Electrolyte imbalances as poor prognostic markers in COVID-19: a systemic review and meta-analysis.

PURPOSE: Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. We aim to systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome. METHODS: PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR + , LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed. RESULTS: We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR = 2.08, 95% CI = 1.48-2.94, I2 = 93%, N = 8), hypernatremia (OR = 4.32, 95% CI = 3.17-5.88, I2 = 45%, N = 7) and hypocalcemia (OR = 3.31, 95% CI = 2.24-4.88, I2 = 25%, N = 6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR + 4.0, PPV = 55%, AUC = 0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV = 87%, AUC = 0.71). Overall quality of evidence ranged from very low to moderate. CONCLUSION: Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome, and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.

In-Practice Endocrine Surgery Fellowship: A Novel Training Model.

OBJECTIVE: Endocrine surgery is an expanding field within otolaryngology. We hypothesized that a novel endocrine surgery fellowship model for in-practice otolaryngologists could result in expert-level training. STUDY DESIGN: Qualitative clinical study with chart review. SETTING: Urban community practice and academic medical center. METHODS: Two board-certified general otolaryngologists collaborated with a senior endocrine surgeon to increase their endocrine surgery expertise between March 2015 and December 2017. The senior surgeon provided intensive surgical training to both surgeons for all of their endocrine surgeries. Both parties collaborated with endocrinology to coordinate medical care and receive referrals. All patients undergoing endocrine surgery during this time frame were reviewed retrospectively. RESULTS: A total of 235 endocrine surgeries were performed. Of these, 198 thyroid surgeries were performed, including 98 total thyroidectomies (48%), 90 lobectomies (45%), and 10 completion thyroidectomies (5%). Sixty cases demonstrated papillary thyroid carcinoma, 11 follicular thyroid carcinoma, and 4 medullary thyroid carcinoma. Neck dissections were performed in 14 of the cases. Thirty-seven parathyroid explorations were performed. There were no reports of permanent hypoparathyroidism. Thirteen patients (5.5%) developed temporary hypoparathyroidism. Six patients (2.5%) developed postoperative seroma. Three patients (1.3%) developed postoperative hematomas requiring reoperation. One patient (0.4%) developed permanent vocal fold paralysis, and 3 patients (1.3%) had temporary dysphonia. Thirty-five of 37 (94.5%) parathyroid explorations resulted in biochemical resolution of the patient's primary hyperparathyroidism. CONCLUSION: This is the first description of a new fellowship paradigm where a senior surgeon provides fellowship training to attending surgeons already in practice.

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.

Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.

Relaxation oscillations and frequency entrainment in quantum mechanics.

Frequency entrainment of continuous-variable oscillators has to date been restrained to the weakly nonlinear regime. Here we overcome this bottleneck and extend frequency entrainment of quantum continuous-variable oscillators to arbitrary nonlinearities. The previously known steady state of such quantum oscillators in the weakly nonlinear regime (also known as a Stuart-Landau oscillator) is shown to emerge as a special case. Most importantly, the hallmark of strong nonlinearity-relaxation oscillations-is shown in quantum mechanics. Depending on the oscillator's nonlinearity, relaxation oscillations are found to occur via two distinct mechanisms in phase space.

Phase-Preserving Linear Amplifiers Not Simulable by the Parametric Amplifier.

It is commonly accepted that a parametric amplifier can simulate a phase-preserving linear amplifier regardless of how the latter is realized [C. M. Caves et al., Phys. Rev. A 86, 063802 (2012)PLRAAN1050-294710.1103/PhysRevA.86.063802]. If true, this reduces all phase-preserving linear amplifiers to a single familiar model. Here we disprove this claim by constructing two counterexamples. A detailed discussion of the physics of our counterexamples is provided. It is shown that a Heisenberg-picture analysis facilitates a microscopic explanation of the physics. This also resolves a question about the nature of amplifier-added noise in degenerate two-photon amplification.

Impact of pharmacist-involved collaborative care on the clinical, humanistic and cost outcomes of high-risk patients with type 2 diabetes (IMPACT): a randomized controlled trial.

