Time-course of heart rate variability after total hip arthroplasty.

Heart rate variability (HRV) is a measure of the autonomic nervous system function and possibly related to postoperative outcome. Despite several HRV studies in different surgical settings, optimal indices and timepoints for measuring have not been adequately determined. Consequently, there is a need for detailed descriptive procedure-specific studies on the time-course of perioperative HRV within a modern fast-track surgical setting. We measured HRV continuously in 24 patients from 4 days before until 9 days after total hip arthroplasty (THA). Statistical methods included mainly ANOVA and t-tests or Kruskal-Wallis and pairwise Wilcoxon test. Patients completed the Orthostatic Discriminant and Severity Scale five times during the study describing autonomic nervous system dysfunction. Standard deviation between normal-to-normal beats and the total power of HRV were reduced for at least 9 days following THA, with a trend towards increased HRV leading up to the day of surgery. The balance between low- and high-frequency power of HRV was reduced in the postoperative evenings. There was increased orthostatic intolerance symptoms on the first postoperative day, with symptoms of pain, fatigue and weakness decreasing after the first postoperative day. Median hospital stay was 1 day. We provide the first detailed description of perioperative time-course of HRV and orthostatic symptoms in fast-track THA, showing reduced HRV after surgery for at least a week, and that HRV changes are sensitive to time of day and timing before and after surgery. These results are helpful in designing future HRV studies in perioperative risk assessment and outcome.

Autonomic dysfunction after mild acute ischemic stroke and six months after: a prospective observational cohort study.

INTRODUCTION: Autonomic dysfunction is prevalent in ischemic stroke patients and associated with a worse clinical outcome. We aimed to evaluate autonomic dysfunction over time and the tolerability of the head-up tilt table test in an acute stroke setting to optimize patient care. PATIENTS AND METHOD: In a prospective observational cohort study, patients were consecutively recruited from an acute stroke unit. The patients underwent heart rate and blood pressure analysis during the Valsalva maneuver, deep breathing, active standing, and head-up tilt table test if active standing was tolerated. In addition, heart rate variability and catecholamines were measured. All tests were performed within seven days after index ischemic stroke and repeated at six months follow-up. RESULTS: The cohort was comprised of 91 acute stroke patients, mean (SD) age 66 (11) years, median (IQR) initial National Institute of Health Stroke Scale 2 (1-4) and modified Ranking Scale 2 (1-3). The head-up tilt table test revealed 7 patients (10%) with orthostatic hypotension. The examination was terminated before it was completed in 15%, but none developed neurological symptoms. In the acute state the prevalence of autonomic dysfunction varied between 10-100% depending on the test. No changes were found in presence and severity of autonomic dysfunction over time. CONCLUSION: In this cohort study of patients with mild stroke, autonomic dysfunction was highly prevalent and persisted six months after index stroke. Head-up tilt table test may be used in patients who tolerate active standing. Autonomic dysfunction should be recognized and handled in the early phase after stroke.

Orthostatic intolerance after acute mild hypovolemia: incidence, pathophysiologic hemodynamics, and heart-rate variability analysis-a prospective observational cohort study.

PURPOSE: Early postoperative mobilization can be hindered by orthostatic intolerance (OI). Postoperative OI has multifactorial pathogenesis, possibly involving both postoperative hypovolemia and autonomic dysfunction. We aimed to investigate the effect of mild acute blood loss from blood donation simulating postoperative hypovolemia, on both autonomic function and OI, thus eliminating confounding perioperative factors such as inflammation, residual anesthesia, pain, and opioids. METHODS: This prospective observational cohort study included 26 blood donors. Continuous electrocardiogram data were collected during mobilization and night sleep, both before and after blood donation. A Valsalva maneuver and a standardized mobilization procedure were performed immediately before and after blood donation, during which cardiovascular and tissue oxygenation variables were continuously measured by LiDCOrapid™ and Massimo Root™, respectively. The incidence of OI, hemodynamic responses during mobilization and Valsalva maneuver, as well as heart rate variability (HRV) responses during mobilization and sleep were compared before and 15 min after blood donation. RESULTS: Prior to blood donation, no donors experienced OI during mobilization. After blood donation, 6/26 (23%; 95% CI, 9 to 44) donors experienced at least one OI symptom. Three out of 26 donors (12%; 95% CI, 2 to 30) terminated the mobilization procedure prematurely because of severe OI symptoms. Cardiovascular and cerebral tissue oxygenation responses were reduced in patients with severe OI. After blood loss, HRV indices of total autonomic power remained unchanged but increased sympathetic and decreased parasympathetic outflow was observed during mobilization, but also during sleep, indicating a prolonged autonomic effect of hypovolemia. CONCLUSION: We describe a specific hypovolemic component of postoperative OI, independent of postoperative autonomic dysfunction, inflammation, opioids, and pain. STUDY REGISTRATION: ClinicalTrials.gov (NCT04499664); registered 5 August 2020.

