaine-seeking following prolonged abstinence.

Enduring patterns of epigenomic and transcriptional plasticity within the mesolimbic dopamine system contribute importantly to persistent behavioral adaptations that characterize substance use disorders (SUD). While drug addiction has long been thought of as a disorder of dopamine (DA) neurotransmission, therapeutic interventions targeting receptor mediated DA-signaling have not yet resulted in efficacious treatments. Our laboratory recently identified a non-canonical, neurotransmission-independent signaling moiety for DA in brain, termed dopaminylation, whereby DA itself acts as a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g., histone H3 at glutamine 5; H3Q5dop). In our previous studies, we demonstrated that H3Q5dop plays a critical role in the regulation of neuronal transcription and, when perturbed within monoaminergic neurons of the ventral tegmental area (VTA), critically contributes to pathological states, including relapse vulnerability to both psychostimulants (e.g., cocaine) and opiates (e.g., heroin). Importantly, H3Q5dop is also observed throughout the mesolimbic DA reward pathway (e.g., in nucleus accumbens/NAc and medial prefrontal cortex/mPFC, which receive DA input from VTA). As such, we investigated whether H3Q5dop may similarly be altered in its expression in response to drugs of abuse in these non-dopamine-producing regions. In rats undergoing extended abstinence from cocaine self-administration (SA), we observed both acute and prolonged accumulation of H3Q5dop in NAc, but not mPFC. Attenuation of H3Q5dop in NAc during drug abstinence reduced cocaine-seeking and affected cocaine-induced gene expression programs associated with altered dopamine signaling and neuronal function. These findings thus establish H3Q5dop in NAc, but not mPFC, as an important mediator of cocaine-induced behavioral and transcriptional plasticity during extended cocaine abstinence.

Upside-down swimming: in situ observations of inverted orientation in Gigantactis, with a new depth record for the Ceratioidei.

This note reports on eight observations of inverted swimming behavior by species of ceratioid whipnose anglerfishes in the genus Gigantactis, from the Caribbean, tropical east Atlantic, tropical western Indian Ocean, the north-east and north-west Pacific and south-west Pacific. It covers four putative species and strongly suggests that this is the normal behavior for the genus. A possible reason is briefly discussed. In addition, a new depth record of 5866 m for the ceratioid anglerfish is recorded.

Synthesis of Black Phosphorene Quantum Dots from Red Phosphorus.

Black phosphorene quantum dots (BPQDs) are most commonly derived from high-cost black phosphorus, while previous syntheses from the low-cost red phosphorus (Pred ) allotrope are highly oxidised. Herein, we present an intrinsically scalable method to produce high quality BPQDs, by first ball-milling Pred to create nanocrystalline Pblack and subsequent reductive etching using lithium electride solvated in liquid ammonia. The resultant ~25 nm BPQDs are crystalline with low oxygen content, and spontaneously soluble as individualized monolayers in tertiary amide solvents, as directly imaged by liquid-phase transmission electron microscopy. This new method presents a scalable route to producing quantities of high quality BPQDs for academic and industrial applications.

Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women.

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy.

Profile and quality of life of the adult population in good health according to the level of vitality: European NHWS cross sectional analysis.

BACKGROUND: The World Health Organization's definition of health highlights the importance of mental and physical wellbeing and not only disease state. However, lack of awareness on the burden of impaired vitality and its impact on the quality of life of the general healthy population prevents healthcare providers from delivering appropriate solutions and advice. This study aims to better characterize this population in Europe and identify the profile and the health reported outcomes associated with impaired vitality. METHODS: This retrospective observational study included National Health and Wellness Survey (NHWS) data collected in healthy participants aged 18-65 years from five European Union countries in 2018. Socio-demographic and lifestyle characteristics, comorbidities, attitudes towards healthcare systems, Patient Activation Measure, health-related quality of life outcomes (EQ-5D), and work productivity and activity impairment were analysed according to SF-12 vitality score subgroups (≥ 60, 50- < 60, 40- < 50, < 40). RESULTS: A total of 24,295 participants were enrolled in the main analysis. Being a female, younger, having a lower income and being obese or having sleep and mental disorders was associated with an increased risk of impaired vitality. This was associated with a higher consumption of healthcare resources along with having a weak patient-physician relationship. Participants who were disengaged in the self-management of their health were 2.6 times more likely to have a low level of vitality. For participants in the lowest vitality group, odds of mobility problems increased by 3.4, impairment of usual activity by 5.8, increased of pain and discomfort by 5.6 and depression and anxiety by 10.3, compared with participants in the highest vitality group. Also, odds of presenteeism increased by 3.7, overall work impairment by 3.4 and daily activity losses by 7.1. CONCLUSION: Evidence-based trends facilitate the identification of a healthy population with impaired vitality in real-world practice. This study highlights the actual burden of low vitality on daily life activities, particularly on mental health and reduced work productivity. Additionally, our results underline the importance of self-engagement in the management of vitality impairment and highlights the need to implement strategies to address this public health concern in the affected population (HCP-patient communication, supplements, meditation).

