Discovery of anthelmintic small molecules in the Medicines for Malaria Ventures COVID and Global Health Priority Boxes using an infrared-based assay for Caenorhabditis elegans motility (preprint)

Background: Parasitic nematodes are a public health problem globally, and an economic burden on animal and plant agricultural industries. With their ability to generate drug resistance, new anthelmintic compounds must be constantly sourced. Methods: Using the free-living nematode, Caenorhabditis elegans, in an infrared-based motility assay, we screened 400 compounds from two open-source, small-molecule collections distributed by the Medicines for Malaria Venture, namely, the COVID Box and Global Health Priority Box. The screening assay was first validated for worm number, DMSO concentration and final volume. Results: Primary and secondary (time- and concentration-dependent) screens of both boxes, identified twelve compounds as hits; nine of which were known anthelmintics. Three novel anthelmintic hits, flufenerim, flucofuron and indomethacin were identified with EC50 values ranging from 0.211 to 23.174 M. Counter toxicity screens with HEK293 cells indicated varying degrees of toxicity with EC50 values ranging from 0.453 to >100 M. Conclusions: A C. elegans motility assay was optimized and used to screen two recently-released, small molecule libraries. One or more of these three novel active compounds might serve as starting points for the development of new anthelmintics.

Option Valuation with Business Conditions and Skewness (preprint)

This paper exploits business conditions and skewness to improve option pricing. We construct a user-friendly affine framework that incorporates the observable model-free macroeconomic variables and latent skewed innovations, and this new configuration nests and outperforms a wide range of empirically well-tested models. To facilitate practical implementations, we obtain closed-form formulas for pricing SPX options under a variance-dependent kernel. Several sets of empirical studies over the 2008 Great Recession and the ongoing COVID-19 recession demonstrate significant and robust improvements in option pricing brought about by macroeconomic variables, and we find that these improvements are enhanced by the introduction of innovation skewness.

Geographical Factors Determining the Transmission of COVID-19: Lessons Learned from Turkish Black Sea Region to Face Next Pandemic Crisis (preprint)

The objective of the present study is to analyze COVID-19 transmission in specific dampest regions with excess rainfall and recurring fogs. The working hypothesis is that widespread transmission of SARS CoV 2 (leading to COVID-19) and similar viral agents can be explained by specific climate factors having high air humidity. The main case study of the Turkish Black Sea region is investigated. Results reveal that the provinces in region under study have some climate factors and geographical features that foster the accelerated transmission of viral agents, such as SARS-CoV-2, and consequential negative impact on society. In particular, Spearman's Correlation Coefficient shows a statistically significant positive association between the average atmospheric pressure and the spread of the COVID-19 confirmed cases in Samsun province (Spearman’s correlation coefficient rs =0.86, p-value 0.05). A statistically significant positive association between the average precipitation and the spread of COVID-19 confirmed cases in Sinop province (Spearman’s correlation coefficient rs =0.79, p-value 0.05), and finally, a statistically significant negative association between the average sun hour and the spread of the COVID-19 confirmed cases in Samsun province (Spearman’s correlation coefficient rs = 0.89, p-value 0.01). These findings suggest that regions' geographical characteristics, demographic structure, climate and environmental parameters must be considered in the national scale epidemic management plans to design effective anti-pandemic health policies to cope with future waves of the COVID-19 and new airborne diseases and to reduce negative effects on health, social and economic systems.

Case Report: Acquired Brown Syndrome after COVID-19 Vaccination.

SIGNIFICANCE: Brown syndrome, or superior oblique tendon sheath syndrome, is characterized by limitation of elevation on adduction. The disorder is thought to involve the trochlea/superior oblique tendon complex through traumatic, surgical, and inflammatory mechanisms. It could be an indication of multiple underlying immunological or rheumatological disorders. PURPOSE: This study aimed to report an unusual strabismus after receiving the first dose of a live attenuated coronavirus disease 2019 (COVID-19) vaccine. CASE REPORT: A 31-year-old female patient presented with painful vertical diplopia and tenderness of the left trochlear area 3 days after the first dose of COVID-19 vaccination. She had a compensatory chin elevation and face turn to the right, as well as a left 10-prism-diopter hypotropia in the primary position, which increased to 15 prism diopters in the right gaze and disappeared in the left gaze. Ocular motility revealed the limitation of elevation on adduction. The patient denied any history of ocular trauma and was consequently investigated for dysthyroid disease and various immunological and rheumatological disorders, which were excluded. A Hess chart was obtained to document the motility disorder. CONCLUSIONS: We report a case of acquired Brown syndrome in a 31-year-old otherwise healthy woman shortly after COVID-19 vaccination. It is possible that the patient may have developed trochleitis and/or superior oblique tenosynovitis brought on by cross-reacting antibodies generated by the immune response to the vaccine. In the age of the widest vaccination campaign in human history, it is highly likely that we will continue to observe many unexpected potential adverse effects of these vaccines in our clinical practice.

