Search results for: randomized trials
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 1516

Search results for: randomized trials

16 Effect of Cerebellar High Frequency rTMS on the Balance of Multiple Sclerosis Patients with Ataxia

Authors: Shereen Ismail Fawaz, Shin-Ichi Izumi, Nouran Mohamed Salah, Heba G. Saber, Ibrahim Mohamed Roushdi

Abstract:

Background: Multiple sclerosis (MS) is a chronic, inflammatory, mainly demyelinating disease of the central nervous system, more common in young adults. Cerebellar involvement is one of the most disabling lesions in MS and is usually a sign of disease progression. It plays a major role in the planning, initiation, and organization of movement via its influence on the motor cortex and corticospinal outputs. Therefore, it contributes to controlling movement, motor adaptation, and motor learning, in addition to its vast connections with other major pathways controlling balance, such as the cerebellopropriospinal pathways and cerebellovestibular pathways. Hence, trying to stimulate the cerebellum by facilitatory protocols will add to our motor control and balance function. Non-invasive brain stimulation, both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), has recently emerged as effective neuromodulators to influence motor and nonmotor functions of the brain. Anodal tDCS has been shown to improve motor skill learning and motor performance beyond the training period. Similarly, rTMS, when used at high frequency (>5 Hz), has a facilitatory effect on the motor cortex. Objective: Our aim was to determine the effect of high-frequency rTMS over the cerebellum in improving balance and functional ambulation of multiple sclerosis patients with Ataxia. Patients and methods: This was a randomized single-blinded placebo-controlled prospective trial on 40 patients. The active group (N=20) received real rTMS sessions, and the control group (N=20) received Sham rTMS using a placebo program designed for this treatment. Both groups received 12 sessions of high-frequency rTMS over the cerebellum, followed by an intensive exercise training program. Sessions were given three times per week for four weeks. The active group protocol had a frequency of 10 Hz rTMS over the cerebellar vermis, work period 5S, number of trains 25, and intertrain interval 25s. The total number of pulses was 1250 pulses per session. The control group received Sham rTMS using a placebo program designed for this treatment. Both groups of patients received an intensive exercise program, which included generalized strengthening exercises, endurance and aerobic training, trunk abdominal exercises, generalized balance training exercises, and task-oriented training such as Boxing. As a primary outcome measure the Modified ICARS was used. Static Posturography was done with: Patients were tested both with open and closed eyes. Secondary outcome measures included the expanded Disability Status Scale (EDSS) and 8 Meter walk test (8MWT). Results: The active group showed significant improvements in all the functional scales, modified ICARS, EDSS, and 8-meter walk test, in addition to significant differences in static Posturography with open eyes, while the control group did not show such differences. Conclusion: Cerebellar high-frequency rTMS could be effective in the functional improvement of balance in MS patients with ataxia.

Keywords: brain neuromodulation, high frequency rTMS, cerebellar stimulation, multiple sclerosis, balance rehabilitation

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15 Self-Medication with Antibiotics, Evidence of Factors Influencing the Practice in Low and Middle-Income Countries: A Systematic Scoping Review

Authors: Neusa Fernanda Torres, Buyisile Chibi, Lyn E. Middleton, Vernon P. Solomon, Tivani P. Mashamba-Thompson

Abstract:

Background: Self-medication with antibiotics (SMA) is a global concern, with a higher incidence in low and middle-income countries (LMICs). Despite intense world-wide efforts to control and promote the rational use of antibiotics, continuing practices of SMA systematically exposes individuals and communities to the risk of antibiotic resistance and other undesirable antibiotic side effects. Moreover, it increases the health systems costs of acquiring more powerful antibiotics to treat the resistant infection. This review thus maps evidence on the factors influencing self-medication with antibiotics in these settings. Methods: The search strategy for this review involved electronic databases including PubMed, Web of Knowledge, Science Direct, EBSCOhost (PubMed, CINAHL with Full Text, Health Source - Consumer Edition, MEDLINE), Google Scholar, BioMed Central and World Health Organization library, using the search terms:’ Self-Medication’, ‘antibiotics’, ‘factors’ and ‘reasons’. Our search included studies published from 2007 to 2017. Thematic analysis was performed to identify the patterns of evidence on SMA in LMICs. The mixed method quality appraisal tool (MMAT) version 2011 was employed to assess the quality of the included primary studies. Results: Fifteen studies met the inclusion criteria. Studies included population from the rural (46,4%), urban (33,6%) and combined (20%) settings, of the following LMICs: Guatemala (2 studies), India (2), Indonesia (2), Kenya (1), Laos (1), Nepal (1), Nigeria (2), Pakistan (2), Sri Lanka (1), and Yemen (1). The total sample size of all 15 included studies was 7676 participants. The findings of the review show a high prevalence of SMA ranging from 8,1% to 93%. Accessibility, affordability, conditions of health facilities (long waiting, quality of services and workers) as long well as poor health-seeking behavior and lack of information are factors that influence SMA in LMICs. Antibiotics such as amoxicillin, metronidazole, amoxicillin/clavulanic, ampicillin, ciprofloxacin, azithromycin, penicillin, and tetracycline, were the most frequently used for SMA. The major sources of antibiotics included pharmacies, drug stores, leftover drugs, family/friends and old prescription. Sore throat, common cold, cough with mucus, headache, toothache, flu-like symptoms, pain relief, fever, running nose, toothache, upper respiratory tract infections, urinary symptoms, urinary tract infection were the common disease symptoms managed with SMA. Conclusion: Although the information on factors influencing SMA in LMICs is unevenly distributed, the available information revealed the existence of research evidence on antibiotic self-medication in some countries of LMICs. SMA practices are influenced by social-cultural determinants of health and frequently associated with poor dispensing and prescribing practices, deficient health-seeking behavior and consequently with inappropriate drug use. Therefore, there is still a need to conduct further studies (qualitative, quantitative and randomized control trial) on factors and reasons for SMA to correctly address the public health problem in LMICs.

