Shrinkage-based Random Local Clocks with Scalable Inference.

Molecular clock models undergird modern methods of divergence-time estimation. Local clock models propose that the rate of molecular evolution is constant within phylogenetic subtrees. Current local clock inference procedures exhibit one or more weaknesses, namely they achieve limited scalability to trees with large numbers of taxa, impose model misspecification, or require a priori knowledge of the existence and location of clocks. To overcome these challenges, we present an autocorrelated, Bayesian model of heritable clock rate evolution that leverages heavy-tailed priors with mean zero to shrink increments of change between branch-specific clocks. We further develop an efficient Hamiltonian Monte Carlo sampler that exploits closed form gradient computations to scale our model to large trees. Inference under our shrinkage clock exhibits a speed-up compared to the popular random local clock when estimating branch-specific clock rates on a variety of simulated datasets. This speed-up increases with the size of the problem. We further show our shrinkage clock recovers known local clocks within a rodent and mammalian phylogeny. Finally, in a problem that once appeared computationally impractical, we investigate the heritable clock structure of various surface glycoproteins of influenza A virus in the absence of prior knowledge about clock placement. We implement our shrinkage clock and make it publicly available in the BEAST software package.

Scalable Bayesian Divergence Time Estimation With Ratio Transformations.

Divergence time estimation is crucial to provide temporal signals for dating biologically important events from species divergence to viral transmissions in space and time. With the advent of high-throughput sequencing, recent Bayesian phylogenetic studies have analyzed hundreds to thousands of sequences. Such large-scale analyses challenge divergence time reconstruction by requiring inference on highly correlated internal node heights that often become computationally infeasible. To overcome this limitation, we explore a ratio transformation that maps the original $N-1$ internal node heights into a space of one height parameter and $N-2$ ratio parameters. To make the analyses scalable, we develop a collection of linear-time algorithms to compute the gradient and Jacobian-associated terms of the log-likelihood with respect to these ratios. We then apply Hamiltonian Monte Carlo sampling with the ratio transform in a Bayesian framework to learn the divergence times in 4 pathogenic viruses (West Nile virus, rabies virus, Lassa virus, and Ebola virus) and the coralline red algae. Our method both resolves a mixing issue in the West Nile virus example and improves inference efficiency by at least 5-fold for the Lassa and rabies virus examples as well as for the algae example. Our method now also makes it computationally feasible to incorporate mixed-effects molecular clock models for the Ebola virus example, confirms the findings from the original study, and reveals clearer multimodal distributions of the divergence times of some clades of interest.

Relaxed Random Walks at Scale.

Relaxed random walk (RRW) models of trait evolution introduce branch-specific rate multipliers to modulate the variance of a standard Brownian diffusion process along a phylogeny and more accurately model overdispersed biological data. Increased taxonomic sampling challenges inference under RRWs as the number of unknown parameters grows with the number of taxa. To solve this problem, we present a scalable method to efficiently fit RRWs and infer this branch-specific variation in a Bayesian framework. We develop a Hamiltonian Monte Carlo (HMC) sampler to approximate the high-dimensional, correlated posterior that exploits a closed-form evaluation of the gradient of the trait data log-likelihood with respect to all branch-rate multipliers simultaneously. Our gradient calculation achieves computational complexity that scales only linearly with the number of taxa under study. We compare the efficiency of our HMC sampler to the previously standard univariable Metropolis-Hastings approach while studying the spatial emergence of the West Nile virus in North America in the early 2000s. Our method achieves at least a 6-fold speed increase over the univariable approach. Additionally, we demonstrate the scalability of our method by applying the RRW to study the correlation between five mammalian life history traits in a phylogenetic tree with $3650$ tips.[Bayesian inference; BEAST; Hamiltonian Monte Carlo; life history; phylodynamics, relaxed random walk.].

Optical magnetization, part III: theory of molecular magneto-electric rectification.

A fully quantized analysis is presented of induced magneto-electric rectification in individual diatomic molecules in the steady-state regime. Good agreement is obtained between this quantum theory and a classical model that includes the same key kinematic elements but predicts temporal dynamics as well. At the molecular level, an enhanced magneto-electric optical interaction driven by dual optical fields E and H* is shown to give rise to a static electric dipole (ED) moment oriented along the propagation direction of linearly-polarized light in dielectric materials. This longitudinal Hall effect or "charge separation" interaction is quadratic with respect to the incident field strength and exhibits an induced moment that is limited by the ED transition moment of the molecular resonance. Overall, the two-photon dynamics can be described as first establishing an electric polarization and imparting orbital angular momentum on which the magnetic field exerts torque in the excited state of the molecule. Magnetic torque mediates an exchange of orbital and rotational angular momenta that de-excites the molecule and simultaneously enhances magneto-electric rectification. Material properties that affect magneto-electric response at the molecular level are identified.