Efferent neuro-ophthalmic complications of coronavirus disease 2019.

PURPOSE OF REVIEW: We set out to describe efferent neuro-ophthalmological complications that have been reported in association with coronavirus disease 2019 (COVID-19) infection. We describe syndromes affecting ocular motility and elaborate on mechanisms of disease, including para-infectious inflammation, hypercoagulability, endothelial damage, and direct neurotropic viral invasion. Despite global vaccination programs, COVID-19 continues to pose an international threat that may rarely result in diplopia or nystagmus. RECENT FINDINGS: Efferent complications include cranial nerve palsies leading to diplopia, either isolated or in association with Miller Fisher syndrome. Nystagmus has been observed in the setting of hemorrhagic acute necrotizing encephalopathy and brainstem infarcts, and opsoclonus syndrome has been described. SUMMARY: Observed neuro-ophthalmic associations need to be confirmed through larger comparative studies. Meanwhile, the range of possible complications should be recognized by neurologists and ophthalmologists alike, to facilitate faster diagnosis and treatment of both COVID-19 and its neuro-ophthalmic manifestations.

A novel smartphone App to support the clinical practice of pediatric ophthalmology and strabismus. The validation of visual acuity tests. (preprint)

Purpose This study aims to describe the TreC Oculistica novel smartphone App that facilitated the clinical practice of pediatric ophthalmology and strabismus during the COVID-19 pandemic and to report on the validation of visual acuity tests in a home setting. Methods The Trec Oculistica smartphone App was prescribed to eligible patients at the Pediatric Ophthalmology and Strabismus Clinic, Ophthalmology Unit of Rovereto Hospital between September 2020 and March 2022. Four key indicators were identified for monitoring visual and visuo-motor functions remotely: visual acuity, ocular motility, head posture, and color vision. Clinicians selected few mobile applications (iOS, Android) and printable materials within the Trec Oculistica App: the Snellen Chart Visual Acuity App, the 9Gaze App, the eyeTilt App, the Color Blind test App, the LEA Symbols pdf, and the Snellen Chart pdf. All patients, aged 4 and older, were screened at home for visual acuity at 3 meters and later in the clinic (LEA Symbols cabinet or Snellen computerized optotype).The 9Gaze, the eyeTilt, and the Color Blind test Apps were only recommended to a subset of patients based on clinical suspicion or diagnosis. The Wilcoxon signed rank sum test and Weighted Cohen's kappa coefficient were applied to compare pairs of scores from different settings. Results The Trec Oculistica App was downloaded and activated by 97 patients or their caregiver. 40 patients were tested at home using the 9Gaze App, 7 used the eyeTilt App, and 11 used the Color-Blind test App. Families reported that all the Apps were easy and intuitive to use; clinicians reported that measurements were reliable. 82 eyes of 41 patients (mean age 5.2 years, SD ± 0.4, range 4.4-6.1) were tested for visual acuity using the self-administered LEA Symbols pdf . 92 eyes of 46 patients (mean age 11.6 years, SD ± 5.2, range 6-35) were evaluated using the self-administered Snellen Chart Visual Acuity App or the Snellen Chart pdf. Home median visual acuity score was statistically different from that registered in clinical setting for both the LEA Symbols pdf (P-value 0.0074) and the Snellen Chart App and pdf (P-value 0.0001). The strength of agreement was 0.12 (slight) for the LEA Symbols pdf, 0.50 (moderate) for the Snellen Chart Visual Acuity App, and 0.69 (substantial) for the Snellen Chart pdf. Conclusions The novel TreC Oculistica smartphone App was a useful tool for facilitating the clinical practice of pediatric ophthalmology and strabismus during the COVID-19 pandemic. In the follow-up of strabismus patients and patients with suspected inherited retinal diseases, the 9Gaze, eyeTilt, and Color Blind test applications were deemed to be intuitive and easy to use by families, and were considered reliable by clinicians. In a home setting, visual acuity tested by means of Snellen Charts was moderately congruent with the in-office examination. On the contrary, agreement was poor in younger children tested with the LEA Symbols pdf.

Eye discomfort at close work in Portuguese university students: A comparative analysis between the pre-COVID and confinement period.