Keywords: antibiotics, factors, reasons, self-medication, low and middle-income countries (LMICs)

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14 Optimum Irrigation System Management for Climate Resilient and Improved Productivity of Flood-based Livelihood Systems

Authors: Mara Getachew Zenebe, Luuk Fleskens, Abdu Obieda Ahmed

Abstract:

This paper seeks to advance our scientific understanding of optimizing flood utilization in regions impacted by climate change, with a focus on enhancing agricultural productivity through effective irrigation management. The study was conducted as part of a three-year (2021 to 2023) USAID-supported initiative aimed at promoting Economic Growth and Peace in the Gash Agricultural Scheme (GAS), situated in Sudan's water-stressed Eastern region. GAS is the country's largest flood-irrigated scheme, covering 100,800 hectares of cultivable land, with a potential to provide the food security needs of over a quarter of a million agro-pastoral community members. GAS relies on the Gash River, which sources its water from high-intensity rainfall events in the highlands of Ethiopia and Eritrea. However, climate change and variations in these highlands have led to increased variability in the Gash River's flow. The study conducted water balance analyses based on a ten-year dataset of the annual Gash River flow, irrigated area; as well as the evapotranspiration demand of the major sorghum crop. Data collection methods included field measurements, surveys, remote sensing, and CropWat modelling. The water balance assessment revealed that the existing three-year rotation-based irrigation system management, capping cultivated land at 33,000 hectares annually, is excessively risk-averse. While this system reduced conflicts among the agro-pastoral communities by consistently delivering on the land promised to be annually cultivated, it also increased GAS's vulnerability to flood damage due to several reasons. The irrigation efficiency over the past decade was approximately 30%, leaving significant unharnessed floodwater that caused damage to infrastructure and agricultural land. The three-year rotation resulted in inadequate infrastructural maintenance, given the destructive nature of floods. Additionally, it led to infrequent land tillage, allowing the encroachment of mesquite trees hindering major sorghum crop growth. Remote sensing data confirmed that mesquite trees have overtaken 70,000 hectares in the past two decades, rendering them unavailable for agriculture. The water balance analyses suggest shifting to a two-year rotation, covering approximately 50,000 hectares annually while maintaining risk aversion. This shift could boost GAS's annual sorghum production by two-thirds, exceeding 850,000 tons. The scheme's efficiency can be further enhanced through low-cost on-farm interventions. Currently, large irrigation plots that range from 420 to 756 hectares are irrigated with limited water distribution guidance, leading to uneven irrigation. As demonstrated through field trials, implementing internal longitudinal bunds and horizontal deflector bunds can increase adequately irrigated parts of the irrigation plots from 50% to 80% and thus nearly double the sorghum yield to 2 tons per hectare while reducing the irrigation duration from 30 days to a maximum of 17 days. Flow measurements in 2021 and 2022 confirmed that these changes sufficiently meet the sorghum crop's water requirements, even with a conservative 60% field application efficiency assumption. These insights and lessons from the GAS on enhancing agricultural resilience and sustainability in the face of climate change are relevant to flood-based livelihood systems globally.

Keywords: climate change, irrigation management and productivity, variable flood flows, water balance analysis

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13 Effects of Applying Low-Dye Taping in Performing Double-Leg Squat on Electromyographic Activity of Lower Extremity Muscles for Collegiate Basketball Players with Excessive Foot Pronation

Authors: I. M. K. Ho, S. K. Y. Chan, K. H. P. Lam, G. M. W. Tong, N. C. Y. Yeung, J. T. C. Luk

Abstract:

Low-dye taping (LDT) is commonly used for treating foot problems, such as plantar fasciitis, and supporting foot arch for runners and non-athletes patients with pes planus. The potential negative impact of pronated feet leading to tibial and femoral internal rotation via the entire kinetic chain reaction was postulated and identified. The changed lower limb biomechanics potentially leading to poor activation of hip and knee stabilizers, such as gluteus maximus and medius, may associate with higher risk of knee injuries including patellofemoral pain syndrome and ligamentous sprain in many team sports players. It is therefore speculated that foot arch correction with LDT might enhance the use of gluteal muscles. The purpose of this study was to investigate the effect of applying LDT on surface electromyographic (sEMG) activity of superior gluteus maximus (SGMax), inferior gluteus maximus (IGMax), gluteus medius (GMed) and tibialis anterior (TA) during double-leg squat. 12 male collegiate basketball players (age: 21.72.5 years; body fat: 12.43.6%; navicular drop: 13.72.7mm) with at least three years regular basketball training experience participated in this study. Participants were excluded if they had recent history of lower limb injuries, over 16.6% body fat and lesser than 10mm drop in navicular drop (ND) test. Recruited subjects visited the laboratory once for the within-subject crossover study. Maximum voluntary isometric contraction (MVIC) tests on all selected muscles were performed in randomized order followed by sEMG test on double-leg squat during LDT and non-LDT conditions in counterbalanced order. SGMax, IGMax, GMed and TA activities during the entire 2-second concentric and 2-second eccentric phases were normalized and interpreted as %MVIC. The magnitude of the difference between taped and non-taped conditions of each muscle was further assessed via standardized effect90% confidence intervals (CI) with non-clinical magnitude-based inference. Paired samples T-test showed a significant decrease (4.71.4mm) in ND (95% CI: 3.8, 5.6; p < 0.05) while no significant difference was observed between taped and non-taped conditions in sEMG tests for all muscles and contractions (p > 0.05). On top of traditional significant testing, magnitude-based inference showed possibly increase in IGMax activity (small standardized effect: 0.270.44), likely increase in GMed activity (small standardized effect: 0.340.34) and possibly increase in TA activity (small standardized effect: 0.220.29) during eccentric phase. It is speculated that the decrease of navicular drop supported by LDT application could potentially enhance the use of inferior gluteus maximus and gluteus medius especially during eccentric phase in this study. As the eccentric phase of double-leg squat is an important component of landing activities in basketball, further studies on the onset and amount of gluteal activation during jumping and landing activities with LDT are recommended. Since both hip and knee kinematics were not measured in this study, the underlying cause of the observed increase in gluteal activation during squat after LDT is inconclusive. In this regard, the investigation of relationships between LDT application, ND, hip and knee kinematics, and gluteal muscle activity during sports specific jumping and landing tasks should be focused in the future.

