Ophthalmic manifestations in the COVID-19 clinical spectrum

Purpose:The aim of this study was to determine the frequency and various types of ophthalmic manifestation of patients with COVID-19.Methods:This is a prospective observational study conducted on patients with SARS-Co-V-2 infection, at a dedicated tertiary COVID-19 hospital in South India from April 1 to July 31, 2020. At the time of their admission to the COVID hospital, demographic data such as name, age, sex was recorded. A thorough history regarding the onset, duration, progression, nature of symptoms and its associated factors, medication history, treatment history were elicited and documented. Ocular examination was performed under torchlight by an ophthalmologist posted for COVID duty. Further investigations including imaging were sought for, depending on clinical indications. Serial follow-up examinations of all patients were carried out every 72 hours or when patients complained of any ocular symptoms whichever earlier, until discharge. All relevant data were compiled and statistically analyzed.Results:A total of 2742 patients were examined. Of them, 1461 (53.28%) were males and 1281 (46.72%) were females. The mean age (±SD) was 39.46 ± 17.63 years. None of the patients in our study had any ocular symptoms or signs as the presenting complaint at the time of their admission. On subsequent follow-up, only 20 (0.72%) developed ocular manifestations, of which 19 (95%) had features suggestive of Bilateral viral conjunctivitis. However, 1 (5%) patient had orbital cellulitis secondary to pansinusitis.Conclusion:Ophthalmic manifestations in the clinical spectrum of COVID-19 infection are uncommon and unlikely to be the presenting clinical impression. However, it has broadened our view to a wider spectrum of COVID-19 presentations enhancing our clinical acumen for staunch detection of COVID-19 suspects in our daily practice, augmenting early diagnosis and management and also break the chain of transmission for the greater good of humanity.     

How actual motor competence and perceived motor competence influence motor‐skill engagement of a novel cycling task

In early childhood, factors that contribute to motor‐skill engagement (MSE) are unknown. Our aim was to explore the relationships between actual and perceived motor competence and their influences on MSE on a balance bike (bike with no pedals). A secondary aim was to investigate whether MSE had an effect on ability on a balance bike. This study comprised of 45 children (29% female) aged 4.5 ± 0.5 years. MSE was assessed using distance travelled on a balance bike over an 8‐week period. Actual motor competence was assessed using the Movement Assessment Battery for Children, second edition. Perceived motor competence was assessed using the Pictorial Scale of Perceived Movement Skill Competence. Ability on a balance bike was measured using timed trials on a specifically designed track. Pearson product‐moment correlations were used to assess relationships between actual and perceived motor competence and ability on a balance bike. Linear regressions were used to examine whether actual or perceived motor competence or ability on a balance bike predicted MSE. Repeated measures ANOVA was used to examine whether there was a difference in ability on a balance bike between three MSE groups over 8 weeks. No relationships were found, and none of the variables predicted MSE. There was a significant difference between the MSE groups on ability on a balance bike over time (P = 0.019). Investigating the contributors to MSE on a novel cycling task during early childhood provides knowledge to ensure children are given the best opportunities for practice and acquisition of skills.     

Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.     

An Examination of Gender Differences in the Association of Adolescent Substance use with Eating and Weight Loss Attitudes

Objective: To assess gender differences in the relationship between eating and weight loss attitudes (EWAs), and 30-day tobacco and alcohol use among adolescents, while controlling for potential confounds (age, country of birth, psychological distress, pubertal development, peer alcohol and tobacco use, and sexual activity). Methods: School students aged between 11 and 17 years (N = 10,273) from high schools in the State of Victoria (Australia) completed surveys in class under conditions of anonymity and confidentiality. Results: The interaction between EWAs and gender was significant for tobacco use but not for alcohol use, indicating that the effect of EWAs on tobacco use, but not alcohol use, vary by gender. Conclusions: Tobacco use was related to EWAs in adolescent females but not males, and this is consistent with the possibility that females use tobacco in an instrumental fashion to control weight. Implications and Contribution: Female adolescents high in eating and weight loss attitudes were more likely to engage in tobacco use. In contrast, eating and weight loss attitudes were not related to male tobacco use. These results point to the potential importance of developing gender-specific approaches towards addressing problematic behaviors in adolescent populations.     

Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM‐775)

Lysergic acid diethylamide (LSD) is perhaps one of the best‐known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as ‘research chemicals’ or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM‐775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM‐775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM‐775. A powdered sample of LSM‐775 was characterized by X‐ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC–MS), high mass accuracy electrospray MS/MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid‐state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM‐775 acts as a nonselective agonist at 5‐HT_1A and 5‐HT_2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM‐775 activates 5‐HT_2A receptors and produces hallucinogen‐like effects in vivo. LSM‐775 did not induce the head twitch response unless 5‐HT_1A receptors were blocked by pretreatment with the antagonist WAY‐100,635 (1 mg/kg, subcutaneous). These findings suggest that 5‐HT_1A activation by LSM‐775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM‐775 is only capable of producing weak LSD‐like effects in humans.     