WHAT IS KNOWN AND OBJECTIVE: With the increasing prevalence of diabetes, the physician-centred model is challenged to deliver holistic care in Asia. Diabetes may be managed effectively within a multidisciplinary collaborative care model; however, evidence on its effectiveness in Asian patients is lacking. Therefore, the primary objective was to evaluate the clinical outcomes of multidisciplinary collaborative care vs physician-centred care in diabetes. The secondary objectives were to evaluate humanistic and economic outcomes among the two types of care. METHODS: This 6-month prospective, open-label, parallel-arm, randomized, controlled study was conducted at four outpatient healthcare institutions. High-risk patients aged ≥21 years with uncontrolled type 2 diabetes, polypharmacy and comorbidities were included. Patients with type 1 diabetes or those who were unable to communicate independently were excluded. The control arm received usual care with referrals to nurses and dietitians as needed. The intervention arm (multidisciplinary collaborative care) was followed up with pharmacists regularly, in addition to receiving the usual care. The primary outcomes included HbA1c, systolic blood pressure, low-density lipoprotein and triglycerides. The secondary outcomes included scores from the Problem Areas in Diabetes (PAID) and the Diabetes Treatment Satisfaction Questionnaires (DTSQ), and diabetes-related health service utilization rates and costs. RESULTS AND DISCUSSION: Of 411 eligible patients, 214 and 197 patients were randomized into the intervention and control arms, respectively. At 6 months, 141 patients in the intervention arm (65.9%) and 189 patients in the control arm (95.9%) completed the study. Mean HbA1c reduced from 8.6%±1.5% at baseline to 8.1%±1.3% at 6 months in the intervention arm (P=.04), with up to mean HbA1c improvement of 0.8% in patients with greater levels of uncontrolled glycemia. Whereas the mean HbA1c in the control arm remained unchanged (8.5%±1.4%) throughout the 6-month period. Improvements in PAID and DTSQ scores, reduction in physician workload and an average cost savings of US$91.01 per patient were observed in the intervention arm over 6 months. WHAT IS NEW AND CONCLUSIONS: The positive clinical, humanistic and economic outcomes highlighted the value of multidisciplinary collaborative care for Asian diabetic patients, thereby supporting the effectiveness of this approach in managing chronic diseases.

Coherent chemical kinetics as quantum walks. I. Reaction operators for radical pairs.

Classical chemical kinetics uses rate-equation models to describe how a reaction proceeds in time. Such models are sufficient for describing state transitions in a reaction where coherences between different states do not arise, in other words, a reaction that contains only incoherent transitions. A prominent example of a reaction containing coherent transitions is the radical-pair model. The kinetics of such reactions is defined by the so-called reaction operator that determines the radical-pair state as a function of intermediate transition rates. We argue that the well-known concept of quantum walks from quantum information theory is a natural and apt framework for describing multisite chemical reactions. By composing Kraus maps that act only on two sites at a time, we show how the quantum-walk formalism can be applied to derive a reaction operator for the standard avian radical-pair reaction. Our reaction operator predicts the same recombination dephasing rate as the conventional Haberkorn model, which is consistent with recent experiments [K. Maeda et al., J. Chem. Phys. 139, 234309 (2013)], in contrast to previous work by Jones and Hore [J. A. Jones and P. J. Hore, Chem. Phys. Lett. 488, 90 (2010)]. The standard radical-pair reaction has conventionally been described by either a normalized density operator incorporating both the radical pair and reaction products or a trace-decreasing density operator that considers only the radical pair. We demonstrate a density operator that is both normalized and refers only to radical-pair states. Generalizations to include additional dephasing processes and an arbitrary number of sites are also discussed.

Coherent chemical kinetics as quantum walks. II. Radical-pair reactions in Arabidopsis thaliana.

We apply the quantum-walk approach proposed in the preceding paper [A. Chia et al., preceding paper, Phys. Rev. E 93, 032407 (2016)] to a radical-pair reaction where realistic estimates for the intermediate transition rates are available. The well-known average hitting time from quantum walks can be adopted as a measure of how quickly the reaction occurs and we calculate this for varying degrees of dephasing in the radical pair. The time for the radical pair to react to a product is found to be independent of the amount of dephasing introduced, even in the limit of no dephasing where the transient population dynamics exhibits strong coherent oscillations. This can be seen to arise from the existence of a rate-limiting step in the reaction and we argue that in such examples, a purely classical model based on rate equations can be used for estimating the time scale of the reaction but not necessarily its population dynamics.