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-ß (TGF-ß) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

InFluence: An Open-Source Python Package to Model Images Captured with Direct Electron Detectors.

The high detection efficiencies of direct electron detectors facilitate the routine collection of low fluence electron micrographs and diffraction patterns. Low dose and low fluence electron microscopy experiments are the only practical way to acquire useful data from beam sensitive pharmaceutical and biological materials. Appropriate modeling of low fluence images acquired using direct electron detectors is, therefore, paramount for quantitative analysis of the experimental images. We have developed a new open-source Python package to accurately model any single layer direct electron detector for low and high fluence imaging conditions, including a means to validate against experimental data through computation of modulation transfer function and detective quantum efficiency.

Combined Pulsed Electron Double Resonance EPR and Molecular Dynamics Investigations of Calmodulin Suggest Effects of Crowding Agents on Protein Structures.

Calmodulin (CaM) is a highly dynamic Ca2+-binding protein that exhibits large conformational changes upon binding Ca2+ and target proteins. Although it is accepted that CaM exists in an equilibrium of conformational states in the absence of target protein, the physiological relevance of an elongated helical linker region in the Ca2+-replete form has been highly debated. In this study, we use PELDOR (pulsed electron-electron double resonance) EPR measurements of a doubly spin-labeled CaM variant to assess the conformational states of CaM in the apo-, Ca2+-bound, and Ca2+ plus target peptide-bound states. Our findings are consistent with a three-state conformational model of CaM, showing a semi-open apo-state, a highly extended Ca2+-replete state, and a compact target protein-bound state. Molecular dynamics simulations suggest that the presence of glycerol, and potentially other molecular crowding agents, has a profound effect on the relative stability of the different conformational states. Differing experimental conditions may explain the discrepancies in the literature regarding the observed conformational state(s) of CaM, and our PELDOR measurements show good evidence for an extended conformation of Ca2+-replete CaM similar to the one observed in early X-ray crystal structures.

Retrospective Observational Real-World Outcome Study to Evaluate Safety Among Patients With Erectile Dysfunction (ED) With Co-Possession of Tadalafil and Anti-Hypertensive Medications (anti-HTN).

BACKGROUND: Erectile dysfunction (ED) is a common condition affecting male adults and may be associated with hypertension, diabetes, hyperlipidemia, and obesity. Phosphodiesterase type 5 (PDE5) inhibitors, such as tadalafil, are the first-line drug therapy for ED. Studies and the current prescribing information of these PDE5 inhibitors indicate they are mechanistic mild vasodilators and, as such, concomitant use of a PDE5 inhibitor with anti-hypertensive medication may lead to drops in blood pressure due to possible drug-drug interaction. AIM: Evaluate risks of hypotensive/cardiovascular outcomes in a large cohort of patients with ED that have co-possession of prescriptions for tadalafil and hypertensive medications versus either medication/s alone. METHODS: A cohort study conducted within an electronic health record database (Optum) representing hospitals across the US. Adult male patients prescribed tadalafil and/or anti-hypertensive medications from January 2012 to December 2017 were eligible. Possession periods were defined by the time patients likely had possession of medication, with propensity score-matched groups used for comparison. OUTCOMES: Risk of hypotensive/cardiovascular outcomes were measured using diagnostic codes and NLP algorithms during possession periods of tadalafil + anti-hypertensive versus either medication/s alone. RESULTS: In total there were 127,849 tadalafil + anti-hypertensive medication possession periods, 821,359 anti-hypertensive only medication possession periods, and 98,638 tadalafil only medication possession periods during the study; 126,120 were successfully matched. Adjusted-matched incidence rate ratios (IRRs) for the anti-hypertensive only possession periods compared with tadalafil + anti-hypertensive periods of diagnosed outcomes were all below 1. Two outcomes had a 95% confidence interval (CI) that did not include 1.0: ventricular arrhythmia (IRR 0.79; 95% CI 0.66, 0.94) and diagnosis of hypotension (IRR 0.79; 95% CI 0.71, 0.89). CLINICAL IMPLICATIONS: Provides real world evidence that co-possession of tadalafil and anti-hypertensive medications does not increase risk of hypotensive/cardiovascular outcomes beyond that observed for patients in possession of anti-hypertensive medications only. STRENGTHS AND LIMITATIONS: EHR data are valuable for the evaluation of real world outcomes, however, the data are retrospective and collected for clinical patient management rather than research. Prescription data represent the intent of the prescriber and not use by the patient. Residual bias cannot be ruled out, despite propensity score matching, due to unobserved patient characteristics and severity that are not fully reflected in the EHR database. CONCLUSION: In the studied real world patients, this study did not demonstrate an increased risk of hypotensive or cardiovascular outcomes associated with co-possession of tadalafil and anti-hypertensive medications beyond that observed for patients in possession of anti-hypertensive medications only. Nunes AP, Seeger JD, Stewart A, et al., Retrospective Observational Real-World Outcome Study to Evaluate Safety Among Patients With Erectile Dysfunction (ED) With Co-Possession of Tadalafil and Anti-Hypertensive Medications (anti-HTN). J Sex Med 2022;19:74-82.