Keywords: flat foot, gluteus maximus, gluteus medius, injury prevention

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12 Biological Soil Crust Effects on Dust Control Around the Urmia Lake

Authors: Abbas Ahmadi, Nasser Aliasgharzad, Ali Asghar Jafarzadeh

Abstract:

Nowadays, drying of the Urmia Lake as a largest saline lake in the world and emerging its saline bed from water has caused the risk of salty dune storms, which threats the health of human society and also plants and animal communities living in the region. Biological soil crusts (BSCs) as a dust stabilizer attracted the attention of Soil conservation experts in recent years. Although the presence of water by the impenetrable lake bed and endorheic basin can be an advantage to create BSCs, but the extraordinary of the lake bed salinity is a factor for prevention of its establishment in the region. Therefore, the present research work has been carried out to investigate the effects of inoculating the Cyanobacteria, algae and their combination to create BSCs for dust control. In this study, an algae attributed to Chlamydomonas sp and a cyanobacteria attributed to Anabaena sp isolated from the soils of Urmia Lake margin were used to create BSC in four soil samples which collected from 0-10 cm of the current margin (A), the previous bed (B), affected lands by lake (C) and Quomtappe sand dune (D). The main characteristics of the A, B and C soil samples are their highly salinity (their ECe are 108, 140 and 118 dS/m, respectively) and sodicity. Also, texture class of the soil A was loamy sand, and other two soils had clay textures. Soil D was Non-saline, but it was sodic with a sandy texture class. This study was conducted separately in each soil in a completely randomized design under four inoculation treatments of non-inoculated (T0), Algae (T1), cyanobacteria (T2) and equal mixture of algae and cyanobacteria (T3) with three replications. In the experiment, the soil was placed into wind tunnel trays, and a suspension containing microorganisms mixed with the trays surface soil. During the experiment, water was sprayed to the trays at the morning and evening of every day. After passing the incubation period (30 days), some characteristics of samples such as pH, EC, cold water extractable carbohydrate (CWEC), hot water extractable carbohydrate (HWEC), sulfuric acid extractable carbohydrate (SAEC), organic matter, crust thickness, penetration resistance, wind erosion threshold velocity and soil loss in the wind tunnel were measured, and Correlation between the measured characteristics was obtained through the SPSS software. Analysis of variance and so comparison between the means of treatments were analyzed with MSTATC software. In this research, Chlorophyll, an amount, was used as an indicator of the microorganism's population in the samples. Based on obtained results, the amount of Chlorophyll a in the T2 treatment of soil A and all treatments of soil D was significantly increased in comparison to the control and crust thickness showed increase in all treatments by microorganism’s inoculation. But effect of the treatments was significant in soils A and D. At all treatment’s inoculation of microorganisms in soil A caused to increase %46, %34 and %55 of the wind erosion threshold velocity in T1, T2 and T3 treatments in comparison to the control, respectively, and in soil D all treatments caused wind erosion threshold velocity became two times more than control. However, soil loss in the wind tunnel experiments was significant in T2 and T3 treatments of these soils and T1 treatment had no effect in reducing soil loss. Correlation between Chlorophyll a and salinity shows the important role of salinity in microbial growth prevention and formation of BSCs in the studied samples. In general, according to the obtained results, it can be concluded that salinity reduces the growth of microorganisms in saline soils of the region, and in soils with fine textures, salinity role in prevention of the microbial growth is clear. Also, using the mix of algae and cyanobacteria together caused the synergistic growth of them and consequently, better protection of the soil against wind erosion was provided.

Keywords: wind erosion, algae, cyanobacteria, carbohydrate

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11 Triple Immunotherapy to Overcome Immune Evasion by Tumors in a Melanoma Mouse Model

Authors: Mary-Ann N. Jallad, Dalal F. Jaber, Alexander M. Abdelnoor

Abstract:

Introduction: Current evidence confirms that both innate and adaptive immune systems are capable of recognizing and abolishing malignant cells. The emergence of cancerous tumors in patients is, therefore, an indication that certain cancer cells can resist elimination by the immune system through a process known as “immune evasion”. In fact, cancer cells often exploit regulatory mechanisms to escape immunity. Such mechanisms normally exist to control the immune responses and prohibit exaggerated or autoimmune reactions. Recently, immunotherapies have shown promising yet limited results. Therefore this study investigates several immunotherapeutic combinations and devises a triple immunotherapy which harnesses the innate and acquired immune responses towards the annihilation of malignant cells through overcoming their ability of immune evasion, consequently hampering malignant progression and eliminating established tumors. The aims of the study are to rule out acute/chronic toxic effects of the proposed treatment combinations, to assess the effect of these combinations on tumor growth and survival rates, and to investigate potential mechanisms underlying the phenotypic results through analyzing serum levels of anti-tumor cytokines, angiogenic factors and tumor progression indicator, and the tumor-infiltrating immune-cells populations. Methodology: For toxicity analysis, cancer-free C57BL/6 mice are randomized into 9 groups: Group 1 untreated, group 2 treated with sterile saline (solvent of used treatments), group 3 treated with Monophosphoryl-lipid-A, group 4 with anti-CTLA4-antibodies, group 5 with 1-Methyl-Tryptophan (Indolamine-Dioxygenase-1 inhibitor), group 6 with both MPLA and anti-CTLA4-antibodies, group 7 with both MPLA and 1-MT, group 8 with both anti-CTLA4-antibodies and 1-MT, and group 9 with all three: MPLA, anti-CTLA4-antibodies and 1-MT. Mice are monitored throughout the treatment period and for three following months. At that point, histological sections from their main organs are assessed. For tumor progression and survival analysis, a murine melanoma model is generated by injecting analogous mice with B16F10 melanoma cells. These mice are segregated into the listed nine groups. Their tumor size and survival are monitored. For a depiction of underlying mechanisms, melanoma-bearing mice from each group are sacrificed at several time-points. Sera are tested to assess the levels of Interleukin-12 (IL-12), Vascular-Endothelial-Growth Factor (VEGF), and S100B. Furthermore, tumors are excised for analysis of infiltrated immune cell populations including T-cells, macrophages, natural killer cells and immune-regulatory cells. Results: Toxicity analysis shows that all treated groups present no signs of neither acute nor chronic toxicity. Their appearance and weights were comparable to those of control groups throughout the treatment period and for the following 3 months. Moreover, histological sections from their hearts, kidneys, lungs, and livers were normal. Work is ongoing for completion of the remaining study aims. Conclusion: Toxicity was the major concern for the success of the proposed comprehensive combinational therapy. Data generated so far ruled out any acute or chronic toxic effects. Consequently, ongoing work is quite promising and may significantly contribute to the development of more effective immunotherapeutic strategies for the treatment of cancer patients.

Keywords: cancer immunotherapy, check-point blockade, combination therapy, melanoma

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10 SockGEL/PLUG: Injectable Nano-Scaled Hydrogel Platforms for Oral and Maxillofacial Interventional Application

Authors: Z. S. Haidar

Abstract:

Millions of teeth are removed annually, and dental extraction is one of the most commonly performed surgical procedures globally. Whether due to caries, periodontal disease, or trauma, exodontia and the ensuing wound healing and bone remodeling processes of the resultant socket (hole in the jaw bone) usually result in serious deformities of the residual alveolar osseous ridge and surrounding soft tissues (reduced height/width). Such voluminous changes render the placement of a proper conventional bridge, denture, or even an implant-supported prosthesis extremely challenging. Further, most extractions continue to be performed with no regard for preventing the onset of alveolar osteitis (also known as dry socket, a painful and difficult-to-treat/-manage condition post-exodontia). Hence, such serious resorptive morphological changes often result in significant facial deformities and a negative impact on the overall Quality of Life (QoL) of patients (and oral health-related QoL); alarming, particularly for the geriatric with compromised healing and in light of the thriving longevity statistics. Despite advances in tissue/wound grafting, serious limitations continue to exist, including efficacy and clinical outcome predictability, cost, treatment time, expertise, and risk of immune reactions. For cases of dry socket, specifically, the commercially available and often-prescribed home remedies are highly-lacking. Indeed, most are not recommended for use anymore. Alveogyl is a fine example. Hence, there is a great market demand and need for alternative solutions. Herein, SockGEL/PLUG (patent pending), an innovative, all-natural, drug-free, and injectable thermo-responsive hydrogel, was designed, formulated, characterized, and evaluated as an osteogenic, angiogenic, anti-microbial, and pain-soothing suture-free intra-alveolar dressing, safe and efficacious for use in fresh extraction sockets, immediately post-exodontia. It is composed of FDA-approved, biocompatible and biodegradable polymers, self-assembled electro-statically to formulate a scaffolding matrix to (1) prevent the on-set of alveolar osteitis via securing the fibrin-clot in situ and protecting/sealing the socket from contamination/infection; and (2) endogenously promote/accelerate wound healing and bone remodeling to preserve the volume of the alveolus. The intrinsic properties of the SockGEL/PLUG hydrogel were evaluated physical-chemical-mechanically for safety (cell viability), viscosity, rheology, bio-distribution, and essentially, capacity to induce wound healing and osteogenesis (small defect, in vivo) without any signaling cues from exogenous cells, growth factors or drugs. The proposed animal model of cranial critical-sized and non-vascularized bone defects shall provide new and critical insights into the role and mechanism of the employed natural bio-polymer blend and gel product in endogenous reparative regeneration of soft tissues and bone morphogenesis. Alongside, the fine-tuning of our modified formulation method will further tackle appropriateness, reproducibility, scalability, ease, and speed in producing stable, biodegradable, and sterilizable thermo-sensitive matrices (3-dimensional interpenetrating yet porous polymeric network) suitable for the intra-socket application. Findings are anticipated to provide sufficient evidence to translate into pilot clinical trials and validate the innovation before engaging the market for feasibility, acceptance, and cost-effectiveness studies.