RéSUMé: OBJECTIF: La mobilisation postopératoire précoce peut être entravée par une intolérance orthostatique (IO). L'IO postopératoire a une pathogenèse multifactorielle, impliquant peut-être à la fois une hypovolémie postopératoire et un dysfonctionnement autonome. Notre objectif était d'étudier l'effet d'une légère perte de sang aiguë due au don de sang simulant une hypovolémie postopératoire, à la fois sur la fonction autonome et sur l'IO, éliminant ainsi les facteurs périopératoires confondants tels que l'inflammation, l'anesthésie résiduelle, la douleur et les opioïdes. MéTHODE: Cette étude de cohorte observationnelle prospective comprenait 26 personnes ayant donné leur sang. Des données d'électrocardiogramme continu ont été recueillies pendant la mobilisation et le sommeil nocturne, avant et après le don de sang. Une manœuvre de Valsalva et une procédure de mobilisation standardisée ont été réalisées immédiatement avant et après le don de sang, au cours desquelles les variables d'oxygénation cardiovasculaire et tissulaire ont été mesurées en continu avec les moniteurs LiDCOrapid™ et Massimo Root™, respectivement. L'incidence d'IO, les réponses hémodynamiques pendant la mobilisation et la manœuvre de Valsalva, ainsi que les réponses de variabilité de la fréquence cardiaque (VFC) pendant la mobilisation et le sommeil ont été comparées avant et 15 minutes après le don de sang. RéSULTATS: Avant le don de sang, aucune personne ayant fait un don de sang n'a ressenti d'IO pendant la mobilisation. Après le don de sang, 6/26 (23 %; IC 95 %, 9 à 44) des donneurs et donneuses ont manifesté au moins un symptôme d'IO. Trois personnes sur 26 (12 %; IC 95 %, 2 à 30) ont interrompu prématurément la procédure de mobilisation en raison de symptômes graves d'IO. Les réponses d'oxygénation des tissus cardiovasculaires et cérébraux ont été réduites chez les personnes atteintes d'IO sévère. Après la perte de sang, les indices de VFC de la puissance totale autonome sont demeurés inchangés, mais une augmentation du flux sympathique et une diminution du flux parasympathique ont été observées pendant la mobilisation, mais également pendant le sommeil, indiquant un effet autonome prolongé de l'hypovolémie. CONCLUSION: Nous décrivons une composante spécifique hypovolémique de l'IO postopératoire, indépendante du dysfonctionnement autonome postopératoire, de l'inflammation, des opioïdes et de la douleur. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04499664); enregistrée le 5 août 2020.

Continuous perioperative heart rate variability monitoring in video-assisted thoracoscopic surgery lobectomy-a pilot study.

Heart rate variability (HRV) is a measure of cardiac autonomic modulation and is potentially related to hypotension, postoperative atrial fibrillation, and orthostatic intolerance. However, there is a lack of knowledge on which specific time points and indices to measure. To improve future study design, there is a need for procedure-specific studies in an enhanced recovery after surgery (ERAS) video-assisted thoracic surgery (VATS) lobectomy setting, and for continuous measurement of perioperative HRV. HRV was measured continuously from 2 days before until 9 days after VATS lobectomy in 28 patients. After VATS lobectomy, with median length of stay = 4 days, the standard deviation between normal-to-normal beats and the total power of HRV were reduced for 8 days during the night and day times, while low-to-high frequency variation and detrended fluctuation analysis were stable. This is the first detailed study to show that HRV measures of total variability were reduced following ERAS VATS lobectomy, while other measures were more stable. Further, preoperative HRV measures showed circadian variation. The patch was well tolerated among participants, but actions should be taken to ensure proper mounting of the measuring device. These results demonstrate a valid design platform for future HRV studies in relation to postoperative outcomes.

