Determinants of knowledge and prevention measures towards COVID-19 pandemic among Lebanese dentists: a cross sectional survey.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a major global threat. Healthcare professionals including dentists are facing real challenges during this pandemic. This study aimed to evaluate knowledge, attitudes, and prevention measures of Lebanese dentists towards COVID-19 and determinants of high level of knowledge and prevention practices. METHODS: A cross-sectional study was conducted between May and August 2020 in Lebanon on a random sample of 323 Lebanese dentists. Data were collected through an online survey questionnaire. A multivariate linear regression model was used to evaluate factors associated with COVID-19 knowledge. A multivariate logistic regression was conducted to evaluate the factors associated with high level of prevention measures towards COVID-19. RESULTS: The mean COVID-19 knowledge index was 24.5 over 38 with only 15% achieving high knowledge level. The mean prevention measures index was 11.4 over 16 with only 35% achieving high prevention level. Higher knowledge index was associated with younger age, being employed, and considering dentist's role significant in teaching others about COVID-19. General dental practitioners, dentists living with family members and concerned about their family members to get infected because of their occupational exposure were more likely to report higher level of adopted prevention measures. Higher knowledge was associated with high level of prevention measures. CONCLUSIONS: Given the rapid evolution of information related to COVID-19 pandemic, dentists should be regularly educated through trainings, workshops, and updates of national guidelines for dental healthcare.

Intravaginal Zinc Oxide Tetrapod Nanoparticles as Novel Immunoprotective Agents against Genital Herpes.

Virtually all efforts to generate an effective protection against the life-long, recurrent genital infections caused by HSV-2 have failed. Apart from sexual transmission, the virus can also be transmitted from mothers to neonates, and it is a key facilitator of HIV coacquisition. In this article, we uncover a nanoimmunotherapy using specially designed zinc oxide tetrapod nanoparticles (ZOTEN) with engineered oxygen vacancies. We demonstrate that ZOTEN, when used intravaginally as a microbicide, is an effective suppressor of HSV-2 genital infection in female BALB/c mice. The strong HSV-2 trapping ability of ZOTEN significantly reduced the clinical signs of vaginal infection and effectively decreased animal mortality. In parallel, ZOTEN promoted the presentation of bound HSV-2 virions to mucosal APCs, enhancing T cell-mediated and Ab-mediated responses to the infection, and thereby suppressing a reinfection. We also found that ZOTEN exhibits strong adjuvant-like properties, which is highly comparable with alum, a commonly used adjuvant. Overall, to our knowledge, our study provides the very first evidence for the protective efficacy of an intravaginal microbicide/vaccine or microbivac platform against primary and secondary female genital herpes infections.

Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay.

UNLABELLED: Severe acute respiratory syndrome coronavirus (SARS-CoV) and Ebola, Hendra, and Nipah viruses are members of different viral families and are known causative agents of fatal viral diseases. These viruses depend on cathepsin L for entry into their target cells. The viral glycoproteins need to be primed by protease cleavage, rendering them active for fusion with the host cell membrane. In this study, we developed a novel high-throughput screening assay based on peptides, derived from the glycoproteins of the aforementioned viruses, which contain the cathepsin L cleavage site. We screened a library of 5,000 small molecules and discovered a small molecule that can inhibit the cathepsin L cleavage of all viral peptides with minimal inhibition of cleavage of a host protein-derived peptide (pro-neuropeptide Y). The small molecule inhibited the entry of all pseudotyped viruses in vitro and the cleavage of SARS-CoV spike glycoprotein in an in vitro cleavage assay. In addition, the Hendra and Nipah virus fusion glycoproteins were not cleaved in the presence of the small molecule in a cell-based cleavage assay. Furthermore, we demonstrate that the small molecule is a mixed inhibitor of cathepsin L. Our broad-spectrum antiviral small molecule appears to be an ideal candidate for future optimization and development into a potent antiviral against SARS-CoV and Ebola, Hendra, and Nipah viruses. IMPORTANCE: We developed a novel high-throughput screening assay to identify small molecules that can prevent cathepsin L cleavage of viral glycoproteins derived from SARS-CoV and Ebola, Hendra, and Nipah viruses that are required for their entry into the host cell. We identified a novel broad-spectrum small molecule that could block cathepsin L-mediated cleavage and thus inhibit the entry of pseudotypes bearing the glycoprotein derived from SARS-CoV or Ebola, Hendra, or Nipah virus. The small molecule can be further optimized and developed into a potent broad-spectrum antiviral drug.

OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells.

Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of experimental autoimmune thyroiditis (EAT), experimental autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and experimental autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8α(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM-CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion.

A novel pancreatic ß-cell targeting bispecific-antibody (BsAb) can prevent the development of type 1 diabetes in NOD mice.