10-Year Trends in Healthcare Spending among Patients with Schizophrenia in Alberta, Canada.

OBJECTIVES: Schizophrenia is characterized by high levels of disability often resulting in increased healthcare utilization and spending. With expanding healthcare costs across all healthcare sectors, there is a need to understand how healthcare spending has changed over time. We conducted a population-based study using administrative health data from Alberta, Canada, to describe changes in medical complexity and direct healthcare spending among patients with schizophrenia over a 10-year period. METHODS: A serial cross-sectional study from January 1, 2008, to December 31, 2017, was conducted to determine changes in demographic characteristics, medical complexity, and costs among all adults (18 years or older) with schizophrenia. Total healthcare spending and sector-specific costs attributable to hospitalizations, emergency department visits, practitioner billings, and prescriptions were calculated and compared over time. RESULTS: Over the 10-year period the contact prevalence of patients with schizophrenia increased from 0.6% (n = 16,183) to 1.0% (n = 33,176) within the province. There was a marked change in medical complexity with the number of patients living with 3 or more comorbidities increasing from 33.0% to 47.3%. Direct annual healthcare costs increased 2-fold from 321 to 639 million CAD (493 million USD) with a 7-fold increase in medication expenditures over the 10-year time frame. As of 2017, spending on pharmaceutical treatment surpassed hospitalizations as the leading spending category in this population. CONCLUSIONS: Healthcare spending among patients with schizophrenia continues to increase and may be partially attributable to growing rates of multimorbidity within this population. Although promising second-generation antipsychotic medications have entered the market, this has resulted in considerable changes in the distribution of healthcare spending over time. These findings will inform policy discussions around resource allocation and efforts to curb health spending while also improving care for patients with schizophrenia.

ERP CORE: An open resource for human event-related potential research.

Event-related potentials (ERPs) are noninvasive measures of human brain activity that index a range of sensory, cognitive, affective, and motor processes. Despite their broad application across basic and clinical research, there is little standardization of ERP paradigms and analysis protocols across studies. To address this, we created ERP CORE (Compendium of Open Resources and Experiments), a set of optimized paradigms, experiment control scripts, data processing pipelines, and sample data (N = 40 neurotypical young adults) for seven widely used ERP components: N170, mismatch negativity (MMN), N2pc, N400, P3, lateralized readiness potential (LRP), and error-related negativity (ERN). This resource makes it possible for researchers to 1) employ standardized ERP paradigms in their research, 2) apply carefully designed analysis pipelines and use a priori selected parameters for data processing, 3) rigorously assess the quality of their data, and 4) test new analytic techniques with standardized data from a wide range of paradigms.

Acute inflammatory profiles differ with sex and age after spinal cord injury.

BACKGROUND: Sex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI. METHODS: Male and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance. RESULTS: Flow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia. CONCLUSIONS: These findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression.

Cardiovascular Outcome Risks in Patients With Erectile Dysfunction Co-Prescribed a Phosphodiesterase Type 5 Inhibitor (PDE5i) and a Nitrate: A Retrospective Observational Study Using Electronic Health Record Data in the United States.