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10-7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

Orthostatic intolerance after fast-track knee arthroplasty: Incidence and hemodynamic pathophysiology.

BACKGROUND: Early postoperative mobilization can be hindered by orthostatic intolerance (OI) due to failed orthostatic cardiovascular regulation. The underlying mechanisms are not fully understood and specific data after total knee arthroplasty (TKA) are lacking. Therefore, we evaluated the incidence of OI and the cardiovascular response to mobilization in fast-track TKA. METHODS: This prospective observational cohort study included 45 patients scheduled for primary TKA in spinal anesthesia with a multimodal opioid-sparing analgesic regime. OI and the cardiovascular response to sitting and standing were evaluated with a standardized mobilization procedure preoperatively, and at 6 and 24 h postoperatively. Hemodynamic variables were measured non-invasively (LiDCO™ Rapid). Perioperative bleeding, fluid balance, surgery duration, postoperative hemoglobin, opioid use, and pain during mobilization were recorded. RESULTS: Eighteen (44%) and 8 (22%) patients demonstrated OI at 6 and 24 h after surgery, respectively. Four (10%) and 2 (5%) patients experienced severe OI and terminated the mobilization procedure prematurely. Dizziness was the most common OI symptom during mobilization at 6 h. OI was associated with decreased orthostatic responses in systolic, diastolic, mean arterial pressures, and heart rate (all p < .05), while severe OI patients demonstrated impaired diastolic, mean arterial pressures, heart rate, and cardiac output responses (all p < .05). No statistically significant differences in perioperative bleeding, fluid balance, surgery duration, postoperative hemoglobin, pain, or opioid use were observed between orthostatic tolerant and intolerant patients. CONCLUSION: Early postoperative OI is common following fast-track TKA. Pathophysiologic mechanisms include impaired orthostatic cardiovascular responses. The progression to severe OI symptoms appears to be primarily due to inadequate heart rate response.

Normative values of short-term heart rate variability in a cross-sectional study of a Danish population. The DanFunD study.

AIMS: The autonomic nervous system includes parasympathetic and sympathetic components that monitor and regulate most of the bodily functions and play a central role in the physiology and homeostasis of the human body. Heart rate variability is a non-invasive tool for quantification of rhythmic fluctuations in heart rate that reflects the function of the autonomic nervous system. The study aims to describe the heart rate variability distribution in the general population, stratified in sex and age groups, which is currently insufficiently described. METHODS: A cross-sectional population-based study recruited participants in 10 municipalities in the western part of the greater Copenhagen area in Denmark, including 6891 men and women aged 18-72 years (participation rate was 29.5%). Short-term heart rate variability measures were obtained and related to age and gender. RESULTS: Both time and frequency domain measures showed a huge variation in the different sex and age groups. Women had a higher median heart rate than men, and the association with age was U-shaped. Measures indicating a predominance of the parasympathetic component in relation to the sympathetic component were more frequent in women and younger age groups. CONCLUSIONS: Both sex and age influence the heart rate variability in this adult Danish population. Therefore, our age- and sex-related reference values of heart rate variability in the time and frequency domain should be used in further epidemiological and clinical research.

Preoperative heart rate variability as a predictor of perioperative outcomes: a systematic review without meta-analysis.

Heart rate variability (HRV) is a predictor of mortality and morbidity after non-lethal cardiac ischemia, but the relation between preoperatively measured HRV and intra- and postoperative complications is sparsely studied and most recently reviewed in 2007. We, therefore, reviewed the literature regarding HRV as a predictor for intra- and postoperative complications and outcomes. We carried out a systematic review without meta-analysis. A PICO model was set up, and we searched PubMed, EMBASE, and CENTRAL. The screening was done by one author, but all authors performed detailed review of the included studies. We present data from studies on intraoperative and postoperative complications, which were too heterogeneous to warrant formal meta-analysis, and we provide a pragmatic review of HRV indices to facilitate understanding our findings. The review was registered in PROSPERO (CRD42021230641). We screened 2337 records for eligibility. 131 records went on to full-text assessment, 63 were included. In frequency analysis of HRV, low frequency to high frequency ratio could be a predictor for intraoperative hypotension in spinal anesthesia and lower total power could possibly predict intraoperative hypotension under general anesthesia. Detrended fluctuation analysis of HRV is a promising candidate for predicting postoperative atrial fibrillation. This updated review of the relation between preoperative HRV and surgical outcome suggests a clinically relevant role of HRV but calls for high quality studies due to methodological heterogeneity in the current literature. Areas for future research are suggested.