To prepare a novel Bispecific Antibody (BsAb) as a potential targeted therapy for T1D, we produced a "functionally inert" monoclonal antibody (mAb) against Glucose transporter-2 (GLUT-2) expressed on ß-cells to serve as an anchoring antibody. The therapeutic arm is an agonistic mAb against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), a negative regulator of T-cell activation expressed on activated CD4+ T-cells. A BsAb was prepared by chemically coupling an anti-GLUT2 mAb to an agonistic anti-CTLA-4 mAb. This BsAb was able to bind to GLUT2 and CTLA-4 in vitro, and to pancreatic islets, both in vitro and in vivo. We tested the safety and efficacy of this BsAb by treating Non-Obese Diabetes (NOD) mice and found that it could delay the onset of diabetes with no apparent undesirable side effects. Thus, engagement of CTLA-4 on activated T cells from target tissue can be an effective way to treat type-1 diabetes.

Bacterial lipopolysaccharide hyperpolarizes the membrane potential and is antagonized by the K2p channel blocker doxapram.

Exposure of Drosophila skeletal muscle to bacterial lipopolysaccharides (LPS) rapidly and transiently hyperpolarizes membrane potential. However, the mechanism responsible for hyperpolarization remains unclear. The resting membrane potential of the cells is maintained through multiple mechanisms. This study investigated the possibility of LPS activating calcium-activated potassium channels (KCa) and/or K2p channels. 2-Aminoethyl diphenylborinate (2-APB), blocks uptake of Ca2+ into the endoplasmic reticulum (ER); thus, limiting release from ryanodine-sensitive internal stores to reduce the function of KCa channels. Exposure to 2-APB produces waves of hyperpolarization even during desensitization of the response to LPS and in the presence of doxapram. This finding in this study suggests that doxapram blocked the acid-sensitive K2p tandem-pore channel subtype known in mammals. Doxapram blocked LPS-induced hyperpolarization and depolarized the muscles as well as induced motor neurons to produce evoked excitatory junction potentials (EJPs). This was induced by depolarizing motor neurons, similar to the increase in extracellular K+ concentration. The hyperpolarizing effect of LPS was not blocked by decreased extracellular Ca2+or the presence of Cd2+. LPS appears to transiently activate doxapram sensitive K2p channels independently of KCa channels in hyperpolarizing the muscle. Septicemia induced by gram-negative bacteria results in an increase in inflammatory cytokines, primarily induced by bacterial LPS. Currently, blockers of LPS receptors in mammals are unknown; further research on doxapram and other K2p channels is warranted. (220 words).

The effects of doxapram (blocker of K2p channels) on resting membrane potential and synaptic transmission at the Drosophila neuromuscular junction.

The resting membrane potential of most cells is maintained by potassium K2p channels. The pharmacological profile and distribution of various K2p channel subtypes in organisms are still being investigated. The Drosophila genome contains 11 subtypes; however, their function and expression profiles have not yet been determined. Doxapram is clinically used to enhance respiration in humans and blocks the acid-sensitive K2p TASK subtype in mammals. The resting membrane potential of larval Drosophila muscle and synaptic transmission at the neuromuscular junction are pH sensitive. The present study investigated the effects of doxapram on membrane potential and synaptic transmission using intracellular recordings of larval Drosophila muscles. Doxapram (1 mM and 10 mM) depolarizes the muscle and appears to depolarize motor neurons, causing an increase in the frequency of spontaneous quantal events and evoked excitatory junction potentials. Verapamil (1 and 10 mM) paralleled the action of doxapram. These changes were matched by an extracellular increase in KCl (50 mM) and blocked by Cd2+. It is assumed that the motor nerve depolarizes to open voltage-gated Ca2+ channels in presynaptic nerve terminals because of exposure to doxapram. These findings are significant for building models to better understand the function of pharmacological agents that affect K2p channels and how K2p channels contribute to the physiology of tissues. Drosophila offers a genetically amenable model that can alter the tissue-specific expression of K2p channel subtypes to simulate known human diseases related to this family of channels.

Maternal and infant outcomes of Syrian and Palestinian refugees, Lebanese and migrant women giving birth in a tertiary public hospital in Lebanon: a secondary analysis of an obstetric database.