Optical magnetization, Part I: Experiments on radiant optical magnetization in solids.

Linearly-polarized magnetic dipole (MD) scattering as intense as Rayleigh scattering is reported in transparent garnet crystals and fused quartz through a magneto-electric interaction at the molecular level. Radiation patterns in quartz show the strongest optical magnetization relative to electric polarization ever reported. As shown in an accompanying paper, quantitative agreement is achieved with a strong-field, fully-quantized theory of magneto-electric (M-E) interactions in molecular media. The conclusion is reached that magnetic torque enables 2-photon resonance in an EH* process that excites molecular librations and accounts for the observed upper limit on magnetization. Second-order M-E dynamics can also account for unpolarized scattering from high-frequency librations previously ascribed to first-order collision-induced or third-order, all-electric processes.

Optical magnetization, Part II: Theory of induced optical magnetism.

A fully quantized analysis is presented on the origin of induced magnetic dipole (MD) scattering in two-level diatomic molecules. The interaction is driven by dual optical fields, E and H*, and is universally allowed in dielectric optical materials, including centrosymmetric media. Leading terms of the interaction are shown to be quadratic and cubic with respect to the intensity, predicting an upper limit for the induced magnetic dipole scattering intensity (IMD∝m2) that is equal to the electric dipole scattering (IED∝p2). The optical dynamics proceed by first establishing an electric polarization in the system. Then the magnetic field exerts torque on the orbital angular momentum of the excited state, mediating an exchange of orbital and rotational angular momenta that enhances the magnetic moment. The magneto-electric interaction also accounts for second-order, unpolarized scattering from high-frequency librations previously ascribed to third-order, all-electric processes.

Scalable Bayesian phylogenetics.

Recent advances in Bayesian phylogenetics offer substantial computational savings to accommodate increased genomic sampling that challenges traditional inference methods. In this review, we begin with a brief summary of the Bayesian phylogenetic framework, and then conceptualize a variety of methods to improve posterior approximations via Markov chain Monte Carlo (MCMC) sampling. Specifically, we discuss methods to improve the speed of likelihood calculations, reduce MCMC burn-in, and generate better MCMC proposals. We apply several of these techniques to study the evolution of HIV virulence along a 1536-tip phylogeny and estimate the internal node heights of a 1000-tip SARS-CoV-2 phylogenetic tree in order to illustrate the speed-up of such analyses using current state-of-the-art approaches. We conclude our review with a discussion of promising alternatives to MCMC that approximate the phylogenetic posterior. This article is part of a discussion meeting issue 'Genomic population structures of microbial pathogens'.

Epidemiological hypothesis testing using a phylogeographic and phylodynamic framework.

Computational analyses of pathogen genomes are increasingly used to unravel the dispersal history and transmission dynamics of epidemics. Here, we show how to go beyond historical reconstructions and use spatially-explicit phylogeographic and phylodynamic approaches to formally test epidemiological hypotheses. We illustrate our approach by focusing on the West Nile virus (WNV) spread in North America that has substantially impacted public, veterinary, and wildlife health. We apply an analytical workflow to a comprehensive WNV genome collection to test the impact of environmental factors on the dispersal of viral lineages and on viral population genetic diversity through time. We find that WNV lineages tend to disperse faster in areas with higher temperatures and we identify temporal variation in temperature as a main predictor of viral genetic diversity through time. By contrasting inference with simulation, we find no evidence for viral lineages to preferentially circulate within the same migratory bird flyway, suggesting a substantial role for non-migratory birds or mosquito dispersal along the longitudinal gradient.

Prolonged QT interval, syncope, and delirium with galantamine.