A physiological model of the inflammatory-thermal-pain-cardiovascular interactions during an endotoxin challenge.

KEY POINTS: Inflammation in response to bacterial endotoxin challenge impacts physiological functions, including cardiovascular, thermal and pain dynamics, although the mechanisms are poorly understood. We develop an innovative mathematical model incorporating interaction pathways between inflammation and physiological processes observed in response to an endotoxin challenge. We calibrate the model to individual data from 20 subjects in an experimental study of the human inflammatory and physiological responses to endotoxin, and we validate the model against human data from an independent study. Using the model to simulate patient responses to different treatment modalities reveals that a multimodal treatment combining several therapeutic strategies gives the best recovery outcome. ABSTRACT: Uncontrolled, excessive production of pro-inflammatory mediators from immune cells and traumatized tissues can cause systemic inflammatory conditions such as sepsis, one of the ten leading causes of death in the USA, and one of the three leading causes of death in the intensive care unit. Understanding how inflammation affects physiological processes, including cardiovascular, thermal and pain dynamics, can improve a patient's chance of recovery after an inflammatory event caused by surgery or a severe infection. Although the effects of the autonomic response on the inflammatory system are well-known, knowledge about the reverse interaction is lacking. The present study develops a mathematical model analyzing the inflammatory system's interactions with thermal, pain and cardiovascular dynamics in response to a bacterial endotoxin challenge. We calibrate the model with individual data from an experimental study of the inflammatory and physiological responses to a one-time administration of endotoxin in 20 healthy young men and validate it against data from an independent endotoxin study. We use simulation to explore how various treatments help patients exposed to a sustained pathological input. The treatments explored include bacterial endotoxin adsorption, antipyretics and vasopressors, as well as combinations of these. Our findings suggest that the most favourable recovery outcome is achieved by a multimodal strategy, combining all three interventions to simultaneously remove endotoxin from the body and alleviate symptoms caused by the immune system as it fights the infection.

Investigating the aetiology of adverse events following HPV vaccination with systems vaccinology.

In contrast to the insidious and poorly immunogenic human papillomavirus (HPV) infections, vaccination with the HPV virus-like particles (vlps) is non-infectious and stimulates a strong neutralizing-antibody response that protects HPV-naïve vaccinees from viral infection and associated cancers. However, controversy about alleged adverse events following immunization (AEFI) with the vlps have led to extensive reductions in vaccine acceptance, with countries like Japan dropping it altogether. The AEFIs are grouped into chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). In this review, we present a hypothesis that the AEFIs might arise from malfunctions within the immune system when confronted with the unusual antigen. In addition, we outline how the pathophysiology of the AEFIs can be cost-effectively investigated with the holistic principles of systems vaccinology in a two-step process. First, comprehensive immunological profiles of HPV vaccinees exhibiting the AEFIs are generated by integrating the data derived from serological profiling for prominent HPV antibodies and serum cytokines, with data from serum metabolomics, peripheral white blood cells transcriptomics and gut microbiome profiling. Next, the immunological profiles are compared with corresponding profiles generated for matched (a) HPV vaccinees without AEFIs; (b) non-HPV-vaccinated individuals with CFS/ME-like symptoms; and (c) non-HPV-vaccinated individuals without CFS/ME. In these comparisons, any causal links between HPV vaccine and the AEFIs, as well as the underlying molecular basis for the links will be revealed. Such a study should provide an objective basis for evaluating HPV vaccine safety and for identifying biomarkers for individuals at risk of developing AEFI with HPV vaccination.

An optimal control approach for blood pressure regulation during head-up tilt.

This paper presents an optimal control approach to modeling effects of cardiovascular regulation during head-up tilt (HUT). Many patients who suffer from dizziness or light-headedness are administered a head-up tilt test to explore potential deficits within the autonomic control system, which maintains the cardiovascular system at homeostasis. This system is complex and difficult to study in vivo, and thus we propose to use mathematical modeling to achieve a better understanding of cardiovascular regulation during HUT. In particular, we show the feasibility of using optimal control theory to compute physiological control variables, vascular resistance and cardiac contractility, quantities that cannot be measured directly, but which are useful to assess the state of the cardiovascular system. A non-pulsatile lumped parameter model together with pseudo- and clinical data are utilized in the optimal control problem formulation. Results show that the optimal control approach can predict time-varying quantities regulated by the cardiovascular control system. Our results compare favorable to our previous study using a piecewise linear spline approach, less a priori knowledge is needed, and results were obtained at a significantly lower computational cost.