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials,utilizing polymer‐supported reagents

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in‐house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer‐supported reagents starting from 2‐amino‐2'‐chloro‐5‐nitrobenzophenone (clonazolam) and 2‐amino‐5‐nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4‐triazole ring moiety was performed within a gas chromatography–mass spectrometry (GC–MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by‐product profiles for both the micro and the preparative scale syntheses are also presented.     

Synthesis,analytical characterization,and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.     

Randomized controlled trial of MICBT for co-existing alcohol misuse and depression: Outcomes to 36-months

Integrated psychological treatment addressing co-existing alcohol misuse and depression has not been compared with single-focused treatment. This trial evaluates changes over 36 months following randomization of 284 outpatients to one of four motivational interviewing and cognitive–behavior therapy (MICBT) based interventions: (1) brief integrated intervention (BI); or BI plus 9 further sessions with (2) an integrated-, (3) alcohol-, or (4) depression-focus. Outcome measures included changes in alcohol consumption, depression (BDI-II: Beck Depression Inventory) and functioning (GAF: Global Assessment of Functioning), with average improvements from baseline of 21.8 drinks per week, 12.6 BDI-II units and 8.2 GAF units. Longer interventions tended to be more effective in reducing depression and improving functioning in the long-term, and in improving alcohol consumption in the short-term. Integrated treatment was at least as good as single-focused MICBT. Alcohol-focused treatment was as effective as depression-focused treatment at reducing depression and more effective in reducing alcohol misuse. The best approach seems to be an initial focus on both conditions followed by additional integrated- or alcohol-focused sessions.     

Synthesis,characterization, and monoamine transporter activity of the new psychoactive substance 3′,4′‐methylenedioxy‐4‐methylaminorex (MDMAR)

The recent occurrence of deaths associated with the psychostimulant cis‐4,4′‐dimethylaminorex (4,4′‐DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4‐methylenedioxy‐4‐methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis‐ and trans‐MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis‐isomer (90%). Exposure of the cis‐isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans‐isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non‐selective monoamine releasing agent (+)‐3,4‐methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis‐ and trans‐4,4′‐DMAR, were assessed under identical conditions. cis‐MDMAR, trans‐MDMAR, cis‐4,4′‐DMAR and trans‐4,4′‐DMAR were more potent than MDMA in their ability to function as efficacious substrate‐type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis‐4,4′‐DMAR, cis‐MDMAR and trans‐MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans‐4,4′‐DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring‐substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side‐effects after high dose exposure. Copyright © 2014 John Wiley & Sons, Ltd.     

Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion

Permissive hypercapnia, involving tolerance to elevated Pa(CO(2)), is associated with reduced acute lung injury (ALI), thought to result from reduced mechanical stretch, and improved outcome in ARDS. However, deliberately elevating inspired CO(2) concentration alone (therapeutic hypercapnia, TH) protects against ALI in ex vivo models. We investigated whether TH would protect against ALI in an in vivo model of lung ischemia-reperfusion (IR). Anesthetized open chest rabbits were ventilated (standard eucapnic settings), and were randomized to TH (FI(CO(2)) 0.12) versus control (FI(CO(2)) 0.00). Pa(CO(2)) and arterial pH values achieved in the TH versus CON groups were 101 +/- 3 versus 44.4 +/- 4 mm Hg and 7.10 +/- 0.03 versus 7.37 +/- 0.03, respectively. Following left lung ischemia and reperfusion, TH versus control was associated with preservation of lung mechanics, attenuation of protein leakage, reduction in pulmonary edema, and improved oxygenation. Indices of systemic protection included improved acid-base and lactate profile, in the absence of systemic hypoxemia. In the TH group, mean BALF TNF-alpha levels were 3.5% of CON levels (p < 0.01), and mean 8-isoprostane levels were 30% of CON levels (p = 0.02). Western blot analysis demonstrated reduced lung tissue nitrotyrosine in TH, indicating attenuation of tissue nitration. Finally, preliminary data suggest that TH may attenuate apoptosis following lung IR. We conclude that in the current model TH is protective versus IR lung injury and mechanisms of protection include preservation of lung mechanics, attenuation of pulmonary inflammation, and reduction of free radical mediated injury. If these findings are confirmed in additional models, TH may become a candidate for clinical testing in critical care.