Clinical value of electrophysiology in determining the diagnosis of visual dysfunction in neuro-ophthalmology patients.

PURPOSE: To assess clinical value of visual electrophysiology in identifying causes of visual dysfunction in patients referred from neuro-ophthalmology clinics. METHODS: A review of 410 subjects (aged 0.3-88 years) referred for visual electrophysiology from neuro-ophthalmologists between 2009 and 2013 was performed. Subjects were divided into those with unexplained poor vision, visual field defects, visual symptoms or other reasons (e.g. monitoring for drug toxicity or known conditions). Subjects underwent pattern, full-field and multifocal electroretinography (ERG) and pattern visual evoked potential (VEP) tests. Flash and multifocal VEP were included where indicated. RESULTS: Most subjects referred for poor vision (n = 158) had electrophysiology findings suggestive of retinopathy (37 %) or post-retinal pathology (34 %). Those with poorer vision (worse than 6/24) were more likely to have abnormal recordings (86 vs. 62 %, p = 0.002). Among subjects with unexplained visual field defects (n = 102), findings of retinopathy, post-retinal pathology and normal recordings were noted in 31, 24 and 28 %, respectively. Most subjects with other visual symptoms (n = 97) had normal findings (69 %). The multifocal ERG was most sensitive for detecting retinopathy (96 %) and maculopathy (95 %), while pattern VEP was most sensitive for post-retinal pathology (94 %). An indeterminate result was noted in 9 %. CONCLUSION: Electrophysiology was effective in differentiating between retinopathy, post-retinal pathology and normality in 91 % of subjects. Pre-testing provisional diagnoses of retinopathy and post-retinal pathology were revised in 30 and 42 %, respectively, after electrophysiology. Appreciation of characteristics of each test, correlation with the clinical picture and interpretation of results in totality are required to localize the site of pathology.

Legal foundations of adaptive licensing.

In April 2012, MIT's Center for Biomedical Innovation and the European Medicines Agency (EMA) cosponsored a workshop on legal foundations of adaptive pharmaceuticals licensing. Past and present attorneys from the US Food and Drug Administration (FDA), the EMA, and Health Sciences Agency Singapore (HSA) found that existing statutes provided authority for adaptive licensing (AL). By contrast, an attorney from Health Canada identified gaps in authority. Reimbursement during initial phases of adaptive approaches to licensing was deemed consistent with existing statutes in all jurisdictions.

Nebulised DNase post-therapeutic bronchoalveolar lavage in near fatal asthma exacerbation in an adult patient refractory to conventional treatment.

Mucus plugging plays a vital role in the pathophysiology of fatal and near fatal asthma as demonstrated in various postmortem studies. There is a paucity of published literature on how to manage mucus plugging in adult patients with refractory asthma exacerbation not responding to conventional therapies as compared with its paediatric cohort. We describe a dramatic improvement with the use of rhDNase, following bronchoalveolar lavage in an intubated adult female patient, with status asthmaticus refractory to conventional treatment.

Unlocking doping and compositional profiles of nanowire ensembles using SIMS.

Dynamic and time-of-flight (TOF) secondary ion mass spectrometry (SIMS) was performed on vertically standing III-V nanowire ensembles embedded in Cyclotene polymer. By embedding the NWs in Cyclotene, the top surface of the sample was made planar, while the space between the NWs was filled to protect the background substrate from the ion beam, thus allowing for the NWs to be sputtered and analyzed evenly as a function of depth. Using thin film standards, SIMS analysis was used to calculate the impurity dopant concentration as a function of height in the NW ensemble. This marked the first use of conventional SIMS to accurately determine the doping density with excellent depth resolution. Additionally, this is the first presentation of SIMS as the only reported tool for characterizing the segment height uniformity of any arbitrary axial heterostructure NW ensemble.

Contact planarization of ensemble nanowires.