OBJECTIVES: This study aims to assess whether the characteristics, management and outcomes of women varied between Syrian and Palestinian refugees, migrant women of other nationalities and Lebanese women giving birth at a public tertiary centre in Beirut, Lebanon. METHODS: This was a secondary data analysis of routinely collected data from the public Rafik Hariri University Hospital (RHUH) between January 2011 and July 2018. Data were extracted from medical notes using text mining machine learning methods. Nationality was categorised into Lebanese, Syrian, Palestinian and migrant women of other nationalities. The main outcomes were diabetes, pre-eclampsia, placenta accreta spectrum, hysterectomy, uterine rupture, blood transfusion, preterm birth and intrauterine fetal death. Logistic regression models estimated the association between nationality and maternal and infant outcomes, and these were presented using ORs and 95% CIs. RESULTS: 17 624 women gave birth at RHUH of whom 54.3% were Syrian, 39% Lebanese, 2.5% Palestinian and 4.2% migrant women of other nationalities. The majority of women had a caesarean section (73%) and 11% had a serious obstetric complication. Between 2011 and 2018, there was a decline in the use of primary caesarean section (caesarean section performed for the first time) from 7% to 4% of births (p<0.001). The odds of preeclampsia, placenta abruption and serious complications were significantly higher for Palestinian and migrant women of other nationalities compared to Lebanese women, but not for Syrian women. Very preterm birth was higher for Syrians (OR: 1.23, 95% CI: 1.08 to 1.40) and migrant women of other nationalities (OR: 1.51, 95% CI: 1.13 to 2.03) compared to Lebanese women. CONCLUSION: Syrian refugees in Lebanon had similar obstetric outcomes compared to the host population, except for very preterm birth. However, Palestinian women and migrant women of other nationalities appeared to have worse pregnancy complications than the Lebanese women. There should be better healthcare access and support for migrant populations to avoid severe complications of pregnancy.

Examining the effect of manganese on physiological processes: Invertebrate models.

Manganese (Mn2+ as MnSO4 &/or MnCl2) is a common and essential element for maintaining life in plants and animals and is found in soil, fresh waters and marine waters; however, over exposure is toxic to organisms. MnSO4 is added to soil for agricultural purposes and people are exposed to Mn2+ in the mining industry. Hypermanganesemia in mammals is associated with neurological issues mimicking Parkinson's disease (PD) and appears to target dopaminergic neural circuits. However, it also seems that hypermanganesemia can affect many aspects of health besides dopaminergic synapses. We examined the effect on development, behavior, survival, cardiac function, and glutamatergic synaptic transmission in the Drosophila melanogaster. In addition, we examined the effect of Mn2+ on a sensory proprioceptive organ and nerve conduction in a marine crustacean and synaptic transmission at glutamatergic neuromuscular junctions of freshwater crayfish. A dose-response effect of higher Mn2+ retards development, survival and cardiac function in larval Drosophila and survival in larvae and adults. MnSO4 as well as MnCl2 blocks stretch activated responses in primary proprioceptive neurons in a dose-response manner. Mn2+ blocks glutamatergic synaptic transmission in Drosophila as well as crayfish via presynaptic action. This study is relevant in demonstrating the effects of Mn2+ on various physiological functions in order to learn more about acute and long-term consequences Mn2+ exposure.

Thunberg's Barospirator, a Fully Encasing Predecessor of the Iron Lung.

Used as a ventilator for assisting victims of polio, the barospirator was described by Swedish physician-scientist Torsten Thunberg in 1924. An immediate predecessor of the iron lung of Philip Drinker, the barospirator fully encased the entire body. Cyclic air-pressure changes within the chamber achieved ventilation during equilibrations of intrapulmonary and ambient pressures. Pulmonary medicine innovator Alvan Leroy Barach used a modified barospirator for lung rest as a treatment of tuberculosis in the 1940s. Adverse effects included damage to patients' tympanic membranes. Despite its limited clinical success, the barospirator was successfully used by one of Drinker's competitors, John H. Emerson, to invalidate Drinker's US patent filings.

Association Between Adherence to Statins, Illness Perception, Treatment Satisfaction, and Quality of Life among Lebanese patients.

OBJECTIVES: The main objective of this study was to evaluate treatment adherence to statin and health-related quality of life (QOL) in Lebanese patients with dyslipidemia. Secondary objectives were to examine associations between treatment adherence, QOL, treatment satisfaction, and illness perception. METHODS: This cross-sectional study, conducted in 20 community pharmacies from all districts of Lebanon between August 2016 and April 2017, enrolled 247 adult patients taking any statin. RESULTS: The mean age of the participants was 52.63 ± 11.92 years (57.5% males); the mean duration of treatment with a statin was 59.72 months. A significant association was found between adherence and marital status ( P < .0001), educational level ( P = .001), cigarette smoking ( P < .0001), and alcohol drinking ( P < .0001). A negative but significant correlation was found between the adherence score and the duration of dyslipidemia ( r = -0.199). A significant but negative correlation was also found between the side effect score and age ( r = -0.137). The monthly salary, the marital status, the educational level, smoking cigarettes or waterpipes, and drinking alcohol were all associated with the Illness Perception Questionnaire scores ( P < 0.0001 for all variables). Secondary level of education (ß = 13.43), smoking more than 3 waterpipes per week (ß = 14.06), global satisfaction score (ß = 0.32), convenience score (ß = 0.29), and effectiveness score (ß = 0.27) would significantly increase the adherence score. Smoking more than 15 cigarettes per day (ß = -11.15) and a divorced status (ß = -14.81) would however significantly decrease the adherence score. Significant associations were found between the illness perception score, the QOL domains, and the satisfaction domains ( P < .05 for all variables). CONCLUSION: This study showed that global satisfaction with treatment, convenience, and effectiveness are important factors that increase treatment adherence. Patient adherence results in patient satisfaction and improved QOL and is an important criterion for achieving desired therapeutic outcomes.

Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling.

Regulatory T-cells (Tregs) play a pivotal role in maintaining peripheral tolerance. Increasing Treg numbers/functions has been shown to ameliorate autoimmune diseases. However, common Treg expansion approaches use T-Cell Receptor (TCR)-mediated stimulation which also causes proliferation of effector T-cells (Teff). To overcome this limitation, purified patient-specific Tregs are expanded ex vivo and transfused. Although promising, this approach is not suitable for routine clinical use. Therefore, an alternative approach to selectively expand functional Tregs in vivo is highly desired. We report a novel TCR-independent strategy for the selective proliferation of Foxp3+Tregs (without Teff proliferation), by co-culturing CD4+ T-cells with OX40 L+Jagged(JAG)-1+ bone marrow-derived DCs differentiated with GM-CSF or treating them with soluble OX40 L and JAG1 in the presence of exogenous IL-2. Tregs expanded using soluble OX40 L and JAG1 were of suppressive phenotype and delayed the onset of diabetes in NOD mice. Ligation of OX40 L and JAG1 with their cognate-receptors OX40 and Notch3, preferentially expressed on Tregs but not on Teff cells, was required for selective Treg proliferation. Soluble OX40L-JAG1-induced NF-κB activation as well as IL-2-induced STAT5 activation were essential for the proliferation of Tregs with sustained Foxp3 expression. Altogether, these findings demonstrate the utility of soluble OX40 L and JAG1 to induce TCR-independent Treg proliferation.

Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice.

Earlier, we have shown that GM-CSF derived bone marrow (BM) dendritic cells (G-BMDCs) can expand Foxp3(+) regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12-week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3(+)CD103(+)CD38(-) stable-phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3(+)CD103(-)CD38(+) labile-phenotype Tregs in the thymus and increased autoreactive CD4(+) T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4(+) T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2.

Inferior oblique overaction/contracture following retrobulbar anesthesia for cataract extraction with a positive Bielschowsky Head Tilt test to the contralateral shoulder. A report of one case.

BACKGROUND AND PURPOSE: This is a report of a patient with diplopia, hypertropia, extorsion and a positive Bielschowsky Head Tilt Test following retrobulbar anesthesia, due to an inferior oblique muscle overaction-contracture. CASE REPORT: Oculomotor and sensorimotor examinations and ocular motility recordings and Bielschowsky Head Tilt Test demonstrated overaction characteristics overpowering the contracture characteristics of the involved inferior oblique muscle. RESULTS: Weakening of the overacting inferior oblique eliminated the vertical and torsional deviations and the forced head tilt difference upon tilting the head to either shoulder. It also normalized ocular motility and resulted in a symptom-free patient. CONCLUSION: Oblique muscle dysfunction with vertical and torsional deviations and a positive Bielschowsky Head Tilt Test can result from retrobulbar anesthesia.

IG20/MADD plays a critical role in glucose-induced insulin secretion.

Pancreatic ß-cell dysfunction is a common feature of type 2 diabetes. Earlier, we had cloned IG20 cDNA from a human insulinoma and had shown that IG20/MADD can encode six different splice isoforms that are differentially expressed and have unique functions, but its role in ß-cell function was unexplored. To investigate the role of IG20/MADD in ß-cell function, we generated conditional knockout (KMA1ko) mice. Deletion of IG20/MADD in ß-cells resulted in hyperglycemia and glucose intolerance associated with reduced and delayed glucose-induced insulin production. KMA1ko ß-cells were able to process insulin normally but had increased insulin accumulation and showed a severe defect in glucose-induced insulin release. These findings indicated that IG20/MADD plays a critical role in glucose-induced insulin release from ß-cells and that its functional disruption can cause type 2 diabetes. The clinical relevance of these findings is highlighted by recent reports of very strong association of the rs7944584 single nucleotide polymorphism (SNP) of IG20/MADD with fasting hyperglycemia/diabetes. Thus, IG20/MADD could be a therapeutic target for type 2 diabetes, particularly in those with the rs7944584 SNP.