OBJECTIVE: To describe a case of QT interval prolongation, syncope, and delirium associated with galantamine use and to analyze similar cases related to acetylcholinesterase inhibitors (AChIs) reported to the Australian Adverse Drug Reaction Advisory Committee (ADRAC). CASE SUMMARY: An 85-year-old man with dementia was treated with prolonged release galantamine 8 mg daily for 1.5 years. Three months prior to the current admission, he had a syncopal episode with low blood pressure and bradycardia. Two months later, galantamine was withdrawn, but within 2 weeks, the man developed marked cognitive, behavioral, and functional deterioration and galantamine was restarted. Three weeks later, he developed syncope, delirium, hypotension, and prolonged QT interval with serious cardiac arrhythmias, in addition to vomiting and diarrhea. A complete blood cell count and biochemistry panel performed on admission were normal. No infection was detected. Galantamine and irbesartan were ceased. The delirium fully resolved in 6 days, and the QT interval shortened from 503 to 443 msec (corrected by Bazett's formula) 4 days after discontinuation of galantamine and remained normal. DISCUSSION: In the ADRAC reports, galantamine was associated with 18 cases of delirium/confusion, 8 of syncope, 13 of bradycardia, 6 of other arrhythmias or conduction abnormalities, and 6 of hypotension. Donepezil was associated with 56, 15, 26, 15, and 5, and rivastigmine with 21, 8, 6, 2, and 2, respectively, of these reactions. Five fatal outcomes were reported in association with galantamine, 11 with donepezil, and 3 with rivastigmine, including 3, 6, and 0 sudden deaths, respectively. This case, along with previously published reports and cases identified from the ADRAC database, illustrates that AChIs may lead to delirium, syncope, hypotension, and life-threatening arrhythmias. The Naranjo probability scale indicated that galantamine was the probable cause of QT interval prolongation, syncope, and delirium in this patient. CONCLUSIONS: Administration of galantamine and other AChIs requires vigilance and assessment of risk factors that may precipitate QT interval prolongation, syncope, and delirium.

Relationships between myocardial injury, all-cause mortality, vitamin D, PTH, and biochemical bone turnover markers in older patients with hip fractures.

This study examined the relationships between myocardial injury as indicated by serum cardiac troponin I (cTnI) elevation, 25 hydroxyvitamin D [25(OH)D], and PTH status and biochemical markers of bone metabolism in older patients with hip fracture (HF). In 238 consecutive patients (mean age 81.9 +/- 7.8 yr; 72% women) with low trauma HF, serum concentrations of cTnI, 25(OH)D, PTH, calcium, phosphorus, magnesium, osteocalcin, bone-specific alkaline phosphatase (BAP), and urine excretion of free deoxypyridinoline (DPD) and N-terminal cross-linked teleopeptide of type I collagen (NTx) were measured and clinical data were collected prospectively. Myocardial injury (cTnI >0.06 microg/L) presented in 29%, 25(OH)D deficiency (<50 nmol/L) in 81.6%, elevated PTH (>6.5 pmol/L) in 53%, and excessive bone resorption (increased DPD and/or NTx excretion) in 93.7%. Multivariate logistic regression showed that elevated serum PTH level is a major predictor of peri-operative myocardial injury (OR = 2.13; 95% CI 1.01-4.51; p = 0.049) and in-hospital all-cause mortality (OR = 18.5; 95% CI 2.0-72.3; p = 0.010), independent of age, sex, 25(OH)D status, and comorbidities. The degree of hyperparathyroidism was associated with the risk of cTnI elevation and the mortality rate. In cTnI positive patients, PTH levels correlated with cTnI concentrations (r = 0.28; p = 0.026) and urine DPD exretion (r = 0.37; p = 0.004). These results suggest for the first time that in older patients with HF, elevated PTH level is associated with peri-operative myocardial injury and in-hospital all-cause mortality, and that elevated PTH level contributes to both disturbed bone metabolism and poor outcomes.

Does heart rate predict mortality in older, low-level care residents?

To determine whether abnormalities in heart rate (HR) were associated with long-term mortality in older, low-level care residents, 179 randomly selected persons aged 65 and older (mean, 83.2+/-7.0 [SD] years; 80% women) were prospectively assessed. At baseline, duplicate measurements of HR and blood pressure were recorded in the supine position and after standing. During the 5-year follow-up period, 97 (54%) participants died. Cox survival analysis revealed no association with total mortality when resting HR was analyzed as a continuous or categoric variable (< or = 60, 61-89, and > 90 bpm). However, HR > or = 90 bpm was associated with increased risk of dying in residents who used a walking aid (relative risk, 3.48; 95% confidence interval, 1.07-11.30; p=0.038). Postural HR change was not associated with mortality risk. The authors concluded that resting HR and postural change in HR are not significant predictors of 5-year mortality in older, low-level care residents, except in persons using a walking aid.

Postprandial hypotension predicts all-cause mortality in older, low-level care residents.