BACKGROUND: Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for erectile dysfunction (ED). Approximately 1-4% of PDE5i recipients co-possess nitrates, despite this combination potentially producing clinically significant hypotension. Real-world data in these patients and insights into prescriber rationales for co-prescription are limited. AIM: This study investigated whether PDE5i and nitrate co-possession is associated with increased rates of cardiovascular (CV) outcomes. METHODS: Adult males with ED and PDE5i prescription and males with nitrate prescription were identified from a U.S. electronic health record database (2012-2016). Quantitative comparisons were made between patients with ED and co-possession (ED + PDE5i + nitrate), only nitrate possession (ED + nitrate and nitrate only [without ED]), and only PDE5i possession (ED + PDE5i). OUTCOMES: We quantified incidence of CV outcomes in co-possession and comparator periods, calculating incidence rate ratios after propensity score matching. Prescriber rationales were derived by reviewing virtual patient records. RESULTS: Over 168,000 patients had ≥1 PDE5i prescription (∼241,000 possession periods); >480,000 patients had ≥1 nitrate prescription (∼486,000 possession periods); and 3,167 patients had 3,668 co-possession periods. Non-significantly different or lower rates of CV outcomes were observed for co-possession periods vs ED + nitrate and nitrate only periods. Most CV outcome rates were non-significantly different between co-possession and ED + PDE5i periods (myocardial infarction, hospitalized unstable angina and fainting were higher with co-possession). From qualitative assessment of patient records with co-possession, 131 of 252 (52%) documented discussion with a physician regarding co-possession; 69 of 131 (53%) warned or instructed on safely managing these contraindicated medications. CLINICAL IMPLICATIONS: Findings from this real-world study indicate that co-possession of nitrate and PDE5i prescriptions is not associated with increased rates of CV outcomes, relative to possession of nitrates alone. Physicians should and often do discuss the risks of using both medications together with their patients. STRENGTHS & LIMITATIONS: Strengths of this study are the large size of the U.S. real-world patient cohort with data available for analysis, and our ability to utilize natural language processing to explore co-prescription rationales and patient-physician interactions. Limitations are the retrospective nature of the analysis and inability to establish whether recorded prescriptions were filled or the medication was consumed. CONCLUSION: Co-exposure of PDE5i and nitrates should continue to be avoided; however, co-possession of PDE5i and nitrate prescriptions is not necessarily associated with increased CV risk. Co-possession can be successfully managed in suitable circumstances. Nunes AP, Seeger JD, Stewart A, et al. Cardiovascular Outcome Risks in Patients With Erectile Dysfunction Co-Prescribed a Phosphodiesterase Type 5 Inhibitor (PDE5i) and a Nitrate: A Retrospective Observational Study Using Electronic Health Record Data in the United States. J Sex Med 2021;18:1511-1523.

Multinational descriptive analysis of the real-world burden of headache using the Migraine Buddy application.

BACKGROUND AND PURPOSE: A large proportion of headache sufferers do not routinely seek medical care. App-based technologies permit the collection of real-world data over time and between countries that can help assess true burden of headache. This study used a mobile phone application to collect information on the real-world burden of self-diagnosed headache and to describe its impact on daily life in headache sufferers who do not routinely seek medical advice. METHODS: This retrospective, non-interventional, cross-sectional study analysed self-reported data from users of the 'Migraine Buddy' app. The main objective was to describe self-reported characteristics of headache and migraine (triggers, duration, frequency), treatment patterns and impact on daily activity in headache sufferers from Australia, Brazil, France, Germany and Japan. Data including demographics, self-diagnosed episode type (headache/migraine), duration, potential triggers and impact on daily activity are reported. All analyses were exploratory and performed per country. RESULTS: Self-reported data were collected from 60,474 users between August 2016 and August 2018. Approximately 90% of users were females; >60% were aged 24-45 years. Over one-third of users reported having two to five episodes of headache or migraine per month; impact included impaired concentration, being slower and missing work or social activities. Variations across countries were observed; within countries, episode characteristics were very similar for self-diagnosed headache versus migraine. CONCLUSIONS: Headache tracking was used to describe the experience, impact and self-management approaches of migraine and headache sufferers in a real-world setting. Headache disorders present a range of important issues for patients that deserve more study and reinforce the need for better approaches to management.

The road goes ever on and on-a socio-physiological analysis of travel-related issues in Super Rugby.

Air travel is a key factor in Super Rugby and can have a negative influence on players' performance and well-being. The aim of this study was to identify the current practice to reduce the effects of air travel and to understand the rationale behind these interventions. "Travel managers" from eight Super Rugby teams were interviewed and answered a questionnaire. A qualitative description was performed to identify common themes and differences between participants' answers. To protect the privacy and identity of the participants, all data have been de-identified and represented as two fictionalised amalgams (Bob and Peter). The rationale behind each intervention appeared to be based on a mix of anecdotal, practice and, occasionally, literature, confirming that scientific findings are not always easily translatable to applied settings. Two different approaches, clinical (Bob) and holistic (Peter), were identified. Even if both characters acknowledge that travel variables are too many to control, it appears that team culture and practices are perceived as important as biological interventions in controlling the negative effects of travel on players' performance and well-being.