BACKGROUND: Many individuals experience visual symptoms associated with near work. The level of discomfort appears to increase with the amount of digital screen use. OBJECTIVE: To study the eye discomfort with near tasks in university students in the pre-COVID period and in the period of confinement due to the pandemic. METHODS: Two independent samples of students, aged between 18 and 35 years, were used to assess symptomatic behaviour with the Convergence Insufficiency Symptom Survey (CISS) questionnaire. In the pre-COVID period the sample had 342 participants, 64.6% females and in the COVID period 322 students participated, 71.4% females. The study of differences was carried out by the Mann-Whitney U test. The interpretation of the statistical inference was performed for a significance level≤0.05. RESULTS: There was an increase in the number of symptomatic cases in the COVID period without statistical evidence of differences in the frequency of symptoms reported in the two periods. The dimensions "somatic sensations" and "cognitive performance" were the typology of symptoms that most contributed to visual complaints with near vision. There was a significantly different symptomatic behaviour between genders in the period of confinement (p = 0.001), worsening in females and improving in males. CONCLUSION: These findings suggest that females and males exposed to digital environments, over time, may exhibit different symptomatic behaviour. Our results suggest that boys adapt more quickly than girls. Factors that predispose to these changes, aetiology and potential intervention actions still need further study.

Early Detection of Deterioration in COVID-19 Patients by Continuous Ward Respiratory Rate Monitoring: A Pilot Prospective Cohort Study (preprint)

Background Tachypnea is among the earliest signs of pulmonary decompensation. Contactless continuously respiratory rate monitoring might beuseful in isolated COVID-19 patients admitted in wards. We aim to determine whether continuous untethered ward respiratory rate patterns in hospitalized COVID-19 identify patients who require escalation of pulmonary management 24 hours ahead of time.Methods Single-center pilot prospective cohort study in COVID-19 patients who were cared for in routine wards. COVID-19 patients who has at least one escalation of pulmonary management were matched to 3 non-escalated patients. Contactless Breathing Monitoring was instituted after patients enrolled, and continued for 15 days unless hospital discharge, initiation of invasive mechanical ventilation, or death occurred. Respiratory rate data from the continuous monitor was not available to clinicians. The exposures were respiratory features over rolling periods of 30 min, 24 hours, and 72 hours before respiratory care escalation. The primary outcome was escalation in the pulmonary care beyond Venturi-mask.Results Among 125 included patients, 13 exhibited at least one escalation and were each matched to 3 non-escalated patients. A total of 28 escalation events were matched to 84 non-escalation episodes. The 30-min mean respiratory rate in escalated patients was 23 breaths per minute (bpm) ranging from 13 to 40 bpm, similar to the 22 bpm in non-escalated patients, although with less variability (range 14 to 31 bpm). However, higher respiratory rate variability, especially skewness over 1 day, was associated with higher incidence of an escalation event. Our overall model, based on continuous data, had a moderate accuracy with an AUC 0.81 (95%CI:0.73,0.88) and a good specificity 0.93 (95%CI:0.87,0.99).Conclusions Our pilot observational study suggests that continuous respiratory monitoring and respiratory rate variability are associated with the need for care escalation 24 hours in advance. ur results suggest that continuous respiratory monitoring is a valuable increment over intermittent monitoring.

Development of Personalized Sleep Induction System based on Mental States (preprint)

Sleep is an essential behavior to prevent the decrement of cognitive, motor, and emotional performance and various diseases. However, it is not easy to fall asleep when people want to sleep. There are various sleep-disturbing factors such as the COVID-19 situation, noise from outside, and light during the night. We aim to develop a personalized sleep induction system based on mental states using electroencephalogram and auditory stimulation. Our system analyzes users' mental states using an electroencephalogram and results of the Pittsburgh sleep quality index and Brunel mood scale. According to mental states, the system plays sleep induction sound among five auditory stimulation: white noise, repetitive beep sounds, rainy sound, binaural beat, and sham sound. Finally, the sleep-inducing system classified the sleep stage of participants with 94.7 percent and stopped auditory stimulation if participants showed non-rapid eye movement sleep. Our system makes 18 participants fall asleep among 20 participants.

Parinaud’s syndrome caused by a cerebral infarction in a Covid positive child secondary to diabetic ketoacidosis (preprint)

Cerebral infarction is a very rare complication of diabetic ketoacidosis (DKA) which is a metabolic disorder caused by insulin deficiency. A previously healthy 6-year-old boy with a newly diagnosed Type 1 diabetes mellitus presented with a severe DKA. The patient, who tested positive for SARS-CoC-2 nasopharyngeal PCR, developed about 72 hours after admission a Parinaud’s syndrome (PS), also known as dorsal midbrain syndrome, which is described as an up-gaze saccadic paresis, a convergence-retraction nystagmus, a light-near dissociation of the pupils and occasionally a lid retraction. The brain magnetic resonance imaging revealed an ischemic infarction in the left thalamus and the thalamo-mesencephalic junction with a slight extension in the midbrain tegmentum. His symptoms improved gradually and at 3-weeks follow-up he had a full neuro-ophthalmological recovery. By describing a Parinaud syndrome as a neuro-ophthalmologic complication in diabetic ketoacidosis (DKA) crisis, which, to our best knowledge, has not been described yet, our case expands the knowledge of the neurological manifestations occurring in children during diabetic ketoacidosis and reiterates the importance to keep those patients under strict neurological monitoring for at least 72 hours, especially in severe DKA and to request early brain imaging for any child with neurological deterioration.