Cardiovascular dynamics during head-up tilt assessed via pulsatile and non-pulsatile models.

This study develops non-pulsatile and pulsatile models for the prediction of blood flow and pressure during head-up tilt. This test is used to diagnose potential pathologies within the autonomic control system, which acts to keep the cardiovascular system at homeostasis. We show that mathematical modeling can be used to predict changes in cardiac contractility, vascular resistance, and arterial compliance, quantities that cannot be measured but are useful to assess the system's state. These quantities are predicted as time-varying parameters modeled using piecewise linear splines. Having models with various levels of complexity formulated with a common set of parameters, allows us to combine long-term non-pulsatile simulations with pulsatile simulations on a shorter time-scale. We illustrate results for a representative subject tilted head-up from a supine position to a [Formula: see text] angle. The tilt is maintained for 5 min before the subject is tilted back down. Results show that if volume data is available for all vascular compartments three parameters can be identified, cardiovascular resistance, vascular compliance, and ventricular contractility, whereas if model predictions are made against arterial pressure and cardiac output data alone, only two parameters can be estimated either resistance and contractility or resistance and compliance.

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

Optical coherence tomography in acute optic neuritis: A population-based study.

OBJECTIVES: To measure early structural damage caused by autoimmune inflammatory optic neuritis (ON) by optical coherence tomography (OCT) in a population-based cohort. METHODS: In a prospective population-based study over 24 months in Southern Denmark, patients diagnosed with acute ON and without prior diagnosis of a chronic neuroinflammatory disorder were included and examined with OCT, visual evoked potentials (VEP), visual fields, high contrast visual acuity (HCVA), and low contrast letter acuity (LCLA). Structural and functional outcomes were determined at 6-month follow-up based on interocular differences. RESULTS: The 50 included patients had on average 16.9 µm peripapillary retinal nerve fiber layer loss, 10.6 µm ganglion cell and inner plexiform layer (GCIP) loss, and an average HCVA decrease of 0.22 dec. Based on a linear regression model, average GCIP loss amounted to -0.2 µm per day and started 8 days after onset. OCT outcomes but not VEP correlated well with all visual function measurements at follow-up. Structural and functional damage in 20 patients (40%) diagnosed de novo with multiple sclerosis (MS) and in 2 patients (4%) with positive myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) test did not differ from patients with idiopathic ON. CONCLUSIONS: Optic neuritis causes substantial retinal damage and vision loss independent of the underlying disease. Our study supports that GCIP damage starts closely to clinical onset. Good structure-function correlations between OCT and vision support the importance of OCT in monitoring acute ON.

Intravenous saline administration in patients with severe acquired brain injury and orthostatic intolerance for tilt-table mobilization.

PRIMARY OBJECTIVE: This study aimed to investigate the effect of intravenous saline administration on orthostatic hypotension (OH) during head up tilt (HUT) and the change in the renin-angiotensin-aldosterone system before and after HUT in patients with severe acquired brain injury (ABI). RESEARCH DESIGN: The study is designed as an observational study. METHODS AND PROCEDURES: Fourteen patients with ABI, low level of consciousness and OH were monitored before, during and after HUT with non-invasive beat-to-beat blood pressure measurement, and transcranial Doppler determination of middle cerebral artery blood flow velocity. Blood samples were collected before and after two HUT sessions separated by 1 hour and saline was administered in between. MAIN OUTCOMES AND RESULTS: Patients' ability to stand upright did not change after saline administration due to OH. The patients showed signs of reduced cerebral autoregulation at both HUT sessions. The patients had a significant lower level of renin and angiotensin II but not aldosterone. CONCLUSIONS: Patients with severe ABI and OH demonstrate no improvement in standing time with reduced plasma renin and angiotensin II after two HUT sessions and 1 hour fluid administration. Research focusing on the ability to retain fluid after bed rest is warranted.

Semen Quality as a Predictor of Subsequent Morbidity: A Danish Cohort Study of 4,712 Men With Long-Term Follow-up.