Keywords: hydrogel, nanotechnology, bioengineering, bone regeneration, nanogel, drug delivery

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9 Case Study Hyperbaric Oxygen Therapy for Idiopathic Sudden Sensorineural Hearing Loss

Authors: Magdy I. A. Alshourbagi

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Background: The National Institute for Deafness and Communication Disorders defines idiopathic sudden sensorineural hearing loss as the idiopathic loss of hearing of at least 30 dB across 3 contiguous frequencies occurring within 3 days.The most common clinical presentation involves an individual experiencing a sudden unilateral hearing loss, tinnitus, a sensation of aural fullness and vertigo. The etiologies and pathologies of ISSNHL remain unclear. Several pathophysiological mechanisms have been described including: vascular occlusion, viral infections, labyrinthine membrane breaks, immune associated disease, abnormal cochlear stress response, trauma, abnormal tissue growth, toxins, ototoxic drugs and cochlear membrane damage. The rationale for the use of hyperbaric oxygen to treat ISSHL is supported by an understanding of the high metabolism and paucity of vascularity to the cochlea. The cochlea and the structures within it require a high oxygen supply. The direct vascular supply, particularly to the organ of Corti, is minimal. Tissue oxygenation to the structures within the cochlea occurs via oxygen diffusion from cochlear capillary networks into the perilymph and the cortilymph. . The perilymph is the primary oxygen source for these intracochlear structures. Unfortunately, perilymph oxygen tension is decreased significantly in patients with ISSHL. To achieve a consistent rise of perilymph oxygen content, the arterial-perilymphatic oxygen concentration difference must be extremely high. This can be restored with hyperbaric oxygen therapy. Subject and Methods: A 37 year old man was presented at the clinic with a five days history of muffled hearing and tinnitus of the right ear. Symptoms were sudden onset, with no associated pain, dizziness or otorrhea and no past history of hearing problems or medical illness. Family history was negative. Physical examination was normal. Otologic examination revealed normal tympanic membranes bilaterally, with no evidence of cerumen or middle ear effusion. Tuning fork examination showed positive Rinne test bilaterally but with lateralization of Weber test to the left side, indicating right ear sensorineural hearing loss. Audiometric analysis confirmed sensorineural hearing loss across all frequencies of about 70- dB in the right ear. Routine lab work were all within normal limits. Clinical diagnosis of idiopathic sudden sensorineural hearing loss of the right ear was made and the patient began a medical treatment (corticosteroid, vasodilator and HBO therapy). The recommended treatment profile consists of 100% O2 at 2.5 atmospheres absolute for 60 minutes daily (six days per week) for 40 treatments .The optimal number of HBOT treatments will vary, depending on the severity and duration of symptomatology and the response to treatment. Results: As HBOT is not yet a standard for idiopathic sudden sensorineural hearing loss, it was introduced to this patient as an adjuvant therapy. The HBOT program was scheduled for 40 sessions, we used a 12-seat multi place chamber for the HBOT, which was started at day seven after the hearing loss onset. After the tenth session of HBOT, improvement of both hearing (by audiogram) and tinnitus was obtained in the affected ear (right). Conclusions: In conclusion, HBOT may be used for idiopathic sudden sensorineural hearing loss as an adjuvant therapy. It may promote oxygenation to the inner ear apparatus and revive hearing ability. Patients who fail to respond to oral and intratympanic steroids may benefit from this treatment. Further investigation is warranted, including animal studies to understand the molecular and histopathological aspects of HBOT and randomized control clinical studies.

Keywords: idiopathic sudden sensorineural hearing loss (issnhl), hyperbaric oxygen therapy (hbot), the decibel (db), oxygen (o2)

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8 Acute Severe Hyponatremia in Patient with Psychogenic Polydipsia, Learning Disability and Epilepsy

Authors: Anisa Suraya Ab Razak, Izza Hayat

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Introduction: The diagnosis and management of severe hyponatremia in neuropsychiatric patients present a significant challenge to physicians. Several factors contribute, including diagnostic shadowing and attributing abnormal behavior to intellectual disability or psychiatric conditions. Hyponatraemia is the commonest electrolyte abnormality in the inpatient population, ranging from mild/asymptomatic, moderate to severe levels with life-threatening symptoms such as seizures, coma and death. There are several documented fatal case reports in the literature of severe hyponatremia secondary to psychogenic polydipsia, often diagnosed only in autopsy. This paper presents a case study of acute severe hyponatremia in a neuropsychiatric patient with early diagnosis and admission to intensive care. Case study: A 21-year old Caucasian male with known epilepsy and learning disability was admitted from residential living with generalized tonic-clonic self-terminating seizures after refusing medications for several weeks. Evidence of superficial head injury was detected on physical examination. His laboratory data demonstrated mild hyponatremia (125 mmol/L). Computed tomography imaging of his brain demonstrated no acute bleed or space-occupying lesion. He exhibited abnormal behavior - restlessness, drinking water from bathroom taps, inability to engage, paranoia, and hypersexuality. No collateral history was available to establish his baseline behavior. He was loaded with intravenous sodium valproate and leveritircaetam. Three hours later, he developed vomiting and a generalized tonic-clonic seizure lasting forty seconds. He remained drowsy for several hours and regained minimal recovery of consciousness. A repeat set of blood tests demonstrated profound hyponatremia (117 mmol/L). Outcomes: He was referred to intensive care for peripheral intravenous infusion of 2.7% sodium chloride solution with two-hourly laboratory monitoring of sodium concentration. Laboratory monitoring identified dangerously rapid correction of serum sodium concentration, and hypertonic saline was switched to a 5% dextrose solution to reduce the risk of acute large-volume fluid shifts from the cerebral intracellular compartment to the extracellular compartment. He underwent urethral catheterization and produced 8 liters of urine over 24 hours. Serum sodium concentration remained stable after 24 hours of correction fluids. His GCS recovered to baseline after 48 hours with improvement in behavior -he engaged with healthcare professionals, understood the importance of taking medications, admitted to illicit drug use and drinking massive amounts of water. He was transferred from high-dependency care to ward level and was initiated on multiple trials of anti-epileptics before achieving seizure-free days two weeks after resolution of acute hyponatremia. Conclusion: Psychogenic polydipsia is often found in young patients with intellectual disability or psychiatric disorders. Patients drink large volumes of water daily ranging from ten to forty liters, resulting in acute severe hyponatremia with mortality rates as high as 20%. Poor outcomes are due to challenges faced by physicians in making an early diagnosis and treating acute hyponatremia safely. A low index of suspicion of water intoxication is required in this population, including patients with known epilepsy. Monitoring urine output proved to be clinically effective in aiding diagnosis. Early referral and admission to intensive care should be considered for safe correction of sodium concentration while minimizing risk of fatal complications e.g. central pontine myelinolysis.