COVID-19 provoked internuclear ophthalmoplegia in a child with arrested hydrocephalus.

Internuclear ophthalmoplegia (INO) is a neuro-ophthalmic disorder caused by damage in the medial longitudinal fasciculus between the third and sixth cranial nerve nuclei. We present a 4-year-old female diagnosed with INO triggered by coronavirus disease 2019 (COVID-19) infection. The patient had history of neonatal meningitis with hydrocephalus without history of surgical intervention. To the best of our knowledge, this is the first case with combined COVID-19 and chronic hydrocephalus as an etiology for INO in a child. COVID-19 may trigger neurological manifestations as INO in susceptible cases.

The visual consequences of virtual school: acute eye symptoms in healthy children.

PURPOSE: To investigate acute eye symptoms in healthy children after a typical day of virtual school during the COVID-19 pandemic. METHODS: The study population included 110 healthy children 10-17 years of age who were enrolled in full-time or hybrid virtual school. Children with a history of central nervous system or ocular pathology, recent concussions, reported poor vision, convergence insufficiency, history of orthoptic therapy, strabismus, amblyopia, or learning disorders were excluded. Background information was collected, including demographics, family and personal ocular history, and virtual school specifications. Eligible children completed a modified convergence insufficiency symptom survey (CISS) and an asthenopia survey before and after a virtual school session. CISS and asthenopia survey symptoms were scored, and the differences in symptomatology before and after school were calculated. RESULTS: The average sum of the CISS scores increased from 5.17 before school to 9.82 after (P < 0.001), with 61% of children recording an increase in convergence insufficiency symptoms and 17% experiencing severe convergence insufficiency symptoms after school. Average asthenopia symptom scores increased from 1.58 to 2.74 (P < 0.001), with 53% of children recording an increase in asthenopia symptoms. Significant increases were seen in 12 of 15 CISS questions and in 4 of 5 asthenopia questions. CONCLUSIONS: In this study cohort, otherwise healthy children experienced acute ocular symptoms following virtual school.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

Estimation of excess all-cause mortality due to COVID-19 in Thailand (preprint)

Thailand has experienced the most prominent COVID-19 outbreak, resulting in a new record for COVID-19 cases and deaths in 2021. To assess the influence of the COVID-19 outbreak on mortality, we estimated excess all-cause and pneumonia mortality in Thailand during the COVID-19 outbreak from April to October 2021. We used the previous five years’ mortality to estimate the baseline number of deaths using generalized linear mixed models (GLMMs). The models were adjusted for seasonality and demographics. We found that the estimated cumulative excess death was 14.3% (95% CI: 8.6%-18.8%) higher than the baseline. The results also showed that the excess deaths in males were higher than in females by approximately 26.3%. The excess deaths directly caused by the COVID-19 infections accounted for approximately 75.0% of the all-cause excess deaths. Furthermore, excess pneumonia deaths were also found to be 26.2% (95% CI: 4.8%-46.0%) above baseline. There was a significant rise in excess fatalities, especially in the older age groups. Therefore, the age and sex structure of the population are essential to assessing the mortality impact of COVID-19. Our modeling results could potentially provide insights into the COVID-19 outbreaks and provide a guide for outbreak control and intervention.

Enoxaparin-induced Wunderlich syndrome in a young patient with anti-GAD 65-associated opsoclonus and limbic encephalitis: a rare complication in a rare disease.

Wunderlich syndrome is a rare condition characterised by acute spontaneous non-traumatic renal haemorrhage into the subcapsular and perirenal spaces. Our case of anti-GAD65-associated autoimmune encephalitis (AE), aged 30 years, developed this complication following use of enoxaparin and was managed by selective glue embolisation of subsegmental branches of right renal cortical arteries. Our case had opsoclonus as one of the clinical manifestations, which has till now been described in only two patients of this AE. This patient received all forms of induction therapies (steroids, plasmapheresis, intravenous immunoglobulin and rituximab) following which she had good improvement in her clinical condition. The good response to immunotherapy is also a point of discussion as this has been rarely associated with anti-GAD65 AE.