The viability of four organic polymers (S1808, SC200, SU8 and Cyclotene) as filling materials to achieve planarization of ensemble nanowire arrays is reported. Analysis of the porosity, surface roughness and thermal stability of each filling material was performed. Sonication was used as an effective method to remove the tops of the nanowires (NWs) to achieve complete planarization. Ensemble nanowire devices were fully fabricated and I-V measurements confirmed that Cyclotene effectively planarizes the NWs while still serving the role as an insulating layer between the top and bottom contacts. These processes and analysis can be easily implemented into future characterization and fabrication of ensemble NWs for optoelectronic device applications.

Prevalence and causes of decreased visual acuity in Singaporean Chinese preschoolers.

AIMS: To describe the prevalence and causes of decreased visual acuity (VA) in Singaporean Chinese children. METHODS: A population-based survey of Singaporean Chinese children aged 6 to 72 months was conducted. Participants underwent an orthoptic evaluation, cycloplegic refraction and biometric measurements. A sub-group of children aged 30 to 72 months with presenting logMAR VA were included in this analysis. Retesting was performed on the same day or another day by predefined criteria with best refractive correction. Decreased VA was defined as worse than 20/50 (0.4 logMAR) for ages 30 to 47 months and worse than 20/40 (0.3 logMAR) for ages 48 to 72 months. RESULTS: The study examined 3009 children (participation rate 72.3%) of which 2017 children aged 30 to 72 months were eligible for VA testing and completed in 1684 (83.5%). In children aged 30-47 months, the prevalence of decreased presenting VA was 2.1%, and in children 48-72 months, it was 2.05%, with no significant difference between boys and girls in both age groups (p=0.15 and p=0.85). Causes for decreased presenting VA in those 30-47 months were refractive error (7/11, 63.6%), amblyopia (1/11, 9.1%) and "no explanation" (3/11, 27.3%), and 17/24 (70.8%), 5/24 (20.8%) and 2/24 (8.3%), respectively, for those aged 48-72 months. The types of refractive error were astigmatism (15/24, 62.5%), myopia (6/24, 25.0%), hyperopia (2/24, 8.3%) and hyperopia with astigmatism (1/24, 4.2%). CONCLUSIONS: The prevalence of decreased VA among Singaporean Chinese preschoolers is low, with uncorrected refractive error being the main cause in both children 30-47 and 48-72 months.

Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence.

AIMS: Enteroviruses are well-known causes of acute respiratory and/or gastrointestinal infections and non-specific flu-like illness. Although enterovirus protein, RNA and non-cytopathic viruses have been demonstrated in the stomach biopsies of patients with myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), causality for chronic diseases is difficult to establish without having well-documented cases of acute enterovirus infections. The aim of this study was to link acute enteroviral infection to viral persistence in patients with ME/CFS. METHOD: Patients admitted to the hospital with acute febrile illnesses were screened for enteroviral infections. Acutely infected patients were followed longitudinally, and those who developed symptoms of ME/CFS underwent oesophagogastroduodenoscopy and biopsies of the antrum to document viral persistence by immunoperoxidase staining for viral protein and viral RNA assay. RESULTS: Three representative patients with different manifestations of acute enterovirus infections progressed to have chronic symptoms of ME/CFS. Persistent viral infection was demonstrated in the antrum years later. CONCLUSION: After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.

Intestinal intussusception in adults due to acute enterovirus infection.

Three adult cases of intussusceptions, associated with enteroviruses occurring within a 3-week period, are reported. Virological studies include viral RNA detection in stool samples and staining for enterovirus protein by immunoperoxidase staining of the resected intestinal tissues. A new mechanism for intussusception associated with enterovirus is proposed. Tap water was implicated in the outbreak. Better monitoring of drinking-water may prevent other cases of non-polio enterovirus infection.

Quantum teleportation of the temporal fluctuations of light.

A scheme for the teleportation of a beam of light including its temporal fluctuations is proposed. Expressions for the teleported degrees of first- and second-order optical coherence are presented. Teleportation of an antibunched photon stream illustrates the proposal.

Cycloplegic refraction in preschool children: comparisons between the hand-held autorefractor, table-mounted autorefractor and retinoscopy.