Keywords: epilepsy, psychogenic polydipsia, seizure, severe hyponatremia

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7 Emerging Positive Education Interventions for Clean Sport Behavior: A Pilot Study

Authors: Zeinab Zaremohzzabieh, Syasya Firzana Azmi, Haslinda Abdullah, Soh Kim Geok, Aini Azeqa Ma'rof, Hayrol Azril Mohammed Shaffril

Abstract:

The escalating prevalence of doping in sports, casting a shadow over both high-performance and recreational settings, has emerged as a formidable concern, particularly within the realm of young athletes. Doping, characterized by the surreptitious use of prohibited substances to gain a competitive edge, underscores the pressing need for comprehensive and efficacious preventive measures. This study aims to address a crucial void in current research by unraveling the motivations that drive clean adolescent athletes to steadfastly abstain from performance-enhancing substances. In navigating this intricate landscape, the study adopts a positive psychology perspective, investigating into the conditions and processes that contribute to the holistic well-being of individuals and communities. At the heart of this exploration lies the application of the PERMA model, a comprehensive positive psychology framework encapsulating positive emotion, engagement, relationships, meaning, and accomplishments. This model functions as a distinctive lens, dissecting intervention results to offer nuanced insights into the complex dynamics of clean sport behavior. The research is poised to usher in a paradigm shift from conventional anti-doping strategies, predominantly fixated on identifying deficits, towards an innovative approach firmly rooted in positive psychology. The objective of this study is to evaluate the efficacy of a positive education intervention program tailored to promote clean sport behavior among Malaysian adolescent athletes. Representing unexplored terrain within the landscape of anti-doping efforts, this initiative endeavors to reshape the focus from deficiencies to strengths. The meticulously crafted pilot study engages thirty adolescent athletes, divided into a control group of 15 and an experimental group of 15. The pilot study serves as the crucible to assess the effectiveness of the prepared intervention package, providing indispensable insights that will meticulously guide the finalization of an all-encompassing intervention program for the main study. The main study adopts a pioneering two-arm randomized control trial methodology, actively involving adolescent athletes from diverse Malaysian high schools. This approach aims to address critical lacunae in anti-doping strategies, specifically calibrated to resonate with the unique context of Malaysian schools. The study, cognizant of the imperative to develop preventive measures harmonizing with the cultural and educational milieu of Malaysian adolescent athletes, aspires to cultivate a culture of clean sport. In conclusion, this research aspires to contribute unprecedented insights into the efficacy of positive education interventions firmly rooted in the PERMA model. By unraveling the intricacies of clean sport behavior, particularly within the context of Malaysian adolescent athletes, the study seeks to introduce transformative preventive methods. The adoption of positive psychology as an avant-garde anti-doping tool represents an innovative and promising approach, bridging a conspicuous gap in scholarly research and offering potential panaceas for the sporting community. As this study unfurls its chapters, it carries the promise not only to enrich our understanding of clean sport behavior but also to pave the way for positive metamorphosis within the realm of adolescent sports in Malaysia.

Keywords: positive education interventions, a pilot study, clean sport behavior, adolescent athletes, Malaysia

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6 An Intelligent Search and Retrieval System for Mining Clinical Data Repositories Based on Computational Imaging Markers and Genomic Expression Signatures for Investigative Research and Decision Support

Authors: David J. Foran, Nhan Do, Samuel Ajjarapu, Wenjin Chen, Tahsin Kurc, Joel H. Saltz

Abstract:

The large-scale data and computational requirements of investigators throughout the clinical and research communities demand an informatics infrastructure that supports both existing and new investigative and translational projects in a robust, secure environment. In some subspecialties of medicine and research, the capacity to generate data has outpaced the methods and technology used to aggregate, organize, access, and reliably retrieve this information. Leading health care centers now recognize the utility of establishing an enterprise-wide, clinical data warehouse. The primary benefits that can be realized through such efforts include cost savings, efficient tracking of outcomes, advanced clinical decision support, improved prognostic accuracy, and more reliable clinical trials matching. The overarching objective of the work presented here is the development and implementation of a flexible Intelligent Retrieval and Interrogation System (IRIS) that exploits the combined use of computational imaging, genomics, and data-mining capabilities to facilitate clinical assessments and translational research in oncology. The proposed System includes a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide insight into the underlying tumor characteristics that are not be apparent by human inspection alone. A key distinguishing feature of the System is a configurable Extract, Transform and Load (ETL) interface that enables it to adapt to different clinical and research data environments. This project is motivated by the growing emphasis on establishing Learning Health Systems in which cyclical hypothesis generation and evidence evaluation become integral to improving the quality of patient care. To facilitate iterative prototyping and optimization of the algorithms and workflows for the System, the team has already implemented a fully functional Warehouse that can reliably aggregate information originating from multiple data sources including EHR’s, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology PAC systems, Digital Pathology archives, Unstructured Clinical Documents, and Next Generation Sequencing services. The System enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information about patient tumors individually or as part of large cohorts to identify patterns that may influence treatment decisions and outcomes. The CRDW core system has facilitated peer-reviewed publications and funded projects, including an NIH-sponsored collaboration to enhance the cancer registries in Georgia, Kentucky, New Jersey, and New York, with machine-learning based classifications and quantitative pathomics, feature sets. The CRDW has also resulted in a collaboration with the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at the U.S. Department of Veterans Affairs to develop algorithms and workflows to automate the analysis of lung adenocarcinoma. Those studies showed that combining computational nuclear signatures with traditional WHO criteria through the use of deep convolutional neural networks (CNNs) led to improved discrimination among tumor growth patterns. The team has also leveraged the Warehouse to support studies to investigate the potential of utilizing a combination of genomic and computational imaging signatures to characterize prostate cancer. The results of those studies show that integrating image biomarkers with genomic pathway scores is more strongly correlated with disease recurrence than using standard clinical markers.