OBJECTIVES: To evaluate which indices of blood pressure (BP) homeostasis are the strongest predictors of mortality in older low-level-care residents in long-term health facilities. DESIGN: Prospective cohort study. SETTING: Eight long-term healthcare facilities in Canberra, Australia. PARTICIPANTS: A total of 179 randomly selected semi-independent residents aged 65 and older (mean age+/-standard deviation 83.2+/-7.0; 80% women). MEASUREMENTS: Baseline BP levels taken while lying, after standing for 1 and 3 minutes, and sitting before and 1 hour after meal intake were recorded, as well as demographic information, chronic medical conditions, medications, and all-cause mortality during follow-up. Postprandial hypotension (PPH) was defined as a fall in systolic BP (SBP) of 20 mmHg or more 1 hour postmeal while sitting. Orthostatic hypotension (OH) was defined as a fall in SBP of 20 mmHg or more or in diastolic BP (DBP) of 10 mmHg or more within 3 minutes of standing from a supine position. Hypertension was defined as BP greater than 160/90 mmHg at commencement of the study. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated. RESULTS: At baseline, 47% of participants had hypertension, 38% PPH, and 23% OH; PP was 70 mmHg or greater in 54%, and DBP was 65 mmHg or lower in 6%. Over 4.7 years, 97 (54%) participants died. Those who died were significantly older and more likely to have PPH (47% vs 28%) and atrial fibrillation (35% vs 17%) and a significantly greater decrease in BP after meal intake. Mortality rates in those with and without PPH were 145.0 and 98.5 per 1,000 person-years, respectively. Using multivariate Cox proportional hazards models after adjustment for age, sex, presence of atrial fibrillation, Parkinson's disease, and use of diuretics, PPH was the only BP parameter that significantly and independently predicted 4.7-year all-cause mortality (relative risk (RR)=1.79; 95% confidence interval (CI)=1.19-2.68; P=.005). Further adjustment for the presence of OH, hypertension, low resting BP, coronary artery disease, cerebrovascular disease, congestive heart failure, history of syncope, cognitive impairment, cancer, diabetes mellitus, chronic obstructive pulmonary disease, and history of smoking did not reveal any new statistically significant associations. There was a dose-response relationship between postprandial fall in SBP and mortality rates. Absolute postprandial SBP of 120 mmHg or less was also significantly associated with total mortality (RR=1.69, 95% CI=1.04-2.78; P=.04). Low DBP was also associated with increased mortality (RR=1.10, 95% CI=1.01-1.13; P=.03), although this association became nonsignificant in multivariate analysis. CONCLUSION: In older low-level-care residents, PPH is an independent predictor of all-cause mortality with no added predictive value explained by other BP indices: OH, hypertension, PP, MAP.

Clinical profiles and risk factors for outcomes in older patients with cervical and trochanteric hip fracture: similarities and differences.

BACKGROUND: Data on clinical characteristics and outcomes in regard to hip fracture (HF) type are controversial. This study aimed to evaluate whether clinical and laboratory predictors of poorer outcomes differ by HF type. METHODS: Prospective evaluation of 761 consecutively admitted patients (mean age 82.3 ± 8.8 years; 74.9% women) with low-trauma non-pathological HF. Clinical characteristics and short-term outcomes were recorded. Haematological, renal, liver and thyroid status, C-reactive protein, cardiac troponin I, serum 25(OH) vitamin D, PTH, leptin, adiponectin and resistin were determined. RESULTS: The cervical compared to the tronchanteric HF group was younger, have higher mean haemoglobin, albumin, adiponectin and resistin and lower PTH levels (all P < 0.05). In-hospital mortality, length of hospital stay (LOS), incidence of post-operative myocardial injury and need of institutionalisation were similar in both groups. Multivariate analysis revealed as independent predictors for in-hospital death in patient with cervical HF male sex, hyperparathyroidism and lower leptin levels, while in patients with trochanteric HF only hyperparathyroidism; for post-operative myocardial injury dementia, smoking and renal impairment in the former group and coronary artery disease (CAD), hyperparathyroidism and hypoleptinaemia in the latter; for LOS > 20 days CAD, and age > 75 years and hyperparathyroidism, respectively. Need of institutionalisation was predicted by age > 75 years and dementia in both groups and also by hypovitaminosis D in the cervical and by hyperparathyroidism in the trochanteric HF. CONCLUSIONS: Clinical characteristics and incidence of poorer short-term outcomes in the two main HF types are rather similar but risk factors for certain outcomes are site-specific reflecting differences in underlying mechanisms.

Prevalence of vitamin K and vitamin D deficiency in patients with hepatobiliary and pancreatic disorders.