AIMS: It is common for refraction to be measured using different testing methods in children, with much debate still ongoing on the preferred method. Therefore, we compared cycloplegic refraction measurements using three objective methods in a large cohort of children. METHODS: We present the findings from a total of 51 children who were recruited and examined as part of the Strabismus, Amblyopia and Refractive error in Singapore preschool children (STARS) study. Each child underwent a comprehensive eye examination, which included cycloplegic refraction using a hand-held autorefractor (Retinomax), a table mounted autorefractor (Canon FK-1) and streak retinoscopy. Spherical equivalent (SE) was calculated as (sphere + half of minus cylinder) and astigmatism was determined using the negative cylindrical component. RESULTS: The current study sample consisted of 29 boys and 22 girls aged between 24 and 72 months (mean age 52.3 months). The mean spherical equivalent (SE) using the table-mounted autorefractor (1.03 +/- 1.64 D) was not significantly different from the streak retinoscopy (1.09 +/- 1.58 D, p = 0.66). However, the mean SE using the hand-held Retinomax (0.80 +/- 1.43 D) was significantly different (more 'minus'p = 0.0004) to streak retinoscopy. The astigmatism measured using the hand held (-0.89 +/- 0.51 D) and table-mounted autorefractor (-0.83 +/- 0.61 D) were significantly greater than that obtained with streak retinoscopy (-0.58 +/- 0.56, p = 0.0003). CONCLUSIONS: The table-mounted autorefractor provided a reading more similar to that of streak retinoscopy than to that of the hand-held autorefractor. However, there were only small differences in mean SE (<0.32 D) between the hand-held Retinomax and the other methods, which will have implications in research investigations of refractive error.

Effect of topical atropine on astigmatism.

AIM: The aim of this study was to determine if topical atropine, used to retard axial length elongation and myopia progression, had any effect on ocular astigmatism. METHODS: Data collected from subjects enrolled in the Atropine in the Treatment of Myopia (ATOM) study were analysed. In this study, 400 myopic children (aged 6-12 years) were randomly assigned to administer atropine 1% or a placebo daily to a randomly selected eye for 2 years. Cycloplegic autorefraction and keratomy readings were measured using a Canon RK5 autorefractor. The refractive error was then split into its power vector components: J0 and J45. RESULTS: Astigmatism increased by 0.12-0.16 D per year in both treated and placebo groups. There was no difference between groups (p = 0.182). The increase was mirrored by an increase in corneal astigmatism of 0.10-0.13 D per year, suggesting that most of the change was corneal in nature. There was an increase in J0 vector (with-the-rule astigmatism) with no change in the J45 (oblique) vector over time. The change in the J0 vector was significantly larger in the atropine-treated versus atropine-untreated eyes during the 2-year treatment period (p = 0.011), but this difference disappeared after atropine was stopped. CONCLUSION: The use of atropine on a daily basis over 2 years did not have any clinically significant effect on astigmatism.

Outdoor activity and myopia in Singapore teenage children.

AIM: To investigate the relationship of outdoor activities and myopia in Singapore teenage children. METHODS: Teenage children (1249 participants), examined in the Singapore Cohort study Of Risk factors for Myopia (SCORM), during 2006 were included in analyses. Participants completed questionnaires that quantified total outdoor activity, and underwent an eye examination. RESULTS: The mean total time spent on outdoor activity was 3.24 h/day. The total outdoor activity (h/day) was significantly associated with myopia, odds ratio 0.90 (95% CI 0.84 to 0.96) (p = 0.004), after adjusting for age, gender, ethnicity, school type, books read per week, height, parental myopia, parental education and intelligence quotient. In addition, the total time spent outdoors was associated with significantly less myopic refraction (regression coefficient = 0.17; CI 0.10 to 0.25, p<0.001) and shorter axial length (regression coefficient -0.06 (CI -0.1 to -0.03, p<0.001). Total sports was also significantly negatively associated with myopia (p = 0.008) but not indoor sports (p = 0.16). CONCLUSIONS: Participants who spent more time outdoors were less likely to be myopic. Thus, outdoor activity may protect against development of myopia in children, supporting recent Australian data. As near work did not predict outdoor activity, this can be viewed as an independent factor and not merely the reciprocal of near work.