Semen quality has been suggested to be a biological marker of long-term morbidity and mortality; however, few studies have been conducted on this subject. We identified 5,370 men seen for infertility at Frederiksberg Hospital, Denmark, during 1977-2010, and 4,712 of these men were followed in the Danish National Patient Registry until first hospitalization, death, or the end of the study. We classified patients according to hospitalizations and the presence of cardiovascular disease, diabetes, testicular cancer, or prostate cancer. We found a clear association between sperm concentration below 15 million/mL and all-cause hospitalizations (hazard ratio = 1.5, 95% confidence interval: 1.4, 1.6) and cardiovascular disease (hazard ratio = 1.4, 95% confidence interval: 1.2, 1.6), compared with men with a concentration above 40 million/mL. The probabilities for hospitalizations were also higher with a low total sperm count and low motility. Men with a sperm concentration of 195-200 million/mL were, on average, hospitalized for the first time 7 years later than were men with a sperm concentration of 0-5 million/mL. Semen quality was associated with long-term morbidity, and a significantly higher risk of hospitalization was found, in particular for cardiovascular diseases and diabetes mellitus. Our study supports the suggestion that semen quality is a strong biomarker of general health.

Integrated Inflammatory Stress (ITIS) Model.

During the last decade, there has been an increasing interest in the coupling between the acute inflammatory response and the Hypothalamic-Pituitary-Adrenal (HPA) axis. The inflammatory response is activated acutely by pathogen- or damage-related molecular patterns, whereas the HPA axis maintains a long-term level of the stress hormone cortisol which is also anti-inflammatory. A new integrated model of the interaction between these two subsystems of the inflammatory system is proposed and coined the integrated inflammatory stress (ITIS) model. The coupling mechanisms describing the interactions between the subsystems in the ITIS model are formulated based on biological reasoning and its ability to describe clinical data. The ITIS model is calibrated and validated by simulating various scenarios related to endotoxin (LPS) exposure. The model is capable of reproducing human data of tumor necrosis factor alpha, adrenocorticotropic hormone (ACTH) and cortisol and suggests that repeated LPS injections lead to a deficient response. The ITIS model predicts that the most extensive response to an LPS injection in ACTH and cortisol concentrations is observed in the early hours of the day. A constant activation results in elevated levels of the variables in the model while a prolonged change of the oscillations in ACTH and cortisol concentrations is the most pronounced result of different LPS doses predicted by the model.

Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Early postoperative mobilization is essential for rapid recovery but may be impaired by orthostatic intolerance (OI) and orthostatic hypotension (OH), which are highly prevalent after major surgery. Pathogenic mechanisms include an insufficient postoperative vasopressor response. The oral α-1 agonist midodrine hydrochloride increases vascular resistance, and the authors hypothesized that midodrine would reduce the prevalence of OH during mobilization 6 h after total hip arthroplasty relative to placebo. METHODS: This double-blind, randomized trial allocated 120 patients 18 yr or older and scheduled for total hip arthroplasty under spinal anesthesia to either 5 mg midodrine hydrochloride or placebo orally 1 h before mobilization at 6 and 24 h postoperatively. The primary outcome was the prevalence of OH (decrease in systolic or diastolic arterial pressures of > 20 or 10 mmHg, respectively) during mobilization 6 h after surgery. Secondary outcomes were OI and hemodynamic responses to mobilization at 6 and 24 h. RESULTS: At 6 h, 14 (25%; 95% CI, 14 to 38%) versus 23 (39.7%; 95% CI, 27 to 53%) patients had OH in the midodrine and placebo group, respectively, relative risk 0.63 (0.36 to 1.10; P = 0.095), whereas OI was present in 15 (25.0%; 15 to 38%) versus 22 (37.3%; 25 to 51%) patients, relative risk 0.68 (0.39 to 1.18; P = 0.165). At 24 h, OI and OH prevalence did not differ between groups. CONCLUSIONS: Preemptive use of oral 5 mg midodrine did not significantly reduce the prevalence of OH during early postoperative mobilization compared with placebo. However, further studies on dose and timing are warranted since midodrine is effective in chronic OH conditions.

Blunted autonomic response in cluster headache patients.

BACKGROUND: Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. METHODS AND MATERIALS: Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. RESULTS: CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (-2.86 vs. -13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, -0.05 vs. -0.17, p < 0.05). CONCLUSIONS: CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.