Little is known about the role of fat-soluble vitamins K and D in liver function and bone metabolism in biliary and pancreatic diseases associated with cholestasis and/or fat malabsorption. The aim of this study was to determine vitamin K of bone, vitamin D and parathyroid hormone status in patients with biliary and pancreatic disorders. In 90 consecutive patients (mean +/- SD age, 65.5 +/- 17.7 years; 45 females) undergoing endoscopic retrograde cholangiopancreatography (68 with choledocholithiasis, 14 with other benign condition, and 8 with cholangiopancreatic cancers) fasting concentrations of carboxylated (cOC) and undercarboxylated osteocalcin (ucOC), 25-hydroxyvitamin D, calcium, phosphorus, magnesium, prothrombin time, liver function tests, lipase, and creatinine were measured. Vitamin D deficiency (25-hydroxyvitamin D <50 nmol/L) was found in 45.6% of patients and elevated parathyroid hormone levels in 27.8%. The ratio ucOC/cOC (index of vitamin K deficiency) was above 20% in 50.6% of patients, above 30% in 31%, and above 50% in 18.4%. Hyperbilirubinemia was a significant independent predictor of low cOC (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.9-59.4; P = .07). The ratio ucOC/cOC positively correlated with alanine aminotransferase levels (r = 0.410; P < .001). Elevated gamma-glutamyltransferase (>180 U/L) and international normalized ratio (>1.1) levels were significant independent predictors of ucOC/cOC greater than 30% after adjustment for other covariants (OR, 5.5; 95% CI, 1.2-25.2; P = .027, and OR, 3.1; 95% CI, 1.1-8.8; P = .036, respectively). This study demonstrates that vitamin K and vitamin D deficiencies are common in patients undergoing endoscopic retrograde cholangiopancreatography. Liver dysfunction is associated with and predictive of vitamin K deficiency of bone and decreased production of osteocalcin, indicating the need for appropriate supplementation.

Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review.

Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. It is characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of large joints. Less common manifestations include cardiovascular abnormalities, renal, urethral and prostate calculi. Bone fractures are unusual in ochronosis. In this report, we describe a woman, 69 years of age, with a history of dark urine since childhood and progressive pigmentation of the skin, sclera, and auricular cartilages. She had severe arthropathy requiring total joint replacement in both of her knees and right hip. She also had severe aortic stenosis requiring valve replacement, and asymptomatic nephrolithiasis. She presented with a low trauma fracture of the distal femur despite two years of alendroate therapy. We review the etiology, pathogenesis, clinical presentation, diagnosis and treatment of alkaptonuric ochronosis. Early detection is important for prevention and treatment of multiple systems. Nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces production and urinary excretion of homogentisic acid; however, the long-term efficacy and side effects of such therapy are unknown. Identifying the gene for alkaptonuria offers the potential for a new therapeutic approach (replacement therapy with a recombinant enzyme) in the treatment of alkaptonuric ochronosis.

Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction.

OBJECTIVE: To report 2 cases of serotonin syndrome with serious extrapyramidal movement disorders occurring when metoclopramide was coadministered with sertraline or venlafaxine. CASE SUMMARY: A 72-year-old white woman was treated with sertraline for depression for 18 months and was then admitted to the hospital with a fractured tibia. She was administered metoclopramide because of nausea and, within 2 hours, developed agitation, dysarthria, diaphoresis, and a movement disorder. These symptoms recurred following 2 subsequent administrations of metoclopramide. Treatment with diazepam led to resolution of symptoms within 6 hours, and there was no recurrence at 6 weeks' follow-up. A 32-year-old white woman with major depression was treated with venlafaxine for 3 years. She was admitted following a fall and, after being given metoclopramide, developed movement disorder and a period of unresponsiveness. After a second dose of metoclopramide, these symptoms recurred and were associated with confusion, agitation, fever, diaphoresis, tachypnea, tachycardia, and hypertension. She improved with administration of diazepam, but needed repetition of this treatment over the next 16 hours. Symptoms resolved within 2 days, and she continued venlafaxine with no further adverse effects. DISCUSSION: Both cases met Stembach's criteria for serotonin syndrome and had serious extrapyramidal movement disorders. The possible pathophysiologic mechanisms for the adverse reactions include a single-drug effect, a pharmacodynamic interaction, and a pharmacokinetic interaction. We believe that a pharmacodynamic interaction is most likely. CONCLUSIONS: Clinicians should be aware of a risk of serotonin syndrome with serious extrapyramidal reactions in patients receiving sertraline or venlafaxine when metoclopramide is coadministered even in a single, conventional dose.