Keywords: clinical data warehouse, decision support, data-mining, intelligent databases, machine-learning.

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5 Effectiveness of Peer Reproductive Health Education Program in Improving Knowledge, Attitude, and Use Health Service of High School Adolescent Girls in Eritrea in 2014

Authors: Ghidey Ghebreyohanes, Eltahir Awad Gasim Khalil, Zemenfes Tsighe, Faiza Ali

Abstract:

Background: reproductive health (RH) is a state of physical, mental and social well-being in all matters relating to the reproductive system at all stages of life. In East Africa including Eritrea, adolescents comprise more than a quarter of the population. The region holds the highest rates of sexually transmitted diseases, HIV, unwanted pregnancy and unsafe abortion with its complications. Young girls carry the highest burden of reproductive health problems due to their risk taking behavior, lack of knowledge, peer pressure, physiologic immaturity and low socioeconomic status. Design: this was a Community-based, randomized, case-controlled and pre-test-post-test intervention study. Setting: Zoba Debub was randomly selected out of the six zobas in Eritrea. The four high schools out of the 26 in Zoba Debub were randomly selected as study target schools. Over three quarter of the people live on farming. The target population was female students attending grade nine with majority of these girls live in the distant villages and walk to school. The study participants were randomly selected (n=165) from each school. Furthermore, the 1 intervention and 3 controls for the study arms were assigned randomly. Objectives: this study aimed to assess the effectiveness of peer reproductive health education in improving knowledge, attitude, and health service use of high school adolescent girls in Eritrea Methods: the protocol was reviewed and approved by the Scientific and Ethics Committees of Faculty of Nursing Sciences, University of Khartoum. Data was collected using pre-designed and pretested questionnaire emphasizing on reproductive health knowledge, attitude and practice. Sample size was calculated using proportion formula (α 0.01; power of 95%). Measures used were scores and proportions. Descriptive and inferential statistics, t-test and chi square at (α .01), 99% confidence interval were used to compare changes of pre and post-intervention scores using SPSS soft ware. Seventeen students were selected for peer educators by the school principals and other teachers based on inclusion criteria that include: good academic performance and acceptable behavior. One peer educator educated one group composed of 8-10 students for two months. One faculty member was selected to supervise peer educators. The principal investigator conducted the training of trainers and provided supervision and discussion to peer educators every two weeks until the end of intervention. Results: following informed consent, 627 students [164 in intervention and 463 in the control group] with a ratio of 1 to 3, were enrolled in the study. The mean age for the total study population was 15.4±1.0 years. The intervention group mean age was 15.3±1.0 year; while the control group had a mean age of 15.4±1.0. The mean ages for the study arms were similar (p= 0.4). The majority (96 %) of the study participants are from Tigrigna ethnic group. Reproductive knowledge scores which was calculated out of a total 61 grade points: intervention group (pretest 6.7 %, post-test 33.6 %; p= 0.0001); control group (pretest 7.3 %, posttest 7.3 %, p= 0.92). Proportion difference in attitude calculated out of 100%: intervention group (pretest 42.3 % post test 54.7% p= 0.001); controls group (pretest 45%, post test 44.8 p= 0.7). Proportion difference in Practice calculated out of 100 %: intervention group (pretest 15.4%, post test 80.4 % p= 0.0001); control group (pretest 16.8%, posttest 16.9 % p= 0.8). Mothers were quoted as major (> 90 %) source of reproductive health information. All focus group discussants and most of survey participants agreed on the urgent need of reproductive health information and services for adolescent girls. Conclusion: reproductive health knowledge and use of facilities is poor among adolescent girls in sub-urban Eretria. School-based peer reproductive health education is effective and is the best strategy to improve reproductive health knowledge and attitudes.

Keywords: reproductive health, adolescent girls, eretria, health education

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4 Development of an Omaha System-Based Remote Intervention Program for Work-Related Musculoskeletal Disorders (WMSDs) Among Front-Line Nurses

Authors: Tianqiao Zhang, Ye Tian, Yanliang Yin, Yichao Tian, Suzhai Tian, Weige Sun, Shuhui Gong, Limei Tang, Ruoliang Tang

Abstract:

Introduction: Healthcare workers, especially the nurses all over the world, are highly vulnerable to work-related musculoskeletal disorders (WMSDs), experiencing high rates of neck, shoulder, and low back injuries, due to the unfavorable working conditions. To reduce WMSDs among nursing personnel, many workplace interventions have been developed and implemented. Unfortunately, the ongoing Covid-19 (SARS-CoV-2) pandemic has posed great challenges to the ergonomic practices and interventions in healthcare facilities, particularly the hospitals, since current Covid-19 mitigation measures, such as social distancing and working remotely, has substantially minimized in-person gatherings and trainings. On the other hand, hospitals throughout the world have been short-staffed, resulting in disturbance of shift scheduling and more importantly, the increased job demand among the available caregivers, particularly the doctors and nurses. With the latest development in communication technology, remote intervention measures have been developed as an alternative, without the necessity of in-person meetings. The Omaha System (OS) is a standardized classification system for nursing practices, including a problem classification system, an intervention system, and an outcome evaluation system. This paper describes the development of an OS-based ergonomic intervention program. Methods: First, a comprehensive literature search was performed among worldwide electronic databases, including PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), between journal inception to May 2020, resulting in a total of 1,418 scientific articles. After two independent screening processes, the final knowledge pool included eleven randomized controlled trial studies to develop the draft of the intervention program with Omaha intervention subsystem as the framework. After the determination of sample size needed for statistical power and the potential loss to follow-up, a total of 94 nurses from eight clinical departments agreed to provide written, informed consent to participate in the study, which were subsequently assigned into two random groups (i.e., intervention vs. control). A subgroup of twelve nurses were randomly selected to participate in a semi-structured interview, during which their general understanding and awareness of musculoskeletal disorders and potential interventions was assessed. Then, the first draft was modified to reflect the findings from these interviews. Meanwhile, the tentative program schedule was also assessed. Next, two rounds of consultation were conducted among experts in nursing management, occupational health, psychology, and rehabilitation, to further adjust and finalize the intervention program. The control group had access to all the information and exercise modules at baseline, while an interdisciplinary research team was formed and supervised the implementation of the on-line intervention program through multiple social media groups. Outcome measures of this comparative study included biomechanical load assessed by the Quick Exposure Check and stresses due to awkward body postures. Results and Discussion: Modification to the draft included (1) supplementing traditional Chinese medicine practices, (2) adding the use of assistive patient handling equipment, and (3) revising the on-line training method. Information module should be once a week, lasting about 20 to 30 minutes, for a total of 6 weeks, while the exercise module should be 5 times a week, each lasting about 15 to 20 minutes, for a total of 6 weeks.

Keywords: ergonomic interventions, musculoskeletal disorders (MSDs), omaha system, nurses, Covid-19

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3 “MaxSALIVA-II” Advancing a Nano-Sized Dual-Drug Delivery System for Salivary Gland Radioprotection, Regeneration and Repair in a Head and Neck Cancer Pre-Clinical Murine Model

Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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2 “SockGEL/PLUG” Injectable Smart/Intelligent and Bio-Inspired Sol-Gel Nanomaterials for Simple and Complex Oro-Dental and Cranio-Maxillo-Facial Interventional Applications

Authors: Ziyad S. Haidar

Abstract:

Millions of teeth are removed annually, and dental extraction is one of the most commonly performed surgical procedures globally. Whether due to caries, periodontal disease or trauma, exodontia and the ensuing wound healing and bone remodeling processes of the resultant socket (hole in the jaw bone) usually result in serious deformities of the residual alveolar osseous ridge and surrounding soft tissues (reduced height/width). Such voluminous changes render the placement of a proper conventional bridge, denture or even an implant-supported prosthesis extremely challenging. Further, most extractions continue to be performed with no regard for preventing the onset of alveolar osteitis (also known as dry socket, a painful and difficult-to-treat/-manage condition post-exodontia). Hence, such serious resorptive morphological changes often result in significant facial deformities and a negative impact on the overall Quality of Life (QoL) of patients (and oral health-related QoL), alarming, particularly for the geriatric with compromised healing and in light of the thriving longevity statistics. Opportunity: Despite advances in tissue/wound grafting, serious limitations continue to exist, including efficacy and clinical outcome predictability, cost, treatment time, expertise and risk of immune reactions. For cases of dry sockets, specifically, the commercially-available and often-prescribed home remedies are highly lacking. Indeed, most are not recommended for use anymore. Alveogyl is a fine example. Hence, there is a great market demand and need for alternative solutions. Solution: Herein, SockGEL/PLUG (patent pending), an all-natural, drug-free and injectable stimuli-responsive hydrogel, was designed, formulated, characterized and evaluated as an osteogenic, angiogenic, anti-microbial and pain-soothing suture-free intra-alveolar dressing, safe and efficacious for use in several oro-dental and cranio-maxillo-facial interventional applications; for example: in fresh dental extraction sockets, immediately post-exodontia. It is composed of FDA-approved, biocompatible and biodegradable polymers, self-assembled electro-statically to formulate a scaffolding matrix to (a) prevent the onset of alveolar osteitis via securing the fibrin-clot in situ and protecting/sealing the socket from contamination/infection; and (b) endogenously promote/accelerate wound healing and bone remodeling to preserve the volume of the alveolus. Findings: The intrinsic properties of the SockGEL/PLUG hydrogel were evaluated physico-chemico-mechanically for safety (cell viability), viscosity, rheology, bio-distribution and essentially, capacity to induce wound healing and osteogenesis (small defect, in vivo) without any signaling cues from exogenous cells, growth factors or drugs. The performed animal model of cranial critical-sized and non-vascularized bone defects shall provide vitally critical insights into the role and mechanism of the employed natural bio-polymer blend and gel product in endogenous reparative regeneration of soft tissues and bone morphogenesis. Alongside, the fine-tuning of our modified formulation method will further tackle appropriateness, reproducibility, scalability, ease and speed in producing stable, biodegradable and sterilizable stimuli (thermo-sensitive and photo-responsive) matrices (3-dimensional interpenetrating yet porous polymeric network) suitable for an intra-socket application, and beyond. Conclusions and Perspective: Findings are anticipated to provide sufficient evidence to translate into pilot clinical trials and validate the bionanomaterial before engaging the market for feasibility, acceptance and cost-effectiveness studies. The SockGEL/PLUG platform is patent pending: SockGEL is a bio-inspired drug-free hydrogel; SockPLUG is a drug-loaded hydrogel designed for complex indications.

Keywords: hydrogel, injectable, dentistry, craniomaxillofacial complex, bioinspired, nanobiotechnology, biopolymer, sol-gel, stimuli-responsive, matrix, tissue engineering, regenerative medicine

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1 “MaxSALIVA”: A Nano-Sized Dual-Drug Delivery System for Salivary Gland Radioprotection and Repair in Head and Neck Cancer

Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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